UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, DC 20549

 

FORM 10-Q

 

(Mark One)

x

QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the quarterly period ended March 31, 2016

OR

o

TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the transition period from                      to                      .

Commission file number 001-34655

 

AVEO PHARMACEUTICALS, INC.

(Exact Name of Registrant as Specified in Its Charter)

 

 

Delaware

04-3581650

(State or Other Jurisdiction of

Incorporation or Organization)

(I.R.S. Employer

Identification No.)

One Broadway, 14th Floor, Cambridge, Massachusetts 02142

(Address of Principal Executive Offices) (Zip Code)

(617) 588-1960

(Registrant’s Telephone Number, Including Area Code)

 

 

Indicate by check mark whether the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.    Yes   x     No   ¨

Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such files).    Yes   x     No   ¨

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting company. See the definitions of “large accelerated filer,” “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act. (Check one):

 

Large accelerated filer

¨

Accelerated filer

x

 

 

 

 

Non-accelerated filer

¨   (Do not check if a smaller reporting company)

Smaller reporting company

¨

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act).    Yes   ¨     No   x

Number of shares of the registrant’s Common Stock, $0.001 par value, outstanding on May 5, 2016: 58,181,715

 

 

 

 


AVEO PHARMACEUTICALS, INC.

FORM 10-Q

FOR THE QUARTER ENDED MARCH 31, 2016

TABLE OF CONTENTS

 

   

 

Page

No.

 

 

 

PART I. FINANCIAL INFORMATION

 

3

 

 

 

 

 

Item 1.

 

Financial Statements

 

3

 

 

 

 

 

 

 

Condensed Consolidated Balance Sheets as of March 31, 2016 and December 31, 2015

 

3

 

 

 

 

 

 

 

Condensed Consolidated Statements of Operations for the Three Months Ended March 31, 2016 and 2015

 

4

 

 

 

 

 

 

 

Condensed Consolidated Statements of Comprehensive Loss for the Three Months Ended March 31, 2016 and 2015

 

5

 

 

 

 

 

 

 

Condensed Consolidated Statements of Cash Flows for the Three Months Ended March 31, 2016 and 2015

 

6

 

 

 

 

 

 

 

Notes to Condensed Consolidated Financial Statements

 

7

 

 

 

 

 

Item 2.

 

Management’s Discussion and Analysis of Financial Condition and Results of Operations

 

27

 

 

 

 

 

Item 3.

 

Quantitative and Qualitative Disclosures About Market Risk

 

41

 

 

 

 

 

Item 4.

 

Controls and Procedures

 

42

 

 

 

PART II. OTHER INFORMATION

 

43

 

 

 

 

 

Item 1.

 

Legal Proceedings

 

43

 

 

 

 

 

Item 1A.

 

Risk Factors

 

44

 

 

 

 

 

Item 6.

 

Exhibits

 

71

 

 

 

 

 

 

 

Signatures

 

72

 

 

 

 

2


PART I. FINANC IAL INFORMATION

Item 1. Financial Statements.

AVEO PHARMACEUTICALS, INC.

Condensed Consolidated Balance Sheets

(In thousands, except par value amounts)

(Unaudited)

 

 

 

March 31,

2016

 

 

December 31,

2015

 

Assets

 

 

 

 

 

 

 

 

Current assets:

 

 

 

 

 

 

 

 

Cash and cash equivalents

 

$

18,056

 

 

$

26,634

 

Marketable securities

 

 

5,749

 

 

 

7,501

 

Restricted cash

 

 

4,000

 

 

 

 

Accounts receivable

 

 

1,736

 

 

 

4,641

 

Prepaid expenses and other current assets

 

 

1,123

 

 

 

1,600

 

Total current assets

 

 

30,664

 

 

 

40,376

 

Property and equipment, net

 

 

18

 

 

 

23

 

Other assets

 

 

124

 

 

 

143

 

Total assets

 

$

30,806

 

 

$

40,542

 

Liabilities and stockholders’ equity

 

 

 

 

 

 

 

 

Current liabilities:

 

 

 

 

 

 

 

 

Accounts payable

 

$

340

 

 

$

1,425

 

Accrued expenses

 

 

2,843

 

 

 

4,106

 

Loans payable, net of discount

 

 

3,019

 

 

 

2,053

 

Deferred revenue

 

 

660

 

 

 

814

 

Settlement liability (Note 11)

 

 

4,000

 

 

 

4,000

 

Total current liabilities

 

 

10,862

 

 

 

12,398

 

Loans payable, net of current portion and discount

 

 

6,537

 

 

 

7,418

 

Deferred revenue

 

 

2,832

 

 

 

2,881

 

Other liabilities

 

 

660

 

 

 

618

 

Stockholders’ equity:

 

 

 

 

 

 

 

 

Preferred stock, $.001 par value: 5,000 shares authorized; no shares issued and

   outstanding

 

 

 

 

 

 

Common stock, $.001 par value: 200,000 shares authorized; 58,182 and 58,182 shares

  issued and outstanding at March 31, 2016 and December 31, 2015, respectively

 

 

58

 

 

 

58

 

Additional paid-in capital

 

 

512,594

 

 

 

512,201

 

Accumulated other comprehensive income (loss)

 

 

2

 

 

 

(3

)

Accumulated deficit

 

 

(502,739

)

 

 

(495,029

)

Total stockholders’ equity

 

 

9,915

 

 

 

17,227

 

Total liabilities and stockholders’ equity

 

$

30,806

 

 

$

40,542

 

 

The accompanying notes are an integral part of these unaudited, condensed consolidated financial statements.

 

 

 

 

3


AVEO PHARMACEUTICALS, INC.

Condensed Consolidated Statements of Operations

(In thousands, except per share amounts)

(Unaudited)

 

 

 

Three Months Ended

March 31,

 

 

 

 

2016

 

 

2015

 

 

Collaboration and licensing revenue

 

$

1,203

 

 

$

134

 

 

Operating expenses:

 

 

 

 

 

 

 

 

 

Research and development

 

 

5,972

 

 

 

2,695

 

 

General and administrative

 

 

2,463

 

 

 

3,255

 

 

Restructuring and lease exit

 

 

 

 

 

4,333

 

 

 

 

 

8,435

 

 

 

10,283

 

 

Loss from operations

 

 

(7,232

)

 

 

(10,149

)

 

Other income and expense:

 

 

 

 

 

 

 

 

 

Other expense, net

 

 

(9

)

 

 

(14

)

 

Interest expense

 

 

(386

)

 

 

(716

)

 

Interest income

 

 

17

 

 

 

5

 

 

Other expense, net

 

 

(378

)

 

 

(725

)

 

Loss before provision for income taxes

 

 

(7,610

)

 

 

(10,874

)

 

Provision for income taxes

 

 

(100

)

 

 

 

 

Net loss

 

$

(7,710

)

 

$

(10,874

)

 

Net loss per share ─ basic and diluted

 

$

(0.13

)

 

$

(0.21

)

 

Weighted average number of common shares outstanding

 

 

58,166

 

 

 

52,638

 

 

 

The accompanying notes are an integral part of these unaudited, condensed consolidated financial statements.

 

 

 

 

4


AVEO PHARMACEUTICALS, INC.

Condensed Consolidated Statements of Comprehensive Loss

(In thousands)

(Unaudited)

 

 

 

Three Months Ended

March 31,

 

 

 

 

 

2016

 

 

2015

 

 

 

Net loss

 

$

(7,710

)

 

$

(10,874

)

 

 

Other comprehensive income (loss):

 

 

 

 

 

 

 

 

 

 

Unrealized gain (loss) on available-for-sale securities

 

 

5

 

 

 

 

 

 

Comprehensive loss

 

$

(7,705

)

 

$

(10,874

)

 

 

 

The accompanying notes are an integral part of these unaudited, condensed consolidated financial statements.

 

 

 

 

5


AVEO PHARMACEUTICALS, INC.

Condensed Consolidated Statements of Cash Flows

(In thousands)

(Unaudited)

 

 

 

Three Months Ended

March 31,

 

 

 

2016

 

 

2015

 

Operating activities

 

 

 

 

 

 

 

 

Net loss

 

$

(7,710

)

 

$

(10,874

)

Adjustments to reconcile net loss to net cash used in operating activities:

 

 

 

 

 

 

 

 

Impairment of property and equipment

 

 

 

 

 

232

 

Depreciation and amortization

 

 

5

 

 

 

4,488

 

Accretion

 

 

 

 

 

199

 

Loss on disposal of fixed assets

 

 

 

 

 

(20

)

Stock-based compensation

 

 

390

 

 

 

427

 

Non-cash interest expense

 

 

86

 

 

 

125

 

Amortization of premium and discount on investments

 

 

3

 

 

 

14

 

Changes in operating assets and liabilities:

 

 

 

 

 

 

 

 

Restricted cash

 

 

(4,000

)

 

 

37

 

Accounts receivable

 

 

2,905

 

 

 

1,394

 

Prepaid expenses and other current assets

 

 

492

 

 

 

337

 

Other noncurrent assets

 

 

19

 

 

 

26

 

Accounts payable

 

 

(1,085

)

 

 

(626

)

Accrued expenses

 

 

(1,263

)

 

 

(2,900

)

Deferred revenue

 

 

(203

)

 

 

(76

)

Lease exit obligation

 

 

 

 

 

(3,345

)

Deferred rent

 

 

 

 

 

(5,200

)

Other liabilities

 

 

42

 

 

 

(58

)

Net cash used in operating activities

 

 

(10,319

)

 

 

(15,820

)

Investing activities

 

 

 

 

 

 

 

 

Purchases of marketable securities

 

 

(5,746

)

 

 

(6,048

)

Proceeds from maturities and sales of marketable securities

 

 

7,500

 

 

 

1,500

 

Proceeds from sale of property and equipment

 

 

 

 

 

928

 

Net cash provided by (used in) investing activities

 

 

1,754

 

 

 

(3,620

)

Financing activities

 

 

 

 

 

 

 

 

Proceeds from issuance of common stock, net of issuance costs

 

 

 

 

 

4,353

 

Proceeds from exercise of stock options and issuance of common and restricted stock

 

 

2

 

 

 

73

 

Debt issuance costs

 

 

(15

)

 

 

 

Principal payments on loans payable

 

 

 

 

 

(2,757

)

Net cash (used by) provided by financing activities

 

 

(13

)

 

 

1,669

 

Net decrease in cash and cash equivalents

 

 

(8,578

)

 

 

(17,771

)

Cash and cash equivalents at beginning of period

 

 

26,634

 

 

 

52,306

 

Cash and cash equivalents at end of period

 

$

18,056

 

 

$

34,535

 

Supplemental cash flow information

 

 

 

 

 

 

 

 

Cash paid for interest

 

$

301

 

 

$

617

 

 

The accompanying notes are an integral part of these unaudited, condensed consolidated financial statements.

 

 

 

 

6


AVEO Pharmaceuticals, Inc.

Notes to Condensed Consolidated Financial Statements

(Unaudited)

 

(1) Organization

AVEO Pharmaceuticals, Inc. (the “Company”) is a biopharmaceutical company dedicated to advancing a broad portfolio of targeted therapeutics for oncology and other areas of unmet medical need. The Company’s proprietary platform has delivered un ique insights into cancer and related disease. The Company’s strategy is to leverage these biomarker insights and partner resources to advance the development of its clinical pipeline.

The Company’s pipeline of product candidates includes tivozanib, a potent, selective, long half-life vascular endothelial growth factor tyrosine kinase inhibitor of all three vascular endothelial growth factors. In June 2013 , the U.S. Food and Drug Administration issued a complete response letter denying the Company’s applica tion for approval of the use of tivozanib in first-line treatment of advanced renal cell carcinoma (“ RCC”), citing concerns regarding the negative trend in overall survival in the Company’s pivotal phase 3 trial. Subject to the availability of sufficient financial resources, the Company is planning to conduct a second phase 3 trial of tivozanib in the third-line treatment of patients with refractory RCC in order to address the overall survival concerns presented in the June 2013 complete response letter from the FDA and to support a request for regulatory approval of tivozanib in the United States as a third-line treatment and as a first-line treatment . The Company is also planning to conduct a phase 1/2 trial of tivozanib in combination with an immune checkpoint (PD-1) inhibitor for the treatment of RCC. The Company is evaluating all options for funding, including partnerships, for the clinical and regulatory advancement of tivozanib as a single agent and in combination. I n February 2016, a strategic partner submitted a Marketing Authorization Application for tivozanib with the European Medicines Agency (“EMA”) for the treatment of RCC. The application was validate d in March 2016, confirming that the submission was complete and that the EMA would initiate its review process. Another strategic partner has submitted a registration dossier for tivozanib with the Ministry of Health of the Russian Federation for the trea tment of RCC in December 2015 that was accepted for review in February 2016.

The Company also has a pipeline of monoclonal antibodies, including:

 

(i)

Ficlatuzumab, a potent anti-HFG antibody that inhibits the activity of the HGF/c-Met pathway and for which the Company has completed a phase 2 clinical trial and has entered into a partnership with Biodesix, Inc. (“Biodesix”) to advance clinical development;

 

(ii)

AV-203, a potent, high affinity inhibitor of ErbB3 function that has demonstrated anti-tumor activity in multiple preclinical models and for which the Company has completed a phase 1 dose escalation trial and has entered into a partnership with CANbridge Life Sciences Ltd. (“CANbridge”) to advance clinical development;

 

(iii)

AV-380, a potent humanized IgG1 inhibitory monoclonal antibody targeting growth differentiating factor-15, or GDF15, a divergent member of the TGF-ß family, for the potential treatment or prevention of cachexia, which the Company has licensed to Novartis International Pharmaceutical Ltd. (“Novartis”); and

 

(iv)

AV-353, a potent inhibitory antibody specific to Notch 3, which has demonstrated an ability in preclinical models to potentially reverse disease phenotype for pulmonary arterial hypertension (“PAH”), and for which the Company is currently seeking a partner to advance development in PAH.

As used throughout these condensed consolidated financial statements, the terms “AVEO,” and the “Company” refer to the business of AVEO Pharmaceuticals, Inc. and its two wholly-owned subsidiaries, AVEO Pharma Limited and AVEO Securities Corporation.  

The Company has devoted substantially all of its resources to its drug discovery efforts, comprising research and development, conducting clinical trials for its product candidates, protecting its intellectual property and general and administrative functions relating to these operations.

The Company has an accumulated deficit as of March 31, 2016 of approximately $502.7 million, and is subject to a number of risks including the need for substantial additional capital for research and product development. The Company will need additional funding to support its planned operating activities, and the timing and nature of activities contemplated for 2016 and thereafter will be conducted subject to the availability of sufficient financial resources.

 

 

 

7


(2) Basis of Presentation

These condensed consolidated financial statements include the accounts of the Company and its wholly-owned subsidiaries, AVEO Pharma Limited and AVEO Securities Corporation. The Company has eliminated all significant intercompany accounts and transactions in consolidation.

The accompanying condensed consolidated financial statements have been prepared in accordance with generally accepted accounting principles for interim financial information and with the instructions to Form 10-Q and Article 10 of Regulation S-X. Accordingly, they do not include all of the information and footnotes required by generally accepted accounting principles for complete financial statements. In the opinion of management, all adjustments, consisting of normal recurring accruals and revisions of estimates, considered necessary for a fair presentation of the condensed consolidated financial statements have been included. Interim results for the three months ended March 31, 2016 are not necessarily indicative of the results that may be expected for the fiscal year ending December 31, 2016 or any other future period.

The information presented in the condensed consolidated financial statements and related footnotes at March 31, 2016, and for the three months ended March 31, 2016 and 2015, is unaudited, and the condensed consolidated balance sheet amounts and related footnotes as of December 31, 2015 have been derived from the Company’s audited financial statements. For further information, refer to the consolidated financial statements and accompanying footnotes included in the Company’s annual report on Form 10-K for the fiscal year ended December 31, 2015, which was filed with the U.S. Securities and Exchange Commission (“SEC”) on March 15, 2016.

 

(3) Significant Accounting Policies

Revenue Recognition

The Company’s revenues are generated primarily through collaborative research, development and commercialization agreements. The terms of these agreements generally contain multiple elements, or deliverables, which may include (i) licenses, or options to obtain licenses, to the Company’s technology, (ii) research and development activities to be performed on behalf of the collaborative partner, and (iii) in certain cases, services in connection with the manufacturing of pre-clinical and clinical material. Payments to the Company under these arrangements typically include one or more of the following: non-refundable, up-front license fees; option exercise fees; funding of research and/or development efforts; milestone payments; and royalties on future product sales.

When evaluating multiple element arrangements, the Company considers whether the deliverables under the arrangement represent separate units of accounting. This evaluation requires subjective determinations and requires management to make judgments about the individual deliverables and whether such deliverables are separable from the other aspects of the contractual relationship. In determining the units of accounting, management evaluates certain criteria, including whether the deliverables have standalone value, based on the relevant facts and circumstances for each arrangement. The consideration received is allocated among the separate units of accounting using the relative selling price method, and the applicable revenue recognition criteria are applied to each of the separate units.

The Company determines the estimated selling price for deliverables within each agreement using vendor-specific objective evidence (“VSOE”) of selling price, if available, third-party evidence (“TPE”) of selling price if VSOE is not available, or best estimate of selling price if neither VSOE nor TPE is available. Determining the best estimate of selling price for a deliverable requires significant judgment. The Company typically uses best estimate of selling price to estimate the selling price for licenses to the Company’s proprietary technology, since the Company often does not have VSOE or TPE of selling price for these deliverables. In those circumstances where the Company utilizes best estimate of selling price to determine the estimated selling price of a license to the Company’s proprietary technology, the Company considers market conditions as well as entity-specific factors, including those factors contemplated in negotiating the agreements and internally developed models that include assumptions related to the market opportunity, estimated development costs, probability of success and the time needed to commercialize a product candidate pursuant to the license. In validating the Company’s best estimate of selling price, the Company evaluates whether changes in the key assumptions used to determine the best estimate of selling price will have a significant effect on the allocation of arrangement consideration among multiple deliverables.

The Company typically receives non-refundable, up-front payments when licensing its intellectual property in conjunction with a research and development agreement. When management believes the license to its intellectual property does not have stand-alone value from the other deliverables to be provided in the arrangement, the Company generally recognizes revenue attributed to the license on a straight-line basis over the Company’s contractual or estimated performance period, which is typically the term of the Company’s research and development obligations. If management cannot reasonably estimate when the Company’s performance obligation ends, then revenue is deferred until management can reasonably estimate when the performance obligation ends. When management believes the license to its intellectual property has stand-alone value, the Company generally recognizes revenue attributed to the license upon delivery. The periods over which revenue should be recognized are subject to estimates by management

 

8


and may change over the course of the research and development agreement. Such a change could have a material impact on the amount of revenue the Company records in future periods.

Payments or reimbursements resulting from the Company’s research and development efforts for those arrangements where such efforts are considered as deliverables are recognized as the services are performed and are presented on a gross basis so long as there is persuasive evidence of an arrangement, the fee is fixed or determinable, and collection of the related receivable is reasonably assured. Amounts received prior to satisfying the above revenue recognition criteria are recorded as deferred revenue in the accompanying balance sheets.

At the inception of each agreement that includes milestone payments, the Company evaluates whether each milestone is substantive and at risk to both parties on the basis of the contingent nature of the milestone. This evaluation includes an assessment of whether (a) the consideration is commensurate with either (1) the entity’s performance to achieve the milestone, or (2) the enhancement of the value of the delivered item(s) as a result of a specific outcome resulting from the entity’s performance to achieve the milestone, (b) the consideration relates solely to past performance, and (c) the consideration is reasonable relative to all of the deliverables and payment terms within the arrangement. The Company evaluates factors such as the scientific, regulatory, commercial and other risks that must be overcome to achieve the respective milestone, the level of effort and investment required to achieve the respective milestone and whether the milestone consideration is reasonable relative to all deliverables and payment terms in the arrangement in making this assessment.

The Company aggregates its milestones into four categories: (i) clinical and development milestones, (ii) regulatory milestones, (iii) commercial milestones, and (iv) patent-related milestones. Clinical and development milestones are typically achieved when a product candidate advances into a defined phase of clinical research or completes such phase. For example, a milestone payment may be due to the Company upon the initiation of a phase 3 clinical trial for a new indication, which is the last phase of clinical development and could eventually contribute to marketing approval by the U.S. Food and Drug Administration (“FDA”) or other global regulatory authorities. Regulatory milestones are typically achieved upon acceptance of the submission for marketing approval of a product candidate or upon approval to market the product candidate by the FDA or other global regulatory authorities. For example, a milestone payment may be due to the Company upon the FDA’s acceptance of a New Drug Application (“NDA”). Commercial milestones are typically achieved when an approved pharmaceutical product reaches certain defined levels of net sales by the licensee, such as when a product first achieves global sales or annual sales of a specified amount. Patent-related milestones are typically achieved when a patent application is filed or a patent is issued with respect to certain intellectual property related to the applicable collaboration.

Revenues from clinical and development, regulatory, and patent-related milestone payments, if the milestones are deemed substantive and the milestone payments are nonrefundable, are recognized upon successful accomplishment of the milestones. The Company has concluded that the clinical and development, regulatory and patent-related milestones pursuant to its current research and development arrangements are substantive. Milestones that are not considered substantive are accounted for as license payments and recognized on a straight-line basis over the remaining period of performance. Revenues from commercial milestone payments are accounted for as royalties and are recorded as revenue upon achievement of the milestone, assuming all other revenue recognition criteria are met.

Research and Development Expenses

Research and development expenses are charged to expense as incurred. Research and development expenses consist of costs incurred in performing research and development activities, including personnel-related costs such as salaries and stock-based compensation, facilities, research-related overhead, clinical trial costs, manufacturing costs and costs of other contracted services, license fees, and other external costs. Nonrefundable advance payments for goods and services that will be used in future research and development activities are expensed when the activity has been performed or when the goods have been received.

Cash and Cash Equivalents

The Company considers highly liquid investments with a maturity of three months or less when purchased to be cash equivalents. Cash equivalents at March 31, 2016 consisted of money market funds and corporate debt securities maintained by an investment manager totaling $9.1 million. Cash equivalents at December 31, 2015 consisted of money market funds, U.S. government agency securities and corporate debt securities, including commercial paper, maintained by an investment manager totaling $16.3 million. The carrying values of the Company’s cash equivalent securities approximate fair value due to their short term maturities.

Marketable Securities

Marketable securities at March 31, 2016 consisted of U.S. government agency securities and corporate debt securities, including commercial paper, maintained by an investment manager. Marketable securities at December 31, 2015 consisted of government

 

9


agency and corporate debt securities, including commercial paper, maintained by an investment manager. Credit risk is reduced as a result of the Company’s policy to limit the amount in vested in any one issuance . Marketable securities consist primarily of investments which have expected average maturity dates in excess of three months, but not longer than 24 months. The Company classifies these investments as available-for-sale. Unrealiz ed gains and losses are included in other comprehensive loss until realized. The cost of securities sold is based on the specific identification method. There were no realized gains or losses recognized on the sale or maturity of marketable securities duri ng the three months ended March 31, 2016 and 2015 .

Available-for-sale securities at March 31, 2016 and December 31, 2015 consisted of the following:

 

 

 

Amortized

Cost

 

 

Unrealized

Gains

 

 

Unrealized

Losses

 

 

Fair

Value

 

 

 

(in thousands)

 

March 31, 2016:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Corporate debt securities (Due within 1 year)

 

$

4,748

 

 

$

2

 

 

$

 

 

$

4,750

 

Government agency securities (Due within 1 year)

 

 

999

 

 

 

 

 

 

 

 

 

999

 

 

 

$

5,747

 

 

$

2

 

 

$

 

 

$

5,749

 

December 31, 2015:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Corporate debt securities (Due within 1 year)

 

$

6,504

 

 

$

 

 

$

(3

)

 

$

6,501

 

Government agency securities (Due within 1 year)

 

 

1,000

 

 

 

 

 

 

 

 

 

1,000

 

 

 

$

7,504

 

 

$

 

 

$

(3

)

 

$

7,501

 

 

The aggregate unrealized loss for the Company’s corporate debt securities was less than $1,000 as of March 31, 2016.

Marketable securities in an unrealized loss position at December 31, 2015 consisted of the following:

 

 

 

Aggregate

Fair Value

 

 

Unrealized

Losses

 

 

 

 

(in thousands)

 

Corporate debt securities (Due within 1 year)

 

$

4,100

 

 

$

(3

)

Government agency securities (Due within 1 year)

 

 

1,000

 

 

 

 

 

 

$

5,100

 

 

$

(3

)

 

 

Concentrations of Credit Risk

Financial instruments that potentially subject the Company to credit risk primarily consist of cash and cash equivalents, marketable securities and accounts receivable. The Company maintains deposits in federally insured financial institutions in excess of federally insured limits.

Management believes that the Company is not exposed to significant credit risk related to cash deposits due to the financial position of the depository institutions in which those deposits are held. The Company’s credit risk related to marketable securities is reduced as a result of the Company’s policy to limit the amount invested in any one issuance.

The Company’s accounts receivable primarily consist of amounts due to the Company from licensees and collaborators. As of March 31, 2016, the Company had $1.7 million of receivables outstanding, including $0.9 million due from CANbridge pursuant to the Company’s licensing arrangement for AV-203 (refer to Note 7), $0.7 million due from Biodesix pursuant to the Company’s collaboration arrangement for AV-299 (refer to Note 7) and $0.2 million due from Astellas pursuant to the Company’s former collaboration arrangement for tivozanib. The Company has not experienced any material losses related to receivables from individual licensees or collaborators.

 

10


Fair Value Measurements

The Company records cash equivalents and marketable securities at fair value. The accounting standards for fair value measurements establish a hierarchy that distinguishes between fair value measurements based on market data (observable inputs) and those based on the Company’s own assumptions (unobservable inputs). The hierarchy consists of three levels:

 

·

Level 1—Quoted market prices in active markets for identical assets or liabilities. Assets that are valued utilizing only Level 1 inputs include money market funds.

 

·

Level 2—Inputs other than Level 1 inputs that are either directly or indirectly observable, such as quoted market prices, interest rates and yield curves. Assets that are valued utilizing Level 2 inputs include U.S. government agency securities and corporate bonds, including commercial paper. These investments have been initially valued at the transaction price and are subsequently valued, at the end of each reporting period, utilizing third party pricing services or other observable market data. The pricing services utilize industry standard valuation models, including both income and market based approaches and observable market inputs to determine value. These observable market inputs include reportable trades, benchmark yields, credit spreads, broker/dealer quotes, bids, offers, current spot rates, and other industry and economic events. The Company validates the prices provided by third party pricing services by reviewing their pricing methods and matrices, obtaining market values from other pricing sources, analyzing pricing data in certain instances and confirming that the relevant markets are active. After completing its validation procedures, the Company did not adjust or override any fair value measurements provided by pricing services as of March 31, 2016.

 

·

Level 3—Unobservable inputs developed using estimates and assumptions developed by the Company, which reflect those that a market participant would use. The Company currently has no assets or liabilities measured at fair value on a recurring basis that utilize Level 3 inputs.

The following tables summarize the cash equivalents and marketable securities measured at fair value on a recurring basis in the accompanying condensed consolidated balance sheets as of March 31, 2016 and December 31, 2015.

 

 

 

 

Fair Value Measurements of Cash Equivalents and

Marketable Securities as of March 31, 2016

 

 

 

Level 1

 

 

Level 2

 

 

Level 3

 

 

Total

 

 

 

(in thousands)

 

Cash equivalents

 

$

6,907

 

 

$

2,143

 

 

$

 

 

$

9,050

 

Marketable securities

 

 

 

 

 

5,749

 

 

 

 

 

 

5,749

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

$

6,907

 

 

$

7,892

 

 

$

 

 

$

14,799

 

 

 

 

 

Fair Value Measurements of Cash Equivalents and

Marketable Securities as of December 31, 2015

 

 

 

Level 1

 

 

Level 2

 

 

Level 3

 

 

Total

 

 

 

(in thousands)

 

Cash equivalents

 

$

11,462

 

 

$

4,812

 

 

$

 

 

$

16,274

 

Marketable securities

 

 

 

 

 

7,501

 

 

 

 

 

 

7,501

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

$

11,462

 

 

$

12,313

 

 

$

 

 

$

23,775

 

 

 

The fair value of the Company’s loans payable at March 31, 2016, computed pursuant to a discounted cash flow technique using a market interest rate, was $10.1 million and is considered a Level 3 fair value measurement. The effective interest rate, which reflects the current market rate, considers the fair value of the warrant issued in connection with the loan, loan issuance costs and the deferred financing charge.

Property and Equipment

Property and equipment are stated at cost and are depreciated using the straight-line method over the estimated useful lives of the respective assets. Maintenance and repair costs are charged to expense as incurred.

 

11


Long-lived Assets

The Company reviews long-lived assets, including property and equipment, for impairment whenever changes in business circumstances indicate that the carrying amount of the asset may not be fully recoverable. No impairment charges were recognized during the three months ended March 31, 2016. The Company recognized $0.2 million of impairment losses for the three months ended March 31, 2015 related to leasehold improvements.

Basic and Diluted Loss per Common Share

Basic loss per share is computed by dividing net loss available to common stockholders by the weighted-average number of common shares outstanding during the period. Diluted loss per share is computed by dividing net loss available to common stockholders by the weighted-average number of common shares and dilutive common share equivalents then outstanding which excludes unvested restricted stock. Potential common share equivalents consist of the incremental common shares issuable upon the exercise of stock options and warrants. Since the Company had a net loss for all periods presented, the effect of all potentially dilutive securities is anti-dilutive. Accordingly, basic and diluted net loss per common share is the same.

 

The following table sets forth the potential common shares excluded from the calculation of net loss per common share-diluted for the three months ended March 31, 2016 and 2015 because their inclusion would have been anti-dilutive:

 

 

 

Outstanding at

March 31,

 

 

 

2016

 

 

2015

 

 

 

 

(in thousands)

 

Options outstanding

 

 

5,584

 

 

 

5,861

 

Warrants outstanding

 

 

609

 

 

 

609

 

 

 

 

6,193

 

 

 

6,470

 

Stock-Based Compensation

Under the Company’s stock-based compensation programs, the Company periodically grants stock options and restricted stock to employees, directors and nonemployee consultants. The Company also issues shares under an employee stock purchase plan. The fair value of all awards is recognized in the Company’s statements of operations over the requisite service period for each award. Awards that vest as the recipient provides service are expensed on a straight-line basis over the requisite service period. Other awards, such as performance-based awards that vest upon the achievement of specified goals, are expensed using the accelerated attribution method if achievement of the specified goals is considered probable. The Company has also granted awards that vest upon the achievement of market conditions. Per Accounting Standards Codification (“ASC”) 718 Share-Based Payments, market conditions must be considered in determining the estimated grant-date fair value of share-based payments and the market conditions must be considered in determining the requisite service period over which compensation cost is recognized. The Company estimates the fair value of the awards with market conditions using a Monte Carlo simulation, which utilizes several assumptions including the risk-free interest rate, the volatility of the Company’s stock and the exercise behavior of award recipients. The grant-date fair value of the awards is then recognized over the requisite service period, which represents the derived service period for the awards as determined by the Monte Carlo simulation.

The fair value of equity-classified awards to employees and directors are measured at fair value on the date the awards are granted. Awards to nonemployee consultants are recorded at their fair values and are re-measured as of each balance sheet date until the recipient’s services are complete. During the three months ended March 31, 2016 and 2015, the Company recorded the following stock-based compensation expense:

 

 

 

Three Months Ended

March 31,

 

 

 

 

2016

 

 

2015

 

 

 

 

(in thousands)

 

Research and development

 

$

125

 

 

$

125

 

 

General and administrative

 

 

265

 

 

 

233

 

 

Restructuring

 

 

 

 

 

69

 

 

 

 

$

390

 

 

$

427

 

 

 

 

 

12


Stock-based compensation expense is allocated to research and development and general and administrative expense based upon the department of the employee to whom each award was granted. Expenses recognized in connection with the modification of awards in connection with the Company’s strategic restructurings are allocated to restructuring expense. No related tax benefits of the stock-based compensation expense have been recognized.

Income Taxes

The Company provides for income taxes using the asset-liability method. Under this method, deferred tax assets and liabilities are recognized based on differences between financial reporting and tax bases of assets and liabilities, and are measured using the enacted tax rates and laws that will be in effect when the differences are expected to reverse. The Company calculates its provision for income taxes on ordinary income based on its projected annual tax rate for the year. Uncertain tax positions are recognized if the position is more-likely-than-not to be sustained upon examination by a tax authority. Unrecognized tax benefits represent tax positions for which reserves have been established. As of March 31, 2016, the Company is forecasting a net loss for the year ended December 31, 2016. The Company maintains a full valuation allowance on all deferred tax assets. For the three months ended March 31, 2016, the Company recorded a $0.1 million provision for income taxes related to withholding taxes incurred in a foreign jurisdiction.

Segment and Geographic Information

Operating segments are defined as components of an enterprise engaging in business activities for which discrete financial information is available and regularly reviewed by the chief operating decision maker in deciding how to allocate resources and in assessing performance. The Company views its operations and manages its business in one operating segment principally in the United States. As of March 31, 2016, the Company has $0.9 million of net assets located in the United Kingdom.

Use of Estimates

The preparation of financial statements in conformity with accounting principles generally accepted in the United States (“GAAP”) requires the Company’s management to make estimates and assumptions that affect the amounts reported in the financial statements and accompanying notes. Actual results could differ from those estimates.

Recent Accounting Pronouncements

For a discussion of recent accounting pronouncements adopted by the Company, please refer to Note 2, “Significant Accounting Policies,” included in the Company’s Annual Report on Form 10-K for the fiscal year ended December 31, 2015, filed with the SEC on March 15, 2016. The Company did not adopt any new accounting pronouncements during the three months ended March 31, 2016 that had a material effect on the Company’s condensed consolidated financial statements.

In May 2014, the Financial Accounting Standards Board (“FASB”) issued a comprehensive new revenue recognition standard that will supersede nearly all existing revenue recognition guidance under US GAAP. The standard was originally scheduled to be effective for public entities for annual and interim periods beginning after December 15, 2016. In July 2015, the standard was deferred and will now be effective for annual and interim periods beginning after December 15, 2017. Early adoption is permitted for annual and interim periods beginning after December 15, 2016. The Company is currently evaluating the effect this standard will have on its revenue recognition policies and its financial statements, including how the standard will be adopted.

In August 2014, the FASB issued Accounting Standards Update (“ASU”) No. 2014-15,  Presentation of Financial Statements—Going Concern (Subtopic 205-40): Disclosure of Uncertainties about an Entity’s Ability to Continue as a Going Concern.   This ASU is intended to define management’s responsibility to evaluate whether there is substantial doubt about an organization’s ability to continue as a going concern within one year of the date of issuance of the entity’s financial statements and to provide related footnote disclosures. This guidance is effective for fiscal years ending after December 15, 2016, with early application permitted. If this standard had been adopted as of March 31, 2016 and applied to these financial statements, the Company believes that there would be no significant impact to its disclosure as no substantial doubt about the Company’s ability to continue as a going concern exists. The Company faces certain risks and uncertainties, however, as further described in Note 1, “Organization,” that may have an effect on the Company’s disclosures in future periods.

 

In March 2016, the FASB issued ASU No. 2016-09, Compensation─Stock Compensation (Topic 718): Improvements to Employee Share-Based Payment Accounting . This ASU is intended to simplify certain aspects of the accounting for share-based payment transactions, such as allowing entities to elect to account for forfeitures as they occur or to continue to estimate the number of awards that are expected to vest. The standard is effective for public entities for annual and interim periods beginning after December 15, 2016. The Company is currently evaluating the impact that the adoption of this standard will have on its financial statements.

 

 

 

13


(4) Collaborations and License Agreements

CANbridge

In March 2016, the Company entered into a collaboration and license agreement with CANbridge Life Sciences Ltd. (“CANbridge”). Under the terms of the license agreement, the Company granted CANbridge the exclusive right to develop, manufacture and commercialize AV-203, the Company’s proprietary ErbB3 (HER3) inhibitory antibody, for the diagnosis, treatment and prevention of disease in humans and animals in all countries other than the United States, Canada and Mexico (the “Licensed Territory”). Under the terms of the license agreement, if the Company determines to grant a license to any ErbB3 inhibitory antibody in the United States, Canada or Mexico, the Company is obligated to first negotiate with CANbridge for the grant to CANbridge of a license to such rights. In addition, for a period of time following the completion of certain proof-of-concept clinical studies by CANbridge involving the use of AV-203 for the treatment of squamous cell esophagus cancer, the Company has agreed to negotiate exclusively with CANbridge for (a) the right to co-develop ErbB3 inhibitory antibody products for the treatment of squamous cell esophagus cancer or (b) the right to include the United States, Canada and Mexico as part of the Licensed Territory under the license agreement.  The effective date of the license agreement is March 16, 2016 (the “Effective Date”).

CANbridge made an upfront payment to the Company of $1.0 million in April 2016. This amount was included in accounts receivable on the Company’s balance sheet as of March 31, 2016 net of $0.1 million of withholding taxes. CANbridge has agreed to reimburse the Company $1.0 million for certain manufacturing costs and expenses previously incurred by the Company with respect to AV-203, $0.5 million of which will be due to the Company on the earlier of (i) the date of validation by CANbridge of certain manufacturing development activities conducted by the Company prior to the Effective Date or (ii) twelve months from the Effective Date, and the remaining $0.5 million of which will be due to the Company on the earlier of (i) the date of validation by CANbridge of such manufacturing development activities or (ii) eighteen months from the Effective Date. The Company is also eligible to receive up to $42.0 million in potential development and regulatory milestone payments and up to $90.0 million in potential sales based milestone payments based on annual net sales of licensed products. Upon commercialization, the Company is eligible to receive a tiered royalty, with a percentage range in the low double digits, on net sales of approved licensed products. CANbridge’s obligation to pay royalties for each licensed product expires on a country-by-country basis on the later of the expiration of patent rights covering such licensed product in such country, the expiration of regulatory data exclusivity in such country and ten years after the first commercial sale of such licensed product in such country.

CANbridge is obligated to use commercially reasonable efforts to develop and commercialize AV-203 in each of China, Japan, the United Kingdom, France, Italy, Spain, and Germany. CANbridge has responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of AV-203 in the Licensed Territory.

The term of the license agreement commenced on the Effective Date and will continue until the last to expire royalty term applicable to licensed products. Either party may terminate the license agreement in the event of a material breach by the other party that remains uncured for a period of 45 days, in the case of a material breach of a payment obligation, and 90 days in the case of any other material breach. CANbridge may terminate the license agreement without cause at any time upon 180 days’ prior written notice to the Company. The Company may terminate the license agreement upon thirty days’ prior written notice if CANbridge challenges any of the patent rights licensed to CANbridge under the license agreement.

The Company and CANbridge have each agreed to not directly or indirectly develop or commercialize any ErbB3 inhibitory antibody product during the term of the license agreement other than pursuant to the license agreement.

A percentage of any milestone and royalty payments received by the Company, excluding upfront and reimbursement payments, are due to Biogen Idec International GMBH (“Biogen”) as a sublicensing fee under the option and license agreement between the Company and Biogen dated March 18, 2009, as amended.

Activities under the agreement were evaluated under ASC 605-25 Revenue Recognition—Multiple Element Arrangements , or ASC 605-25, to determine whether such activities represented a multiple element revenue arrangement. The agreement with CANbridge includes the following non-contingent deliverables: (i) the Company’s grant of an exclusive license to develop and commercialize AV-203 in the licensed territories, (ii) the Company’s obligation to transfer all technical knowledge and data useful in the development and manufacture of AV-203 and (iii) the Company’s obligation to participate on a joint steering committee during the proof-of-concept development period. The relative selling price of the Company’s joint steering committee participation had de minimis value. The Company determined that the delivered license and know-how did have stand-alone value from the undelivered element and have accounted for these items as separate deliverables. The Company allocated the up-front consideration of $1.0 million to the units of accounting and recognized the $1.0 million attributed to the delivered license and know-how during the three months ended March 31, 2016.

The Company believes the regulatory milestones that may be achieved under the license agreement are consistent with the definition of a milestone included in ASU 2010-17,  Revenue Recognition—Milestone Method , and, accordingly, the Company will

 

14


recognize payments related to the achievement of such milestones, if any, when each such milestone is achieved. Factors consid ered in this determination included scientific and regulatory risks that must be overcome to achieve each milestone, the level of effort and investment required to achieve each milestone, and the monetary value attributed to each milestone.

EUSA

In December 2015, the Company entered into a license agreement with EUSA Pharma (UK) Limited (“EUSA”) under which the Company granted to EUSA the exclusive, sublicensable right to develop, manufacture and commercialize tivozanib in the territories of Europe (excluding Russia, Ukraine and the Commonwealth of Independent States), Latin America (excluding Mexico), Africa, Australasia and New Zealand (the “Licensed Territories”) for all diseases and conditions in humans, excluding non-oncologic diseases or conditions of the eye.  EUSA filed an application with the EMA in February 2016 for approval of marketing authorization for tivozanib for the treatment of RCC.

Under the license agreement, EUSA made a research and development funding payment to the Company of $2.5 million during the year ended December 31, 2015.  EUSA is required to make a further research and development funding payment of $4.0 million upon the grant by the European Medicines Agency (“EMA”) of marketing approval for tivozanib for treatment of RCC. The Company is eligible to receive additional research funding from EUSA, including up to $20.0 million if the Company conducts a phase 3 study in third-line RCC and EUSA elects to utilize data generated by the study, and up to $2.0 million for a potential phase 1 combination study with a checkpoint inhibitor. The Company will be entitled to receive milestone payments of $2.0 million per country upon reimbursement approval for RCC in each of France, Germany, Italy, Spain and the United Kingdom, and an additional $2.0 million for the grant of marketing approval in three of the following five countries: Argentina, Australia, Brazil, South Africa and Venezuela. The Company is also eligible to receive a payment of $2.0 million in connection with EUSA’s filing with the EMA for marketing approval for tivozanib for the treatment of each of up to three additional indications and $5.0 million per indication in connection with the EMA’s grant of marketing approval for each of up to three additional indications, as well as potentially up to $335.0 million upon EUSA’s achievement of certain sales thresholds. The Company is also eligible to receive tiered double digit royalties on net sales, if any, of licensed products in the Licensed Territories ranging from a low double digit up to mid-twenty percent depending on the level of annual net sales. A percentage of any milestone and royalty payments received by AVEO are due to Kyowa Hakko Kirin Co., Ltd. (formerly Kirin Brewery Co., Ltd.) (“KHK”) as a sublicensing fee under the license agreement between AVEO and KHK dated as of December 21, 2006 , pursuant to which the Co mpany acquired exclusive rights to develop and commercialize tivozanib for all human diseases outside of Asia (the “KHK License Agreement”).   The research and development funding payments under the EUSA license agreement are not subject to sublicensing payment to KHK.

EUSA is obligated to use commercially reasonable efforts to develop and commercialize tivozanib throughout the Licensed Territories. With the exception of certain support to be provided by the Company in connection with the application for marketing approval by the EMA, EUSA has responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of tivozanib in the Licensed Territories.

Activities under the agreement were evaluated under ASC 605-25 to determine whether such activities represented a multiple element revenue arrangement. The agreement with EUSA includes the following non-contingent deliverables: (i) the Company’s grant of an exclusive license to develop and commercialize the tivozanib in the licensed territories; (ii) the Company’s obligation to transfer all technical knowledge and data useful in the development and manufacture of tivozanib; (iii) the Company’s obligation to cooperate with EUSA and support its efforts to file for marketing approval in the licensed territories, (iv) the Company’s obligation to provide access to certain regulatory information resulting from the Company’s ongoing development activities outside of the licensed territories and (v) the Company’s participation in a joint steering committee. The Company determined that the delivered license did not have stand-alone value from the undelivered elements and have accounted for these items as a single bundled deliverable. The Company allocated up-front consideration of $2.5 million to the bundled unit of accounting and is recognizing it over the Company’s performance period through April 2022, the remaining patent life of tivozanib. The Company recognized approximately $0.1 million as revenue during the three months ended March 31, 2016.

The Company believes the regulatory milestones that may be achieved under the EUSA agreement are consistent with the definition of a milestone included in ASU 2010-17,  Revenue Recognition—Milestone Method , and, accordingly, the Company will recognize payments related to the achievement of such milestones, if any, when each such milestone is achieved. Factors considered in this determination included scientific and regulatory risks that must be overcome to achieve each milestone, the level of effort and investment required to achieve each milestone, and the monetary value attributed to each milestone. No milestone payments have been earned as of March 31, 2016.

Novartis

In August 2015, the Company entered into a license agreement with Novartis. Under the license agreement, the Company has granted to Novartis the exclusive right to develop and commercialize worldwide the Company’s proprietary antibody AV-380 and related AVEO antibodies that bind to Growth Differentiation Factor 15 (“GDF15”) for the treatment and prevention of diseases and other conditions in all indications in humans (the “Product”).

 

15


Pursuant to the license agreement, Novartis made an upfront payment to the Company of $15.0 million within fifte en days of the effective date. Novartis also has acquired the Company’s inventory of clinical quality, AV-380 biological drug substance and reimbursed the Company for approximately $3.5 million for such existing inventory. The Company is also eligible to r eceive (a) up to $53.0 million in potential clinical and development milestone payments and up to $105.0 million in potential regulatory milestone payments tied to the commencement of clinical trials and to regulatory approvals of products developed under the license agreement in the United States, the European Union and Japan; and (b) up to $150.0 million in potential commercial milestone payments based on annual net sales of such products. Upon commercialization, the Company is eligible to receive tiered royalties on net sales of approved products ranging from the high single digits to the low double digits. Novartis has responsibility under the license agreement for the development, manufacture and commercialization of the Company’s antibodies and any res ulting approved therapeutic products.

The Company has agreed that it will not directly or indirectly develop, manufacture or commercialize any GDF15 modulator as a human therapeutic during the term of the license agreement.

Activities under the agreement with Novartis were evaluated under ASC 605-25, to determine whether such activities represented a multiple element revenue arrangement. The agreement with Novartis includes the following non-contingent deliverables: (i) the Company’s grant of an exclusive, worldwide license to develop and commercialize the Product; (ii) the Company’s obligation to transfer all technical knowledge and data useful in the development and manufacture of the Product; and (iii) the Company’s obligation to cooperate with Novartis’ requests for transition assistance during a 90 day period.  The Company determined that the option to purchase the Company’s existing inventory was a contingent deliverable.

The Company determined the delivered license and obligation to transfer technical knowledge and data have standalone value from the undelivered cooperation. The Company allocated up-front consideration of $15.0 million to the delivered license and technical knowledge and recognized this amount as revenue during the year ended December 31, 2015. The relative selling price of the undelivered cooperation had   de minimis   value.

 

The Company received a cash payment of $3.5 million related to the delivery of its inventory of clinical quality drug substance to Novartis during the three months ended March 31, 2016. No amounts were due to the Company from Novartis as of March 31, 2016.

Pharmstandard

In August 2015, the Company entered into a license agreement with JSC “Pharmstandard-Ufimskiy Vitamin Plant,” a company registered under the laws of the Russian Federation (“Pharmstandard”). Pharmstandard is a subsidiary of Pharmstandard OJSC. Under the license agreement, the Company has granted to Pharmstandard the exclusive, sublicensable right to develop, manufacture and commercialize tivozanib in the territories of Russia, Ukraine and the Commonwealth of Independent States (the “Licensed Territories”) for all diseases and conditions in humans, excluding non-oncologic ocular conditions.

Pharmstandard is obligated to use commercially reasonable efforts to develop and commercialize tivozanib throughout the Licensed Territories, and Pharmstandard has responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of tivozanib in the Licensed Territories. Pharmstandard filed an application for marketing authorization in Russia for tivozanib for the treatment of renal cell carcinoma in December 2015.

Under the license agreement, Pharmstandard is required to make an upfront payment to AVEO of $1.5 million, of which $1.0 million was paid during the year ended December 31, 2015 and $0.5 million is payable within fifteen business days of the date the license agreement is registered with the Federal Service for Intellectual Property of the Russian Federation. The Company is also eligible to receive $7.5 million in connection with the first marketing authorization of tivozanib in Russia. If Russian regulatory authorities require additional studies to be conducted by Pharmstandard prior to approval, this amount would be reduced to $3.0 million. In addition, the Company is eligible to receive $3.0 million for each additional approved indication of tivozanib, if Pharmstandard elects to seek any such approvals, as well as a high single-digit royalty on net sales in the Licensed Territories.  A percentage of all upfront, milestone and royalty payments received by AVEO are due to KHK as a sublicensing fee under the KHK License Agreement. Pharmstandard has recently informed the Company that, based on adverse economic and financial conditions in Russia, they are seeking to renegotiate their obligation to make milestone payments to the Company under the license agreement.

Activities under the agreement with Pharmstandard were evaluated under   ASC 605-25   to determine whether such activities represented a multiple element revenue arrangement. The agreement with Pharmstandard includes the following non-contingent deliverables:   (i)   the Company’s grant of an exclusive license to develop and commercialize tivozanib in the Licensed Territories,   (ii)   the Company’s obligation to provide access , upon request, to all clinical data, regulatory filings, safety data and manufacturing data   to Pharmstandard for use in the development and commercialization of tivozanib in the Licensed Territories ,   (iii)   the Company’s obligation to participate in certain development and commercialization planning meetings and   (iv)   the

 

16


Company’s obligation to provide support for certain development, regulatory or manufacturing activities if re quested by Pharmstandard.

The Company determined the delivered license does not have standalone value from the undelivered items and that the arrangement should be treated as a single unit of accounting. The Company allocated the upfront payment of $1.0 million to the bundled unit of accounting and is recognizing it over the Company’s performance period through April 2022, the remaining patent life of tivozanib. The Company recognized approximately $38,000 as revenue during the three months ended March 31, 2016.

The Company believes the regulatory milestones that may be achieved under the Pharmstandard agreement are consistent with the definition of a milestone included in ASU 2010-17,  Revenue Recognition—Milestone Method , and, accordingly, the Company will recognize payments related to the achievement of such milestones, if any, when such milestone is achieved. Factors considered in this determination included scientific and regulatory risks that must be overcome to achieve each milestone, the level of effort and investment required to achieve each milestone, and the monetary value attributed to each milestone.

Ophthotech Corporation

In November 2014 the Company entered into a research and exclusive option agreement (the “Option Agreement”), with Ophthotech Corporation (“Ophthotech”) pursuant to which the Company provided Ophthotech an exclusive option to enter into a definitive license agreement whereby the Company would grant Ophthotech the right to develop and commercialize tivozanib outside of Asia for the potential diagnosis, prevention and treatment of non-oncologic diseases or conditions of the eye in humans.

Pursuant to this Option Agreement, the Company granted to Ophthotech an exclusive, royalty-free license or sublicense, as applicable, under intellectual property rights controlled by the Company solely to perform the research and development activities related to the use of tivozanib for the specific purposes outlined in the agreement during the Option Period (as defined below). These activities include formulation work for ocular administration, preclinical research and the conduct of a phase 1/2a, proof of concept clinical trial of a product containing tivozanib in patients with wet age-related macular degeneration, (the “POC Study”).

Ophthotech paid the Company $0.5 million in consideration for the grant of the option. Such amount is non-refundable and not creditable against any other amounts due under the agreement. The Company is obligated to make available to Ophthotech, at no cost to Ophthotech, certain quantities of tivozanib hydrochloride solely for conducting its Option Period research including manufacturing additional quantities of tivozanib in the event stability data indicates that the current supply will expire prior to the end of February 2017.

During the Option Period, if Ophthotech elects to continue the development of tivozanib for non-oncologic diseases of the eye, the Company is entitled to receive a one-time milestone payment of $2.0 million upon acceptance of the first Investigational New Drug application for the purpose of conducting a human clinical study of tivozanib in ocular diseases (the “IND Submission Milestone Payment”). The Company is also entitled to receive a one-time milestone payment of $6.0 million (the “Clinical Efficacy Milestone Payment”), on the earlier of (a) December 31, 2016 and (b) the later to occur of: (i) the achievement of a clinical milestone in the POC Study (the “Clinical Efficacy Milestone”) and (ii) the earlier of (A) the date twelve (12) months after our and Ophthotech’s agreement as to the form and substance of the KHK Amendment (as defined below) or (B) the date ninety (90) days after the entry into the KHK Amendment, subject to the Company’s right to terminate the Option Agreement on 90 days’ written notice (the date on which such payment is due, referred to as the “Clinical Efficacy Milestone Payment Trigger Date”).

Ophthotech may exercise the option at any time until the latest to occur of: (i) twelve (12) months after the achievement of the Clinical Efficacy Milestone, (ii) ninety (90) days after the Clinical Efficacy Milestone Payment Trigger Date, and (iii) thirty (30) days after the Company and Ophthotech agree as to the definitive form of license agreement (the “Option Period”).

During the Option Period, the Company will not grant a license to any third party that would preclude the Company from being able to grant to Ophthotech the rights and licenses that are contemplated by the definitive license agreement, and the Company will not engage in any research, development or commercialization of tivozanib in the field covered by the contemplated definitive license agreement, except as specified in the Option Agreement.

The terms of the Option Agreement are subject to the Company’s obligations to KHK under the KHK License Agreement. A percentage of all payments received by the Company under the Option Agreement and any definitive license agreement must be paid to KHK. The Company is required to maintain the KHK License Agreement in effect, and not enter into any amendment or termination thereof that would adversely affect the Company’s rights, during the option period.

During the Option Period, the Company and Ophthotech are obligated to negotiate in good faith the form and substance of a definitive license agreement, as well as the form and substance of an amendment to the KHK License Agreement (the “KHK

 

17


Amendment”) to modify certain rights and obligations of the parties and sublicensees thereunder, particularly with respect to rights to improvements that are not specifically related to tivozanib, and regulatory affairs matters.

If Ophthotech exercises the option, Ophthotech is required to pay the Company a one-time option exercise fee of $2.0 million in addition to the IND Submission Milestone Payment if such payment has not then been previously paid. If upon exercise of the option, the Clinical Efficacy Milestone Payment Trigger Date has not yet occurred, the Company shall be entitled to the Clinical Efficacy Milestone Payment at such time that the Clinical Efficacy Milestone Payment Date does occur if the license agreement remains in effect as of such date. The license agreement, if entered into upon Ophthotech’s exercise of the option, will provide for the Company to be entitled to receive (i) $10.0 million upon meeting certain efficacy and safety endpoints in phase 2 clinical trials that would enable the commencement of a phase 3 clinical trial, (ii) $20.0 million upon marketing approval in the United States, (iii) $20.0 million upon marketing approval in the UK, Germany, Spain, Italy and France and (iv) up to $45.0 million in sales-based milestone payments. Ophthotech would also be required to pay tiered, double digit royalties, up to the mid-teens, on net sales of tivozanib or products containing tivozanib.

Activities under the agreement with Ophthotech were evaluated under ASC 605-25 to determine whether such activities represented a multiple element revenue arrangement. The agreement with Ophthotech includes the following non-contingent deliverables: (i) the Company’s obligation to grant an exclusive option to Ophthotech to enter into a license agreement to develop and commercialize products incorporating tivozanib for treatment of diseases of the eye outside of Asia during the Option Period (the “Option Grant Deliverable”); (ii) the Company’s obligation to enter into an amendment with KHK to modify the terms of the existing KHK agreement to negotiate a mutually acceptable form of license agreement; and (iii) the Company’s obligation to transfer research-grade tivozanib drug substance for Ophthotech to conduct the Option Period research.

The Company determined that the delivered Option Grant Deliverable did not have standalone value from the remaining deliverables since Ophthotech could not obtain the intended benefit of the option without the remaining deliverables. Similarly, the remaining deliverables have no standalone value without the Option Grant Deliverable. The Company is accounting for the deliverables as one unit of accounting.

Under the Option Agreement, the Company received a cash payment of $0.5 million during the year ended December 31, 2014. The Company deferred the payment and is recording the deferred revenue over the Company’s period of performance, which is currently estimated to be through December 2017. The Company recorded approximately $28,000 and $58,000 of revenue during the three months ended March 31, 2016 and 2015, respectively.

Biodesix

In April 2014, the Company entered into a worldwide agreement with Biodesix to develop and commercialize ficlatuzumab, the Company’s its hepatocyte growth factor (“HGF”) inhibitory antibody, with BDX004, a proprietary companion diagnostic test developed by Biodesix and derived from VeriStrat ® , a serum protein test that is commercially available to help physicians guide treatment decisions for patients with advanced non-small cell lung cancer (“NSCLC”). Under the agreement, the Company granted Biodesix perpetual, non-exclusive rights to certain intellectual property, including all clinical and biomarker data related to ficlatuzumab, to develop and commercialize BDX004. Biodesix granted the Company perpetual, non-exclusive rights to certain intellectual property, including diagnostic data related to BDX004, with respect to the development and commercialization of ficlatuzumab; each license includes the right to sublicense, subject to certain exceptions. Pursuant to a joint development plan, the Company retains primary responsibility for clinical development of ficlatuzumab in a proof of concept (“POC”) clinical study of ficlatuzumab for NSCLC, in which VeriStrat will be used to select clinical trial subjects, referred to as the NSCLC POC Trial. The NSCLC POC Trial will be fully funded by Biodesix up to a cap of $15.0 million. After the cap is reached, the Company and Biodesix will share all costs of the NSCLC trial equally.  Under the Biodesix agreement all manufacturing costs are shared equally, and the Company and Biodesix will each be responsible for 50% of development and regulatory costs associated with all future clinical trials agreed-upon by Biodesix and the Company, including all milestone payments and royalties payable to third parties, if any.

Pending marketing approval of ficlatuzumab and subject to a commercialization agreement to be entered into after receipt of results from the NSCLC POC Trial, each party would share equally in commercialization profits and losses, subject to the Company’s right to be the lead commercialization party.

Biodesix is solely responsible for the BDX004 development costs, as well as BDX004 sales and marketing costs. Subject to and following the approval of the BDX004 test as a companion diagnostic for ficlatuzumab, Biodesix has agreed to make the BDX004 test available and use commercially reasonable efforts to seek reimbursement in all geographies where ficlatuzumab is approved. The Company has agreed to reimburse Biodesix a pre-specified amount, under certain circumstances for BDX004 tests performed.

Prior to the first commercial sale of ficlatuzumab and after the earlier of (i) the Cap being reached or (ii) the completion of the NSCLC POC Trial, each party has the right to elect to discontinue participating in further development or commercialization efforts

 

18


with respect to ficlatuzumab, which is referred to a s an “Opt-Out”. If either AVEO or Biodesix elects to Opt-Out, with such party referred to as the “Opting-Out Party”, then the Opting-Out Party shall not be responsible for any future costs associated with developing and commercializing ficlatuzumab other t han any ongoing clinical trials. After election of an Opt-Out, the non-opting out party shall have sole decision-making authority with respect to further development and commercialization of ficlatuzumab. Additionally, the Opting-Out Party shall be entitle d to receive, if ficlatuzumab is successfully developed and commercialized, a royalty equal to 10% of net sales of ficlatuzumab throughout the world, if any, subject to offsets under certain circumstances.

If Biodesix elects to Opt-Out, it will continue to be responsible for its development and commercialization obligations with respect to BDX004. If AVEO elects to Opt-Out, it will continue to make the existing supply of ficlatuzumab available to Biodesix for the purposes of enabling Biodesix to complete the development of ficlatuzumab, and Biodesix will have the right to commercialize ficlatuzumab.

Prior to any Opt-Out, the parties shall share equally in any payments received from a third party licensee; provided, however, after any Opt-Out, the Opting-Out Party shall be entitled to receive only a reduced portion of such third party payments. The agreement will remain in effect until the expiration of all payment obligations between the parties related to development and commercialization of ficlatuzumab, unless earlier terminated.

Activities under the agreement with Biodesix were evaluated under ASC 605-25 to determine whether such activities represented a multiple element revenue arrangement. The agreement with Biodesix includes the following non-contingent deliverables: (i) the Company’s obligation to deliver perpetual, non-exclusive rights to certain intellectual property including clinical and biomarker data related to ficlatuzumab for use in developing and commercializing BDX004; (ii) the Company’s obligation to deliver technology improvements and data developed during the NSCLC POC Trial to Biodesix; (iii) the Company’s obligation to participate in the joint steering committee during the NSCLC POC Trial; (iv) the Company’s obligation to perform certain development activities associated with the NSCLC POC Trial; (v) the Company’s obligation to supply clinical material for use in conducting the NSCLC POC Trial; and (vi) the Company’s obligation to deliver clinical specimens and data during the NSCLC POC Trial. The Company concluded that any deliverables that would be delivered after the NSCLC POC Trial is complete are contingent deliverables because these services are contingent upon the results of the NSCLC POC Trial. As these deliverables are contingent, and are not at an incremental discount, they are not evaluated as deliverables at the inception of the arrangement. These contingent deliverables will be evaluated and accounted for separately as each related contingency is resolved. As of March 31, 2016, no contingent deliverables had been provided by the Company.

The Company determined that the delivered item, or the perpetual, non-exclusive rights to certain intellectual property for use in developing and commercializing BDX004 did not have standalone value from the remaining deliverables since Biodesix could not obtain the intended benefit of the license without the remaining deliverables. Since the remaining deliverables will be performed over the same period of performance there is no difference in accounting for the deliverables as one unit or multiple units of accounting, and therefore, the Company is accounting for the deliverables as one unit of accounting.

The Company records the consideration earned while conducting the NSCLC POC Trial, which consists of reimbursements from Biodesix for expenses related to the trial under the Cap, as a reduction to research and development expense using the proportional performance method over the respective period of performance. As a result of the cost sharing provisions in the agreement, the Company reduced research and development expenses by approximately $0.9 million during the three months ended March 31, 2016 and 2015. The amount due to the Company from Biodesix pursuant to the cost-sharing provision was $0.7 million and $0.9 million at March 31, 2016 and 2015, respectively. Under the agreement, the Company received cash payments of $1.3 million and $1.8 million during the three months ended March 31, 2016 and 2015, respectively.

St. Vincent’s

In July 2012, the Company entered into a license agreement with St. Vincent’s Hospital Sydney Limited (“St. Vincent’s”), under which the Company obtained an exclusive, worldwide license to research, develop, manufacture and commercialize products for human therapeutic, preventative and palliative applications that benefit from inhibition or decreased expression or activity of MIC-1, which is also referred to as GDF15. Under the agreement, the Company has the right to grant sublicenses subject to certain restrictions. Under the license agreement, St. Vincent’s also granted the Company non-exclusive rights for certain related diagnostic products and research tools.

In order to sublicense certain necessary intellectual property rights to Novartis in August 2015, the Company and St. Vincent’s amended and restated the license agreement (the “Amended St. Vincent’s Agreement”). Under the Amended St. Vincent’s Agreement, the Company was required to make an upfront payment to St. Vincent’s of $1.5 million. St. Vincent’s is also eligible to receive up to approximately $18.9 million in connection with development and regulatory milestones under the Amended St. Vincent’s Agreement. Royalties for approved products resulting from the Amended St. Vincent’s Agreement will also be payable to St. Vincent’s, and the Company and Novartis will share that obligation equally. Under the license agreement with Novartis, the Company is required to

 

19


maintain the Amended St. Vincent’s Agreement in effect, and not enter into any amendment that would a dversely affect Novartis’ rights during the term of the license agreement with Novartis.

During the three months ended March 31, 2016, the Company made a $0.4 million milestone payment to St. Vincent’s related to the selection of a development candidate.

Biogen Idec International GmbH

In March 2009, the Company entered into an exclusive option and license agreement with Biogen regarding the development and commercialization of the Company’s discovery-stage ErbB3-targeted antibodies, AV-203, for the potential treatment and diagnosis of cancer and other diseases outside of North America. Under the agreement, the Company was responsible for developing ErbB3 antibodies through completion of the first phase 2 clinical trial designed in a manner that, if successful, will generate data sufficient to support advancement to a phase 3 clinical trial.

In March 2014, the Company and Biogen amended the exclusive option and license agreement (the “Amendment”). Pursuant to the Amendment, Biogen agreed to the termination of its rights and obligations under the agreement, including Biogen’s option to (i) obtain a co-exclusive (with AVEO) worldwide license to develop and manufacture ErbB3 targeted antibodies and (ii) obtain exclusive commercialization rights to ErbB3 products in countries in the world other than North America. As a result, AVEO has worldwide rights to AV-203. Pursuant to the Amendment, the Company was obligated to use reasonable efforts to seek a collaboration partner for the purpose of funding further development and commercialization of ErbB3 targeted antibodies. The Company is also obligated to pay Biogen a percentage of milestone payments received by AVEO from future partnerships after March 28, 2016 and single digit royalty payments on net sales related to the sale of ErbB3 products, if any, up to cumulative maximum amount of $50 million.

The Company concluded that the Amendment materially modified the terms of the agreement and, as a result, required the application of ASC 605-25. Based upon the terms of the Amendment, the remaining deliverables included the Company’s obligation to seek a collaboration partner to fund further development of the program and the Company’s obligation to continue development and commercialization of the licensed products if a collaboration partner is secured (“Development Deliverable”). The Company concluded that its obligation to use best efforts to seek a collaboration partner does not have standalone value from the Development Deliverable upon delivery and thus the deliverables should be treated as a single unit of accounting.

Upon modifying the arrangement, the Company had $14.7 million of deferred revenue remaining to be amortized. The Company is not entitled to receive any further consideration from Biogen Idec under the amended arrangement. The Company allocated a portion of the remaining deferred revenue to the undelivered unit of accounting based upon the Company’s best estimate of the selling price, as the Company determined that neither VSOE or TPE were available. The Company determined the best estimate of selling price to be approximately $0.6 million and recognized the remaining $14.1 million as collaboration revenue in March 2014. The deferred revenue associated with the undelivered unit of accounting is being recognized on a straight-line basis over the period of performance, or through March 2016, when the Company executed its agreement with CANbridge.

Under the agreement, the Company recorded revenue of $38,000 and $76,000 during the three months ended March 31, 2016 and 2015, respectively.

In March 2016, the Company entered into a collaboration and license agreement for AV-203 with CANbridge. See “Collaborations and License Agreements—CANbridge” herein for a further description of that arrangement.

Astellas Pharma

In February 2011, the Company, together with its wholly-owned subsidiary AVEO Pharma Limited, entered into a collaboration and license agreement (the “Astellas Agreement”) with Astellas Pharma Inc. and certain of its subsidiaries (together, “Astellas”), pursuant to which the Company and Astellas intended to develop and commercialize tivozanib for the treatment of a broad range of cancers. Astellas elected to terminate the agreement effective on August 11, 2014, at which time the tivozanib rights were returned to the Company. In accordance with the Astellas Agreement, committed development costs, including the costs of completing certain tivozanib clinical development activities, will be shared equally. There are no refund provisions in the Astellas Agreement.

The Company accounted for the joint development and commercialization activities in North America and Europe as a joint risk-sharing collaboration in accordance with ASC 808, Collaborative Arrangements . Payments from Astellas with respect to Astellas’ share of tivozanib development and commercialization costs incurred by the Company pursuant to the joint development plan were recorded as a reduction to research and development expense and general and administrative expense in the accompanying consolidated financial statements due to the joint risk-sharing nature of the activities in North America and Europe. As a result of the cost-sharing provisions in the Astellas Agreement, the Company increased (decreased) research and development expense by ($0.2)

 

20


million and $0.2 million during the three months ended March 31, 2016 and 2015, respecti vely. The net amount due to (due from) the Company from (to) Astellas pursuant to the cost-sharing provisions was $0.2 million and ($0.2) million at March 31, 2016 and 2015, respectively.

Under the agreement, the Company received cash payments related to reimbursable payments of $0.1 million and $0.5 million during the three months ended March 31, 2016 and 2015, respectively.

 

(5) Accrued Expenses

Accrued expenses consisted of the following as of March 31, 2016 and December 31, 2015:

 

 

 

March 31,

2016

 

 

December 31,

2015

 

 

 

(in thousands)

 

Clinical expenses

 

$

1,108

 

 

$

1,793

 

Professional fees

 

 

675

 

 

 

573

 

Salaries and benefits

 

 

423

 

 

 

938

 

Manufacturing and distribution

 

 

198

 

 

 

173

 

Restructuring

 

 

196

 

 

 

357

 

Other

 

 

243

 

 

 

272

 

 

 

$

2,843

 

 

$

4,106

 

 

 

(6) Loans Payable

On May 28, 2010, the Company entered into a loan and security agreement (the “Loan Agreement”) with Hercules Technology II, L.P. and Hercules Technology III, L.P., affiliates of Hercules Technology Growth (collectively, “Hercules”), pursuant to which the Company received a loan in the aggregate principal amount of $25.0 million. The Company was required to repay the aggregate principal balance under the Loan Agreement in 30 equal monthly installments of principal starting on January 1, 2012. On March 31, 2012, the Company entered into an amendment to the Loan Agreement, pursuant to which the Company increased the principal amount under the Loan Agreement to $26.5 million. Under the amendment to the Loan Agreement, the date on which the Company was required to begin repaying the aggregate principal balance was extended to April 1, 2013, at which point the Company began repaying such balance in 30 equal monthly installments.

On September 24, 2014, the Company further amended the Loan Agreement with Hercules (the “Amended Loan Agreement”). Pursuant to the Amended Loan Agreement, the Company received a new loan in the aggregate principal amount of $10.0 million and amended the terms of the Loan Agreement with an outstanding principal balance of $11.6 million. The Company was not required to pay principal on the original loan until January 1, 2015, at which time the Company was required to commence making 12 principal and interest payments ending December 1, 2015. The original loan was fully paid as of December 2015.

Pursuant to the Amended Loan Agreement, the Company is not required to pay principal on the new loan of $10.0 million for a period of time until May 1, 2016. The period during which the Company is not required to pay principal was extended six months from November 1, 2015 to May 1, 2016 upon executing the Company’s license agreement with Novartis and may be further extended if the Company continues to achieve certain performance milestones, after which time, the Company is required to make monthly principal and interest payments with the last principal and interest payment due on January 1, 2018. The Amended Loan Agreement has an end-of-term payment of approximately $0.5 million due on January 1, 2018 or on such earlier date as the new loan is prepaid. The Company accounted for the Amended Loan Agreement as a loan modification in accordance with ASC 470-50, Debt—Modifications and Extinguishments.

The Company must make interest payments on the loan each month it remains outstanding. Per annum interest is payable on the principal balance of both loans at the greater of 11.9% and an amount equal to 11.9% plus the prime rate of interest minus 4.75% as determined daily, provided however, that the per annum interest shall not exceed 15.0% (11.9% as of March 31, 2016).

In addition to the obligations and covenants existing under the Loan Agreement, the Amended Loan Agreement contains a financial covenant, whereby the Company has agreed to maintain, with respect to the new loan of $10.0 million, a liquidity ratio equal to or greater than 1.25 to 1.00 of the then outstanding loan balance or the equivalent of $12.5 million in unrestricted and unencumbered cash and cash equivalents as of March 31, 2016. The financial covenant shall not apply after such time that the Company receives favorable data both with respect to its phase 2 clinical trial of ficlatuzumab and a phase 1 clinical trial of AV-380. The Company was in compliance with this and all other financial covenants at March 31, 2016 that are included in the Loan Agreement and Amended Loan Agreement.

 

21


The Loan Agreement required a deferred financing charge of $1.3 million which was paid in May 2012 rela ted to the amendment of the Loan Agreement. The Loan Agreement also included an additional deferred financing charge of $1.2 million which was paid in June 2014, and was recorded as a loan discount and is being amortized to interest expense over the term o f the loan borrowed under the Loan Agreement using the effective interest rate method. The Company had recorded a liability for the full amount of the charge since the payment of such amount was not contingent on any future event. The Company incurred appr oximately $0.2 million in loan issuance costs paid directly to Hercules under the Loan Agreement, which were offset against the loan proceeds and are accounted for as a loan discount.

As part of the Loan Agreement, on June 2, 2010, the Company issued warrants to the lenders to purchase up to 156,641 shares of the Company’s common stock at an exercise price equal to $7.98 per share. The Company recorded the relative fair value of the warrants of approximately $0.8 million as stockholders’ equity and as a discount to the related loan outstanding and is amortizing the value of the discount to interest expense over the term of the loan using the effective interest method. On July 21, 2011, Hercules exercised these warrants and they are no longer outstanding.

As part of the Amended Loan Agreement, on September 24, 2014, the Company issued warrants to the lenders to purchase up to 608,696 shares of the Company’s common stock at an exercise price equal to $1.15 per share. The Company recorded the relative fair value of the warrants of approximately $0.4 million as stockholders’ equity and as a discount to the related loan outstanding and is amortizing the value of the discount to interest expense over the term of the loan using the effective interest method.

As part of the Loan Agreement, Hercules also received an option, subject to the Company’s written consent, not to be unreasonably withheld, to purchase, either with cash or through conversion of outstanding principal under the loan, up to $2.0 million of equity of the Company sold in any sale by the Company to third parties of equity securities resulting in at least $10.0 million in net cash proceeds to the Company, subject to certain exceptions. The Company has evaluated the embedded conversion option, and has concluded that it does not need to be bifurcated and separately accounted for. No amount will be recognized for the conversion feature until such time as the conversion feature is exercised and it can be determined whether a beneficial conversion feature exists. As of March 31, 2016, the aggregate principal balance outstanding was $10.0 million.

The loans are secured by a lien on all the Company’s personal property (other than intellectual property), whether owned as of, or acquired after, the date of the Amended Loan Agreement. The Amended Loan Agreement defines events of default, including the occurrence of an event that results in a material adverse effect upon the Company’s business operations, properties, assets or condition (financial or otherwise), its ability to perform its obligations under and in accordance with the terms of the Amended Loan Agreement, or upon the ability of the lenders to enforce any of their rights or remedies with respect to such obligations, or upon the collateral under the Loan Agreement, the related liens or the priority thereof. As of March 31, 2016, Hercules has not asserted any events of default and the Company does not believe that there has been a material adverse change as defined in the loan agreement. The Company has determined that the risk of subjective acceleration under the material adverse events clause is remote and therefore has classified the outstanding principal in current and long-term liabilities based on the timing of scheduled principal payments.

Future minimum payments under the loans payable outstanding as of March 31, 2016 are as follows (amounts in thousands):

 

Years Ending December 31:

 

 

 

 

2016 (9 months remaining)

 

$

3,199

 

2017

 

 

4,645

 

2018

 

 

4,269

 

 

 

 

12,113

 

Less amount representing interest

 

 

(1,572

)

Less discount

 

 

(445

)

Less deferred charges

 

 

(540

)

Less current portion

 

 

(3,019

)

Loans payable, net of current portion and discount

 

$

6,537

 

 

 

(7) Common Stock

ATM Sales Agreement

In February 2015, the Company entered into an at-the-market issuance sales agreement (the “Sales Agreement”) with FBR & Co. (formerly MLV & Co. LLC) (“FBR”), pursuant to which the Company could issue and sell shares of its common stock from time to time up to an aggregate amount of $17.9 million, at the Company’s option, through FBR as its sales agent. Sales of common stock through FBR may be made by any method that is deemed an “at-the-market” offering as defined in Rule 415 promulgated under the

 

22


Securitie s Act of 1933, as amended, including by means   of ordinary brokers’ transactions at market prices, in block transactions or as otherwise agreed by the Company and FBR. Subject to the terms and conditions of the Sales Agreement , FBR will use commercially reasonable efforts to sell the common stock based upon the Company’s instructions (including any price, time or size limits or other customary parameters or conditions the Company may impose). The Company is not obligated to make any sales of its common st ock under the Sales Agreement. Any shares sold will be sold pursuant to an effective shelf registration statement on Form S-3. The Company will pay FBR a commission of up to 3% of the gross proceeds. The Sales Agreement may be terminated by the Company   at any time.

On May 7, 2015, the Company filed a shelf registration statement on Form S-3 with the SEC, which covers the offering, issuance and sale by the Company of up to $100.0 million of its common stock, preferred stock, debt securities, warrants and/or units (the “2015 Shelf”). The 2015 Shelf was filed to replace the Company’s existing $250.0 million shelf registration statement (the “2012 Shelf”). On May 7, 2015, the Company also amended its Sales Agreement with FBR to provide for the offering, issuance and sale by the Company of up to $15.0 million of its common stock under the 2015 Shelf, which replaced the Company’s existing $17.9 million offering that expired along with the expired 2012 Shelf. As of March 31, 2016, the Company has sold approximately 5.9 million shares pursuant to the Sales Agreement, as amended, resulting in proceeds of approximately $10.2 million, net of commissions and issuance costs. No additional shares were issued during the three months ended March 31, 2016.

Approximately $9.0 million remains available for sale under the Sales Agreement.

 

 

 

(8) Stock-based Compensation

Stock Plans

The Company issued stock options and had restricted stock awards outstanding during the three months ended March 31, 2016. A summary of the status of the Company’s stock option activity at March 31, 2016 and changes during the three months then ended is presented in the table and narrative below.

 

 

 

Options

 

 

Weighted-

Average

Exercise Price

 

 

Weighted-

Average

Remaining

Contractual

Term

 

 

Aggregate

Intrinsic

Value

 

Outstanding at December 31, 2015

 

 

4,796,005

 

 

$

3.78

 

 

 

 

 

 

 

 

 

Granted

 

 

1,139,500

 

 

$

1.08

 

 

 

 

 

 

 

 

 

Exercised

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Forfeited

 

 

(351,085

)

 

$

1.38

 

 

 

 

 

 

 

 

 

Outstanding at March 31, 2016

 

 

5,584,420

 

 

$

3.38

 

 

 

7.17

 

 

$

88,258

 

Vested or expected to vest at March 31, 2016

 

 

3,176,655

 

 

$

5.04

 

 

 

5.82

 

 

$

43,329

 

Exercisable at March 31, 2016

 

 

2,537,373

 

 

$

6.00

 

 

 

4.99

 

 

$

27,625

 

 

Stock options to purchase 321,000 shares of common stock contain market conditions which were not deemed probable of vesting at March 31, 2016.

The fair value of stock options subject only to service or performance conditions that are granted to employees is estimated on the date of grant using the Black-Scholes option-pricing model using the assumptions noted in the following table:

 

 

 

Three Months Ended

March 31,

 

 

 

2016

 

 

2015

 

Volatility factor

 

73.79%-73.91%

 

 

78.7%

 

Expected term (in years)

 

6.25

 

 

6.25

 

Risk-free interest rates

 

 

1.38%

 

 

 

1.54%

 

Dividend yield

 

 

 

 

 

 

 

The risk-free interest rate is determined based upon the United States Treasury’s rates for U.S. Treasury zero-coupon bonds with maturities similar to those of the expected term of the options being valued. The Company does not expect to pay dividends in the foreseeable future.

 

23


The Company does not have sufficient history to support a calculation of volatility and expecte d term using only its historical data. As such, the Company has used a weighted-average volatility considering the Company’s own volatility since March 2010, and the volatilities of several peer companies. For purposes of identifying similar entities, the Company considered characteristics such as industry, length of trading history, similar vesting terms and in-the-money option status. Due to lack of available option activity data, the Company elected to use the “simplified” method for “plain vanilla” opti ons to estimate the expected term of the stock option grants. Under this approach, the weighted-average expected life is presumed to be the average of the vesting term and the contractual term of the option. Based upon these assumptions, the weighted-avera ge grant date fair value of stock options granted to employees during the three months ended March 31, 2016 and 2015 was $ 0 . 7 1 per share and $ 0. 62 per share, respectively.

The Company is required to include an estimate of the value of the awards that will be forfeited in calculating compensation costs, which the Company estimates based upon actual historical forfeitures. The forfeiture estimates are recognized over the requisite service period of the awards on a straight-line basis. The Company estimated its forfeiture rate to be approximately 76% and 70% as of March 31, 2016 and 2015, respectively.

As of March 31, 2016, there was $0.7 million of total unrecognized stock-based compensation expense related to stock options granted to employees under the Company’s 2002 Stock Incentive Plan and 2010 Stock Incentive Plan (collectively, the “Plans”). The expense is expected to be recognized over a weighted-average period of 3.0 years. The intrinsic value of options exercised during the three months ended March 31, 2015 was $13,000. No options were exercised during the three months ended March 31, 2016.

The restricted stock activity for the three months ended March 31, 2016 is as follows:

 

 

 

Number   of   Shares

 

 

Weighted-

Average

Fair-Value

 

Unvested at December 31, 2015

 

 

42,750

 

 

$

1.61

 

Granted

 

 

 

 

 

 

Vested/Released

 

 

(42,750

)

 

 

1.61

 

Unvested at March 31, 2016

 

 

 

 

 

 

 

As of March 31, 2016, there was no unrecognized stock-based compensation expense related to restricted stock awards granted under the Plan.

 

 

(9) Strategic Restructuring

On January 6, 2015, the Board of the Company approved a strategic restructuring of the Company that eliminated the Company’s internal research function and aligned the Company’s resources with the Company’s future strategic plans. As part of this restructuring, the Company eliminated approximately two-thirds of the Company’s workforce, or 40 positions across the organization. The Company substantially completed the restructuring during the quarter-ended March 31, 2015.

The following table summarizes the components of the Company’s restructuring activity recorded in operating expenses and in accrued expenses in the accompanying consolidated balance sheet:

 

 

 

Restructuring

amounts accrued at

December 31,

2015

 

 

Restructuring

expense

incurred

during the three months ended

March  31,

2016

 

 

Restructuring

amounts

paid

during the three months ended March  31,

2016

 

 

Restructuring

amounts

accrued at

March 31,

2016

 

 

 

(in thousands)

 

Employee severance, benefits and related costs.

 

$

357

 

 

 

 

 

$

(161

)

 

 

196

 

 

The Company is obligated to continue to pay the remaining amounts accrued through the third quarter of 2016.

 

 

(10) Facility Lease Exit

In September 2014, the Company entered into the Lease Termination Agreement pursuant to which the Company immediately surrendered leased space at 650 East Kendall Street in Cambridge, Massachusetts that it had previously ceased using earlier in 2014.

 

24


In connection with the Lease Termination Agreement, the Company agreed to pay the landlord a termination fee totaling $15. 6 million. The Company also agreed to surrender its remaining leased space upon 90 days written notice prior to September 24, 2015.

In February 2015, the Company provided notice that it would surrender the remaining space on May 29, 2015. Accordingly, the Company revised the estimated useful life of its leasehold improvements related to this office space and amortized such assets through May 2015, resulting in an additional $1.4 million of depreciation expense during the three months ended March 31, 2015. Similarly, the Company accelerated the amortization of its deferred rent and leasehold improvement allowance associated with this office space through May 2015, resulting in an additional $1.7 million of amortization during the three months ended March 31, 2015. Upon the surrender of the remaining space, the Company had no further rights or obligations with respect to the lease. The Company secured office space appropriate for its current needs under a cancellable arrangement that began in May 2015.

 

 

(11) Legal Proceedings

Two class action lawsuits have been filed against the Company and certain of its former officers and members of its board of directors, (Tuan Ha-Ngoc, David N. Johnston, William Slichenmyer and Ronald DePinho), in the United States District Court for the District of Massachusetts, one captioned Paul Sanders v. Aveo Pharmaceuticals, Inc., et al., No. 1:13-cv-11157-JLT, filed on May 9, 2013, and the other captioned Christine Krause v. AVEO Pharmaceuticals, Inc., et al., No. 1:13-cv-11320-JLT, filed on May 31, 2013. On December 4, 2013, the District Court consolidated the complaints as In re AVEO Pharmaceuticals, Inc. Securities Litigation et al., No. 1:13-cv-11157-DJC, and an amended complaint was filed on February 3, 2014. The amended compla int purported to be brought on behalf of shareholders who purchased the Company’s common stock between January 3, 2012 and May 1, 2013. The amended complaint generally alleged that the Company and certain of its present and former officers and directors vi olated Sections 10(b) and/or 20(a) of the Securities Exchange Act of 1934 and Rule 10b-5 promulgated thereunder by making allegedly false and/or misleading statements concerning the phase 3 trial design and results for the Company’s TIVO-1 study in an effo rt to lead investors to believe that the drug would receive approval from the FDA. The lawsuit seeks unspecified damages, interest, attorneys’ fees, and other costs.  The consolidated amended complaint was dismissed without prejudice on March 20, 2015, and the lead plaintiffs then filed a second amended complaint bringing similar allegations.  The Company moved to dismiss again, and after a second round of briefing and oral argument, the court ruled in the Company’s favor and dismissed the second amended co mplaint with prejudice on November 18, 2015.  The lead plaintiffs have appealed the court’s decision to the United States Court of Appeals for the First Circuit.  They have also filed a motion to vacate and reconsider the district court’s judgment, which we have opposed.   The Company denies any allegations of wrongdoing and intends to continue to vigorously defend against this lawsuit. However, there is no assurance that the Company will be successful in its defense or that insurance will be available or adequate to fund any settlement or judgment or the litigation costs of the action. Moreover, the Company is unable to predict the outcome or reasonably estimate a range of possible loss at this time.

 

On April 4, 2014, Karen J. van Ingen, a purported purchaser of AVEO stock, filed a derivative complaint allegedly on behalf of AVEO in the United States District Court for the District of Massachusetts, Civil Action No. 1:14-cv-11672-DJC, naming AVEO, as a nominal defendant and also naming as defendants present and former members of the Company’s board of directors, including Tuan Ha-Ngoc, Henri A. Termeer, Kenneth M. Bate, Anthony B. Evnin, Robert Epstein, Raju Kucherlapati, Robert C. Young, and Kenneth E. Weg. The complaint alleged breach of fiduciary duty and abuse of control between January 2012 and May 2013 with respect to allegedly misleading statements and omissions regarding tivozanib. The lawsuit seeks, among other relief, unspecified damages, costs and expenses, including attorneys’ fees, an order requir ing us to implement certain corporate governance reforms, restitution from the defendants and such other relief as the court might find just and proper.  The Company filed a motion to dismiss the derivative complaint, and after briefing and oral argument, on March 18, 2015 the Court ruled in the Company’s favor and dismissed the case with prejudice. The plaintiff then filed a motion seeking to vacate the Court’s order of dismissal and permit filing of an amended complaint, which the Company opposed, and which the Court denied on June 30, 2015.  The plaintiff has appealed the Court’s decision to the United States Court of Appeals for the First Circuit.   The Company denies any allegations of wrongdoing and intends to continue to vigorously defend this lawsuit. However, there is no assurance that the Company will be successful in its defense or that insurance will be available or adequate to fund any settlement or judgment or the litigation costs of this action. Moreover, the Company is unable to predict the outcome or reasonably estimate a range of possible loss at this time.

 

On July 3, 2013, the staff (the “SEC Staff”) of the United States Securities and Exchange Commission (the “Commission”) served a subpoena on the Company for documents and information concerning tivozanib, including related communications with the FDA, investors and others.  The Company fully cooperated with the inquiry.  In September 2015, the SEC Staff invited the Company to discuss the settlement of potential claims that the SEC Staff may recommend that the Commission bring against the Company asserting that it violated federal securities laws by omitting to disclose to investors the recommendation made to the Company by the staff of the U.S. Food and Drug Administration, on May 11, 2012, that the Company conduct an additional clinical trial with respect to tivozanib.  Through these discussions with the SEC Staff, an agreement was reached to settle those claims for a total amount of $4.0 million, subject to the approval of the Commission.   

 

 

25


On March 29, 2016, the Commission filed a complaint against the Company and three of its former officers in the U.S. District Court for the District of Massachusetts (the “Court”) alleging that the Company misled investors about its efforts to obtain FD A approval for tivozanib. Without admitting or denying the allegations in the Commission’s complaint, the Company consented to the entry of a final judgment pursuant to which it would pay the Commission a $4 million civil penalty to settle the Commission’s claims against the Company. The settlement was subject to Court approval.

 

On March 31, 2016, the Court entered a final judgment which (i) approved the settlement; (ii) permanently enjoined the Company from violating Section 17(a) of the Securities Act of 1933, as amended, Sections 10(b) and 13(a) of the Securities Exchange Act of 1934, as amended, and rules 10b-5, 12b-20, 13a-1, 13a-11 and 13a-13 promulgated thereunder; and (iii) ordered the Company to pay the agreed-to civil penalty.

The Commission’s action against the Company’s three former officers is still pending . The Company is not a party to any litigation or discussions between the SEC Staff and the former officers, and the Company can make no assurance regarding the outcome of that action or the Commission’s claims against those individuals.

 

 

 

 

 

26


Item 2. Management’s Discussion and Analysis of Financial Condition and Results of Operations.

Forward-Looking Information

This report contains forward-looking statements regarding, among other things, our future development efforts, our collaborations, our future operating results and financial position, our business strategy, our prospects and other objectives for our operations. You can identify these forward-looking statements by their use of words such as “anticipate,” “believe,” “estimate,” “expect,” “forecast,” “intend,” “plan,” “project,” “target,” “will” and other words and terms of similar meaning. You also can identify them by the fact that they do not relate strictly to historical or current facts. There are a number of important risks and uncertainties that could cause our actual results to differ materially from those indicated by forward-looking statements. These risks and uncertainties include those inherent in pharmaceutical research and development, such as adverse results in our clinical development activities, our ability to obtain any necessary financing to conduct our planned activities, decisions made by the U.S. Food and Drug Administration and other regulatory authorities with respect to the development and commercialization of our drug candidates, our ability to obtain, maintain and enforce intellectual property rights for our drug candidates, our dependence on our existing and future strategic partners, and other risk factors. Please refer to the section entitled “Risk Factors” in Item 1A of Part II and elsewhere in this report for a description of these risks and uncertainties. Unless required by law, we do not undertake any obligation to publicly update any forward-looking statements.

Company Overview

We are a biopharmaceutical company dedicated to advancing a broad portfolio of targeted therapeutics for oncology and other areas of unmet medical need. Our proprietary platform has delivered unique insights into cancer and related diseases. Our strategy is to leverage these biomarker insights and partner resources to advance the development of our clinical pipeline. We are focused on developing our lead candidate tivozanib in North America as a treatment for renal cell carcinoma.  We have entered into partnerships to fund the further development of our clinical stage assets, including AV-380, ficlatuzumab, AV-203, and tivozanib in non-oncologic indications worldwide and oncology indications outside North America.  We are currently seeking a partner to develop AV-353, a preclinical asset, worldwide in pulmonary arterial hypertension, or PAH.  

Tivozanib

Tivozanib is a potent, selective, long half-life vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) of VEGF receptors 1, 2 and 3.  In 2006, we acquired the exclusive rights to develop and commercialize tivozanib in all countries outside of Asia under a license from Kyowa Hakko Kirin Co., Ltd. (formerly Kirin Brewery Co. Ltd.), or KHK.    

Clinical and Regulatory Development in RCC

RCC First Line Phase 3 Trial (TIVO-1) : We conducted a global phase 3 clinical trial comparing the efficacy and safety of tivozanib with Nexavar ® (sorafenib), an approved therapy, for first-line treatment of renal cell carcinoma, or RCC , which we refer to as the TIVO-1 trial.  The trial met its primary endpoint for progression-free survival, or PFS, but showed a non-statistically significant trend favoring the sorafenib arm in overall survival, or OS.  In June 2013, the U.S. Food and Drug Administration, or FDA, issued a complete response letter informing us that it would not approve tivozanib for the first-line treatment of advanced RCC based on the study data from this trial, and recommended that we perform an additional study adequately sized to assure the FDA that there is no adverse effect on OS.  

In January 2015, we announced our receipt of confirmation from the European Medicines Agency, or EMA, that tivozanib is eligible for submission of an application for a European Union Marketing Authorization under the EMA’s centralized procedure for the treatment of RCC. Confirmation of eligibility for submission is not predictive of the EMA’s approval of a Marketing Authorization Application, or MAA. Tivozanib has previously been granted orphan drug designation in Europe for the treatment of RCC.  Our partner, EUSA Pharma (UK) Limited, or EUSA, submitted a MAA for tivozanib for the treatment of RCC with the EMA in February 2016 based on our existing dataset, which includes the results from the TIVO-1 study of tivozanib in the first-line treatment of RCC. In March 2016, the EMA validated the MAA, confirming that the submission was complete and that it would initiate its review process. In December 2015, our partner JSC “Pharmstandard-Ufimskiy Vitamin Plant”, a subsidiary of Pharmstandard OJSC, or Pharmstandard, submitted an application for marketing authorization for tivozanib based on the TIVO-1 trial results in Russia that was accepted for review by the Russian Ministry of Health in February 2016.

TIVO-1 Extension Study - One-way crossover from sorafenib to tivozanib (Study 902) :  We completed a TIVO-1 extension study in which patients with advanced RCC received tivozanib as second-line treatment subsequent to disease progression on the sorafenib arm in the TIVO-1 first-line RCC trial. We presented the final results at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting on June 1, 2015.  The final results showed a median PFS of 11.0 months and a median OS of 21.6 months, demonstrating the clinically meaningful efficacy of tivozanib in a VEGF treatment refractory population.  We believe that the long OS derived from tivozanib following sorafenib in Study 902 contributed to the discordance in the results in the TIVO-1 trial between the PFS benefit, which significantly favored tivozanib, and the OS, which trended in favor of sorafenib.  The FDA did not accept this

 

27


explanation, finding that the OS results were confounded by the one-way crossover, and recommended that w e perform a second phase 3 trial.

RCC Third Line Phase 3 Trial (TIVO-3) :  We are planning to conduct a second phase 3 trial of tivozanib in the third-line treatment of patients with refractory RCC to address the OS concerns from the TIVO-1 trial presented in the June 2013 complete response letter from the FDA and to support a request for regulatory approval of tivozanib in the United States as a third-line treatment and as a first-line treatment .  Our study design, which we have shared with the FDA, contemplates a randomized, controlled, multi-center, open-label phase 3 study of approximately 322 subjects randomized 1:1 to receive either tivozanib or sorafenib. Subjects enrolled in the study may include those who have received prior immunotherapy, including immune checkpoint (PD-1) inhibitors, reflecting a potentially evolving treatment landscape. The primary objective of the study would be to show improved PFS. Secondary endpoints would include OS and objective response rate, or ORR, as well as safety and pharmacokinetic endpoints.    

RCC PD-1 Combination Trial : We are planning to conduct a phase 1/2 study of tivozanib combined with a PD-1 inhibitor for the treatment of patients with RCC.  In recent studies, TKIs and PD-1 inhibitors have shown promising efficacy in treating RCC in combination.  However, several TKI/PD-1 combinations have encountered toxicity levels that are likely to prohibit such TKIs from safely combining with PD-1 inhibitors for RCC treatment.  In our clinical trials, tivozanib has demonstrated a superior tolerability profile than many other TKIs, including lower rates of key potential overlapping toxicities with PD-1 inhibitors.  We believe that tivozanib’s tolerability profile has the potential to allow tivozanib to combine with PD-1 inhibitors more safely than other TKIs.     

We are evaluating all options for funding, including partnerships, for the clinical and regulatory advancement of tivozanib.  If we are unable to raise funding to support the planned TIVO-3 trial, PD-1 combination trial or other programs, we would be forced to delay, reduce or eliminate such clinical and regulatory advancement plans.  For a further discussion of our operating capital requirements see “-Liquidity and Capital Resources – Operating Capital Requirements” below.

Tivozanib Partnerships

EUSA License Agreement :  In December 2015, we entered into a license agreement with EUSA Pharma (UK) Limited, or EUSA, under which we granted EUSA the right to develop and commercialize tivozanib for all diseases and conditions in humans, excluding non-oncologic diseases or conditions of the eye, in Europe (excluding Russia, Ukraine and the Commonwealth of Independent States), Latin America (excluding Mexico), Africa, Australasia and New Zealand.

Pharmstandard License Agreement :  In August 2015, we entered into a license agreement under which we granted to Pharmstandard the exclusive right to develop, manufacture and commercialize tivozanib in the territories of Russia, Ukraine and the Commonwealth of Independent States, or CIS, for all conditions excluding non-oncologic ocular conditions.   Pharmstandard has recently informed us that, based on adverse economic and financial conditions in Russia, they are seeking to renegotiate their obligation to make milestone payments to us .

Ophthotech Option for Ocular Conditions (Non-Oncologic):   In November 2014, we entered into a research and exclusive option agreement with Ophthotech Corporation, or Ophthotech, under which we granted Ophthotech an option to develop and commercialize tivozanib outside of Asia for the potential diagnosis, prevention and treatment of non-oncologic diseases or conditions of the eye in humans.

CRC Development

CRC Phase 2 Results :  In March 2015, we announced results from a predefined biomarker analysis of our BATON-CRC study, a randomized phase 2 clinical trial of modified FOLFOX6, a commonly used chemotherapy, combined with tivozanib or Avastin ® (bevacizumab), which both target angiogenesis signaling pathways, in first-line treatment of metastatic CRC. In this st udy, among prospectively defined biomarkers, patients with low (below the median, representing 50% of the population) serum neuropilin-1, or NRP-1, demonstrated longer PFS when treated with tivozanib compared to bevacizumab, which suggests that first-line colorectal cancer patients with low NRP-1 levels may benefit from treatment with tivozanib over bevacizumab, a standard of care in this disease.  However, the assay used to measure serum NRP-1 is not suitable for development as a companion diagnostic.  We continue to look for alternate means to identify those patients. We do not plan to conduct further clinical studies until such an assay is identified.

Ficlatuzumab

Ficlatuzumab is a potent Hepatocyte Growth Factor, or HGF, inhibitory antibody. HGF is the sole known ligand of the c-Met receptor which is believed to trigger many activities that are involved in cancer development and metastasis. We have completed two phase 1 clinical studies of ficlatuzumab administered as a single agent and in combination with erlotinib, a TKI, of the epidermal growth factor receptor, or EGFR, and a phase 2 clinical study evaluating ficlatuzumab in combination with gefitinib, an EGFR TKI, in first-line non-small cell lung cancer, or NSCLC. The phase 2 trial failed to demonstrate a statistically significant benefit in the intent-to-treat population. However, an exploratory analysis using a serum-based proteomic diagnostic test, known as VeriStrat ® , identified a sub-population of patients who experienced a progression free survival and overall survival benefit from the addition of ficlatuzumab to gefitinib. VeriStrat is commercially available to help physicians guide treatment decisions for patients with second line advanced NSCLC. Data from the exploratory analyses with VeriStrat prompted the development of a separate investigational companion

 

28


diagnostic test called BDX004. Based upon the exploratory analyses, BDX004 may be indicative of a predictive biomarker for the combination of ficlatuzumab a nd EGFR TKI over EGFR TKI alone in the first - line EGFR mutation patients who have been previously identified to not respond well to the current standard of care.

In April 2014, we entered into a worldwide agreement with Biodesix, Inc., or Biodesix, to develop and commercialize ficlatuzumab with BDX004, a serum based diagnostic test which has been derived from the VeriStrat test, employing the same methodology and data processing algorithms as VeriStrat, for use in a confirmatory clinical trial. Pursuant to the Biodesix agreement, in December 2014 we initiated a phase 2 confirmatory study of ficlatuzumab, which we refer to as the FOCAL study, in combination with erlotinib in first-line advanced NSCLC patients who have an EGFR mutation and who are identified b y the BDX004 test as being most likely to benefit from the addition of ficlatuzumab to the EGFR TKI. We began enrolling patients during the second half of 2015. Biodesix will fund up to $15 million of the costs of this study, after which costs will be shared equally. Any additional development, regulatory and commercial costs under the Biodesix agreement will be shared equally. Under the Biodesix agreement, subject to regulatory approval, we would lead worldwide commercialization of ficlatuzumab.    

AV-203

AV-203 is a potent anti-ErbB3 (also known as HER3) specific monoclonal antibody with high ErbB3 affinity. We have observed potent anti-tumor activity in mouse models. AV-203 selectively inhibits the activity of the ErbB3 receptor, and our preclinical studies suggest that neuregulin-1, or NRG1 (also known as heregulin), levels predict AV-203 anti-tumor activity in preclinical models. We have completed a phase 1 dose escalation study of AV-203, which established a recommended phase 2 dose of AV-203 at 20mg/kg intravenously every 2 weeks, demonstrated good tolerability and promising early signs of activity, and reached the maximum planned dose of AV-203 monotherapy. No anti-drug antibodies were detected, and pharmacokinetic results indicated a dose-proportional increase in levels of AV-203.  The expansion cohort of this study among patients with a specific biomarker was discontinued.

In March 2016, we entered into collaboration and license agreement with with CANbridge Life Sciences Ltd., or CANbridge , under which we granted CANbridge the exclusive right to develop, manufacture and commercialize AV-203 in all countries other than the United States, Canada and Mexico.

AV-380

AV-380 is a potent humanized IgG1 inhibitory monoclonal antibody targeting growth differentiating factor-15, or GDF15, a divergent member of the TGF-ß family, for the potential treatment or prevention of cachexia. Cachexia is defined as a multi-factorial syndrome of involuntary weight loss characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Cachexia is associated with various cancers as well as diseases outside of cancer including chronic kidney disease, congestive heart failure, and chronic obstructive pulmonary disease, or COPD. We believe that AV-380 represents a unique approach to treating cachexia because it addresses key underlying mechanisms of the syndrome and focuses on a significant area of patient need. It is estimated that approximately 30% of all cancer patients die due to cachexia and over half of cancer patients who die do so with cachexia present. ( J Cachexia Sarcopenia Muscle 2010). In the United States alone, the estimated prevalence of cancer cachexia is over 400,000 patients, and the prevalence of cachexia due to cancer, COPD, congestive heart failure, frailty and end stage renal disease combined is estimated to total more than 5 million patients ( Am J Clin Nutr 2006).  

We have demonstrated preclinical proof-of-concept for AV-380 in multiple cancer cachexia models and have completed cell line development.  In September 2014, we presented the results from four preclinical studies of AV-380 in various in vivo cachexia models and in vitro assays at the 2nd Cancer Cachexia Conference in Montreal Canada. Our research was also selected for presentation in an oral session at the conference. In April 2015, we also presented the results from a preclinical study of AV-380 in a cachectic human tumor xenograft model at the Annual Meeting of the American Association of Cancer Research. We have established preclinical proof of concept for GDF15 as a key driver of cachexia by demonstrating, in animal models, that the administration of GDF15 induces cachexia, and that inhibition of GDF15 reverses cachexia and provides a potential indication of an overall survival benefit.

In August 2015, we entered into a license agreement under which we granted Novartis International Pharmaceutical Ltd., or Novartis, the exclusive right to develop and commercialize AV-380 and our related antibodies. Under this agreement, Novartis is responsible for all activities and costs associated with the further development, regulatory filing and commercialization of AV-380 worldwide.  In connection with the AV-380 program, we have in-licensed certain patents and patent applications from St. Vincent’s Hospital in Sydney, Australia.

AV-353

AV-353 is a potent inhibitory antibody specific to Notch 3. The Notch 3 signaling pathway is important in cell-to-cell communication involving gene regulation mechanisms that control multiple cell differentiation processes during the entire life cycle.

 

29


Scientific literature has implicated the Notch 3 receptor pathway in multiple disease s, including cancer, cardiovascular diseases and neurodegenerative conditions. Recent publication s, including Nature Medicine (2009), have implicated the Notch 3 pathway in PAH, a rare and life-threatening disorder that affects approximately 250,000 people worldwide and is caused by enlargement of the arterial walls in small arteries between the heart and the lungs, resul ting in restricted blood flow. Currently, no known cure for PAH exists. Existing tr eatments in PAH have focus ed on controlling symptoms by avoiding vasoconstriction and increasing vasodilation of blood vessels and have not reversed the underlying cause of the disease.  In contrast, with the results of a recently concluded research study supported by the Company , AV-353 has generated a growin g body of preclinical data that supports AV-353’s ability to potentially reverse the disease phenotype, which would represent a potential disease-modifying approach to treatment. A manuscript of the results is being prepared for submission to a peer-review ed journal.  

We own worldwide rights to AV-353, which was developed utilizing our research and development platform and for which we have filed three composition of matter patent applications.  We are currently seeking a partner to develop AV-353 worldwide in PAH.

Strategic Partnerships

CANbridge

In March 2016, we entered into a collaboration and license agreement with CANbridge under which we granted CANbridge the exclusive right to develop, manufacture and commercialize AV-203, our proprietary ErbB3 (HER3) inhibitory antibody, for the diagnosis, treatment and prevention of disease in humans and animals in all countries other than the United States, Canada and Mexico. Under the terms of the license agreement, if we determine to grant a license to any ErbB3 inhibitory antibody in the United States, Canada or Mexico, we are obligated to first negotiate with CANbridge for the grant to CANbridge of a license to such rights. In addition, for a period of time following the completion of certain proof-of-concept clinical studies by CANbridge involving the use of AV-203 for the treatment of squamous cell esophagus cancer, we have agreed to negotiate exclusively with CANbridge for (a) the right to co-develop ErbB3 inhibitory antibody products for the treatment of squamous cell esophagus cancer or (b) the right to include the United States, Canada and Mexico as part of the licensed territory under the license agreement. The parties have both agreed not to directly or indirectly develop or commercialize any ErbB3 inhibitory antibody product during the term of the license agreement other than pursuant to the license agreement . The effective date of the license agreement is March 16, 2016 (the “Effective Date”).

CANbridge is obligated to use commercially reasonable efforts to develop and commercialize AV-203 in each of China, Japan, the United Kingdom, France, Italy, Spain, and Germany. CANbridge has responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of AV-203 in the licensed territory.    

Under the terms of the license agreement, CANbridge made an upfront payment to us of $1.0 million in April 2016. CANbridge has also agreed to reimburse us $1.0 million for certain manufacturing cos ts and expenses incurred by us with respect to AV-203 prior to the Effective Date of the licensing agreement, $0.5 million of which will be due to us on the earlier of (i) the date of validation by CANbridge of certain manufacturing development activities conducted by us and (ii) twelve months from the Effective Date , and the remaining $0.5 million of which will be due to us on the earlier of (i) the date of validation by CANbridge of such manufacturing development activities and (ii) eighteen months from t he Effective Date . We are also eligible to receive up to $42.0 million in potential development and regulatory milestone payments and up to $90.0 million in potential sales based milestone payments based on annual net sales of licensed products. Upon commercialization, we are eligible to receive a tiered royalty, with a percentage range in the low double digits, on net sales of approved licensed products. CANbridge’s obligation to pay royalties for each licensed product expires on a country-by-country basis on the later of the expiration of patent rights covering such licensed product in such country, the expiration of regulatory data exclusivity in such country and ten years after the first commercial sale of such licensed product in such country.   A percentage of any milestone and royalty payments received by us, excluding upfront and reimbursement payments, are due to Biogen Idec International GMBH as a sublicensing fee under our option and license agreement with Biogen dated March 18, 2009, as amended.

EUSA

In December 2015, we entered into a license agreement with EUSA under which we granted to EUSA the exclusive, sublicensable right to develop, manufacture and commercialize tivozanib in the territories of Europe (excluding Russia, Ukraine and the Commonwealth of Independent States), Latin America (excluding Mexico), Africa, Australasia and New Zealand for all diseases and conditions in humans, excluding non-oncologic diseases or conditions of the eye. EUSA filed an application with the EMA in February 2016 for approval of marketing authorization for tivozanib in the treatment of RCC.

EUSA is obligated to use commercially reasonable efforts to develop and commercialize tivozanib throughout the licensed territories. With the exception of certain support to be provided by us in connection with the application for marketing approval by the

 

30


EMA, EUSA has responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of tivozanib in the licensed territories.

Under the license agreement, EUSA made a research and development funding payment to us of $2.5 million in 2015.  EUSA is required to make a further research and development funding payment of $4.0 million upon the grant by the European Medicines Agency, or the EMA, of marketing approval for tivozanib for treatment of RCC. We are eligible to receive additional research funding from EUSA, including up to $20.0 million if the Company conducts a phase 3 study in third-line RCC and EUSA elects to utilize data generated by the study, and up to $2.0 million for a potential phase 1 combination study with a checkpoint inhibitor. We will be entitled to receive milestone payments of $2.0 million per country upon reimbursement approval for RCC in each of France, Germany, Italy, Spain and the United Kingdom, and an additional $2.0 million for the grant of marketing approval in three of the following five countries: Argentina, Australia, Brazil, South Africa and Venezuela. We are also eligible to receive a payment of $2.0 million in connection with EUSA’s filing with the EMA for marketing approval for tivozanib for the treatment of each of up to three additional indications and $5.0 million per indication in connection with the EMA’s grant of marketin g approval for each of up to three additional indications, as well as up to $335.0 million upon EUSA’s achievement of certain sales thresholds. We are also eligible to receive tiered double digit royalties on net sales, if any, of licensed products in the licensed territories ranging from a low double digit up to mid-twenty percent depending on the level of annual net sales. A percentage of any milestone and royalty payments we receive are due to KHK as a sublicensing fee under the license agreement between us and KHK dated as of December 21, 2006, pursuant to which we acquired exclusive rights to develop and commercialize tivozanib for all human diseases outside of Asia.  The research and development funding payments under the EUSA license agreement are not subject to sublicensing payment to KHK.

Novartis

In August 2015, we entered into a license agreement with Novartis, under which we granted Novartis the exclusive right to develop and commercialize AV-380 and our related antibodies that bind to GDF15 worldwide. Under this agreement, Novartis is responsible for all activities and costs associated with the further development, regulatory filing and commercialization of AV-380 worldwide.

Novartis made an upfront payment to us of $15.0 million during September 2015. We are also eligible to receive (a) up to $53 million in potential clinical milestone payments and up to $105 million in potential regulatory milestone payments tied to the commencement of clinical trials and to regulatory approvals of products developed under the license agreement in the United States, the European Union and Japan; and (b) up to $150 million in potential sales based milestone payments based on annual net sales of such products. Upon commercialization, we are eligible to receive tiered royalties on net sales of approved products ranging from the high single digits to the low double digits. Novartis has responsibility under the license agreement for the development, manufacture and commercialization of the licensed antibodies and any resulting approved therapeutic products. In December 2015, Novartis also exercised its right under the license agreement to acquire our inventory of clinical quality drug substance, reimbursing us approximately $3.5 million for such existing inventory.

Pharmstandard Group

In August 2015, we entered into an exclusive license agreement with Pharmstandard, under which we granted Pharmstandard the exclusive right to develop, manufacture and commercialize tivozanib in the territories of Russia, Ukraine and the Commonwealth of Independent States for all conditions excluding non-oncologic ocular conditions.  

Pharmstandard is obligated to use commercially reasonable efforts to develop and commercialize tivozanib throughout the licensed territories and has responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of tivozanib in the licensed territories .   Pharmstandard has filed an application for marketing authorization in Russia for tivozanib for the treatment of renal cell carcinoma that was accepted by the Ministry of Health of the Russian Federation in February 2016.

Pharmstandard made an upfront payment to us of $1.0 million and will be obligated to pay an additional $0.5 million upon registration of the license agreement with a Russian regulatory agency.  We are also eligible to receive $7.5 million in connection with the first marketing authorization of tivozanib in Russia.  If Russian regulatory authorities require additional studies to be conducted prior to approval, this amou nt will be reduced to $3.0 million.  In addition, we are eligible to receive $3.0 million for each additional approved indication of tivozanib, if Pharmstandard elects to seek any such approvals, as well as a high single-digit royalty on net sales in the s ublicensed territories.  A percentage of all upfront, milestone and royalty payments received by us are due to KHK as a sublicensing fee under our license agreement with KHK. Pharmstandard has recently informed us that, based on adverse economic and financial conditions in Russia, they are seeking to renegotiate their obligation to make milestone payments to us under the license agreement.

 

31


Ophthotech Corporation

In November 2014 we entered into a research and exclusive option agreement with Ophthotech, pursuant to which we provided Ophthotech an exclusive option to enter into a definitive license agreement whereby we would grant Ophthotech the right to develop and commercialize tivozanib, our VEGF factor tyrosine kinase inhibitor, outside of Asia for the potential diagnosis, prevention and treatment of non-oncologic diseases or conditions of the eye in humans.

Pursuant to this agreement , we granted to Ophthotech an exclusive, royalty-free license or sublicense, as applicable, under intellectual property rights controlled by us solely to perform the research and development activities related to the use of tivozanib for the specific purposes outlined in the agreement during the option period. These activities include formulation work for ocular administration, preclinical research and the conduct of a Phase 1/2a, proof of concept clinical trial of a product containing tivozanib in patients with wet age-related macular degeneration.

Ophthotech paid us $0.5 million in consideration for the grant of the option. Such amount is non-refundable and not creditable against any other amounts due under the agreement. We are obligated to make available to Ophthotech, at no cost to Ophthotech, certain quantities of tivozanib hydrochloride solely for conducting its option period research, including manufacturing additional quantities of tivozanib in the event stability data indicates that the current supply will expire prior to the end of February 2017. A percentage of all payments received by us under this agreement, or any definitive license agreement, are due to KHK as a sublicensing fee under our license agreement with KHK.

Biodesix

In April 2014, we entered into a worldwide agreement with Biodesix to develop and commercialize ficlatuzumab, our HGF inhibitory antibody, with BDX004, a proprietary companion diagnostic test developed by Biodesix and based upon an exploratory analyses with VeriStrat ® , a serum protein test that is commercially available to help physicians guide treatment decisions for patients with advanced NSCLC.

Pursuant to a joint development plan, we retain primary responsibility for clinical development of ficlatuzumab in a proof of concept clinical study of ficlatuzumab for NSCLC in which VeriStrat will be used to select clinical trial subjects. The trial is fully funded by Biodesix up to a cap of $15.0 million, other than manufacturing costs for the trial, which are shared equally. After the cap is reached, we and Biodesix will share equally in all costs of the NSCLC trial.  We will each be responsible for 50% of development and regulatory costs associated with all future clinical trials agreed-upon by both parties, including all milestone payments and royalties payable to third parties, if any. Biodesix is responsible for all of the costs associated with development and registration of BDX004. Under the Biodesix agreement, subject to regulatory approval, we would lead worldwide commercialization of ficlatuzumab.

St. Vincent’s Hospital

In July 2012, we entered into a license agreement with St. Vincent’s Hospital Sydney Limited, which we refer to as St. Vincent’s, under which we obtained an exclusive, worldwide license to research, develop, manufacture and commercialize products for therapeutic applications that benefit from inhibition or decreased expression or activity of MIC-1, which is also known as GDF15. We believe GDF15 is a novel target for cachexia and we are exploiting this license in our AV-380 program for cachexia. Under the agreement, we have the right to grant sublicenses subject to certain restrictions. We have a right of first negotiation to obtain an exclusive license to certain improvements that St. Vincent’s or third parties may make to licensed therapeutic products. Under the license agreement, St. Vincent’s also granted us non-exclusive rights for certain related diagnostic products and research tools.

In August 2015, in connection with the execution of our license agreement with Novartis, we entered into an amended and restated agreement with St. Vincent’s, pursuant to which we made an upfront payment to St. Vincent’s of $1.5 million. St. Vincent’s is also eligible to receive up to approximately $18.9 million in connection with development and regulatory milestones. We made a $0.4 million milestone payment to St. Vincent’s during the three months ended March 31, 2016 related to the selection of a development candidate. Royalties for approved products resulting from the license agreement will also be payable to St. Vincent’s, and we and Novartis will share that obligation equally.

Biogen Idec

In March 2009, we entered into an exclusive option and license agreement with Biogen Idec International GmbH, or Biogen Idec, regarding the development and commercialization of our discovery-stage ErbB3-targeted antibodies for the potential treatment and diagnosis of cancer and other diseases in humans outside of North America. Under the agreement, we were responsible for developing ErbB3 antibodies through completion of the first phase 2 clinical trial designed in a manner that, if successful, will generate data sufficient to support advancement to a phase 3 clinical trial. In March 2014, we amended our agreement with Biogen Idec, whereby Biogen Idec agreed to the termination of its rights and obligations under the agreement, including Biogen Idec’s option

 

32


to (i) obtain a co-exclusive (with us) license to develop and manufacture ErbB3 targeted antibodies and (ii) obtain exclusive commercialization rights to ErbB3 products in countries in the world other than North America. As a result, we retain worldwide rights to AV-203, a clinical stage ErbB3-targeted antibody. P urs uant to the amendment, we were obligated to in good faith use reasonable efforts to seek a collaboration partner for the purpose of funding further development and commercialization of ErbB3-targeted antibodies. We satisfied this obligation in March 2016 u pon entering into our license agreement with CANbridge. W e are obligated to pay Biogen Idec a percentage of milestone paym ents we receive under the CANbridge agreement and single digit royalty payments on net sales related to the sale of AV-203 , up to cumu lative maximum amount of $50.0 million.

Astellas Pharma

In February 2011, we entered into a collaboration and license agreement with Astellas Pharma Inc. and certain of its indirect wholly-owned subsidiaries, which we collectively refer to as Astellas, pursuant to which we and Astellas made plans to develop and seek to commercialize tivozanib for the treatment of a broad range of cancers. On February 12, 2014, Astellas exercised its right to terminate the agreement. The termination of the agreement became effective August 11, 2014, at which time tivozanib rights returned to us. In accordance with the collaboration and license agreement, we and Astellas agreed to equally share committed development costs, including the costs of completing certain tivozanib clinical development activities that were initiated as part of our partnership with Astellas.

Kyowa Hakko Kirin

In December 2006, we entered into a license agreement with KHK under which we obtained an exclusive license, with the right to grant sublicenses subject to certain restrictions, to research, develop, manufacture and commercialize tivozanib, pharmaceutical compositions thereof and associated biomarkers. Our exclusive license covers all territories in the world except for Asia, where KHK has retained rights to tivozanib. Under the license agreement, we obtained exclusive rights in our territory under certain KHK patents, patent applications and know-how related to tivozanib, to research, develop, make, have made, use, import, offer for sale, and sell tivozanib for the diagnosis, prevention and treatment of any and all human diseases and conditions. We and KHK each have access to and can benefit from the other party’s clinical data and regulatory filings with respect to tivozanib and biomarkers identified in the conduct of activities under the license agreement.

Under the license agreement, we are obligated to use commercially reasonable efforts to develop and commercialize tivozanib in our territory, including meeting certain specified diligence goals. Prior to the first anniversary of the first post-marketing approval sale of tivozanib in our territory, neither we nor any of our subsidiaries has the right to conduct certain clinical trials of, seek marketing approval for or commercialize any other cancer product that also works by inhibiting the activity of the VEGF receptor.

Upon entering into the license agreement with KHK, we made a one-time cash payment in the amount of $5.0 million. In March 2010, we made a $10.0 million milestone payment to KHK in connection with the dosing of the first patient in our phase 3 clinical trial of tivozanib. In December 2012, we made a $12.0 million milestone payment to KHK in connection with the acceptance by the FDA of our NDA filing for tivozanib. The total remainin g payments for clinical and regulatory milestones under our license agreement with KHK are $38.0 million, in the aggregate, provided that the associated clinical and regulatory milestones specific to licensed territories will be replaced by a specified per centage of any non-research and development amounts we receive from any third party in the event we sublicense our rights under the agreement.

We also made a $22.5 million payment to KHK during the year ended December 31, 2011 related to the up-front license payment received under the collaboration and license agreement with Astellas that we entered into in February 2011. We are required to pay to KHK 30% of certain amounts we receive from sublicensees, including up-front license fees, milestone payments and royalties, other than amounts we receive in respect of research and development funding or equity investments, subject to certain limitations.

Financial Overview

We have devoted substantially all of our resources to our drug discovery efforts, comprising research and development, conducting clinical trials for our product candidates, protecting our intellectual property and the general and administrative functions relating to these operations. We have generated no revenue from product sales through March 31, 2016, and through such date have principally funded our operations through the proceeds from our strategic partnerships, sales of stock to investors and loan agreements with Hercules Capital, Inc. (formerly known as Hercules Technology Growth Capital, Inc.) and certain of its affiliates, which we sometimes refer to collectively as Hercules.

We do not have a history of being profitable and, as of March 31, 2016, we had an accumulated deficit of $502.7 million. We anticipate that we will continue to incur significant operating costs over the next several years as we continue our planned

 

33


development activities for our preclinical and clinical products. We will need additional funding to support our operating activities , and the timing and nature of activiti es contemplated for 2016 and thereafter will be conducted subject to the availability of sufficient financial resources .

Revenue

To date, we have not generated any revenue from product sales. All of our revenue to date has been derived from license fees, milestone payments, premium over the fair value of convertible preferred shares sold to our strategic partners, and research and development payments received from our strategic partners.

In the future, we may generate revenue from a combination of product sales, license fees, milestone payments and research and development payments in connection with strategic partnerships, and royalties resulting from the sales of products developed under licenses of our intellectual property. We expect that any revenue we generate will fluctuate from quarter to quarter as a result of the timing and amount of license fees, research and development reimbursements, milestone and other payments received under our strategic partnerships, and the amount and timing of payments that we receive upon the sale of our products, to the extent any are successfully commercialized. We do not expect to generate revenue from product sales in the near term. If we or our strategic partners fail to complete the development of our drug candidates in a timely manner or obtain regulatory approval for them, our ability to generate future revenue, and our results of operations and financial position, would be materially adversely affected.

Research and Development Expenses

Research and development expenses have historically consisted of expenses incurred in connection with the discovery and development of our product candidates. These expenses consist primarily of:

 

·

employee-related expenses, which include salaries, benefits and stock-based compensation expense;

 

·

expenses incurred under agreements with contract research organizations, investigative sites and consultants that conduct our clinical trials and a substantial portion of our preclinical studies;

 

·

the cost of acquiring and manufacturing drug development related materials;

 

·

the cost of completing certain tivozanib clinical development activities that were initiated as part of our prior partnership with Astellas;

 

·

facilities, depreciation and other allocated expenses, which include direct and allocated expenses for rent and maintenance of facilities and equipment, and depreciation of fixed assets;

 

·

license fees for, and milestone payments related to, in-licensed products and technology; and

 

·

costs associated with outsourced development activities, regulatory approvals and medical affairs.

We expense research and development costs as incurred. Nonrefundable advance payments for goods and services that will be used in future research and development activities are expensed when the activity has been performed or when the goods have been received rather than when the payment is made.

Research and development expenses are net of amounts reimbursed under our agreements with Astellas and Biodesix for Astellas’ and Biodesix’ respective shares of development costs incurred by us under our joint development plans with each respective partner.

 

34


We track external development expenses and personnel expense on a program-by-program basis and allocate common expenses, such as scientific consultants and laboratory supplie s, to each program based on the personnel resources allocated to such program. Facilities, depreciation, stock-based compensation, research and development management and research and development support services are not allocated among programs and are co nsidered overhead. Below is a summary of our research and development expenses for the three months ended March 31, 2016 and 2015 :

 

 

 

Three Months Ended

March 31,

 

 

 

 

2016

 

 

2015

 

 

 

 

(in thousands)

 

 

Tivozanib

 

$

4,984

 

 

$

1,445

 

 

AV-380 Program in Cachexia

 

 

426

 

 

 

475

 

 

Ficlatuzumab

 

 

249

 

 

 

 

 

AV-203

 

 

70

 

 

 

287

 

 

Other pipeline programs

 

 

 

 

 

11

 

 

Other research and development

 

 

 

 

 

10

 

 

Overhead

 

 

243

 

 

 

467

 

 

Total research and development expenses

 

$

5,972

 

 

$

2,695

 

 

 

Tivozanib

We have pursued partnering options to fund further tivozanib development in appropriate clinical settings outside of our strategic focus. In December 2015 and February 2016, our strategic partners submitted applications for marketing authorization for tivozanib for the treatment of RCC to the Russian Health Ministry and the European Medicines Agency, respectively. Our partners are responsible for all activities and costs associated with the further development and commercialization of tivozanib within the licensed territories. We continue to share the costs of development activities to which we and Astellas were committed at the time the Astellas partnership was terminated. 

Subject to the availability of sufficient financial resources, w e are also planning to conduct an additional phase 3 trial of tivozanib vs. sorafenib in approximately 322 patients in the refractory RCC setting using PFS as the primary endpoint and OS as a secondary endpoint, in order to address the OS concerns presented in the June 2013 complete response letter from the FDA and support a request for approval of tivozanib as a third-line treatment and as a first-line treatment. We expect the remaining uncommitted costs of this trial to be between $32.0 and $34.0 million through completion. We are also planning to conduct a phase 1/2 trial of tivozanib in combination with a PD-1 inhibitor for the treatment of RCC, for which costs could be in the range of $1.5-2.0 million.    The timing and nature of these and other activities contemplated for 2016 and thereafter will be conducted subject to the availability of sufficient financial resources.

AV-380 Program in Cachexia

In August 2015, we entered into a license agreement with Novartis, under which we granted Novartis the exclusive right to develop and commercialize AV-380 and related AVEO antibodies that bind to Growth Differentiation Factor 15 worldwide. Under this agreement, Novartis is responsible for all activities and costs associated with the further development, regulatory filing and commercialization of AV-380 worldwide. We do not expect to incur any significant costs related to AV-380 in future periods beyond any milestone fees and royalties payable to St. Vincent’s pursuant to our in-licensing agreement, which comprises substantially all of the costs incurred during the three months ended March 31, 2016.

AV-203

In March 2014, we regained our worldwide rights from Biogen Idec to develop, manufacture and commercialize AV-203. In March 2016, we entered into a collaboration and license agreement with CANbridge, under which we granted CANbridge the exclusive right to develop and commercialize AV-203 in all countries other than the United States, Canada and Mexico. CANbridge is responsible for all costs of developing and commercializing AV-203 within the licensed territory. For a period of time following the completion of certain proof-of-concept clinical studies by CANbridge involving the use of AV-203 for the treatment of squamous cell esophagus cancer, we agreed to negotiate exclusively with CANbridge for (a) the right to co-develop ErbB3 inhibitory antibody products for the treatment of squamous cell esophagus cancer or (b) the right to include the United States, Canada and Mexico as part of the licensed territories. We do not expect to incur any significant costs related to AV-203 prior to CANbridge’s completion of a proof-of-concept clinical study.

 

35


Ficlatuzumab

In April 2014, we entered into a worldwide agreement with Biodesix to develop and commercialize ficlatuzumab, our potent HGF inhibitory antibody, with BDX004, a proprietary companion diagnostic test, developed by Biodesix and based upon an exploratory analyses with VeriStrat ® , a serum protein test that is commercially available to help physicians guide treatment decisions for patients with advanced NSCLC. Pursuant to the agreement, Biodesix will provide up to $15.0 million for a phase 2 trial of ficlatuzuma b in combination with erlotinib in first-line advanced NSCLC patients selected using BDX004 and fund the further development and registration of BDX004 as a companion diagnostic. Any manufacturing costs incurred are shared equally. After the completion of the phase 2 trial, any additional development, regulatory or commercial expenses for ficlatuzumab will be equally shared.  Due to the unpredictable nature of clinical development, we are unable to estimate with any certainty the costs we will incur in the future development of ficlatuzumab.

Uncertainties of Estimates Related to Research and Development Expenses

The process of conducting preclinical studies and clinical trials necessary to obtain FDA approval for each of our product candidates is costly and time-consuming. The probability of success for each product candidate and clinical trial may be affected by a variety of factors, including, among others, the quality of the product candidate’s early clinical data, investment in the program, competition, manufacturing capabilities and commercial viability.

At this time, we cannot reasonably estimate or know the nature, specific timing and estimated costs of the efforts that will be necessary to complete the development of our product candidates, or the period, if any, in which material net cash inflows may commence from sales of any approved products. This uncertainty is due to the numerous risks and uncertainties associated with developing drugs, including the uncertainty of:

 

·

our ability to establish and maintain strategic partnerships, the terms of those strategic partnerships and the success of those strategic partnerships, if any, including the timing and amount of payments that we might receive from strategic partners;

 

·

the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for any product candidate;

 

·

the progress and results of our clinical trials;

 

·

the costs, timing and outcome of regulatory review of our product candidates;

 

·

the emergence of competing technologies and products and other adverse market developments; and

 

·

the costs of preparing, filing and prosecuting patent applications and maintaining, enforcing and defending intellectual property-related claims.

As a result of the uncertainties associated with developing drugs, including those discussed above, we are unable to determine the duration and completion costs of current or future clinical stages of our product candidates, or when, or to what extent, we will generate revenues from the commercialization and sale of any of our product candidates. Development timelines, probability of success and development costs vary widely. We anticipate that we will make determinations as to which additional programs to pursue and how much funding to direct to each program on an ongoing basis in response to the scientific and clinical success, if any, of each product candidate, as well as ongoing assessment of each product candidate’s commercial potential. We will need to raise substantial additional capital in the future in order to fund the development of our preclinical and clinical product candidates.

General and Administrative Expenses

General and administrative expenses consist principally of salaries and related costs for personnel in executive, finance, corporate development, information technology, legal and human resource functions. Other general and administrative expenses include facility costs not otherwise included in research and development expenses, patent filing, prosecution and defense costs and professional fees for legal, consulting, pre-commercialization activities, auditing and tax services.

We anticipate that our general and administrative expenses will decrease in 2016 as compared to 2015 due to our relocation to a smaller facility during the second quarter of 2015 and decreased legal costs associated with ongoing shareholder litigation and our recently-settled U.S. Securities and Exchange Commission, or SEC, investigation described in this report under the heading “Legal Proceedings” below in Part II—Item 1.

 

36


Interest Income and Interest Expense

Interest income consists of interest earned on our cash, cash equivalents and marketable securities. The primary objective of our investment policy is capital preservation.

Interest expense consists of interest, amortization of debt discount, and amortization of deferred financing costs associated with our loans payable.

Income Taxes

We calculate our provision for income taxes on ordinary income based on our projected annual tax rate for the year. As of March 31, 2016, we are forecasting a net loss for the year ended December 31, 2016, and since we maintain a full valuation allowance on all of our deferred tax assets, we have recorded no income tax benefit in the current quarter. For the three months ended March 31, 2016, we recorded a $0.1 million provision for income taxes related to withholding taxes incurred in a foreign jurisdiction.

Critical Accounting Policies and Significant Judgments and Estimates

Our discussion and analysis of our financial condition and results of operations are based on our condensed consolidated financial statements, which have been prepared in accordance with accounting principles generally accepted in the United States. The preparation of these financial statements requires us to make estimates and judgments that affect the reported amounts of assets, liabilities, revenues and expenses and the disclosure of contingent assets and liabilities in our financial statements. On an ongoing basis, we evaluate our estimates and judgments, including those related to revenue recognition, accrued clinical expenses, and stock-based compensation. We base our estimates on historical experience, known trends and events and various other factors that we and our management believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions.

Our significant accounting policies are described in the notes to our condensed consolidated financial statements appearing elsewhere in this report. There have been no material changes to our critical accounting policies during the three month period ended March 31, 2016. Please refer to Part II, Item 7, “Management’s Discussion and Analysis of Financial Condition and Results of Operations”, of our annual report on Form 10-K for the fiscal year ended December 31, 2015 for further discussion of our critical accounting policies and significant judgments and estimates.

Results of Operations

Comparison of Three Months Ended March 31, 2016 and 2015

The following table summarizes the results of our operations for each of the three months ended March 31, 2016 and 2015, together with the changes in those items in dollars and as a percentage:

 

 

 

Three Months Ended

March 31,

 

 

Increase/

 

 

 

 

 

 

 

2016

 

 

2015

 

 

(decrease)

 

 

%

 

 

 

(in thousands)

 

Revenue

 

$

1,203

 

 

$

134

 

 

$

1,069

 

 

 

798

%

Operating expenses:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Research and development

 

 

5,972

 

 

 

2,695

 

 

 

3,277

 

 

 

122

%

General and administrative

 

 

2,463

 

 

 

3,255

 

 

 

(792

)

 

 

(24

)%

Restructuring and lease exit

 

 

 

 

 

4,333

 

 

 

(4,333

)

 

 

(100

)%

Total operating expenses

 

 

8,435

 

 

 

10,283

 

 

 

(1,848

)

 

 

(18

)%

Loss from operations

 

 

(7,232

)

 

 

(10,149

)

 

 

2,917

 

 

 

(29

)%

Other expense, net

 

 

(9

)

 

 

(14

)

 

 

5

 

 

 

(36

)%

Interest expense

 

 

(386

)

 

 

(716

)

 

 

330

 

 

 

(46

)%

Interest income

 

 

17

 

 

 

5

 

 

 

12

 

 

 

240

%

Loss before income taxes

 

 

(7,610

)

 

 

(10,874

)

 

 

3,264

 

 

 

(30

)%

Income tax provision

 

 

(100

)

 

 

 

 

 

(100

)

 

 

100

%

Net loss

 

$

(7,710

)

 

$

(10,874

)

 

$

3,164

 

 

 

(29)

%

 

 

37


The following table sets forth revenue for the three months ended March 31, 2016 and 2015 :

 

 

 

Three Months Ended

March 31,

 

 

Increase/

 

 

 

 

 

Revenue

 

2016

 

 

2015

 

 

(decrease)

 

 

%

 

 

 

(in thousands)

 

Strategic Partner:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CANbridge

 

$

1,000

 

 

$

 

 

$

1,000

 

 

 

100

%

     EUSA

 

 

99

 

 

 

 

 

 

99

 

 

 

100

%

Biogen Idec

 

 

38

 

 

 

76

 

 

 

(38

)

 

 

(50

%)

Pharmstandard

 

 

38

 

 

 

 

 

 

38

 

 

 

100

%

Ophthotech

 

 

28

 

 

 

58

 

 

 

(30

)

 

 

(52

%)

 

 

$

1,203

 

 

$

134

 

 

$

1,069

 

 

 

798

%

 

Revenue. Revenue for the three months ended March 31, 2016 was $1.2 million compared to $0.1 million for the three months ended March 31, 2015, an increase of approximately $1.1 million. The increase was primarily due to an additional $1.0 million in revenue recognized in the first quarter of 2016 in connection with our out-licensing agreement with CANbridge, which was executed in March 2016.

Research and development.  Research and development, or R&D, expenses for the three months ended March 31, 2016 were $6.0 million compared to $2.7 million for the three months ended March 31, 2015, an increase of $3.3 million or 122%. The increase was primarily attributable to a $3.3 million increase in tivozanib clinical trial costs associated with our preparation for a phase 3 trial in renal cell carcinoma.

General and administrative.  General and administrative expenses for the three months ended March 31, 2016 were $2.5 million compared to $3.3 million for the three months ended March 31, 2015, a decrease of $0.8 million or 24%. The decrease was primarily the result of a $0.3 million decrease in external legal costs associated with various ongoing legal matters, a $0.5 million decrease in employee compensation, consulting, facilities and IT costs following our decreased headcount and the reduction of our utilized facility space following our 2015 restructuring.

Restructuring and lease exit. Restructuring and lease exit expenses for the three months ended March 31, 2016 and 2015 were $0 and $4.3 million, respectively. The expenses incurred during the three months ended March 31, 2015 related to the January 2015 restructuring, which was substantially completed in March 2015. As part of this restructuring, we eliminated our internal research function, reducing our headcount by approximately 40 positions.

Interest expense. Interest expense for the three months ended March 31, 2016 was $0.4 million compared to $0.7 million for the three months ended March 31, 2015. The decrease was primarily attributable to the decrease in the outstanding balance on our loan with Hercules.

Income Tax Provision. Income tax provision for the three months ended March 31, 2016 was $0.1 million compared to $0 for the three months ended March 31, 2015. The increase in the income tax provision relates to withholding taxes incurred in a foreign jurisdiction related income earned from our licensing agreement with CANbridge.

Liquidity and Capital Resources

We have funded our operations principally through the sale of equity securities sold in private placements and underwritten public offerings, revenue and expense reimbursements from strategic partnerships, debt financing and interest income. As of March 31, 2016, we had cash, cash equivalents and marketable securities of approximately $23.8 million. Currently, our funds are invested in money market funds, U.S. government agency securities, and corporate debt securities, including commercial paper. The following table sets forth the primary sources and uses of cash for each of the periods set forth below:

 

 

 

Three Months Ended

March 31,

 

 

 

2016

 

 

2015

 

 

 

(in thousands)

 

Net cash (used in) operating activities

 

$

(10,319

)

 

$

(15,820

)

Net cash provided by (used in) investing activities

 

 

1,754

 

 

 

(3,620

)

Net cash provided by (used in) financing activities

 

 

(13

)

 

 

1,669

 

Net decrease in cash and cash equivalents

 

$

(8,578

)

 

$

(17,771

)

 

 

38


For the three months ended March 31, 2016 and 2015 , our operati ng activities used cash of $10.3 mill ion and $15.8 million, respectively. Cash used by operations for the three months ended March 31, 2016 and 2015 was due primarily to our net loss adjusted for non-cash items and changes in working capital.

 

For the three months ended March 31, 2016 and 2015, our investing activities provided cash of $1.8 million and used cash of $3.6 million, respectively. Cash provided by investing activities for the three months ended March 31, 2016 was primarily the net result of the proceeds from the maturity of marketable securities, partially offset by the purchase of additional marketable securities. Cash used in investing activities for the three months ended March 31, 2015 was primarily the net result of the purchase of marketable securities, partially offset by the maturities and sales of marketable securities and the proceeds from the sale of lab equipment.

For the three months ended March 31, 2016 and 2015, our financing activities used cash of $13,000 and provided cash of $1.7 million, respectively. The decrease in cash provided by financing activities is primarily the result of the receipt of proceeds from sales of common stock during the three months ended March 31, 2015 that did not recur in 2016, partially offset by principal payments on a prior loan with Hercules in 2015 that was fully paid during 2015.

At-The-Market Issuance Sales Agreement with FBR

In February 2015, we entered into an at-the-market issuance sales agreement, which we refer to as the Sales Agreement, with FBR & Co., or FBR, (formerly MLV & Co. LLC), pursuant to which we could issue and sell shares of our common stock from time to time up to an aggregate amount of $17.9 million, at our option, through FBR as our sales agent. Sales of common stock through FBR may be made by any method that is deemed an “at-the-market” offering as defined in Rule 415 promulgated under the Securities Act of 1933, as amended, including by means of ordinary brokers’ transactions at market prices, in block transactions or as otherwise agreed by the Company and FBR. Subject to the terms and conditions of the Sales Agreement, FBR will use commercially reasonable efforts to sell our common stock based upon our instructions (including any price, time or size limits or other customary parameters or conditions we may impose). We are not obligated to make any sales of common stock under the Sales Agreement. Any shares sold will be sold pursuant to an effective shelf registration statement on Form S-3. We are required to pay FBR a commission of up to 3% of the gross proceeds. The Sales Agreement may be terminated by us at any time.

On May 7, 2015, we filed a shelf registration statement on Form S-3 with the SEC, which we refer to as the 2015 Shelf.  The 2015 Shelf covers the offering, issuance and sale of up to $100 million of our common stock, preferred stock, debt securities, warrants and/or units. The 2015 Shelf was filed to replace our existing $250 million shelf registration statement, which expired at the end of May 2015, and which we refer to as the 2012 Shelf.  On May 7, 2015, we also amended the Sales Agreement to provide for the offering, issuance and sale of up to $15 million of our common stock under the 2015 Shelf.  The prior at-the-market offering initiated under the original Sales Agreement expired along with the 2012 Shelf. As of March 31, 2016, we have sold approximately 5.9 million shares pursuant to the Sales Agreement, as amended, resulting in proceeds of approximately $10.2 million, net of commissions and issuance costs. Approximately $9.0 million remains available for sale under the Sales Agreement.

 

Credit Facilities. On September 24, 2014, we amended our loan and security agreement with Hercules Capital, Inc. (formerly known as Hercules Technology Growth Capital, Inc.) and certain of its affiliates , which we refer to collectively as Hercules. We originally entered into the loan agreement on May 28, 2010 a nd previously amended it on December 21, 2011 and March 31, 2012 . We refer to the loan agreement, as amended, as the Amended Loan Agreement. Pursuant to the Amended Loan Agreement, we received a new loan in an aggregate principal amount of $10.0 million and amended the terms of our original loan with Hercules, which had an outstanding principal balance of $11.6 million  at the date of the amendment. The original loan was fully repaid as of December 2015.

We are not required to make any principal payments on the new loan of $10.0 million until May 1, 2016. The date  on which we will be required to begin making principal payments was extended by six months in August 2015 upon executing our license agreement with Novartis and may be further extended if we continue to achieve performance milestones, after which time we will be required to make monthly principal and interest payments with the final payment due on January 1, 2018.

The Amended Loan Agreement has an end-of-term payment of approximately $0.5 million due on January 1, 2018 or on such earlier date as the new loan is prepaid. The Amended Loan Agreement also has a financial covenant with respect to the new loan, whereby we have agreed to maintain a liquidity ratio equal to or greater than 1.25 to 1.00 of the then outstanding principal balance, or the equivalent of $12.5 million based on the outstanding principal balance as of March 31, 2016, in unrestricted and unencumbered cash and cash equivalents. This financial covenant will not apply after such time as we receive favorable data both with respect to our phase 2 clinical study of ficlatuzumab and a phase 1 clinical study of AV-380. We continued to be in compliance with all financial covenants under the Amended Loan Agreement at March 31, 2016. We must make interest payments on the loan each month it

 

39


remains outstanding. Per annum interest is payable on each loan at the greater of 11.9% and an amount equal to 11.9% plus the prime rate minus 4.75%, provided, however, that the per annum interest shall not ex ceed 15.0%. Our annual interest rate as of March 31, 2016 was 11.9%.

We have determined that the risk of subjective acceleration under the material adverse events clause included in this loan and security agreement is remote and, therefore, have classified the outstanding principal amount in current and long-term liabilities based on the timing of scheduled principal payments. As of March 31, 2016 and through the date of this filing, the lenders have not asserted any events of default under the loan.

The loans are secured by a lien on all of our personal property (other than intellectual property), whether owned as of, or acquired after, the date of the Amended Loan Agreement. As of March 31, 2016, the principal balance outstanding was $10.0 million.

Operating Capital Requirements.   We anticipate that we will continue to incur significant operating losses for the next several years as we incur expenses to continue to execute on our clinical development strategy to advance our clinical stage assets. We will require substantial funds to continue our development programs and to fulfill our planned operating goals. In particular, our currently planned operating and capital requirements include the need for substantial working capital to support our development activities for tivozanib. For example, we estimate that the remaining uncommitted costs for a phase 3 trial for RCC such as the one contemplated by us could be in the range of $32-34 million in the aggregate through 2018. We are also designing a phase 1/2 study of tivozanib combined with a PD-1 inhibitor for the treatment of patients with RCC for which costs could be in the range of $1.5-2.0 million. Moreover, we have future payment obligations and cost-sharing arrangements under certain of our collaboration and license agreements. For example, under our agreements with KHK and St. Vincent’s, we are required to make certain clinical and regulatory milestone payments, have royalty obligations with respect to product sales and are required to pay a specified percentage of sublicense revenue in certain instances. Moreover, under our agreement with Biodesix, we are obligated to share any costs for the phase 2 FOCAL study that exceed $15 million, and to share any manufacturing and future development costs. Accordingly, we will need substantial additional funding in connection with our planned operations. If we are unable to raise capital when needed or on attractive terms, or if we are unable to procure partnership arrangements to advance our programs, we would be forced to delay, reduce or eliminate our research and development programs and any future commercialization efforts.

We believe that our cash resources could allow us to fund our current operations into the fourth quarter of 2017. This estimate does not incl ude our payment of potential licensing milestones to third parties or the uncommitted costs of conducting any contemplated clinical trials (such as a second phase 3 trial and PD-1 combination trial for tivozanib in RCC), and assumes no milestone payments from our partners, no additional funding from new partnership agreements, no equity financings, no debt financings, no accelerated repayment thereof and no further sales of equity under our ATM.

Because of the numerous risks and uncertainties associated with research, development and commercialization of pharmaceutical products, we are unable to estimate the exact amounts of our working capital requirements and the period in which we will have working capital to fund our operations. Accordingly, the timing and nature of activities contemplated for 2016 and thereafter will be conducted subject to the availability of sufficient financial resources.

Our future funding requirements will depend on many factors, including, but not limited to:

 

·

our ability to establish and maintain strategic partnerships, licensing or other arrangements and the financial terms of such agreements;

 

·

the number and characteristics of the product candidates we pursue;

 

·

the scope, progress, results and costs of researching and developing our product candidates, and conducting preclinical and clinical trials;

 

·

the timing of, and the costs involved in, obtaining regulatory approvals for our product candidates;

 

·

the costs involved in preparing, filing, prosecuting, maintaining, defending and enforcing patent claims, including litigation costs and the outcome of such litigation;

 

·

the absence of any breach, acceleration event or event of default under our loan agreement with Hercules or under any other agreements with third parties;

 

·

the outcome of legal actions against us, including the current lawsuits described under “Part II, Item 1—Legal Proceedings”;

 

·

the cost of commercialization activities if any of our product candidates are approved for sale, including marketing, sales and distribution costs;

 

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·

the cost of manufacturing our product candidates and any products we successfully commercialize; and

 

·

the timing, receipt and amount of sales of, or royalties on, our future products, if any.

If our available cash and cash equivalents are insufficient to satisfy our liquidity requirements, or if we identify additional opportunities to do so, we may seek to sell additional equity or debt securities or obtain additional credit facilities. The sale of additional equity or convertible debt securities may result in additional dilution to our stockholders. If we raise additional funds through the issuance of debt securities or preferred stock or through additional credit facilities, these securities and/or the loans under credit facilities could provide for rights senior to those of our common stock and could contain covenants that would restrict our operations. We will require additional capital beyond our currently forecasted amounts. Additional funds may not be available when we need them, on terms that are acceptable to us, or at all. If adequate funds are not available to us on a timely basis, we may be required to:

 

·

delay, limit, reduce or terminate our clinical trials or other development activities for one or more of our product candidates; and/or

 

·

delay, limit, reduce or terminate our establishment of sales and marketing capabilities or other activities that may be necessary to commercialize our product candidates, if approved.

Contractual Obligations and Commitments

There have been no material changes to our contractual obligations and commitments outside the ordinary course of business from those disclosed in our Annual Report on Form 10-K for the year ended December 31, 2015 filed with the SEC on March 15, 2016.

Off-Balance Sheet Arrangements

We did not have, during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined under applicable SEC rules.

 

 

Item 3. Quantitative and Qualitative Disclosures About Market Risk.

We are exposed to market risk related to changes in interest rates. As of March 31, 2016, we had cash, cash equivalents and marketable securities of $23.8 million, consisting of cash on deposit with banks, money market funds, U.S. government agency securities, and corporate debt, including commercial paper. Our primary exposure to market risk is interest rate sensitivity, which is affected by changes in the general level of U.S. interest rates, particularly because our investments are in short-term cash equivalents. Our cash equivalents are subject to interest rate risk and could fall in value if market interest rates increase. Due to the short-term duration of our investment portfolio and the low risk profile of our investments, an immediate 10% change in interest rates would not have a material effect on the fair market value of our portfolio. We have the ability to hold our cash equivalents until maturity, and therefore we would not expect our operating results or cash flows to be affected to any significant degree by the effect of a change in market interest rates on our investments. We do not currently have any auction rate securities.

Our long-term debt bears interest at variable rates. In May 2010, we entered into a loan agreement with Hercules pursuant to which we received a loan in the aggregate principal amount of $25.0 million. In March 2012, we entered into an amendment to the loan agreement, pursuant to which we increased the principal amount to $26.5 million. In September 2014, we entered into a further amendment to the loan agreement, pursuant to which we borrowed a new loan of $10.0 million, which is in addition to the existing loan which had an outstanding principal balance of $11.6 million. As of March 31, 2016, our aggregate principal balance outstanding on our loans was $10.0 million. Per annum interest is payable at the greater of 11.9% and 11.9% plus the prime rate of interest minus 4.75%, not to exceed 15%. As a result of the 15% maximum per annum interest rate under the amended loan agreement, we have limited exposure to changes in interest rates on borrowings under this loan agreement. For every 1% increase in the prime rate over 4.75%, given the amount of debt outstanding under the loan agreement as of March 31, 2016, and expected loan payments during 2016, we would have a decrease in future annual cash flows of approximately $0.1 million over the next twelve month period as a result of such 1% increase.

We are also exposed to market risk related to change in foreign currency exchange rates. We contract with contract research organizations and investigational sites that are located around the world. We are subject to fluctuations in foreign currency rates in connection with these agreements. We do not currently hedge our foreign currency exchange rate risk.

 

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Item 4. Controls and Procedures.

Our management, with the participation of our President and Chief Executive Officer (our principal executive officer) and our Chief Financial Officer (our principal financial officer), evaluated the effectiveness of our disclosure controls and procedures as of March 31, 2016. In designing and evaluating our disclosure controls and procedures, management recognized that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving their objectives and our management necessarily applied its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Based on this evaluation, our President and Chief Executive Officer (our principal executive officer) and our Chief Financial Officer (our principal financial officer) concluded that as of March 31, 2016, our disclosure controls and procedures were (1) designed to ensure that material information relating to us is made known to our management including our principal executive officer and principal financial officer by others, particularly during the period in which this report was prepared and (2) effective, in that they provide reasonable assurance that information required to be disclosed by us in the reports we file or submit under the Exchange Act is recorded, processed, summarized and reported within the time periods specified in the SEC’s rules and forms.

There were no changes in our internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) that occurred during the quarter ended March 31, 2016 that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.

 

 

 

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PART II. OTHER INFORMATION

Item 1. Legal Proceedings

Two class action lawsuits have been filed against us and certain of our former officers and members of our board of directors, (Tuan Ha-Ngoc, David N. Johnston, William Slichenmyer and Ronald DePinho), in the United States District Court for the District of Massachusetts, one captioned Paul Sanders v. Aveo Pharmaceuticals, Inc., et al., No. 1:13-cv-11157-JLT, filed on May 9, 2013, and the other captioned Christine Krause v. AVEO Pharmaceuticals, Inc., et al., No. 1:13-cv-11320-JLT, filed on May 31, 2013. On December 4, 2013, the District Court consolidated the complaints as In re AVEO Pharmaceuticals, Inc. Securities Litigation et al., No. 1:13-cv-11157-DJC, and an amended complaint was filed on February 3, 20 14. The amended complaint purported to be brought on behalf of shareholders who purchased our common stock between January 3, 2012 and May 1, 2013. The amended complaint generally alleged that we and certain of our present and former officers and directors violated Sections 10(b) and/or 20(a) of the Securities Exchange Act of 1934 and Rule 10b-5 promulgated thereunder by making allegedly false and/or misleading statements concerning the phase 3 trial design and results for our TIVO-1 study in an effort to l ead investors to believe that the drug would receive approval from the FDA. The lawsuit seeks unspecified damages, interest, attorneys’ fees, and other costs.  The consolidated amended complaint was dismissed without prejudice on March 20, 2015, and the lead plaintiffs then filed a second amended complaint bringing similar allegations.  We moved to dismiss again, and after a second round of briefing and oral argument, the court ruled in our favor and dismissed the second amended complaint with prejudice on November 18, 2015.  The lead plaintiffs have appealed the court’s decision to the United States Court of Appeals for the First Circuit . They have also filed a motion to vacate and reconsider the district court’s judgment, which we have opposed. We deny any allegations of wrongdoing and intend to continue to vigorously defend against this lawsuit. However, there is no assurance that we will be successful in our defense or that insurance will be available or adequate to fund any settlement or judgment or the litigation costs of the action. Moreover, we are unable to predict the outcome or reasonably estimate a range of possible loss at this time.

On April 4, 2014, Karen J. van Ingen, a purported purchaser of AVEO stock, filed a derivative complaint allegedly on behalf of AVEO in the United States District Court for the District of Massachusetts, Civil Action No. 1:14-cv-11672-DJC, naming AVEO, as a nominal defendant and also naming as defendants present and former members of our board of directors, i ncluding Tuan Ha-Ngoc, Henri A. Termeer, Kenneth M. Bate, Anthony B. Evnin, Robert Epstein, Raju Kucherlapati, Robert C. Young, and Kenneth E. Weg. The complaint alleged breach of fiduciary duty and abuse of control between January 2012 and May 2013 with r espect to allegedly misleading statements and omissions regarding tivozanib. The lawsuit seeks, among other relief, unspecified damages, costs and expenses, including attorneys’ fees, an order requiring us to implement certain corporate governance reforms, restitution from the defendants and such other relief as the court might find just and proper.  We filed a motion to dismiss the derivative complaint, and after briefing and oral argument, on March 18, 2015 the Court ruled in our favor and dismissed the case with prejudice. The plaintiff then filed a motion seeking to vacate the Court’s order of dismissal and permit filing of an amended complaint, which we opposed, and which the Court denied on June 30, 2015.  The plaintiff has appealed the Court’s decision to the United States Court of Appeals for the First Circuit .  We deny any allegations of wrongdoing and intend to continue to vigorously defend this lawsuit. However, there is no assurance that we will be successful in our defense or that insurance will be available or adequate to fund any settlement or judgment or the litigation costs of this action. Moreover, we are unable to predict the outcome or reasonably estimate a range of possible loss at this time.

On July 3, 2013, the staff (the “SEC Staff”) of the United States Securities and Exchange Commission (the “Commission”) served a subpoena on us for documents and information concerning tivozanib, including related communications with the FDA, investors and others.  We have fully cooperated with the inquiry.  In September 2015, the SEC Staff invited us to discuss the settlement of potential claims that the SEC Staff may recommend that the Commission bring against us asserting that we violated federal securities laws by omitting to disclose to investors t he recommendation made to us by the staff of the U.S. Food and Drug Administration, on May 11, 2012, that we conduct an additional clinical trial with respect to tivozanib. Through these discussions with the SEC Staff, we agreed to settle those claims for a total amount of $4 million, subject to the approval of the Commission.  

On March 29, 2016, the Commission filed a complaint against us and three of our former officers in the U.S. District Court for the District of Massachusetts (the “Court”) alleging that we misled investors about our efforts to obtain FDA approval for tivozanib. Without admitting or denying the allegations in the Commission’s complaint, we consented to the entry of a final judgment pursuant to which we would pay the Commission a $4 million civil penalty to settle the Commission’s claims against us.

 

On March 31, 2016, the Court entered a final judgment which (i) approved the settlement; (ii) permanently enjoined us from violating Section 17(a) of the Securities Act of 1933, as amended, Sections 10(b) and 13(a) of the Securities Exchange Act of 1934, as amended, and rules 10b-5, 12b-20, 13a-1, 13a-11 and 13a-13 promulgated thereunder; and (iii) ordered us to pay the agreed-to civil penalty.

 

43


The Commission’s action against our three form er officers is still pending . We are not a party to any litigation or discussions between the SEC Staff and the former officers, and we can make no assurance regarding the outcome of that action or the Commission’s claims against those individuals .

Refer to Footnote 11 in the Notes to Condensed Consolidated Financial Statements for further discussion.

Item 1A. Risk Factors

Our business is subject to numerous risks. We caution you that the following important factors, among others, could cause our actual results to differ materially from those expressed in forward-looking statements made by us or on our behalf in this Quarterly Report on Form 10-Q and other filings with the SEC, press releases, communications with investors and oral statements. Any or all of our forward-looking statements in this Quarterly Report on Form 10-Q and in any other public statements we make may turn out to be wrong. They can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. Many factors mentioned in the discussion below will be important in determining future results. Consequently, no forward-looking statement can be guaranteed. Actual future results may differ materially from those anticipated in our forward-looking statements. We undertake no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. You are advised, however, to consult any further disclosure we make in our reports filed with the SEC.

Risks Related to Our Financial Position and Need for Additional Capital

We anticipate that we will continue to incur significant operating losses for the foreseeable future. It is uncertain if we will ever attain profitability, which would depress the market price of our common stock.

We have incurred a net loss of $7.7 million for the three months ended March 31, 2016 and, as of March 31, 2016, had an accumulated deficit of $502.7 million. To date, we have not commercialized any products or generated any revenues from the sale of products, and absent the realization of sufficient revenues from product sales, we may never attain profitability. Our losses have resulted principally from costs incurred in our discovery and development activities. We anticipate that we will con tinue to incur significant operating costs over the next several years as we seek to develop our product candidates.

If we do not successfully develop and obtain regulatory approval for our existing and future pipeline of product candidates and effectively manufacture, market and sell any product candidates that are approved, we may never generate product sales. Even if we do generate product sales, we may never achieve or sustain profitability on a quarterly or annual basis. Our failure to become and remain profitable would depress the market price of our common stock and could impair our ability to raise capital, expand our business, diversify our product offerings or continue our operations.

Our business is in early stage of development, which may make it difficult for you to evaluate the success of our business to date and to assess our future viability.

All of our product candidates are in early stages of development. We have not yet demonstrated our ability to obtain marketing approvals, manufacture a commercial scale medicine, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful commercialization. Typically, it takes about 10 to 15 years to develop one new medicine from the time it is discovered to when it is available for treating patients. Preclinical studies and clinical trials may involve highly uncertain results and a high risk of failure. Moreover, positive data from preclinical studies and clinical trials of our product candidates may not be predictive of results in ongoing or subsequent preclinical studies and clinical trials. Consequently, any predictions you make about our future success or viability may not be as accurate as they could be if we had a longer operating history.

In addition, as an early stage business, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors. To be profitable, we will need to transition from a company with a research and development focus to a company capable of supporting commercial activities. We may not be successful in such a transition.

We will require substantial additional funding, and a failure to obtain this necessary capital when needed would force us to delay, limit, reduce or terminate our research, product development or commercialization efforts.

We will require substantial funds to continue our development programs and to fulfill our planned operating goals. In particular, our currently planned operating and capital requirements include the need for substantial working capital to support our development activities for tivozanib. For example, w e estimate that the remaining uncommitted costs for a Phase 3 trial for RCC such as the one contemplated by us could be in the range of $32-34 million in the aggregate through 2018. We are also designing a phase 1/2 study of tivozanib combined with a PD-1 inhibitor for the treatment of patients with RCC for which costs could be in the range of $1.5-2 million. Moreover, we have future payment obligations and cost-sharing arrangements under certain of our collaboration and license agreements. For example, under our agreements with KHK and St. Vincent’s, we are required to make certain clinical and regulatory

 

44


milestone payments, have royalty obligatio ns with respect to product sales and are required to pay a specified percentage of sublicense revenue in certain instances. Moreover, under our agreement with Biodesix, we are obligated to share any costs for the phase 2 FOCAL study that exceed $15 million . Accordingly, we will need substantial additional funding in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, or if we are unable to procure partnership arrangements to advance our programs, we would be forced to delay, reduce or eliminate our research and development programs and any future commercialization efforts.

We believe that our cash resources would allow us to fund our current operations into the fourth quarter of 2017. This estimate does not include our payment of potential licensing milestones to third parties or the uncommitted costs of conducting any contemplated clinical trials, such as a phase 3 TIVO-3 trial in RCC, and assumes no milestone payments from our partners, no additional funding from new partnership agreements, no equity financings, no debt financings, no accelerated repayment thereof and no further sales of equity under our ATM.

Because of the numerous risks and uncertainties associated with the development and commercialization of pharmaceutical products, we are unable to estimate the exact amounts of our working capital requirements and the period in which we will have working capital to fund our operations. Accordingly, the timing and nature of activities contemplated for 2016 and thereafter will be conducted subject to the availability of sufficient financial resources.

Our future capital requirements depend on many factors, including:

 

·

our ability to establish and maintain strategic partnerships, licensing or other arrangements and the financial terms of such agreements;

 

·

the number and characteristics of the product candidates we pursue;

 

·

the scope, progress, results and costs of developing our product candidates, and conducting preclinical and clinical trials;

 

·

the timing of, and the costs involved in, obtaining regulatory approvals for our product candidates;

 

·

the costs involved in preparing, filing, prosecuting, maintaining, defending and enforcing patent claims, including litigation costs and the outcome of such litigation;

 

·

the absence of any breach, acceleration event or event of default under our loan agreement with Hercules or under any other agreements with third parties;

 

·

the outcome of legal actions against us, including the current lawsuits described under “Part I, Item 3—Legal Proceedings”;

 

·

the cost of commercialization activities if any of our product candidates are approved for sale, including marketing, sales and distribution costs;

 

·

the cost of manufacturing our product candidates and any products we successfully commercialize; and

 

·

the timing, receipt and amount of sales of, or royalties on, our future products, if any.

Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or drug candidates.

We may seek to sell additional equity or debt securities or obtain additional credit facilities. The sale of additional equity or convertible debt securities may result in additional dilution to our stockholders. If we raise additional funds through the issuance of debt securities or preferred stock or through additional credit facilities, these securities and/or the loans under credit facilities could provide for rights senior to those of our common stock and could contain covenants that would restrict our operations. We will require additional capital beyond our currently forecasted amounts. Additional funds may not be available when we need them, on terms that are acceptable to us, or at all.

We also expect to seek additional funds through arrangements with collaborators, licensees or other third parties. These arrangements would generally require us to relinquish or encumber rights to some of our technologies or drug candidates, and we may not be able to enter into such arrangements on acceptable terms, if at all.

We anticipate that we will require additional funding. If we are unable to obtain such additional funding on a timely basis, whether through payments under existing or future collaborations or license agreement or sales of debt or equity, we may be required to delay, limit, reduce or terminate our clinical trials or development activities for one or more of our product candidates.

 

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We may not be successful in establishing and maintaining strategic partnerships to furth er the development of each of our therapeutic programs. A failure to obtain such partnerships in the near future will have a material adverse effect on our operations and business.

Our success will depend in significant part on our ability to attract and maintain strategic partners and strategic relationships with major biotechnology or pharmaceutical companies to support the development and commercialization of our product candidates. In these partnerships, we would expect our strategic partner to provide substantial funding, as well as significant capabilities in research, development, marketing and sales

We face significant competition in seeking appropriate strategic partners and the negotiation process is time-consuming and complex. Moreover, we may not be successful in our efforts to establish a strategic partnership or other alternative arrangements for any product candidates and programs because our development pipeline may be deemed insufficient, our product candidates and programs may be deemed to be at too early of a stage of development for collaborative effort or third parties may not view our product candidates and programs as having the requisite potential to demonstrate safety and efficacy.

Even if we are successful in our efforts to establish new strategic partnerships, the terms that we agree upon may not be favorable to us and we may not be able to maintain such strategic partnerships if, for example, development or approval of a product candidate is delayed or sales of an approved product are disappointing. Any delay in entering into new strategic partnership agreements related to our product candidates could have an adverse effect on our business or our operating plan, including delaying the development and commercialization of our product candidates.

Moreover, if we fail to establish and maintain additional strategic partnerships related to our product candidates:

 

·

we will have limited resources with which to continue to operate our business and we may not be able to successfully complete any other strategic transactions;

 

·

the development of certain of our product candidates may be terminated or delayed; and

 

·

our cash expenditures related to development of our product candidates would increase significantly and we do not have the cash resources to develop our product candidates on our own.

Risks Related to our Litigation

We and certain of our former officers and present and former directors have been named as defendants in multiple lawsuits that could result in substantial costs and divert management’s attention.

We, and certain of our former officers and directors, were named as defendants in a consolidated class action lawsuit initiated in 2013 that generally alleges that we and those individuals violated federal securities laws by making allegedly false and/or misleading statements concerning the development of our drug tivozanib and its prospects for FDA approval.  The lawsuit seeks unspecified damages, interest, attorneys’ fees, and other costs. The consolidated amended complaint was dismissed without prejudice on March 20, 2015, and the lead plaintiffs then filed a second amended complaint bringing similar allegations. This second amended complaint was dismissed with prejudice on November 18, 2015.  The lead plaintiffs have appealed the court’s decision to the United States Court of Appeals for the First Circuit and have also filed a motion to vacate and reconsider the district court’s judgment, which we have opposed.  Another plaintiff has also filed a derivative complaint, allegedly on our behalf, naming us as a nominal defendant and also naming as defendants present and former members of our board of directors, alleging breach of fiduciary duty and abuse of control on the part of those directors with respect to the same statements at issue in the securities litigation.  The derivative complaint seeks, among other relief, unspecified damages, costs and expenses, including attorneys’ fees, an order requiring us to implement certain corporate governance reforms, restitution from the defendants and such other relief as the court might find just and proper. The derivative complaint was dismissed with prejudice on March 18, 2015.  The plaintiff has appealed the court’s decision to the United States Court of Appeals for the First Circuit.

We intend to continue to deny these allegations and to engage in a vigorous defense of these lawsuits. However, we are unable to predict the outcome of these matters at this time. Moreover, any conclusion of these matters in a manner adverse to us could have a material adverse effect on our financial condition and business. For example, we could incur substantial costs not covered by our liability insurance, suffer a significant adverse impact on our reputation and divert management’s attention and resources from other priorities, including the execution of business plans and strategies that are important to our ability to grow our business, any of which could have a material adverse effect on our business. In addition, any of these matters could require payments that are not covered by, or exceed the limits of, our available liability insurance, which could have a material adverse effect on our operating results or financial condition.

We have concluded a settlement with the SEC, but the SEC is still pursuing an action against our former officers.

 

46


   We have agreed to pay $4 million to settle a lawsuit filed by the SEC in federal court alleging that we violated federal securities laws by omitting to disclose the recommendation of the staff of the U.S. Food and Drug Admi nistration, on May 11, 2012, that we conduct an additional clinical trial with respect to tivozanib .  See “Part II, Item 1 – Legal Proceedings” for a further discussion of these claims. The SEC also named three of our former officers as defendants in the s ame lawsuit, and those claims are still pending.  We are not a party to, nor are we involved in any litigation or discussions between the SEC and the former officers. However, those individuals may seek advancement of legal expenses or indemnification for any losses, either of which could be material to the extent not covered by our director and officer liability insurance.   

Risks Related to Development and Commercialization of Our Drug Candidates

 

In the near term, we are dependent on the success of tivo zanib . If we are unable to initiate or complete the clinical development of, obtain marketing approval for or successfully commercialize tivozanib, either alone or with our collaborators, or if we experience significant delays in doing so, our business could be substantially harmed.

We currently have no products approved for sale and are investing a significant portion of our efforts and financial resources in the development of tivozanib. Our prospects are substantially dependent on our ability, or that of our collaborators, to develop, obtain marketing approval for and successfully commercialize tivozanib in one or more disease indications.

The success of tivozanib will depend on several factors, including the following:

 

·

our ability to secure the substantial additional working capital required to initiate and conduct our planned clinical trials of tivozanib, including the planned TIVO-3 trial and the phase 1/2 PD-1 combination trial in RCC;

 

·

initiation and successful enrollment and completion of clinical trials;

 

·

a safety, tolerability and efficacy profile that is satisfactory to the U.S. Food and Drug Administration, or FDA, or any comparable foreign regulatory authority for marketing approval;

 

·

timely receipt of marketing approvals from applicable re gulatory authorities;

 

·

the performance of our collaborators;

 

·

the extent of any required post‑marketing approval commitments to applicable regulatory authorities;

 

·

establishment of supply arrangements with third‑party raw materials suppliers and manufacturers including with respect to the supply of active pharmaceutical ingredient for tivozanib;

 

·

establishment of arrangements with third‑party manufacturers to obtain finished drug product that is appropriately packaged for sale;

 

·

adequate ongoing availability of raw materials and drug product for clinical development and any commercial sales;

 

·

obtaining and maintaining patent, trade secret protection and regulatory exclusivity, both in the United States and internationally, including our ability to maintain our license agreement with Kyowa Hakko Kirin Co., Ltd.;

 

·

protection of our rights in our intellectual property portfolio;

 

·

successful launch of commercial sales following any marketing approval;

 

·

a continued acceptable safety profile following any marketing approval;

 

·

commercial acceptance by patients, the medical community and third‑party payors;

 

·

successful identification of biomarkers for patient selection; and

 

·

our ability to compete with other therapies.

Many of these factors are beyond our control, including clinical development, the regulatory submission process, potential threats to our intellectual property rights and the manufacturing, marketing and sales efforts of our collaborators. If we are unable to develop, receive marketing approval for and successfully commercialize tivozanib on our own or with our collaborators, or experience delays as a result of any of these factors or otherwise, our business could be substantially harmed.

 

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If clinical trials of any product candidates that we , or any collaborators, may develop fail to satisfactorily demonstrate safety and efficacy to the FDA and other regulators, we, or any collaborators, may incur additional costs or experience delays in completing, or ultimately be unable to complete, the develop ment and commercialization of these product candidates .

We, and any collaborators, are not permitted to commercialize, market, promote or sell any product candidate in the United States without obtaining marketing approval from the FDA. Foreign regulatory authorities, such as the European Medicines Agency, or the EMA, impose similar requirements. We, and any collaborators, must complete extensive preclinical development and clinical trials to demonstrate the safety and efficacy of our product candidates in humans before we will be able to obtain these approvals.

Clinical testing is expensive, is difficult to design and implement, can take many years to complete and is inherently uncertain as to outcome. We cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all. The clinical development of our product candidates is susceptible to the risk of failure inherent at any stage of product development, including failure to demonstrate efficacy in a clinical trial or across a broad population of patients, the occurrence of adverse events that are severe or medically or commercially unacceptable, failure to comply with protocols or applicable regulatory requirements and determination by the FDA or any comparable foreign regulatory authority that a product candidate may not continue development or is not approvable.  It is possible that even if one or more of our product candidates has a beneficial effect, that effect will not be detected during clinical evaluation as a r esult of one or more of a variety of factors, including the size, duration, design, measurements, conduct or analysis of our clinical trials. Conversely, as a result of the same factors, our clinical trials may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any. Similarly, in our clinical trials we may fail to detect toxicity of or intolerability caused by our product candidates, or mistakenly believe that our product candidates are toxic or not well tolerated when that is not in fact the case.

Any inability to successfully complete preclinical and clinical development could result in additional costs to us, or any collaborators, and impair our ability to generate revenues from product sales, regulatory and commercialization milestones and royalties. Moreover, if we, or any collaborators, are required to conduct additional clinical trials or other testing of our product candidates beyond the trials and testing that we or they contemplate, if we, or they, are unable to successfully complete clinical trials of our product candidates or other testing, or the results of these trials or tests are unfavorable, uncertain or are only modestly favorable, or there are unacceptable safety concerns associated with our product candidates, we, or any collaborators, may:

 

·

incur additional unplanned costs;

 

·

be delayed in obtaining marketing approval for our product candidates;

 

·

not obtain marketing approval at all;

 

·

obtain approval for indications or patient populations that are not as broad as intended or desired;

 

·

obtain approval with labeling that includes significant use or distribution restrictions or significant safety warnings, including boxed warnings;

 

·

be subject to additional post‑marketing testing or other requirements ; or

 

·

be required to remove the product from the market after obtaining marketing approval.

Our failure to successfully initiate and complete clinical trials of our product candidates and to demonstrate the efficacy and safety necessary to obtain regulatory approval to market any of our product candidates would significantly harm our business.

Adverse events or undesirable side effects caused by, or other unexpected properties of, tivozanib or any future product candidates that we develop may be identified during development and could delay or prevent their marketing approval or limit their use.

Adverse events or undesirable side effects caused by, or other unexpected properties of, tivozanib or any future product candidates that we may develop could cause us, any collaborators, an institutional review board or regulatory authorities to interrupt, delay or halt clinical trials of one or more of our product candidates and could result in a more restrictive label or the delay or denial of marketing approval by the FDA or comparable foreign regulatory authorities.  If any of our product candidates is associated with adverse events or undesirable side effects or has properties that are unexpected, we, or any collaborators, may need to abandon development or limit development of that product candidate to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk‑benefit perspective. Many compounds that initially showed promise in clinical or earlier stage testing have later been found to cause undesirable or unexpected side effects that prevented further development of the compound.

 

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If we, or any collaborators, experience any of a number of possible unforeseen e vents in connection with clinical trials of our current or any future product candidates that we, or any collaborators, may develop, potential clinical development, marketing approval or commercialization of our product candidates could be delayed or preve nted.

We, or any collaborators, may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent clinical development, marketing approval or commercialization of our current product candidates or any future product candidates that we, or any collaborators, may develop, including:

 

·

regulators or institutional review boards may not authorize us, any collaborators or our or their investigators to commence a clinical trial or conduct a clinical trial at a prospect ive trial site;

 

·

we, or any collaborators, may have delays in reaching or fail to reach agreement on acceptable clinical trial contracts or clinical trial protocols with prospective trial sites;

 

·

clinical trials of our product candidates may produce unfavorable or inconclusive results;

 

·

we, or any collaborators, may decide, or regulators may require us or them, to conduct additional clinical trials or abandon product development programs;

 

·

the number of patients required for clinical trials of our product candi dates may be larger than we, or any collaborators, anticipate, patient enrollment in these clinical trials may be slower than we, or any collaborators, anticipate or participants may drop out of these clinical trials at a higher rate than we, or any collaborators, anticipate;

 

·

the cost of planned clinical trials of our product candidates may be greater than we anticipate;

 

·

our third ‑party contractors or those of any collaborators, including those manufacturing our product candidates or components or ingredients thereof or conducting clinical trials on our behalf or on behalf of any collaborators, may fail to comply with regulatory requirements or meet their contractual obligations to us or any collaborators in a timely manner or at all;

 

·

patients that enroll in a clinical trial may misrepresent their eligibility to do so or may otherwise not comply with the clinical trial protocol, resulting in the need to drop the patients from the clinical trial, increase the needed enrollment size for the clinical trial or extend the clinical trial’s duration;

 

·

we, or any collaborators, may have to delay, suspend or terminate clinical trials of our product candidates for various reasons, including a finding that the participants are being exposed to unacceptable health risks, undesirable side effects or other unexpected characteristics of the product candidate;

 

·

regulators or institutional review boards may require that we, or any collaborators, or our or their investigators suspend or terminate clinical research for various reas ons, including noncompliance with regulatory requirements or their standards of conduct, a finding that the participants are being exposed to unacceptable health risks, undesirable side effects or other unexpected characteristics of the product candidate or findings of undesirable effects caused by a chemically or mechanistically similar product or product candidate;

 

·

the FDA or comparable foreign regulatory authorities may disagree with our, or any collaborators’, clinical trial designs or our or their interpretation of data from preclinical studies and clinical trials;

 

·

the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault with the manufacturing processes or facilities of third‑party manufacturers with which we, or any collaborators, enter into agreements for clinical and commercial supplies;

 

·

the supply or quality of raw materials or manufactured product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient, inadequate or not available at an acceptable cost, or we may experience interruptions in supply; and

 

·

the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient to obtain marketing approval.

Product development costs for us, or any collaborators, will increase if we, or they, experience delays in testing or pursuing marketing approvals and we, or they, may be required to obtain additional funds to complete clinical trials and prepare for possible commercialization. We do not know whether any trials will begin as planned, will need to be restructured, or will be completed on schedule or at all. Significant clinical trial delays also could shorten any periods during which we, or any collaborators, may have the exclusive right to commercialize our product candidates or allow our competitors, or the competitors of any collaborators, to bring products to market before we, or any collaborators, do and impair our ability, or the ability of any collaborators, to successfully commercialize our product candidates and may harm our business and results of operations. In addition, many of the factors that lead to clinical trial delays may ultimately lead to the denial of marketing approval of any of our product candidates.

 

49


If we, or any collaborators, experience delays or difficulties in the enrollment of patients in clinical trials, our or their receipt of necessary regulatory approvals could be delayed or prevented.

We, or any collaborators, may not be able to initiate or continue clinical trials for our current product candidates or any future product candidates that we, or any collaborators, may develop if we, or they, are unable to locate and enroll a sufficient number of eligible patients to participate in clinical trials. Patient enrollment is a significant factor in the timing of clinical trials, and is affected by many factors, including:

 

·

the size and nature of the patient population;

 

·

the severity of the disease under investigation;

 

·

the availability of approved therapeutics for the relevant disease;

 

·

the proximity of patients to clinical sites;

 

·

the eligibility criteria for the trial;

 

·

the design of the clinical trial;

 

·

efforts to facilitate timely enrollment;

 

·

competing clinical trials; and

 

·

clinicians’ and patients’ perceptions as to the potential advantages and risks of the drug being studied in relation to other available therapies, including any new drugs that may be approved for the indications we are investigating.

Our inability, or the inability of any collaborators, to enroll a sufficient number of patients for our, or their, clinical trials could result in significant delays or may require us or them to abandon one or more clinical trials altogether. Enrollment delays in our, or their, clinical trials may result in increased development costs for our product candidates, delay or halt the development of and approval processes for our product candidates and jeopardize our, or any collaborators’, abili ty to commence sales of and generate revenues from our product candidates, which could cause the value of our company to decline and limit our ability to obtain additional financing, if needed.

Results of early clinical trials may not be predictive of results of future late‑stage clinical trials.

The outcome of early clinical trials may not be predictive of the success of later clinical trials, and interim results of clinical trials do not necessarily predict success in future clinical trials. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late‑stage clinical trials after achieving positive results in earlier development, and we have and could, in the future, face similar setbacks. For example, in June 2013, the FDA issued a response letter informing us that it would not approve tivozanib for the treatment of first-line advanced renal cell carcinoma based on the study data from our initial Phase 3 trial, and recommended that we perform an additional study that is adequately sized to assure the FDA that there is no adverse effect on overall survival. The design of a clinical trial can determine whether its results will support approval of a product and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. We have limited experience in designing clinical trials and may be unable to design and execute a clinical trial to support marketing approval. In addition, preclinical and clinical data are often susceptible to varying interpretations and analyses. Many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval for the product candidates. Even if we, or any collaborators, believe that the results of clinical trials for our product candidates warrant marketing approval, the FDA or comparable foreign regulatory authorities may disagree and may not grant marketing approval of our product candidates.

In some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors, including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the dosing regimen and other clinical trial protocols and the rate of dropout among clinical trial participants. If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most advanced product candidates, and, correspondingly, our business and financial prospects would be negatively impacted.

We have never obtained marke ting approval for a product candidate and we may be unable to obtain, or may be delayed in obtaining, marketing approval for our current product candidates or any future product candidates that we, or any collaborators, may develop.

We have never obtained marketing approval for a product candidate. It is possible that the FDA may refuse to accept for substantive review any new drug applications, or NDAs, that we submit for our product candidates or may conclude after review of

 

50


our data that our application is insufficient to obtain marketing approval of our product candidate. If the FDA does not accept or approve NDAs for any of our product candidates, it may require that we conduct additional clinical trials, preclinical studies or manufacturing validation studies and submit that data before it will reconsider our applications. Depending on the extent of these or any other FDA ‑required trials or studies, approval of any NDA or application that we submit may be delayed by several years, or may require us to e xpend more resources than we have available. It is also possible that additional trials or studies, if performed and completed, may not be considered sufficient by the FDA to approve our NDAs. Any delay in obtaining, or an inability to obtain, marketing ap provals would prevent us from commercializing our product candidates or any companion diagnostics, generating revenues and achieving and sustaining profitability. If any of these outcomes occurs, we may be forced to abandon our development efforts for our product candidates, which could significantly harm our business.

Even if any product candidates that we, or any collaborators, may develop receive marketing approval, we or others may later discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, which could compromise our ability, or that of any collaborators, to market the product.

Clinical trials of any product candidates that we, or any collaborators, may develop will be conducted in carefully defined subsets of patients who have agreed to enter into clinical trials. Consequently, it is possible that our clinical trials, or those of any collaborator, may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any, or alternatively fail to identify undesirable side effects. If, following approval of a product candidate, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur:

 

·

regulatory authorities may withdraw their approval of the product or seize the product;

 

·

we, or any collaborators, may be required to recall the product, change the way the product is administered or conduct additional clinical trials;

 

·

additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular product;

 

·

we may be subject to fines, injunctions or the imposition of civil or criminal penalties;

 

·

regulatory authorities may require the addition of labeling statements, such as a “black box” warning or a contraindication;

 

·

we, or any collaborators, may be required to create a Medication Guide outlining the risks of the previously unidentified side effects for distribution to patients;

 

·

we, or any collaborators, could be sued and held liable for harm caused to patients;

 

·

the product may become less competitive; and

 

·

our reputation may suffer.

Any of these events could harm our business and operations, and could negatively impact our stock price.

Even if our current product candidates, or any future product candidates that we, or any collaborators, may develop receives marketing approval, it may fail to achieve the degree of market acceptance by physicians, patients, third‑party payors and others in the medical community necessary for commercial success, in which case we may not generate significant revenues or become profitable.

We have never commercialized a product, and even if one of our product candidates is approved by the appropriate regulatory authorities for marketing and sale, it may nonetheless fail to gain sufficient market acceptance by physicians, patients, third‑party payors and others in the medical community. Physicians are often reluctant to switch their patients from existing therapies even when new and potentially more effective or convenient treatments enter the market. Further, patients often acclimate to the therapy that they are currently taking and do not want to switch unless their physicians recommend switching products or they are required to switch therapies due to lack of reimbursement for existing therapies.

Efforts to educate the medical community and third‑party payors on the benefits of our product candidates may require significant resources and may not be successful. If any of our product candidates is approved but does not achieve an adequate level of market acceptance, we may not generate significant revenues and we may not become profitab le. The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on a number of factors, including:

 

·

the efficacy and safety of the product;

 

·

the potential advantages of the product compared to competitive therapies;

 

51


 

·

the prevalence and severity of any side effects;

 

·

whether the product is designated under physician treatment guidelines as a first‑, second‑ or third‑line therapy;

 

·

our ability, or the ability of any collaborators, to offer the product for sale at competitive prices;

 

·

the product’s convenience and ease of administration compared to alternative treatments;

 

·

the willingness of the target patient population to try, and of physicians to prescribe, the product;

 

·

limitations or warnings, including distribution or use restrictions, contained in the product’s approved labeling;

 

·

the strength of sales, marketing and distribution support;

 

·

changes in the standard of care for the targeted indications for the product; and

 

·

availability and amount of coverage and reimbursement from government payors, managed care plans and other third‑party payors.

If we are unable to establish sales, marketing and distribution capabilities or enter into sales, marketing and distribution arrangements with third parties, we may not be successful in commercializing any product candidates if approved.

We do not have a sales, marketing or distribution infrastructure and have no experience in the sale, marketing or distribution of pharmaceutical products. To achieve commercial success for any approved product, we must either develop a sales and marketing organization or outsource these functions to third parties. We plan to build focused capabilities to commercialize development programs for certain indications where we believe that the medical specialists for the indications are sufficiently concentrated to allow us to effectively promote the product with a targeted sales team. The development of sales, marketing and distribution capabilities will require substantial resources, will be time consuming and could delay any product launch. If the commercial launch of a product candidate for which we recruit a sales force and establish marketing and distribution capabilities is delayed or does not occur for any reason, we could have prematurely or unnecessarily incurred these commercialization costs. This may be costly, and our investment could be lost if we cannot retain or reposition our sales and marketing personnel. In addition, we may not be able to hire or retain a sales force in the United States that is sufficient in size or has adequate expertise in the medical markets that we plan to target. If we are unable to establish or retain a sales force and marketing and distribution capabilities, our operating results may be adversely affected. If a potential partner has development or commercialization expertise that we believe is particularly relevant to one of our products, then we may seek to collaborate with that potential partner even if we believe we could otherwise develop and commercialize the product independently.

In certain indications, we seek to enter into collaborations that we believe may contribute to our ability to advance development and ultimately commercialize our product candidates. We also seek to enter into collaborations where we believe that realizing the full commercial value of our development programs will require access to broader geographic markets or the pursuit of broader patient populations or indications. As a result of entering into arrangements with third parties to perform sales, marketing and distribution services, our product revenues or the profitability of these product revenues may be lower, perhaps substantially lower, than if we were to directly market and sell products in those markets. Furthermore, we may be unsuccessful in entering into the necessary arrangements with third parties or may be unable to do so on terms that are favorable to us. In addition, we may have little or no control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our products effectively.

If we do not establish sales, marketing and distribution capabilities, either on our own or in collaboration with third parties, we will not be successful in commercializing any of our product candidates that receive marketing approval.

If we are unable to successfully develop companion diagnostics for certain of our therapeutic product candidates, or experience significant delays in doing so, we may not realize the full commercial potential of these therapeutics.

 

A component of our business strategy may be to develop, in collaboration with a third party, companion diagnostics for some of our therapeutic product candidates. There has been limited success to date industry-wide in developing companion diagnostics. To be successful, our collaborator will need to address a number of scientific, technical, regulatory and logistical challenges. We have limited experience in the development of diagnostics and may not be successful in developing appropriate diagnostics to pair with any

of our therapeutic product candidates. The FDA and similar regulatory authorities outside the United States are generally expected to regulate companion diagnostics as medical devices. In each case, companion diagnostics require separate regulatory approval prior to commercialization. For example, BDX004, our companion diagnostic test for ficlatuzumab in our FOCAL study, requires separate approval by the FDA, for which we must rely on Biodesix to obtain. In addition, we require a commercializable companion diagnostic assay to identify patients with low NRP-1 in order to proceed with the development of tivozanib in CRC.  We expect to rely in part on third parties for the design, development and manufacture of any companion diagnostic. If we, or any third parties that we engage to

 

52


assist us, are unable to successfully develop companion diagnostics for our therapeutic product candidates, or experience delays in doing so, the development of our therapeutic product candi dates may be adversely affected, our therapeutic product candidates may not receive marketing approval and we may not realize the full commercial potential of any therapeutics that receive marketing approval. As a result, our business would be harmed, poss ibly materially.

We face substantial competition from existing approved products.  Our competitors may also discover, develop or commercialize new competing products before, or more successfully, than we do.

The biotechnology and pharmaceutical industries are highly competitive. Our future success depends on our ability to demonstrate and maintain a competitive advantage with respect to the design, development and commercialization of product candidates. Our objective is to design, develop and commercialize new products with superior efficacy, convenience, tolerability and safety. We expect any product candidate that we commercialize with our strategic partners will compete with existing, market-leading products.

 

There are many pharmaceutical companies, biotechnology companies, public and private universities and research organizations actively engaged in the research and development of products that may be similar to our products. A number of multinational pharmaceutical companies, as well as large biotechnology companies, including, but not limited to, Roche Laboratories, Inc., Pfizer Inc., Bayer HealthCare AG, Amgen, Inc., Eli Lilly and Company, GlaxoSmithKline plc, GTx, Inc., Helsinn and XBiotech, Novartis, Bristol-Myers Squibb, Merck, Merrimack Pharmaceuticals, Inc., Arqule, Inc., Exelixis, Inc., Easai Co., Ltd., AstraZeneca, Gilead Sciences, Inc., Actelion Pharmaceuticals Ltd. and United Therapeutics Corporation are pursuing the development or are currently marketing pharmaceuticals that target VEGF, HGF, ErbB3, Notch 3 or other pathways on which we may focus, as well as cachexia. It is probable that the number of companies seeking to develop competing products and therapies will increase.

Many of our competitors, either alone or with their strategic partners, have greater financial, technical and human resources than we do and greater experience in the discovery and development of product candidates, obtaining FDA and other regulatory approvals of products, and the commercialization of those products.  Many are already marketing products to treat the same indications, and having the same biological targets, as the product candidates we are developing, including with respect to renal cell carcinoma. In addition, many of these competitors have significantly greater commercial infrastructures than we have. We will not be able to compete successfully unless we effectively:

 

·

design and develop products that are superior to other products in the market in terms of, among other things, both safety and efficacy;

 

·

obtain patent and/or other proprietary protection for our processes and product candidates;

 

·

obtain required regulatory approvals;

 

·

obtain favorable reimbursement, formulary and guideline status; and

 

·

collaborate with others in the design, development and commercialization of new products.

 

Established competitors may invest heavily to quickly discover and develop novel compounds that could make our product candidates obsolete. In addition, any new product that competes with an approved product must demonstrate compelling advantages in efficacy, convenience, tolerability and safety in order to obtain approval, to overcome price competition and to be commercially successful. If we are not able to compete effectively against our current and future competitors, our business will not grow and our financial condition and operations will suffer.  

There are currently 11 FDA-approved drugs in oncology which, like tivozanib, target the VEGF pathway as a part or all of their inhibitory mechanism. Eight of the FDA-approved VEGF pathway inhibitors are oral small molecule receptor tyrosine kinase inhibitors, or TKIs. Many of the approved VEGF pathway inhibitor agents are in ongoing development in additional cancer indications including RCC. Additionally, we are aware of a number of companies that have ongoing programs to develop both small molecules and biologics that target the VEGF pathway.  In addition, the emergence of PD1/PDL1 inhibitor therapies present additional competition for tivozanib in advanced RCC. Additional clinical trials for mono and combination therapies of PD1/PDL1 with VEGF TKIs are in the pipeline targeting RCC.

We believe the products that are considered competitive with ficlatuzumab include those agents targeting the HGF/c-Met pathway.  We believe the most direct competitors to our AV-203 program are monoclonal antibodies that specifically target the ErbB3 receptor.  There are also other agents that target ErbB3 as a part or all of their inhibitory mechanism.  Only a limited number of agents have been approved for the treatment or prevention of cachexia caused by any disease. However, a number of agents with different mechanisms of action have completed or are currently being studied in phase 2 trials in cachexia or muscle wasting.  There are no currently approved Notch 3 inhibitors, although there is at least one Notch 3 inhibitor currently in clinical trials.  There are multiple treatments approved for PAH through various mechanisms.  

 

53


Even if we, or any c ollaborators, are able to commercialize any product candidate that we, or they, develop, the product may become subject to unfavorable pricing regulations, third ‑party payor reimbursement practices or healthcare reform initiatives, any of which could harm our business.

The commercial success of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by third‑party payors, including government health care programs and private health insurers. If coverage is not available, or reimbursement is limited, we, or any collaborators, may not be able to successfully commercialize our product candidates. Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us, or any collaborators, to establish or maintain pricing sufficient to realize a sufficient return on our or their investments. In the United States, no uniform policy of coverage and reimbursement for products exists among third‑party payors and coverage and reimbursement levels for products can differ significantly from payor to payor. As a result, the coverage determination process is often a time consuming and costly process that may require us to provide scientific and clinic al support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

There is significant uncertainty related to third‑party payor coverage and reimbursement of newly approved drugs. Marketing approvals, pricing and reimbursement for new drug products vary widely from country to country. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a result, we, or any collaborators, might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay commercial launch of the product, possibly for lengthy time periods, which may negatively impact the revenues we are able to generate from the sale of the product in that country. Adverse pricing limitations may hinder our ability or the ability of any collaborators to recoup our or their investment in one or more product candidates, even if our product candidates obtain marketing approval.

Patients who are provided medical treatment for their conditions generally rely on third‑party payors to reimburse all or part of the costs associated with their treatment. Therefore, our ability, and the ability of any col laborators, to commercialize successfully any of our product candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from third‑party payors. Third‑party payors decide which medications they will cover and establish reimbursement levels. The healthcare industry is acutely focused on cost containment, both in the United States and elsewhere. Government authorities and other third‑party payors have attempted to contr ol costs by limiting coverage and the amount of reimbursement for particular medications, which could affect our ability or that of any collaborators to sell our product candidates profitably. These payors may not view our products, if any, as cost‑effecti ve, and coverage and reimbursement may not be available to our customers, or those of any collaborators, or may not be sufficient to allow our products, if any, to be marketed on a competitive basis. Cost‑control initiatives could cause us, or any collaborators, to decrease the price we, or they, might establish for products, which could result in lower than anticipated product revenues. If the prices for our products, if any, decrease or if governmental and other third‑party payors do not provide coverage or adequate reimbursement, our prospects for revenue and profitability will suffer.

There may also be delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the indications for which the drug is appro ved by the FDA or comparable foreign regulatory authorities. Moreover, eligibility for reimbursement does not imply that any drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution. Reimbursement rates may vary, by way of example, according to the use of the product and the clinical setting in which it is used. Reimbursement rates may also be based on reimbursement levels already set for lower cost drugs or may be incorporated into existing payments for other services.

In addition, increasingly, third‑party payors are requiring higher levels of evidence of the benefits and clinical outcomes of new technologies and are challenging the prices charged. Further, the net reimbursement for drug products may be subject to additional reductions if there are changes to laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States. An inability to promptly obtain coverage and adequate payment rates from both government ‑funded and private payors for any of our product candidates for which we, or any collaborator, obtain marketing approval could significantly harm our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.

If product liability lawsuits are brought against us, we may incur substantial liabilities and may be required to limit commercialization of our product candidates.

We face an inherent risk of product liability as a result of the clinical testing of our product candidates and will face an even greater risk if we commercialize any products. For example, we may be sued if any product we develop allegedly causes injury or is found to be otherwise unsuitable during product testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability, and a breach of warranties. Claims could also be asserted under state consumer protection acts. If we cannot

 

54


successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit commercializati on of our product candidates. Even successful defense could require significant financial and management resources. Regardless of the merits or eventual outcome, product liability claims may result in:

 

·

decreased demand for our product candidates or products that we may develop;

 

·

injury to our reputation;

 

·

withdrawal of clinical trial participants;

 

·

costs to defend the related litigation;

 

·

diversion of management’s time and our resources;

 

·

substantial monetary awards to trial participants or patients;

 

·

product recalls, withdrawals or labeling, marketing or promotional restrictions;

 

·

loss of revenue;

 

·

the inability to commercialize our product candidates; and

 

·

a decline in our stock price.

Our inability to obtain and retain sufficient product liability insurance at an acceptable cost to protect against potential product liability claims could prevent or inhibit the commercialization of products we develop. We currently carry product liability insurance covering our clinical studies in the amount of $20 million in the aggregate. Although we maintain such insurance, any claim that may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in part, by our insurance or that is in excess of the limits of our insurance coverage. Our insurance policies also have various exclusions, and we may be subject to a product liability claim for which we have no coverage. We will have to pay any amounts awarded by a court or negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts.

R isks Related to Our Dependence on Third Parties

We rely on third parties, such as clinical research organizations, or CROs, to conduct clinical trials for our product candidates, and if they do not properly and successfully perform their obligations to us, we may not be able to obtain regulatory approvals for our product candidates.

We, in consultation with our collaborators , where applicable, design the clinical trials for our product candidates, but we have relied, and will rely, on contract research organizations and other third parties to assist us in managing, monitoring and otherwise carrying out many of these trials. W e compete with larger companies for the resources of these third parties.

Although we plan to continue to rely on these third parties to conduct our ongoing any future clinical trials, we are responsible for ensuring that each of our clinical trials is conducted in accordance with its general investigational plan and protocol. Moreover, the FDA and foreign regulatory agencies require us to comply with regulations and standards, commonly referred to as good clinical practices, for designing, conducting, monitoring, recording, analyzing, and reporting the results of clinical trials to assure that the data and results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected. Our reliance on third parties that we do not control does not relieve us of these responsibilities and requirements.

The third parties on whom we rely generally may terminate their engagements with us at any time. If we are required to enter into alternative arrangements because of any such termination, the introduction of our product candidates to market could be delayed.

If these third parties do not successfully carry out their duties under their agreements with us, if the quality or accuracy of the data they obtain is compromised due to their failure to adhere to our clinical trial protocols or regulatory requirements, or if they otherwise fail to comply with clinical trial protocols or meet expected deadlines, our clinical trials may not meet regulatory requirements. If our clinical trials do not meet regulatory requirements or if these third parties need to be replaced, our preclinical development activities or clinical trials may be extended, delayed, suspended or terminated. If any of these events occur, we may not be able to obtain regulatory approval of our product candidates and our reputation could be harmed.

 

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We rely on third-party manufacturers to produce our preclinical and clinical product candidate supplies and we intend to rely on third parties to produce commercial supplie s of any approved product candidates. Any failure by a third-party manufacturer to produce supplies for us may delay or impair our ability to complete our clinical trials or commercialize our product candidates.

We do not possess all of the capabilities to fully commercialize any of our product candidates on our own. We have relied upon third-party manufacturers for the manufacture of our product candidates for preclinical and clinical testing purposes and intend to continue to do so in the future. If we are unable to arrange for third-party manufacturing sources, or to do so on commercially reasonable terms, we may not be able to complete development of such other product candidates or market them.

Reliance on third-party manufacturers entails risks to which we would not be subject if we manufactured product candidates ourselves, including reliance on the third party for regulatory compliance and quality assurance, the possibility of breach of the manufacturing agreement by the third party because of factors beyond our control (including a failure to synthesize and manufacture our product candidates in accordance with our product specifications), failure of the third party to accept orders for supply of drug substance or drug product and the possibility of termination or nonrenewal of the agreement by the third-party, based on its own business priorities, at a time that is costly or damaging to us. In addition, the FDA and other regulatory authorities require that our product candidates be manufactured according to cGMP and similar foreign standards. Any failure by our third-party manufacturers to comply with cGMP or failure to scale-up manufacturing processes as needed, including any failure to deliver sufficient quantities of product candidates in a timely manner, could lead to a delay in, or failure to obtain, regulatory approval of any of our product candidates. In addition, such failure could be the basis for action by the FDA to withdraw approvals for product candidates previously granted to us and for other regulatory action, including recall or seizure, fines, imposition of operating restrictions, total or partial suspension of production or injunctions.

We rely on our manufacturers to purchase from third-party suppliers the materials necessary to produce our product candidates for our clinical studies. There are a small number of suppliers for certain capital equipment and raw materials that we use to manufacture our product candidates. Such suppliers may not sell this capital equipment or these raw materials to our manufacturers at the times we need them or on commercially reasonable terms. We do not have any control over the process or timing of the acquisition of this capital equipment or these raw materials by our manufacturers. Moreover, we currently do not have any agreements for the commercial production of these raw materials. Any significant delay in the supply of a product candidate or the raw material components thereof for an ongoing clinical trial due to the need to replace a third-party manufacturer could considerably delay completion of our clinical studies, product testing and potential regulatory approval of our product candidates. If our manufacturers or we are unable to purchase these raw materials after regulatory approval has been obtained for our product candidates, the commercial launch of our product candidates would be delayed or there would be a shortage in supply, which would impair our ability to generate revenues from the sale of our product candidates.

Because of the complex nature of many of our early stage compounds and product candidates, our manufacturers may not be able to manufacture such compounds and product candidates at a cost or in quantities or in a timely manner necessary to develop and commercialize related products. If we successfully commercialize any of our drugs, we may be required to establish or access large-scale commercial manufacturing capabilities. In addition, as our drug development pipeline increases and matures, we will have a greater need for clinical trial and commercial manufacturing capacity. We do not own or operate manufacturing facilities for the production of clinical or commercial quantities of our product candidates and we currently have no plans to build our own clinical or commercial scale manufacturing capabilities. To meet our projected needs for commercial manufacturing in the event that one or more of our product candidates gains marketing approval, third parties with whom we currently work will need to increase their scale of production or we will need to secure alternate suppliers.

If any of our current or future strategic partners fails to perform its obligations or terminates its agreement with us, the development and commercialization of the product candidates under such agreement could be delayed or terminated and our business could be substantially harmed.

As part of our business strategy, we have entered into strategic partnerships for each of our development programs, and we plan to enter into additional strategic partnerships in the future. If any current or future strategic partners do not devote sufficient time and resources to its arrangements with us, we may not realize the potential commercial benefits of the arrangement, and our results of operations may be adversely affected. In addition, if any strategic partner were to breach or terminate its arrangements with us, the development and commercialization of the affected product candidate could be delayed, curtailed or terminated because we may not have sufficient financial resources or capabilities to continue development and commercialization of the product candidate on its own, and we may find it difficult to attract a new alliance partner for such product candidate. For example, Biodesix can opt-out of its agreement with us after the completion of the proof of concept trial prior to the first commercial sale of ficlatuzumab, at which point Biodesix would not be responsible for any future costs associated with developing and commercializing ficlatuzumab other than any ongoing clinical studies.

 

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Much of the potential revenue from any of our strategic partnerships will likely consist of contingent payments, such as royalties payable on sales of any successfully developed drugs. Any such contingent revenue will depend upon our, and o ur strategic partners’, ability to successfully develop, introduce, market and sell new drugs. In some cases, we are not involved in these processes, and we depend entirely on our strategic partners. Any of our strategic partners may fail to develop or eff ectively commercialize these drugs because it:

 

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decides not to devote the necessary resources because of internal constraints, such as limited personnel with the requisite scientific expertise, limited cash resources or specialized equipment limitations, or the belief that other product candidates may have a higher likelihood of obtaining regulatory approval or may potentially generate a greater return on investment;

 

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does not have sufficient resources necessary to carry the product candidate through clinical development, regulatory approval and commercialization; or

 

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cannot obtain the necessary regulatory approvals.

For example, Pharmstandard has recently informed us that, based on adverse economic and financial conditions in Russia, they are seeking to renegotiate their obligation to make milestone payments to us under their license agreement with us. If one or more of our strategic partners fails to develop or effectively commercialize product candidates for any of the foregoing reasons, we may not be able to replace the strategic partner with another partner to develop and commercialize a product candidate under the terms of the strategic partnership. We may also be unable to obtain, on terms acceptable to us, a license from such strategic partner to any of its intellectual property that may be necessary or useful for us to continue to develop and commercialize a product candidate. Any of these events could have a material adverse effect on our business, results of operations and our ability to achieve future profitability, and could cause our stock price to decline.

Risks Related to Our Intellectual Property Rights

We could be unsuccessful in obtaining adequate patent protection for one or more of our product candidates, which could result in competition and a decrease in the potential market share for our product candidates.

We cannot be certain that patents will be issued or granted with respect to applications that are currently pending, or that issued or granted patents will not later be found to be invalid and/or unenforceable. The patent position of biotechnology and pharmaceutical companies is generally uncertain because it involves complex legal and factual considerations. The standards applied by the United States Patent and Trademark Office and foreign patent offices in granting patents are not always applied uniformly or predictably. For example, there is no uniform worldwide policy regarding patentable subject matter or the scope of claims allowable in biotechnology and pharmaceutical patents. Consequently, patents may not issue from our pending patent applications. As such, we do not know the degree of future protection that we will have on our proprietary products and technology. The scope of patent protection that the U.S. Patent and Trademark Office will grant with respect to the antibodies in our antibody product pipeline is uncertain. It is possible that the U.S. Patent and Trademark Office will not allow broad antibody claims that cover closely related antibodies as well as the specific antibody. Upon receipt of FDA approval, competitors would be free to market antibodies almost identical to ours, including biosimilar antibodies, thereby decreasing our market share.

Issued patents covering one or more of our products could be found invalid or unenforceable if challenged in patent office proceedings, or in court.

If we or one of our corporate partners were to initiate legal proceedings against a third-party to enforce a patent covering one of our products, the defendant could counterclaim that our patent is invalid and/or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity and/or unenforceability are commonplace. Grounds for a validity challenge could be an alleged failure to meet one or more statutory requirements for patentability, including, for example, lack of novelty, obviousness, lack of written description or non-enablement. In addition, patent validity challenges may, under certain circumstances, be based upon non-statutory obviousness-type double patenting, which, if successful, could result in a finding that the claims are invalid for obviousness-type double patenting or the loss of patent term, including a patent term adjustment granted by the United States Patent and Trademark Officer, if a terminal disclaimer is filed to obviate a finding of obviousness-type double patenting. Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information from the U.S. Patent and Trademark Office, or made a misleading statement, during prosecution. Additionally, third parties are able to challenge the validity of issued patents through administrative proceedings in the patent offices of certain countries, including the United States Patent and Trademark Office and the European Patent Office.  Although we have conducted due diligence on patents we have exclusively in-licensed, and we believe that we have conducted our patent prosecution in accordance with the duty of candor and in good faith, the outcome following legal assertions of invalidity and unenforceability during patent litigation is unpredictable. With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution. If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability,

 

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we would lose at least part, and perhaps all, of the patent protection on one of our products or certain aspects of our Human Response Platform. Such a loss of patent protection could have a material adverse impact on our busin ess.

Claims that our platform technologies, our products or the sale or use of our products infringe the patent rights of third parties could result in costly litigation or could require substantial time and money to resolve, even if litigation is avoided.

We cannot guarantee that our platform technologies, our products, or the use of our products, do not infringe third-party patents. Third parties might allege that we are infringing their patent rights or that we have misappropriated their trade secrets. Such third parties might resort to litigation against us. The basis of such litigation could be existing patents or patents that issue in the future.

It is also possible that we failed to identify relevant third-party patents or applications. For example, applications filed before November 29, 2000 and certain applications filed after that date that will not be filed outside the United States remain confidential until patents issue. Patent applications in the United States and elsewhere are published approximately 18 months after the earliest filing, which is referred to as the priority date. Therefore, patent applications covering our products or platform technology could have been filed by others without our knowledge. Additionally, pending patent applications which have been published can, subject to certain limitations, be later amended in a manner that could cover our platform technologies, our products or the use of our products.

With regard to tivozanib, we are aware of a third-party United States patent, and corresponding foreign counterparts, that contain broad claims related to use of an organic compound, that, among other things, inhibits the tyrosine phosphorylation of a VEGF receptor caused by VEGF binding to such VEGF receptor. We are also aware of third-party United States patents that contain broad claims related to the use of a tyrosine kinase inhibitor in combination with a DNA damaging agent such as chemotherapy or radiation and we have received written notice from the owners of such patents indicating that they believe we may need a license from them in order to avoid infringing their patents. With regard to ficlatuzumab, we are aware of two separate families of United States patents, United States patent applications and foreign counterparts, with each of the two families being owned by a different third-party, that contain broad claims related to anti-HGF antibodies having certain binding properties and their use. With regard to AV-203, we are aware of a third-party United States patent that contains broad claims relating to anti-ErbB3 antibodies. Additionally, we are aware of a United States patent application and foreign counterparts that contains claims to the use of a companion diagnostic in conjunction with AV-203. Based on our analyses, if any of the above third-party patents were asserted against us, we do not believe our proposed products or activities would be found to infringe any valid claim of these patents. If we were to challenge the validity of any issued United States patent in court, we would need to overcome a statutory presumption of validity that attaches to every United States patent. This means that in order to prevail, we would have to present clear and convincing evidence as to the invalidity of the patent’s claims. There is no assurance that a court would find in our favor on questions of infringement or validity.

In order to avoid or settle potential claims with respect to any of the patent rights described above or any other patent rights of third parties, we may choose or be required to seek a license from a third-party and be required to pay license fees or royalties or both. These licenses may not be available on acceptable terms, or at all. Even if we or our strategic partners were able to obtain a license, the rights may be non-exclusive, which could result in our competitors gaining access to the same intellectual property. Ultimately, we could be prevented from commercializing a product, or be forced to cease some aspect of our business operations, if, as a result of actual or threatened patent infringement claims, we are unable to enter into licenses on acceptable terms. This could harm our business significantly.

Defending against claims of patent infringement or misappropriation of trade secrets could be costly and time-consuming, regardless of the outcome. Thus, even if we were to ultimately prevail, or to settle at an early stage, such litigation could burden us with substantial unanticipated costs. In addition, litigation or threatened litigation could result in significant demands on the time and attention of our management team, distracting them from the pursuit of other company business.

Unfavorable outcomes in an intellectual property litigation could limit our research and development activities and/or our ability to commercialize certain products.

If third parties successfully assert intellectual property rights against us, we might be barred from using aspects of our technology platform, or barred from developing and commercializing related products. Prohibitions against using specified technologies, or prohibitions against commercializing specified products, could be imposed by a court or by a settlement agreement between us and a plaintiff. In addition, if we are unsuccessful in defending against allegations of patent infringement or misappropriation of trade secrets, we may be forced to pay substantial damage awards to the plaintiff. There is inevitable uncertainty in any litigation, including intellectual property litigation. There can be no assurance that we would prevail in any intellectual property litigation, even if the case against us is weak or flawed. If litigation leads to an outcome unfavorable to us, we may be required to obtain a license from the patent owner in order to continue our research and development programs or our partnerships or to market our product(s). It is possible that the necessary license will not be available to us on commercially acceptable terms, or at all. This could limit our research and development activities, our ability to commercialize specified products, or both.

 

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Most of our competitors are larger than we are and have substantially greater resources. They are, therefore, likely to be able to sustain the costs of complex patent litigation longer than we could. In addi tion, the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical trials, continue our internal research programs, in-license needed technology, or enter into strate gic partnerships that would help us bring our product candidates to market.

In addition, any future patent litigation, interference or other administrative proceedings will result in additional expense and distraction of our personnel. An adverse outcome in such litigation or proceedings may expose us or our strategic partners to loss of our proprietary position, expose us to significant liabilities, or require us to seek licenses that may not be available on commercially acceptable terms, if at all.

An intellectual property litigation could lead to unfavorable publicity that could harm our reputation and cause the market price of our common stock to decline.

During the course of any patent litigation, there could be public announcements of the results of hearings, rulings on motions, and other interim proceedings in the litigation. If securities analysts or investors regard these announcements as negative, the perceived value of our products, programs, or intellectual property could be diminished. In such event, the market price of our common stock may decline.

AV-380 and tivozanib are protected by patents exclusively licensed from other companies or institutions. If the licensors terminate the licenses or fail to maintain or enforce the underlying patents, our competitive position would be harmed and our partnerships could be terminated.

Certain of our product candidates and out-licensing arrangements depend on patents and/or patent applications owned by other companies or institutions with which we have entered into intellectual property licenses. In particular, we hold exclusive licenses from St. Vincent’s for therapeutic applications that benefit from inhibition or decreased expression or activity of MIC-1, which we refer to as GDF15 and which we used in our AV-380 program, and from KHK for tivozanib. We may enter into additional license agreements as part of the development of our business in the future. Our licensors may not successfully prosecute certain patent applications under which we are licensed and on which our business depends. Even if patents issue from these applications, our licensors may fail to maintain these patents, may decide not to pursue litigation against third-party infringers, may fail to prove infringement, or may fail to defend against counterclaims of patent invalidity or unenforceability. In addition, in spite of our best efforts, a licensor could claim that we have materially breached a license agreement and terminate the license, thereby removing our or our licensees’ ability to obtain regulatory approval for and to market any product covered by such license. If these in-licenses are terminated, or if the underlying patents fail to provide the intended market exclusivity, competitors would have the freedom to seek regulatory approval of, and to market, identical products. In addition, the partners to which we have sublicensed certain rights under these licenses, including Novartis and Pharmstandard, would likely have grounds for terminating our partnerships if these licenses are terminated or the underlying patents are not maintained or enforced.  This could have a material adverse effect on our results of operations, our competitive business position and our business prospects.

Confidentiality agreements with employees and third parties may not prevent unauthorized disclosure of trade secrets and other proprietary information.

In addition to patents, we rely on trade secrets, technical know-how, and proprietary information concerning our business strategy in order to protect our competitive position in the field of oncology. In the course of our research, development and business activities, we often rely on confidentiality agreements to protect our proprietary information. Such confidentiality agreements are used, for example, when we talk to vendors of laboratory or clinical development services or potential strategic partners. In addition, each of our employees is required to sign a confidentiality agreement upon joining our company. We take steps to protect our proprietary information, and we seek to carefully draft our confidentiality agreements to protect our proprietary interests. Nevertheless, there can be no guarantee that an employee or an outside party will not make an unauthorized disclosure of our proprietary confidential information. This might happen intentionally or inadvertently. It is possible that a competitor will make use of such information, and that our competitive position will be compromised, in spite of any legal action we might take against persons making such unauthorized disclosures.

Trade secrets are difficult to protect. Although we use reasonable efforts to protect our trade secrets, our employees, consultants, contractors, or outside scientific collaborators might intentionally or inadvertently disclose our trade secret information to competitors. Enforcing a claim that a third-party illegally obtained and is using any of our trade secrets is expensive and time-consuming, and the outcome is unpredictable. In addition, courts outside the United States sometimes are less willing than U.S. courts to protect trade secrets. Moreover, our competitors may independently develop equivalent knowledge, methods and know-how.

Our research and development strategic partners may have rights to publish data and other information to which we have rights. In addition, we sometimes engage individuals or entities to conduct research relevant to our business. The ability of these individuals

 

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or entities to publish or otherwise publicly disclose data and other information generated during the course of their research is subject to certain contractual limitation s. These contractual provisions may be insufficient or inadequate to protect our confidential information. If we do not apply for patent protection prior to such publication, or if we cannot otherwise maintain the confidentiality of our proprietary technol ogy and other confidential information, then our ability to obtain patent protection or to protect our trade secret information may be jeopardized.

Intellectual property rights do not necessarily address all potential threats to our competitive advantage.

The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations, and may not adequately protect our business, or permit us to maintain our competitive advantage. The following examples are illustrative:

 

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Others may be able to make compounds that are similar to our product candidates but that are not covered by the claims of the patents that we own or have exclusively licensed.

 

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We or our licensors or strategic partners might not have been the first to make the inventions covered by the issued patent or pending patent application that we own or have exclusively licensed.

 

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We or our licensors or strategic partners might not have been the first to file patent applications covering certain of our inventions.

 

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Others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our intellectual property rights.

 

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It is possible that our pending patent applications will not lead to issued patents.

 

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Issued patents that we own or have exclusively licensed may not provide us with a competitive advantage; for example, our issued patents may not be broad enough to prevent the commercialization of competitive antibodies that are biosimilar to one or more of our antibody products, or may be held invalid or unenforceable, as a result of legal challenges by our competitors.

 

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Our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets.

 

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We may not develop additional proprietary technologies that are patentable.

 

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The patents of others may have an adverse effect on our business.

Changes in U.S. patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.

As is the case with other biopharmaceutical companies, our success is heavily dependent on intellectual property, particularly patents. Obtaining and enforcing patents in the biopharma industry involve both technological complexity and legal complexity. Therefore, obtaining and enforcing biopharma patents is costly, time-consuming and inherently uncertain. In addition, several recent events have increased uncertainty with regard to our ability to obtain patents in the future and the value of patents once obtained. Among these, in September 2011, patent reform legislation passed by Congress was signed into law. The new patent law introduces changes including a first-to-file system for determining which inventors may be entitled to receive patents, and a new post-grant review process that allows third parties to challenge newly issued patents. It remains to be seen how the biopharma industry will be affected by such changes in the patent system. In addition, the Supreme Court has ruled on several patent cases in recent years, either narrowing the scope of patent protection available in specified circumstances or weakening the rights of patent owners in specified situations. Depending on decisions by the U.S. Congress, the federal courts, and the U.S. Patent and Trademark Office, the laws and regulations governing patents could change in unpredictable ways that could weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.

 

Risks Related to Regulatory Approval and Marketing of Our Product Candidates and Other Legal Compliance Matters

Even if we complete the necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain and may prevent us from obtaining approvals for the commercialization of some or all of our product candidates.  If we or our collaborators are not able to obtain, or if there are delays in obtaining, required regulatory approvals, we or they will not be able to commercialize our product candidates, and our ability to generate revenue will be materially impaired.  

Our product candidates and the activities associated with their development and commercialization, including their design, testing, manufacture, safety, efficacy, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, export

 

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and import, are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States and by the European Medicines Agency and comparable regulatory authorities in other countries.  Failure to obtain marketing approval for a product candidate will prevent us from commercializing the product candidate.  We and our collaborators have not received approval to market any of our product candidates from regulatory authorities in any jurisdiction.  We have only limited experie nce in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party contract research organizations to assist us in this process.  

Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information to the various regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy.  Securing regulatory approval also requires the submission of information about the product manufacturing process to, and inspection of manufacturing facilities by, the relevant regulatory authority.  Our product candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude our obtaining marketing approval or prevent or limit commercial use.  

The process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years if additi onal clinical trials are required, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved.  Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application.  The FDA and comparable authorities in other countries have substantial discretion in the approval process and may refuse to accept any application or may decide that our data is insufficient for approval and require additional preclinical, clinical or other studies.  In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product candidate.  Any marketing approval we or our collaborators ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable.  

Accordingly, if we or our collaborators experience delays in obtaining approval or if we or they fail to obtain approval of our product candidates, the commercial prospects for our product candidates may be harmed and our ability to generate revenues will be materially impaired.  

Failure to obtain marketing approval in foreign jurisdictions would prevent our product candidates from being marketed in such jurisdictions.  

In order to market and sell our medicines in the European Union and many other jurisdictions, we or our third party collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements.  The approval pro cedure varies among countries and can involve additional testing.  The time required to obtain approval may differ substantially from that required to obtain FDA approval.  The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval.  In addition, in many countries outside the United States, a product be approved for reimbursement before the product can be approved for sale in that country.  We or our third party collaborators may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at all .  Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outsi de the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA.   We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our products in any mark et.  

We, or any future collaborators, may not be able to obtain orphan drug designation or orphan drug exclusivity for our product candidates and, even if we do, that exclusivity may not prevent the FDA or the EMA from approving other competing products.

Regulatory authorities in some jurisdictions, including the United States and Europe, may designate drugs and biologics for relatively small patient populations as orphan drugs. Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is intended to treat a rare disease or condition, which is generally defined as a patient population of fewer than 200,000 individuals annually in the United States. We, or any future collaborators, may seek orphan drug designations for other product candidates and may be unable to obtain such designations.

Even if we, or any future collaborators, obtain orphan drug designation for a product candidate, we, or they, may not be able to obtain orphan drug exclusivity for that candidate. Generally, a pro duct with orphan drug designation only becomes entitled to orphan drug exclusivity if it receives the first marketing approval for the indication for which it has such designation, in which case the FDA or the EMA will be precluded from approving another marketing application for the same product for that indication for the applicable exclusivity period. The applicable exclusivity period is seven years in the United States and ten years in Europe. The European exclusivity period can be reduced to six years if a product no longer meets the criteria for orphan drug designation or if the product is sufficiently profitable so that market exclusivity is no longer justified. Orphan drug exclusivity may be lost if the FDA or the EMA

 

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determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or condition.

Even if we, or any future collaborators, obtain orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because different products can be approved for the same condition. Even after an orphan drug is approved, the FDA can subsequently approve the same drug or biologic for the same condition if the FDA concludes that the later product is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.

Even if we, or any current or future collaborators, obtain marketing approvals for our product candidates, the terms of approvals and ongoing regulation of our products may limit how we, or they, manufacture and market our products, which could materially impair our ability to generate revenue.

Once marketing approval has been granted, an approved product and its manufacturer and marketer are subject to ongoing review and extensive regulation. We, and any current or future collaborators, must therefore comply with requirements concerning advertising and promotion for any of our product candidates for which we or they obtain marketing approval. Promotional communications with respect to prescription products are subject to a variety of legal and regulatory restrictions and must be consistent with the information in the product’s approved labeling. Thus, we and any current or future collaborators will not be able to promote any products we develop for indications or uses for which they are not approved.

In addition, manufacturers of approved products and those manufacturers’ facilities are required to comply with extensive FDA requirements, including ensuring that quality control and manufacturing procedures conform to cGMPs, which include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and documentation and reporting requirements. We, our contract manufacturers, any current or future collaborators and their contract manufacturers could be subject to periodic unannounced inspections by the FDA to monitor and ensure compliance with cGMPs.

Accordingly, assuming we, or any current or future collaborators, receive marketing approval for one or more of our product candidates, we, and any current or future collaborators, and our and their contract manufacturers will continue to expend time, money and effort in all areas of regulatory compliance, including manufacturing, production, product surveillance and quality control.

If we, and any current or future collaborators, are not able to comply with post-approval regulatory requirements, we, and any current or future collaborators, could have the marketing approvals for our products withdrawn by regulatory authorities and our, or any current or future collaborators’, ability to market any products could be limited, which could adversely affect our ability to achieve or sustain profitability. Further, the cost of compliance with post-approval regulations may have a negative effect on our operating results and financial condition.

Any product candidate for which we or our collaborators obtain marketing approval could be subject to restrictions or withdrawal from the market and we may be subject to substantial penalties if we fail to comply with regulat ory requirements or if we experience unanticipated problems with our product candidates, when and if any of them are approved.  

Any product candidate for which we or our collaborators obtain marketing approval, along with the manufacturing processes, post-approval clinical data, labeling, advertising and promotional activities for such product, will be subject to continual requirements of and review by the FDA and other regulatory authorities.  These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, cGMP requirements relating to quality control and manufacturing, quality assurance and corresponding maintenance of records and documents, and requirements regarding the distributi on of samples to physicians and recordkeeping.  Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, or contai n requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a risk evaluation and mitigation strategy.  

The FDA and other agencies, including the Department of Justice, or the DOJ, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling.  The FDA and DOJ impose stringent restrictions on manufacturers’ communications regarding off-label use and if we do not market our products for their approved indications, we may be subject to enforcement action for off-label marketing.  Violations of the Fed eral Food, Drug, and Cosmetic Act and other statutes, including the False Claims Act, relating to the promotion and advertising of prescription products may lead to investigations and enforcement actions alleging violations of federal and state health care fraud and abuse laws, as well as state consumer protection laws.

 

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In addition, later discovery of previously unknown adverse events or other problems with our products, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may yield various results, including:  

 

·

restrictions on such products, manufacturers or manufacturing processes;

 

·

restrictions on the labeling or marketing of a product;

 

·

restrictions on distribution or use of a product;

 

·

requirements to conduct post-marketing studies or clinical trials;

 

·

warning letters or untitled letters;

 

·

withdrawal of the products from the market;

 

·

r efusal to approve pending applications or supplements to approved applications that we submit;

 

·

recall of products;

 

·

damage to relationships with any potential collaborators;

 

·

unfavorable press coverage and damage to our reputation;

 

·

fines, restitution or disgorgement of profits or revenues;

 

·

suspension or withdrawal of marketing approvals;

 

·

r efusal to permit the import or export of our products;

 

·

product seizure;

 

·

injunctions or the imposition of civil or criminal penalties; and

 

·

litigation involving patients using our products.

Non-compliance with European Union requirements regarding safety monitoring or pharmacovigilance, and with requirements related to the development of products for the pediatric population, can also result in significant financial penalties.  Similarly, failure to comply with the European Union’s requirements regarding the protection of personal information can also lead to significant penalties and sanctions.

Our relationships with healthcare providers, physicians and third party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which, in the event of a violation, could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.  

Healthcare providers, physicians and third party payors will play a primary role in the recommendation and prescription of any product candidates for which we obtain marketing approval.  Our future arrangements with healthcare providers, physicians and third party payors may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any products for which we obtain marketing approval.  Restrictions under applicable federal and state healthcare laws and regulations include the following:  

 

·

the federal Anti-Kickback Statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation or arranging of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;

 

·

the federal False Claims Act imposes criminal and civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented, false or fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties, currently set at $5,500 to $11,000 per false claim;

 

·

the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;

 

·

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;

 

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·

t he federal Physician Payments Sunshine Act requires applicable manufacturers of covered products to report payments and other transfers of value to physicia ns and teaching hospitals, with data collection beginning in August 2013; and

 

·

analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws and transparency statutes, may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third party payors, including private insurers.  

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government and may require product manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures.  State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.  

If our operations are found to be in violation of any of the laws described above or any governmental regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines and the curtailment or restructuring of our operations. Any penalties, damages, fines, curtailment or restructuring of our operations could adversely affect our financial results.  We are developing and implementing a corporate compliance program designed to ensure that we will market and sell any future products that we successfully develop from our product candidates in compliance with all applicable laws and regulations, but we cannot guarantee that this program will protect us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.  If any such actions are instituted against us and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs.  It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.  If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of products from government funded healthcare programs, such as Medicar e and Medicaid, and the curtailment or restructuring of our operations.  If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

Current and future legislation may increase the difficulty and cost for us and any collaborators to obtain marketing approval of our other product candidates and affect the prices we, or they, may obtain.  

In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other things, prevent or delay marketing approval of our other product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of any collaborators, to profitably sell any products for which we, or they, obtain marketing approval.  We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators, may receive for any approved products.  

For example, in March 2010, President Obama signed into law the Patient Protection and Affordable Care Act , as amended by the Health Care and Education Affordability Reconciliation Act, or collectively the PPACA.  Among the provisions of the PPACA of potential importance to our business and our product candidates are the following:  

 

·

an annual, non-deductible fee on any entity that manufactures or imports specified branded prescription products and biologic agents;

 

·

an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;

 

·

a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for products that are inhaled, infused, instilled, implanted or injected;

 

·

expansion of healthcare fraud and abuse laws, including the civil False Claims Act and the federal Anti-Kickback Statute, new government investigative powers and enhanced penalties for noncompliance;

 

·

a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off negotiated prices of applicable brand products to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient products to be covered under Medicare Part D;

 

·

extension of manufacturers’ Medicaid rebate liability to individuals enrolled in Medicaid managed care organizations;

 

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·

e xpansion of eligibility criteria for Medicaid programs;

 

·

expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;

 

·

new requirements to report certain financial arrangements with physicians and teaching hospitals;

 

·

a new requirement to annually report product samples that manufacturers and distributors provide to physicians;

 

·

a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

 

·

a new Independent Payment Advisory Board, or IPAB, which has authority to recommend certain changes to the Medicare program to reduce expenditures by the program that could result in reduced payments for prescription products; and

 

·

established the Center for Medicare and Medicaid Innovation within CMS to test innovative payment and service delivery models.

Other legislative changes have been proposed and adopted since the PPACA was enacted.  These changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions to Medicare payments to providers of up to 2% per fiscal year that started in 2013 and, due to subsequent legislation, will continue until 2025.  In addition, the American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.  These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which regulatory approval is obtained.  

We expect that the PPACA, as well as other healthcare reform measures that may be adopted in the future, may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria, new payment methodologies and in additional downward pressure on the price that we receive for any approved product.  Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.  The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our products.  Moreover, legislative and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for pharmaceutical products.  We canno t be sure whether additional legislative changes will be enacted, or whether the FDA regulations, guidance or interpretations will be changed, or what the impact of such changes on the marketing approvals of our product candidates, if any, may be.  In addition, increased scrutiny by the United States Congress of the FDA’s approval process may significantly delay or prevent marketing approval, as well as subject us and any collaborators to more stringent product labeling and post-marketing testing and other requirements.

Laws and regulations governing any international operations we may have in the future may preclude us from developing, manufacturing and selling certain products outside of the United States and require us to develop and implement costly compliance programs.

If we expand our operations outside of the United States, we must dedicate additional resources to comply with numerous laws and regulations in each jurisdiction in which we plan to operate. The Foreign Corrupt Practices Act, or FCPA, prohibits any U.S. individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with certain accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

Compliance with the FCPA is expensive and difficult, particularly in countries in which corruption is a recognized problem. In addition, the FCPA presents particular challenges in the pharmaceutical industry, because, in many countries, hospitals are operated by the government, and doctors and other hospital employees are considered foreign officials. Certain payments to hospitals in connection with clinical trials and other work have been deemed to be improper payments to government officials and have led to FCPA enforcement actions.

Various laws, regulations and executive orders also restrict the use and dissemination outside of the United States, or the sharing with certain non-U.S. nationals, of information classified for national security purposes, as well as certain products and technical data relating to those products. If we expand our presence outside of the United States, it will require us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain products and product candidates outside of the United States, which could limit our growth potential and increase our development costs.

 

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The failure to comply with laws governing international business practices may result in substantial civi l and criminal penalties and suspension or debarment from government contracting. The Securities and Exchange Commission, or SEC, also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions.

If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. From time to time and in the future, our operations may involve the use of hazardous and flammable materials, including chemicals and biological materials, and may also produce hazardous waste products. Even if we contract with third parties for the disposal of these materials and waste products, we cannot completely eliminate the risk of contamination or injury resulting from these materials. In the event of contamination or injury resulting from the use or disposal of our hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.

We maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, but this insurance may not provide adequate coverage against potential liabilities. However, we do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. Current or future environmental laws and regulations may impair our research, development or production efforts, which could adversely affect our business, financial condition, results of operations or prospects. In addition, failure to comply with these laws and regulations may result in substantial fines, penalties or other sanctions.

Governments outside the United States tend to impose strict price controls, which may adversely affect our revenues, if any.

In some countries, such as the countries of the European Union, the pricing of prescription pharmaceuticals is subject to governmental control and access. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product. To obtain reimbursement or pricing approval in some countries, we, or any current or future collaborators, may be required to conduct a clinical trial that compares the cost-effectiveness of our product to other available therapies. If reimburs ement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be materially harmed.

We rely significantly upon information technology and any failure, inadequacy, interruption or security lapse of that technology, including any cyber security incidents, could harm our ability to operate our business effectively.

Despite the implementation of security measures, our internal computer systems and those of third parties with which we contract are vulnerable to damage from cyber-attacks, computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. System failures, accidents or security breaches could cause interruptions in our operations, and could result in a material disruption of our clinical and commercialization activities and business operations, in addition to possibly requiring substantial expenditures of resources to remedy. The loss of clinical trial data could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate public disclosure of confidential or proprietary information, we could incur liability and our product development and commercialization efforts could be delayed.

Risks Related to Employee Matters and Managing Growth

If we fail to attract and keep senior management, we may be unable to successfully develop our product candidates, conduct our clinical trials and commercialize our product candidates.

Our success depends in part on our continued ability to attract, retain and motivate highly qualified management personnel. We are highly dependent upon our senior management, as well as others on our management team. The reduction in force related to the restructuring we completed this year could make it more difficult to retain or attract employees in the future. The loss of services of employees, and in particular, of a member of management could delay or prevent our ability to successfully maintain or enter into new licensing arrangements or collaborations, the successful development of our product candidates, the completion of our planned clinical trials or the commercialization of our product candidates. We do not carry “key person” insurance covering any members of our senior management. Our employment arrangements with all of these individuals are “at will,” meaning they or we can terminate their service at any time.

 

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We face intense competition for qualified individuals from numerous pharmaceutical and biotechnology companies, universities, governmental entities and other research institutions, many of which have su bstantially greater resources with which to reward qualified individuals than we do. We may face challenges in retaining our existing senior management and key employees and recruiting new employees to join our company as our business needs change. We may be unable to attract and retain suitably qualified individuals, and our failure to do so could have an adverse effect on our ability to implement our future business plans.

Our employees may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements and insider trading.

We are exposed to the risk of employee fraud or other misconduct. Misconduct by employees could include intentional failures to comply with FDA regulations, to provide accurate information to the FDA, to comply with manufacturing standards we have established, to comply with federal and state health-care fraud and abuse laws and regulations, to report financial information or data accurately or to disclose unauthorized activities to us. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Employee misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. We have adopted a code of business conduct and ethics, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

In addition, during the course of our operations, our directors, executives and employees may have access to material, nonpublic information regarding our business, our results of operations or potential transactions we are considering. Despite the adoption of an insider trading policy, we may not be able to prevent a director, executive or employee from trading in our common stock on the basis of, or while having access to, material, nonpublic information. If a director, executive or employee was to be investigated, or an action was to be brought against a director, executive or employee for insider trading, it could have a negative impact on our reputation and our stock price. Such a claim, with or without merit, could also result in substantial expenditures of t ime and money, and divert attention of our management team from other tasks important to the success of our business.

Risks Related to Ownership of Our Common Stock

If we fail to meet the requirements for continued listing on the NASDAQ Global Select Market, our common stock could be delisted from trading, which would decrease the liquidity of our common stock and our ability to raise additional capital.

 

Our common stock is currently listed for quotation on the NASDAQ Global Select Market. We are required to meet specified requirements in order to maintain our listing on the NASDAQ Global Select Market, including, among other things, a minimum bid price of $1.00 per share and stockholders’ equity of at least $10.0 million. Our stockholders’ equity was $9.9 million for the quarter ended March 31, 2016 and does not comply with such continued listing requirements. Pursuant to the requirements of the NASDAQ Stock Market LLC, or NASDAQ, we anticipate receiving a letter from the Listing Qualifications Department of NASDAQ notifying us that we are no longer in compliance with the minimum stockholders' equity requirement for continued listing on the NASDAQ Global Select Market, as set forth in NASDAQ Listing Rule 5450(b)(1)(A), which we refer to as the Rules. NASDAQ’S letter would have no immediate effect on the listing of our common stock on the NASDAQ Global Select Market. However, we would have 45 calendar days from the date of the letter to submit to NASDAQ a plan to regain compliance. If we submit a plan, NASDAQ would determine whether to accept the plan, considering such criteria as it determines to be relevant. If the plan were accepted, NASDAQ may grant an extension of up to 180 calendar days from the date of the letter for us to evidence compliance.  If NASDAQ does not accept the plan, we would have the opportunity to appeal that decision to a Hearings Panel.  However, there is no guarantee that we would be able to regain compliance with the continued listing requirement of the Rules or that our plan will be accepted by NASDAQ.

 

We are also required to maintain a minimum bid price of at least $1.00 per share for our common stock in order to maintain our listing on the NASDAQ Global Select Market. Our bid price has recently fallen below $1.00 from time to time.  If our bid price falls below $1.00 per share for 30 consecutive business days, we will receive a deficiency notice from NASDAQ advising us that we have 180 days to regain compliance by maintaining a minimum bid price of at least $1.00 for a minimum of ten consecutive business days. Under certain circumstances, NASDAQ could require that the minimum bid price exceed $1.00 for more than ten consecutive days before determining that a company complies.

 

If we fail to satisfy the NASDAQ Global Select Market’s continued listing requirements, we may transfer to the NASDAQ Capital Market, which generally has lower financial requirements for initial listing, to avoid delisting, or, if we fail to meet its listing requirements, the OTC Bulletin Board A transfer of our listing to the NASDAQ Capital Market or having our common stock trade on

 

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the OTC B ulletin B oard could adversely affect the liquidity of our common stock.  Any such event could make it more difficult to dispose of, or obtain accurate quotations for the price of, our common st ock, and there also would likely be a reduction in our coverage by securities analysts and the news media, which could cause the price of our common stock to decline further.  We may also face other material adverse consequences in such event, such as nega tive publicity, a decreased ability to obtain additional financing, diminished investor and/or employee confidence, and the loss of business development opportunities, some or all of which may contribute to a further decline in our stock price.

The market price of our common stock has been, and is likely to be, highly volatile, and could fall below the price you paid. A significant decline in the value of our stock price could also result in securities class-action litigation against us.

The market price of our common stock has been, and is likely to continue to be, highly volatile and subject to wide fluctuations in price in response to various factors, many of which are beyond our control, including:

 

·

new products, product candidates or new uses for existing products introduced or announced by our strategic partners, or our competitors, and the timing of these introductions or announcements;

 

·

actual or anticipated results from and any delays in our clinical trials;

 

·

results of regulatory reviews relating to our product candidates;

 

·

the results of our efforts to discover, develop, acquire or in-license additional product candidates or products;

 

·

disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection for our technologies;

 

·

announcements by us of material developments in our business, financial condition and/or operations;

 

·

announcements by us or our competitors of significant acquisitions, strategic partnerships, joint ventures and capital commitments;

 

·

additions or departures of key scientific or management personnel;

 

·

conditions or trends in the biotechnology and biopharmaceutical industries;

 

·

actual or anticipated changes in earnings estimates, development timelines or recommendations by securities analysts;

 

·

general economic and market conditions and other factors that may be unrelated to our operating performance or the operating performance of our competitors, including changes in market valuations of similar companies; and

 

·

sales of common stock by us or our stockholders in the future, as well as the overall trading volume of our common stock.

In addition, the stock market in general and the market for biotechnology and biopharmaceutical companies in particular have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of those companies. These broad market and industry factors may seriously harm the market price of our common stock, regardless of our operating performance.

Periods of volatility in the market for a company’s stock are often followed by litigation against the company. For example, since our May 2, 2013 announcement regarding the vote of the Oncologic Drugs Advisory Committee of the FDA, we an d certain of our former officers and directors have been involved in a number of legal proceedings, including those described below under the heading “Legal Proceedings” in Part II—Item 1 of this Form 10-Q . These proceedings and other similar litigation, if instituted against us, could result in substantial costs and diversion of management’s attention and resources, which could materially and adversely affect our business and financial condition.

We may not achieve development and commercialization goals in the time frames that we publicly estimate, which could have an adverse impact on our business and could cause our stock price to decline.

We set goals, and make public statements regarding our expected timing for certain accomplishments, such as the initiation and completion of clinical trials, filing and approval of regulatory applications for our product candidates and other developments and milestones under our research and development programs. The actual timing of these events can vary significantly due to a number of factors, including, without limitation, delays or failures in our and our current and potential collaborators’ preclinical studies or clinical trials, the amount of time, effort and resources committed to our programs by us and our curr ent and potential collaborators and the uncertainties inherent in the regulatory approval process. As a result, there can be no assurance that our or our current and potential collaborators’ preclinical studies and clinical trials will advance or be comple ted in the time frames we expect or announce, that we or our current and potential collaborators will make regulatory submissions or receive regulatory approvals as planned or that we or our current and potential collaborators will be able to adhere to our current schedule for the achievement of key milestones

 

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under any of our programs. If we or any collaborators fail to achieve one or more of the milestones described above as planned, our business could be materially adversely affected and the price of our common stock could decline.

Our management has broad discretion over our use of available cash and cash equivalents and might not spend our available cash and cash equivalents in ways that increase the value of your investment.

Our management has broad discretion on where and how to use our cash and cash equivalents and you will be relying on the judgment of our management regarding the application of our available cash and cash equivalents to fund our operations. Our management might not apply our cash or cash equivalents in ways that increase the value of your investment. We expect to use a substantial portion of our cash to fund existing and future research and development of our preclinical and clinical product candidates, with the balance, if any, to be used for working capital and other general corporate purposes, which may in the future include investments in, or acquisitions of, complementary businesses, joint ventures, partnerships, services or technologies. Our management might not be able to yield a significant return, if any, on any investment of this cash. You will not have the opportunity to influence our decisions on how to use our cash reserves.

Fluctuations in our quarterly operating results could adversely affect the price of our common stock.

Our quarterly operating results may fluctuate significantly. Some of the factors that may cause our operating results to fluctuate on a period-to-period basis include:

 

·

the status of our clinical development programs;

 

·

the level of expenses incurred in connection with our clinical development programs, including development and manufacturing costs relating to our clinical development candidates;

 

·

any intellectual property infringement lawsuit or other litigation in which we may become involved;

 

·

the implementation of our current restructuring and cost-savings strategies;

 

·

the implementation or termination of collaboration, licensing, manufacturing or other material agreements with third parties, and non-recurring revenue or expenses under any such agreement;

 

·

c osts associated with lawsuits against us, including the current purported class action and derivative lawsuits described elsewhere in this report under “Part II, Item 1—Legal Proceedings;”

 

·

changes in our loan agreement with Hercules, including the existence of any event of default that may accelerate payments due thereunder; and

 

·

compliance with regulatory requirements.

Period-to-period comparisons of our historical and future financial results may not be meaningful, and investors should not rely on them as an indication of future performance. Our fluctuating results may fail to meet the expectations of securities analysts or investors. Our failure to meet these expectations may cause the price of our common stock to decline.

Unstable market and economic conditions may have serious adverse consequences on our business, financial condition and stock price.

As widely reported, global credit and financial markets have been experiencing extreme volatility, and in some cases, disruptions, over the past several years, in many cases, over extended periods. Although certain of these trends have recently showed signs of reversing, there can be no assurance that rapid or extended periods of deterioration in credit and financial markets and confidence in economic conditions will not occur. Our general business strategy may be adversely affected by external economic conditions and a volatile business environment or unpredictable and unstable market conditions. If the equity and credit markets are not favorable at any time we seek to raise capital, it may make any necessary debt or equity financing more difficult, more costly, and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on our growth strategy, financial performance and stock price and could require us to delay or abandon clinical development plans. In addition, there is a risk that one or more of our current service providers, manufacturers or other partners may not survive economically turbulent times, which could directly affect our ability to attain our operating goals on schedule and on budget.

At March 31, 2016, we had 23.8 million of cash, cash equivalents and marketable securities consisting of cash on deposit with banks, money market funds, U.S. government agency securities, and corporate debt securities, including commercial paper. As of the date of this report, we are not aware of any downgrades, material losses, or other significant deterioration in the fair value of our cash equivalents. However, no assurance can be given that deterioration in conditions of the global credit and financial markets would not

 

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negatively impact our current portfolio of cash equivalents or our ability to meet our financing objectives. Dislocatio ns in the credit market may adversely impact the value and/or liquidity of cash equivalents owned by us.

There is a possibility that our stock price may decline because of volatility of the stock market and general economic conditions.

Future sales of shares of our common stock, including shares issued upon the exercise of currently outstanding options, could negatively affect our stock price.

A substantial portion of our outstanding common stock can be traded without restriction at any time. Some of these shares are currently restricted as a result of securities laws, but will be able to be sold, subject to any applicable volume limitations under federal securities laws with respect to affiliate sales, in the near future. As such, sales of a substantial number of shares of our common stock in the public market could occur at any time. These sales, or the perception in the market that the holders of a large number of shares intend to sell such shares, could reduce the market price of our common stock. In addition, we have a significant number of shares that are subject to outstanding options. The exercise of these options and the subsequent sale of the underlying common stock could cause a further decline in our stock price. These sales also might make it difficult for us to sell equity securities in the future at a time and at a price that we deem appropriate.

If securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our share price and trading volume could decline.

The trading market for our common stock may depend in part on the research and reports that securities or industry analysts publish about us or our business. We do not have any control over these analysts. There can be no assurance that analysts will cover us, or provide favorable coverage. A lack of research coverage may negatively impact the market price of our common stock. To the event we do have analyst coverage, if one or more analysts downgrade our stock or change their opinion of our stock, our share price would likely decline. In addition, if one or more analysts cease coverage of our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which could cause our share price or trading volume to decline.

A decline in our stock price may affect future fundraising efforts.

We currently have no product revenues, and depend entirely on funds raised through other sources. One source of such funding is future debt and/or equity offerings. Our ability to raise funds in this manner depends upon, among other things, our stock price, which may be affected by capital market forces, evaluation of our stock by securities analysts, product development success (or failure), and internal management operations and controls.

Provisions in our certificate of incorporation, our by-laws or Delaware law might discourage, delay or prevent a change in control of our company or changes in our management and, therefore, depress the market price of our common stock.

Provisions of our certificate of incorporation, our by-laws or Delaware law may have the effect of deterring unsolicited takeovers or delaying or preventing a change in control of our company or changes in our management, including transactions in which our stockholders might otherwise receive a premium for their shares over then current market prices. In addition, these provisions may limit the ability of stockholders to approve transactions that they may deem to be in their best interest. These provisions include:

 

·

advance notice requirements for stockholder proposals and nominations;

 

·

the inability of stockholders to act by written consent or to call special meetings;

 

·

the ability of our board of directors to make, alter or repeal our by-laws; and

 

·

the ability of our board of directors to designate the terms of and issue new series of preferred stock without stockholder approval, which could be used to institute a rights plan, or a poison pill, that would work to dilute the stock ownership of a potential hostile acquirer, likely preventing acquisitions that have not been approved by our board of directors.

In addition, Section 203 of the Delaware General Corporation Law prohibits a publicly-held Delaware corporation from engaging in a business combination with an interested stockholder, generally a person which together with its affiliates owns, or within the last three years has owned, 15% of our voting stock, for a period of three years after the date of the transaction in which the person became an interested stockholder, unless the business combination is approved in a prescribed manner.

The existence of the foregoing provisions and anti-takeover measures could limit the price that investors might be willing to pay in the future for shares of our common stock. They could also deter potential acquirers of our company, thereby reducing the likelihood that a stockholder could receive a premium for shares of our common stock held by a stockholder in an acquisition.

 

70


Our business could be negatively affecte d as a result of the actions of activist shareholders.

Proxy contests have been waged against companies in the biopharmaceutical industry over the last few years. If faced with a proxy contest, we may not be able to successfully respond to the contest, which would be disruptive to our business. Even if we are successful, our business could be adversely affected by a proxy contest because:

 

·

responding to proxy contests and other actions by activist shareholders may be costly and time-consuming, and may disrupt our operations and divert the attention of management and our employees;

 

·

perceived uncertainties as to the potential outcome of any proxy contest may result in our inability to consummate potential acquisitions, collaborations or in-licensing opportunities and may make it more difficult to attract and retain qualified personnel and business partners; and

 

·

if individuals that have a specific agenda different from that of our management or other members of our board of directors are elected to our board as a result of any proxy contest, such an election may adversely affect our ability to effectively and timely implement our strategic plan and create additional value for our stockholders.

Failure to maintain effective internal controls in accordance with Section 404 of the Sarbanes-Oxley Act could have a material adverse effect on our ability to produce accurate financial statements and on our stock price.

Section 404 of the Sarbanes-Oxley Act of 2002 requires us, on an annual basis, to review and evaluate our internal controls, and requires our independent registered public accounting firm to attest to the effectiveness of our internal controls. Despite our efforts, we can provide no assurance as to our, or our independent registered public accounting firm’s, conclusions with respect to the effectiveness of our internal control over financial reporting under Section 404. There is a risk that neither we nor our independent registered public accounting firm will be able to continue to conclude within the prescribed timeframe that our internal control over financial reporting is effective as required by Section 404. This could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of our financial statements.

We do not expect to pay any cash dividends for the foreseeable future.

You should not rely on an investment in our common stock to provide dividend income. We do not anticipate that we will pay any cash dividends to holders of our common stock in the foreseeable future. Instead, we plan to retain any earnings to maintain and expand our existing operations. In addition, our ability to pay cash dividends is currently prohibited by the terms of our debt financing arrangements and any future debt financing arrangement may contain terms prohibiting or limiting the amount of dividends that may be declared or paid on our common stock. Accordingly, investors must rely on sales of their common stock after price appreciation, which may never occur, as the only way to realize any return on their investment. As a result, investors seeking cash dividends should not purchase our common stock.

 

We might not be able to utilize a significant portion of our net operating loss carryforwards and research and development tax credit carryforwards.

As of December 31, 2015, we had federal and state net operating loss carryforwards of $444.5 million and $338.7 million, respectively, and federal and state research and development tax credit carryforwards of $10.1 million and $4.0 million, respectively, each of which if not utilized will expire at various dates through 2035. These net operating loss and tax credit carryforwards could expire unused and be unavailable to offset future income tax liabilities. In addition, under Section 382 of the Internal Revenue Code of 1986, as amended, and corresponding provisions of state law, if a corporation undergoes an “ownership change,” which is generally defined as a greater than 50% change, by value, in its equity ownership over a three‑year period, the corporation’s ability to use its pre‑change net operating loss carryforwards and other pre‑change tax attributes to offset its post‑change income may be limited. We may experience ownership changes in the future as a result of subsequent shifts in our stock ownership, some of which may be outside of our control. We have not conducted a detailed study to document whether our historical activities qualify to support the research and development credit carryforwards. A detailed study could result in adjustment to our research and development credit carryforwards. If we determine that an ownership change has occurred and our ability to use our historical net operating loss and tax credit carryforwards is materially limited, or if our research and development carryforwards are adjusted, it would harm our future operating results by effectively increasing our future tax obligations.

Item 6. Exhibits.

The exhibits listed in the Exhibit Index to this Quarterly Report on Form 10-Q are incorporated herein by reference.

 

71


SIGNA TURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.

 

 

 

AVEO PHARMACEUTICALS, INC.

 

 

 

 

Date: May 10, 2016

 

By:

/s/    Keith S. Ehrlich

 

 

 

Keith S. Ehrlich, C.P.A.

 

 

 

Chief Financial Officer and Principal Financial
and Accounting Officer

 

72


Exhibit Index

 

 

 

 

 

Incorporated by Reference

 

 

 

 

 

 

Exhibit

Number

 

Description of Exhibit

 

Form

 

File Number

 

Date of
Filing

 

Exhibit
Number

 

Filed
Herewith

 

 

 

 

 

 

 

 

 

 

 

 

 

10.1✝

 

Collaboration and License Agreement, dated March 17, 2016, by and between the Registrant and CANbridge Life Sciences Ltd.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

31.1

 

Certification of principal executive officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

31.2

 

Certification of principal financial officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

32.1

 

Certification of principal executive officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

32.2

 

Certification of principal financial officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

101.INS

 

XBRL Instance Document.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

101.SCH

 

XBRL Taxonomy Extension Schema Document.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

101.CAL

 

XBRL Taxonomy Calculation Linkbase Document.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

101.DEF

 

XBRL Taxonomy Extension Definition Linkbase Document.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

101.LAB

 

XBRL Taxonomy Label Linkbase Document.

 

 

 

 

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

101.PRE

 

XBRL Taxonomy Presentation Linkbase Document.

 

 

 

 

 

 

 

 

 

X

 

✝Confidential treatment has been requested as to certain portions, which portions have been omitted and separately filed with the Securities and Exchange Commission.

 

 

73

Confidential Materials omitted and filed separately with the

Securities and Exchange Commission. Double asterisks denote omissions.

 

Exhibit 10.1

 

EXECUTION VERSION

 

COLLABORATION AND LICENSE AGREEMENT

BY AND BETWEEN

canbridge LIFE SCIENCES LTD.

and

aveo pharmaceuticalS, INC.

 

 

 

 

 

 

 

 

 

 

 

 

 

March 17, 2016

 

 

 


 

TABLE OF CONTENTS

 

ARTICLE 1   DEFINITIONS

1

ARTICLE 2   GOVERNANCE; JOINT STEERING COMMITTEE

18

2.1

Formation; Purposes and Principles

18

2.2

Specific Responsibilities

18

2.3

Membership

19

2.4

Meetings; Reports

19

2.5

Decision-Making; Escalation to Executive Officers

19

2.6

Alliance Managers

20

ARTICLE 3   LICENSE GRANTS

21

3.1

AVEO License Grant; Right of Reference

21

3.2

CANbridge License Grant; Right of Reference

21

3.3

Sublicensing and Subcontracting

21

3.4

Exclusivity Covenant

22

3.5

Acquisition Transactions

22

3.6

Reservation of Rights

23

3.7

Bankruptcy Code § 365(n) Election

23

3.8

No Inconsistent Third Party Agreements

24

ARTICLE 4   DEVELOPMENT

24

4.1

Development Responsibilities

24

4.2

Development Authorities

25

4.3

Development Diligence; Manner of Performance; Reports

26

4.4

Rights of First Negotiation

27

4.5

Regulatory Submissions and Regulatory Approvals

29

4.6

Third Party Partners

31

ARTICLE 5   MANUFACTURE AND COMMERCIALIZATION

31

5.1

Technology Transfer and Manufacture

31

5.2

Commercialization

32

ARTICLE 6   FINANCIAL PROVISIONS

34

6.1

Upfront Payment; Reimbursement of Manufacturing Development Costs; Milestone Payments

34

6.2

Sublicense Revenue

35

6.3

Royalties

36

6.4

Royalty Payments and Reports

37

6.5

Profit Share Payments

37

6.6

Payment Reductions

37

6.7

Reimbursement of Third Party Expenses

38

-i-

 


 

6.8

Financial Audits

39

6.9

Tax Matters

40

6.10

Currency of Payments

40

ARTICLE 7   INTELLECTUAL PROPERTY OWNERSHIP, PROTECTION AND RELATED MATTERS

40

7.1

Ownership of Inventions

40

7.2

Prosecution and Maintenance of the Licensed Patents

41

7.3

Prosecution and Maintenance of the CANbridge Program Patents

43

7.4

Third Party Infringement

43

7.5

Claimed Infringement

44

7.6

EU Unitary Patent System

45

7.7

Trademarks

45

ARTICLE 8   CONFIDENTIALITY AND PUBLICITY

45

8.1

Confidential Information

45

8.2

Publicity

46

ARTICLE 9   REPRESENTATIONS AND WARRANTIES; CERTAIN COVENANTS

48

9.1

Mutual Representations and Warranties

48

9.2

Additional Representations and Warranties of AVEO

48

9.3

No Debarment

51

ARTICLE 10   INDEMNIFICATION; DAMAGES

51

10.1

Indemnification by AVEO

51

10.2

Indemnification by CANbridge

52

10.3

Claims for Indemnification

52

10.4

Insurance

52

ARTICLE 11   LIMITATION OF LIABILITY

53

11.1

No Consequential or Punitive Damages

53

11.2

Exclusion from Liability Limitation

53

ARTICLE 12   TERM AND TERMINATION

54

12.1

Term

54

12.2

Early Termination

54

12.3

Effects of Termination

55

ARTICLE 13   DISPUTE RESOLUTION

59

13.1

Dispute Resolution Escalation

59

13.2

Arbitration

59

13.3

Jury Waiver

60

ARTICLE 14   MISCELLANEOUS

60

14.1

Assignment; Successors

60

14.2

Choice of Law

60

-ii-

 


 

14.3

Notices

61

14.4

Severability

61

14.5

Integration

62

14.6

Waivers and Amendments

62

14.7

Independent Contractors; No Agency

62

14.8

Affiliates

62

14.9

Force Majeure

63

14.10

No Third Party Beneficiary Rights

63

14.11

Non-exclusive Remedy

63

14.12

Interpretation

63

14.13

Further Assurances

64

14.14

Ambiguities; No Presumption

64

14.15

Execution in Counterparts; Facsimile Signatures

64

 

LIST OF SCHEDULES and EXHIBITS

 

Schedule 1.60:  Existing Third Party License Agreements

Schedule 1.88:  List of AVEO Individuals for Purposes of Knowledge

Schedule 1.112:  Information to be Included in the POC Study Data Package

Schedule 3.3.4:  Provisions Required by Existing Third Party License Agreements to be Included in Sublicense Agreements

Schedule 4.2.1:  POC Study Requirements

Schedule 7.1.2:  EvoGenix Improvements

Schedule 9.2.1:  Licensed Patents

Exhibit A:  POC Development Plan

Exhibit B:  Initial Press Release

Exhibit C:  Technology Transfer Plan and Transfer of Regulatory Documents

 

 

-iii-

 


 

COLLABORATION AND LICENSE AGREEMENT

THIS COLLABORATION AND LICENSE AGREEMENT (this “ Agreement ”), entered into as of March 17, 2016 (the “ Effective Date ”), is entered into by and between CANbridge Life Sciences Ltd., a corporation organized and existing under the laws of the People’s Republic of China (“ CANbridge ”), and AVEO Pharmaceuticals, Inc., a corporation organized and existing under the laws of the State of Delaware (“ AVEO ”).

INTRODUCTION

WHEREAS , prior to the Effective Date, AVEO has developed an ErbB3 (HER3) inhibitory Antibody Product candidate for the treatment of cancer;

WHEREAS , CANbridge wishes to obtain from AVEO and AVEO wishes to grant to CANbridge certain rights and licenses under Licensed Patents and Licensed Know-How to Develop, Manufacture and Commercialize the Product in the Licensed Territory (each as defined below); and

WHEREAS , CANbridge and AVEO therefore desire to provide for the development, manufacture and commercialization of the Product on and subject to the terms and conditions set forth herein.

NOW, THEREFORE , the Parties hereby agree as follows:

ARTICLE 1
DEFINITIONS

As used in this Agreement, the following terms will have the meanings set forth below:

1.1 Accounting Standards ” means, with respect to a Person, generally accepted accounting principles as practiced in the United States (“ GAAP ”) or applicable international standards followed by such Person.

1.2 Acquirer ” has the meaning set forth in Section 3.5.1 (Effect of Acquisition Transaction).

1.3 Acquired Party ” has the meaning set forth in Section 3.5.1 (Effect of Acquisition Transaction).

1.4 Acquisition Transaction ” has the meaning set forth in Section 3.5.1 (Effect of Acquisition Transaction).

1.5 Action ” means any claim, action, cause of action or suit (whether in contract or tort or otherwise), litigation (whether at law or in equity, whether civil or criminal), assessment, arbitration, investigation, hearing, charge, complaint, demand, notice or proceeding of, to, from, by or before any Governmental Authority.

 


 

1.6 Adverse Event ” or “ AE ” has the meaning set forth in 21 C.F.R. § 312.32 and generally means any untoward medical occurrence associated with the use of a product in human subjects, whether or not considered related to such product. An AE does not necessarily have a causal relationship with a product, that is, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of such product.  

1.7 Adverse Ruling ” has the meaning set forth in Section 12.2.1 (Termination for Material Breach).

1.8 Affiliate ” means, with respect to any Person, any Person controlling, controlled by or under common control with such first Person.  For purposes of this Section 1.8 (Affiliate), “ control ” means (a) direct or indirect ownership of 50% or more of the stock or shares having the right to vote for the election of directors of such Person (or if the jurisdiction where such Person is domiciled prohibits foreign ownership of such entity, the maximum foreign ownership interest permitted under such Laws; provided, however, that such ownership interest provides actual control over such Person), (b) status as a general partner in any partnership, or (c) the possession, directly or indirectly, of the power to direct, or cause the direction of, the management or policies of such Person, whether through the ownership of voting securities, by contract or otherwise.

1.9 Aggregate AVEO Third Party Royalty Obligation ” means the aggregate effective royalty rate that AVEO is obligated to pay Third Parties on the sale of Products by AVEO, its Affiliates or Sublicensees in any Calendar Year pursuant to the terms of the Existing Third Party License Agreements, as such agreements exist as of the Effective Date.

1.10 Alliance Manager ” has the meaning set forth in Section 2.6.1 (Appointment).

1.11 Antibody ” means any immunoglobulin molecule (such as IgG) whether in monospecific, bispecific or any other form, and will include (a) any immunoglobulin fragment (such as Fv, Fab, F(ab')2) of any such immunoglobulin molecule containing one or more complementarity determining regions, (b) any fusion protein comprising any such immunoglobulin molecule or immunoglobulin fragment and any single chain antibody (such as scFv), and (c) any truncation or derivative of any of the foregoing.

1.12 Applicable Percentage ” has the meaning set forth in Section 6.5 (Profit Share Payment).

1.13 AVEO Indemnified Parties ” has the meaning set forth in Section 10.2 (Indemnification by CANbridge).

1.14 AVEO Invention ” has the meaning set forth in Section 7.1.2 (Ownership).

1.15 Bankruptcy Code ” has the meaning set forth in Section 3.7 (Bankruptcy Code § 365(n) Election).

1.16 Biologics License Application ” or “ BLA ” means a biologics license application (as defined in Title 21 of the United States Code of Federal Regulations, parts 211 and 601, as amended) submitted to the FDA containing complete details of the manufacturing processes,

2


 

chemistry, pharmacology, clinical pharmacology and the medical effects of a given biologic product, for purposes of obtaining Regulatory Approval for such biologic product in the United States.  

1.17 Biosimilar Competition ” means, with respect to any country in the Licensed Territory, that any one or more Third Parties sell Biosimilar Products in such country that have, in the aggregate, achieved [**]% or more of the aggregate market share of Products and Biosimilar Products (based on data provided by IMS Health Incorporated, Fairfield, Connecticut) in any Calendar Quarter as measured on an aggregate sales basis (in unit sales), or if such data is not available, a methodology to be mutually agreed upon by the Parties for estimating the percentage of aggregate sales (in unit sales) based on market share of Biosimilar Products in such country.

1.18 Biosimilar Product ” means, as to any Product, a biologic product that is licensed by a Regulatory Authority as a biosimilar or bioequivalent to such Product based upon high similarity to the Product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between such biological product and the Product in terms of the safety, purity, and potency. For purposes of clarity, a biologic product will be deemed to be biosimilar or bioequivalent to a Product for purposes of this definition to the extent such Product is used as the reference product in the application or submission made with respect to such biologic product under applicable Laws (including under the Biologics Price Competition and Innovation Act of 2009 and/or the United States Patient Protection and Affordable Care Act); provided, that, a product licensed or produced by CANbridge will not be deemed to be a Biosimilar Product for purposes of this Agreement.  

1.19 Blocking Third Party Patent Rights ” means, with respect to a Product in any country in the Licensed Territory, any Patent Rights owned or Controlled by a Third Party that are necessary to Manufacture, or necessary or useful to Develop or Commercialize, such Product in such country.

1.20 Blocking Third Party Intellectual Property Costs ” means any royalties paid to a Third Party who owns or Controls Blocking Third Party Patent Rights in order to license or otherwise acquire the relevant rights to such Blocking Third Party Patent Rights.

1.21 Breaching Party ” has the meaning set forth in Section 12.2.1 (Termination for Material Breach).

1.22 Business Day ” means any day other than a Saturday or a Sunday on which the banks in New York, New York and Beijing, China are open for business.

1.23 Calendar Quarter ” means each of the three month periods ending on March 31, June 30, September 30, and December 31 of any Calendar Year.

1.24 Calendar Year ” means each 12 month period commencing on January 1, and ending on December 31.

1.25 CANbridge Indemnified Parties ” has the meaning set forth in Section 10.1 (Indemnification by AVEO).

3


 

1.26 CANbridge Invention ” has the meaning set forth in Section 7.1.2 (Ownership).  

1.27 CANbridge Program Know-How ” means any Safety Data and CMC Data Controlled by CANbridge or any of its Affiliates as of the Effective Date or during the Term that is necessary or useful to Exploit any Product.

1.28 CANbridge Program Patents ” means any Patent Rights that are Controlled by CANbridge or any of its Affiliates as of the Effective Date or during the Term that Cover the Exploitation of any Product, but excluding CANbridge’s interest in the Joint Patent Rights.

1.29 Clinical Data ” means any and all data (together with all clinical trial reports and the results of analyses thereof) derived or generated from any Clinical Study involving any Product conducted by or on behalf of a Party or from the testing of subjects or the analysis of samples used in any such Clinical Study.

1.30 Clinical Trial Application ” or “ CTA ” has the meaning set forth in Section 1.76 (“ IND ”).

1.31 CMC ” means the Chemistry, Manufacturing and Controls portion of any Regulatory Filing.

1.32 CMC Data ” means any data included in the CMC portion of a Regulatory Filing and in the supporting development reports, with respect to any Product.

1.33 Clinical Study ” means a study in which human subjects or patients are dosed with a drug, whether approved or investigational, including any Phase II Clinical Study, Phase IIa Clinical Study, Phase III Clinical Study, or Phase IIIb Clinical Study.

1.34 Code ” means the Internal Revenue Code of 1986, as amended from time to time (or any corresponding provisions of succeeding law).

1.35 Collaboration Agreement ” has the meaning set forth in Section 4.4.2(a) (Exclusive Negotiation Period).

1.36 Combination Product ” means any pharmaceutical product containing a Product and one or more other significantly active pharmaceutical ingredients.

1.37 Commence ” or “ Commencement ” means, when used to describe a Clinical Study of a Product, the first dosing of the first human subject with such Product in such Clinical Study.

1.38 Commercialization ”, “ Commercializing ” or “ Commercialize ” means any and all activities related to the pre-marketing, launching, marketing, promotion (including advertising and detailing), labeling, pricing and reimbursement, distribution, storage, handling, offering for sale, selling, importing and exporting for sale, distribution, customer service and support, and post-marketing safety surveillance and reporting of a product (including a Product), but not including Manufacturing.

4


 

1.39 Commercially Reasonable Efforts ” means, in respect of a Party, the level of efforts and resources (measured as of the time that such efforts and resources are required to be used under this Agreement) that are commonly used by a company in the industry of a similar size and profile as such Party to Develop, Manufacture or Commercialize, as the case may be, a product owned by such company or to which it has rights, which product is at a similar stage in its development or product life and is of a similar market and profitability potential to Product and taking into account all relevant factors including the patent and other proprietary position of the product, product labeling or anticipated labeling, market potential, financial return, medical and clinical considerations, regulatory environments and competitive market conditions, and other technical legal, scientific, medical or commercial factors that such a company would reasonably deem to be relevant.  

1.40 Competitive Program ” has the meaning set forth in Section 3.5.1 (Effect of Acquisition Transaction).

1.41 Confidential Information ” means (a) all trade secrets or confidential or proprietary information or tangible materials of the disclosing Party or its Affiliates provided or disclosed to the other Party or any of its Affiliates pursuant to this Agreement, (b) “ Confidential Information ” (as defined in the Prior CDA) that was disclosed by a Party or any of its Affiliates to the other Party or any of its Affiliates under the Prior CDA, and (c) the terms and conditions of this Agreement; provided, however, that Confidential Information will not include information that:

(i) has been published by a Third Party or otherwise is or hereafter becomes part of the public domain by public use, publication, general knowledge or the like through no wrongful act, fault or negligence on the part of the receiving Party or its Affiliates;

(ii) has been in the receiving Party’s or its Affiliates possession prior to disclosure by the disclosing Party without any obligation of confidentiality with respect to such information (as evidenced by the receiving Party’s or such Affiliate’s written records or other competent evidence);

(iii) is subsequently received by the receiving Party or its Affiliate from a Third Party without restriction and without breach of any agreement between such Third Party and the disclosing Party; or

(iv) has been independently developed by or for the receiving Party or its Affiliates without reference to, or use or disclosure of, the disclosing Party’s Confidential Information (as evidenced by the receiving Party’s or such Affiliate’s written records or other competent evidence);

provided, further, that clauses (ii) through (iv) above will not apply to the terms and conditions of this Agreement.

All Regulatory Filings owned by a Party will be deemed to be the Confidential Information of such Party and such Party will be deemed to be the disclosing Party and the other Party will be deemed to be the receiving Party with respect thereto.

5


 

1.42 Contract Manufacturing Organization ” or “ CMO ” means a Third Party contract manufacturing organization.  

1.43 Control ” or “ Controlled ” means, with respect to any Know-How, Patent Right, Regulatory Filing or other intellectual property right, the legal authority or right (whether by ownership, license (other than a license granted pursuant to this Agreement) or otherwise) of a Person or its Affiliate, to grant access, a license or a sublicense of or under such Know-How, Patent Right, Regulatory Filing or intellectual property right, without breaching the terms of any agreement with a Third Party.

1.44 Cost of Goods Sold ” or “ COGS ” means, with respect to any Product Manufactured by CANbridge or its Affiliates under this Agreement, the reasonable internal and external costs of CANbridge or its Affiliates incurred in Manufacturing such Product, including: (a) to the extent such Product is Manufactured by CANbridge or its Affiliates, the cost of goods sold of such Product, consisting of direct materials and direct labor costs, plus overhead directly attributable to Product supplied (including pre-batch and post-batch specific cleaning, all directly incurred Manufacturing variances and a reasonable allocation of related Manufacturing administrative, facilities operations and facilities depreciation costs (to the extent not otherwise included as direct labor costs or overhead), which allocation will be mutually agreed in good faith by the Parties, but excluding facilities or plant start-up costs and costs associated with excess or idle capacity), all calculated in accordance with GAAP in the United States consistently applied, and (b) to the extent that such Product is Manufactured by a Third Party manufacturer (including a CMO), the actual fees paid by such Party or any of its Affiliates to the Third Party for the Manufacture, supply, testing, packaging, labeling and shipping of such Product, and any reasonable out-of-pocket and direct labor costs actually incurred by such Party or any of its Affiliates in managing or overseeing the Third Party relationship.  For purposes of clarity, if any material used to make a Product may be used to Manufacture multiple batches of Product and/or other compounds or products, the cost of such material will be appropriately allocated to such batches and/or other products or compounds and amortized over the useful life of such material in accordance with CANbridge’s Accounting Standards.

1.45 Cover, ” “ Covering ” or “ Covered ” means, when referring to a Product: (a) with respect to a patent, that, in the absence of a license granted to a Person under a claim included in such patent, the practice by such Person of a specified activity with respect to such Product would infringe such claim (without regard to the validity or enforceability of such claim), or (b) with respect to a patent application, that, in the absence of a license granted to a Person under a claim included in such patent application, the practice by such Person of a specified activity with respect to such Product would infringe such claim if such patent application were to issue as a patent.

1.46 Development ” or “ Develop ” means non-clinical and clinical drug research and development activities, whether before or after Regulatory Approval, including drug metabolism and pharmacokinetics, translational research, toxicology, pharmacology, test method development and stability testing, process and packaging development and improvement, process validation, process scale-up, formulation development, delivery system development, quality assurance and quality control development, statistical analysis, conduct of Clinical Studies, regulatory affairs, and Regulatory Approval and Clinical Study regulatory activities. Development includes use and

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importation of the relevant compound or Product to conduct such Development activities.  Development will not include Commercialization activities.  

1.47 Development Milestone Event ” has the meaning set forth in Section 6.1.3 (Development Milestone Payments).

1.48 Development Milestone Payment ” has the meaning set forth in Section 6.1.3 (Development Milestone Payments).

1.49 Development Report ” has the meaning set forth in Section 4.3.4 (Development Records; Reports).

1.50 Distributor ” means any Third Party appointed by a Party or any of its Affiliates to distribute, market and sell any Product, with or without packaging rights, in one or more countries in its respective territory, where such Third Party purchases its requirements of such Product from such Party or its Affiliates for a transfer price but does not make any royalty, profit share or similar payment to such Party based on sales of such Product.

1.51 Effective Date ” has the meaning set forth in the preamble.

1.52 EPO ” has the meaning set forth in Section 7.2.2 (In the North America Territory).

1.53 EMA ” means the European Medicines Agency or any successor agency thereto.

1.54 ERBB3 ” means the human ErbB3 (aka HER3) polypeptide, including: (a) any species variants or homologs thereof; (b) any amino acid sequence variants or mutations of the foregoing, (c) any post-translational modifications of the foregoing; and (d) any derivative or fragment of the foregoing; provided, however, that the derivative or fragment elicits an Antibody that reacts with native human erbB3, when used as an antigen.

1.55 ERBB3 Antibody ” means an Antibody that binds to ERBB3.

1.56 ESCC ” has the meaning set forth in Section 1.113 (“ POC Study ”).

1.57 European Union ” or “ EU ” means the countries of the European Union as constituted on the Effective Date and as it may be expanded or contracted from time to time after the Effective Date; provided, however, that the EU will always be deemed to include the United Kingdom, France, Germany, Italy and Spain.

1.58 Exclusive Negotiation Period ” has the meaning set forth in Section 4.4.2(a) (Exclusive Negotiation Period).

1.59 Executive Officers ” means (a) with respect to AVEO, the Chief Executive Officer of AVEO, and (b) with respect to CANbridge, the Chief Executive Officer of CANbridge.  If the position of any of the Executive Officers identified in this Section 1.59 (Executive Officers) no longer exists due to a corporate reorganization, corporate restructuring or the like that results in the elimination of the identified position, the applicable title of the Executive Officer set forth herein will be replaced with the title of another executive officer with responsibilities and seniority

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comparable to the eliminated Executive Officer, and the relevant Party will promptly provide notice of such replacement title to the other Party.  

1.60 Existing Third Party License Agreements ” means the license agreements by and between AVEO and Third Parties listed on Schedule 1.60 attached hereto.

1.61 Expanded License ” has the meaning set forth in Section 4.4.2(a) (Exclusive Negotiation Period).

1.62 Exploit ” or “ Exploitation ” means to make, have made, import, export, use, have used, sell, have sold, offer for sale or otherwise exploit, including to Develop, Commercialize, register, modify, enhance, improve, Manufacture, have Manufactured, hold, or keep (whether for disposal or otherwise), or otherwise dispose of.

1.63 FDA ” means the United States Food and Drug Administration or any successor agency thereto.

1.64 FFDCA ” means the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §301 et seq.

1.65 Field ” means with respect to the Product, the diagnosis, treatment or prevention of disease in humans and/or animals.

1.66 First Commercial Sale ” means with respect to a Product in any country, the first sale for monetary value for use or consumption by the end user of such Product in such country after the receipt of the Marketing Authorization for such Product has been obtained in such country.

1.67 Force Majeure Event ” has the meaning set forth in Section 14.9 (Force Majeure).

1.68 FTE ” means the equivalent of the work of one duly qualified employee of CANbridge full time for one year (consisting of a total of [**] hours per year) carrying out work under any this Agreement. The portion of an FTE for an individual during a given accounting period will be determined by dividing the number of hours worked directly by said individual on the work to be conducted under this Agreement during such accounting period and the number of FTE hours applicable for such accounting period based on [**] working hours per Calendar Year.

1.69 GAAP ” has the meaning set forth in Section 1.1 (Accounting Standards).

1.70 GCP ” or “ Good Clinical Practice ” means all applicable then-current standards for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of Clinical Studies, including, as applicable, (a) as set forth in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonised Tripartite Guideline for Good Clinical Practice (CPMP/ICH/135/95) and any other guidelines for good clinical practice for trials on medicinal Products, (b) the Declaration of Helsinki (2013) as last amended at the 64th World Medical Association in October 2013 and any further amendments or clarifications thereto, (c) U.S. Code of Federal Regulations Title 21, Parts 50 (Protection of Human Subjects), 56 (Institutional Review Boards) and 312 (Investigational

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New Drug Application), and (d) the equivalent applicable Laws in any relevant country, in each case, that provide for, among other things, assurance that the clinical data and reported results are credible and accurate and protect the rights, integrity, and confidentiality of trial subjects.  

1.71 GLP ” or “ Good Laboratory Practice ” means all applicable then-current standards for laboratory activities for pharmaceuticals, as set forth in the FDA’s Good Laboratory Practice regulations as defined in 21 C.F.R. Part 58 or the Good Laboratory Practice principles of the Organization for Economic Co-Operation and Development (OECD), and such standards of good laboratory practice as are required by the European Union and other organizations and governmental agencies in countries in which a Product is intended to be sold, to the extent such standards are not less stringent than United States Good Laboratory Practice.

1.72 GMP ” or “ Good Manufacturing Practice ” means all applicable then-current standards for Manufacturing, including, as applicable, (a) the principles detailed in the U.S. Current Good Manufacturing Practices, 21 C.F.R. §§ 201, 211, 600 and 610 and all applicable FDA guidelines and requirements, (b) European Directive 2003/94/EC for medicines and investigational medicines for human use and the applicable guidelines stated in the Eudralex guidelines, (c) the principles detailed in the applicable ICH guidelines, (d) the conduct of an inspection by a Qualified Person and the execution by such Qualified Person of an appropriate certification of inspection; and (e) the equivalent applicable Laws in any relevant country, each as may be amended and applicable from time to time.

1.73 Governmental Authority ” means any multinational, federal, national, state, provincial, local or other entity, office, commission, bureau, agency, political subdivision, instrumentality, branch, department, authority, board, court, arbitral or other tribunal, official or officer, exercising executive, judicial, legislative, police, regulatory, administrative or taxing authority or functions of any nature pertaining to government.

1.74 Government Order ” means any order, writ, judgment, injunction, decree, stipulation, ruling, determination or award entered by or with any Governmental Authority.

1.75 ICH ” means the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

1.76 IND ” means an application filed with a Regulatory Authority for authorization to commence Clinical Studies, including (a) an Investigational New Drug Application as defined in the FFDCA or any successor application or procedure filed with the FDA, (b) any equivalent of a United States IND in other countries or regulatory jurisdictions, including a Clinical Trial Application (“ CTA ”) and (c) all supplements, amendments, variations, extensions and renewals thereof that may be filed with respect to the foregoing.

1.77 Indemnified Party ” means a Person entitled to indemnification under ARTICLE 10 (Indemnification; Damages).

1.78 Indemnifying Party ” means a Party from whom indemnification is sought under ARTICLE 10 (Indemnification; Damages).

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1.79 Infringement Action ” has the meaning set forth in Section 7.4.3 (Enforcement of Licensed Patents in the North America Territory).  

1.80 Infringement Claim ” has the meaning set forth in Section 7.5 (Claimed Infringement).

1.81 Insolvent Party ” has the meaning set forth in Section 3.7 (Bankruptcy Code § 365(n) Election).

1.82 International Chamber of Commerce ” or “ ICC ” has the meaning set forth in Section 13.1 (Arbitration).

1.83 Invention ” has the meaning set forth in Section 7.1.1 (Inventorship).

1.84 Joint Know-How ” means any Know-How that is first conceived or reduced to practice jointly by the Parties or their Affiliates or others acting on behalf of the Parties or their Affiliates in the conduct of Development, Manufacturing or Commercialization of the Product under this Agreement during the Term.

1.85 Joint Patent Rights ” means any Patent Rights that contain one or more claims that Cover Joint Know-How.

1.86 JSC ” has the meaning set forth in Section 2.1 (Formation; Purposes and Principles).

1.87 Know-How ” means all chemical and biological materials and other tangible materials, inventions, practices, methods, protocols, formulae, knowledge, know-how, trade secrets, processes, procedures, assays, skills, experience, techniques, data and results of experimentation and testing, including pharmacological, toxicological and pre-clinical and clinical test data and analytical and quality control data, patentable or otherwise.

1.88 Knowledge ” or “ Known ” means, with respect to AVEO, the actual knowledge of any of the individuals listed on Schedule 1.88 attached hereto.

1.89 Law ” or “ Laws ” means all laws, statutes, rules, codes, regulations, orders, decrees, judgments or ordinances of any Governmental Authority, or any license, permit or similar right granted under any of the foregoing, or any similar provision having the force or effect of law.

1.90 Licensed Know-How ” means any Know-How Controlled by AVEO or its Affiliates as of the Effective Date or during the Term (including any AVEO Inventions and AVEO’s interest in the Joint Know-How) that is necessary or useful to Exploit a Product in the Field and in the Territory.

1.91 Licensed Patents ” means any Patent Rights Controlled by AVEO or its Affiliates as of the Effective Date or during the Term (including (a) the Patent Rights identified on Schedule 9.2.1 (Licensed Patents) and (b) AVEO’s interest in the Joint Patent Rights), in each case, that are necessary or useful to Exploit a Product in the Field and in the Territory.

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1.92 Licensed Territory ” means worldwide, excluding the North America Territory.  

1.93 Licensed Territory Infringement Action ” has the meaning set forth in Section 7.4.2 (Enforcement of Licensed Patents in the Licensed Territory).

1.94 Losses ” means damages, losses, liabilities, costs (including costs of investigation, defense), fines, penalties, taxes, expenses, or amounts paid in settlement (in each case, including reasonable attorneys’ and experts’ fees and expenses), in each case resulting from an Action by a Third Party.

1.95 MAA ” means (a) a marketing authorization application filed with (i) the EMA under the centralized EMA filing procedure or (ii) a Regulatory Authority in any EU country if the centralized EMA filing procedure is not used, or (b) any other equivalent or related regulatory submission, in either case to gain approval to market a Product in any country in the EU, and, in each case, including any amendments thereto, and supplemental applications but excluding Pricing and Reimbursement Approval applications.

1.96 Major Market Country ” means each of China, Japan, the United Kingdom, France, Italy, Spain, and Germany.

1.97 Manufacture ” or “ Manufacturing ” means all activities related to the production of a Product, including the production of any of the following to the extent used in a Product: any drug substance produced in bulk form for use as an active pharmaceutical ingredient, drug product, compounded or finished final packaged and labeled form, and in intermediate states, including but not limited to the following activities: reference standard preparation, cell bank preparation, mammalian cell production, purification, formulation, scale-up, packaging, disposition of product, quality assurance oversight, quality control testing (including in-process release and stability testing), storage of product or any component or ingredient thereof and validation activities directly related to all of the foregoing, and data management and recordkeeping related to all of the foregoing. References to a Person engaging in Manufacturing activities will include having any or all of the foregoing activities performed by a Third Party.

1.98 Marketing Authorization ” means the grant of all necessary permits, registrations, authorizations, licenses and approvals (or waivers) required for the Manufacture and Commercialization of a Product for use in the Field and in the Territory, including any Regulatory Approval for sale or marketing, and, where required, Pricing and Reimbursement Approvals.

1.99 Net Sales ” means, with respect to a Product for any period, the total gross amount billed or invoiced on sales of such Product during such period by CANbridge, its Affiliates, or Sublicensees (other than Distributors and Profit Share Sublicensees) in the Licensed Territory to Third Parties (including Distributors), in bona fide arm’s length transactions, less the following deductions, in each case related specifically to the Product and actually incurred, paid or accrued by CANbridge, its Affiliates or Sublicensees and not otherwise recovered by or reimbursed to CANbridge, its Affiliates, or Sublicensees:

(a) trade, cash, price, and quantity discounts actually given to Third Parties;

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(b) price reductions, rebates or other payments, retroactive or otherwise, imposed by, negotiated with or otherwise paid to Governmental Authorities or other payees;  

(c) taxes and other governmental charges and fees on sales (such as sales, value added, or use taxes, other than income taxes) to the extent added to the sale price and set forth separately as such in the total amount invoiced and borne by such Third Party;

(d) amounts repaid or credited by reason of rejections, defects, return goods allowances, recalls or returns, or because of retroactive price reductions, including rebates or wholesaler charge backs;

(e) the portion of administrative fees, chargeback payments and rebates (or the equivalent thereof) paid during the relevant time period to group purchasing organizations, Governmental Authorities, trade customers, managed health care organizations or pharmaceutical benefit managers or Medicare prescription drug plans (or analogous plans) relating to such Product;

(f) bad debts actually written off which are attributable to sales of Products not to exceed 1% of Net Sales, to the extent such amounts have not been previously deducted;  provided, however, that any such amounts that are written off will be added back in a subsequent period to the extent later collected; and

(g) freight, insurance, import/export, and other transportation charges to the extent added to the sale price and set forth separately as such in the total amount invoiced, as well as any fees for services provided by wholesalers and warehousing chains related to the distribution of such Product.

Net Sales will not include transfers or dispositions of Product for charitable, promotional, pre-clinical, clinical, regulatory, or governmental purposes, in all cases, without consideration.  Net Sales will include the amount or fair market value of all other consideration received by CANbridge, its Affiliates or Sublicensees in respect of the Product, whether such consideration is in cash, payment in kind, exchange or other form.  Net Sales will be calculated only once for the first bona fide arm's length sale of a Product by a CANbridge, its Affiliates or its permitted Sublicensees to a Third Party, and will not include sales between or among CANbridge, its Affiliates, or Sublicensees (other than Distributors or as described in the following paragraph regarding Profit Share Sublicensees).

In the event of a sale of a Product by CANbridge or its Affiliates to a Profit Share Sublicensee, then the Net Sales for such Product in a given Calendar Quarter will (A) include the transfer price payment (minus any applicable deductions set forth in clauses (a) through (g) above) for such Product sold to the Profit Share Sublicensee in such Calendar Quarter and (B) exclude the Profit Share Payment and any amounts paid to the Profit Share Sublicensee in connection with its subsequent resale of such Product.

Subject to the above, Net Sales will be calculated in accordance with the standard internal policies and procedures of CANbridge, its Affiliates, or Sublicensees, if any, copies of which policies and procedures will be furnished to AVEO upon request, and which must in any case be in accordance with its Accounting Standards.

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In the event a Product is sold in the form of a Combination Product, then the Net Sales for any such Combination Product will be determined by multiplying the Net Sales of the Combination Product during the applicable royalty reporting period, by the fraction, A/(A +B), where A is the weighted (by sales volume) average sale price of the Product when sold separately in finished form in the country in which the Combination Product is sold and B is the weighted (by sales volume) average sale price of the other product(s) which contain the other significantly active ingredient(s) included in the Combination Product when sold separately in finished form in the country in which the Combination Product is sold, in each case during the applicable royalty reporting period or, if sales of both the Product and the other product(s) did not occur in such period, then in the most recent royalty reporting period in which sales of both occurred. In the event that such average sale price cannot be determined for both the Product and all other significantly active pharmaceutical ingredient(s) included in the Combination Product, then the Parties will in good faith discuss and agree on a pro-rata allocation of the Net Sales that reflects the Product's contribution to the Combination Product on an equitable basis; provided, however, that, (i) until such time as the Parties reach agreement upon an appropriate pro-rata allocation, the Parties will use a deemed allocation equal to fifty percent (50%) between the Product and the other product(s) which contain the other significantly active ingredient(s) for purposes of determining Net Sales (which allocation the Parties hereby agree will not be used as a benchmark or point of reference for the actual allocation to be agreed upon by the Parties) and (ii) promptly following the Parties reaching agreement on the appropriate pro-rata allocation, an adjustment will be made in future payments of Net Sales for such Combination Product to account for the difference between the deemed allocation and the agreed-upon allocation.  

1.100 Non-Acquired Party ” has the meaning set forth in Section 3.5.2 (Protective Procedures).

1.101 Non-Breaching Party ” has the meaning set forth in Section 12.2.1 (Termination for Material Breach).

1.102 North America Territory ” means the United States, Canada and Mexico, and their respective territories and possessions.

1.103 North America Infringement Action ” has the meaning set forth in Section 7.4.3 (Enforcement of Licensed Patents in the North America Territory).

1.104 On-Going Clinical Study ” has the meaning set forth in Section 12.3.7 (On-Going Trials).

1.105 Party ” means either AVEO or CANbridge; “ Parties ” means AVEO and CANbridge, collectively.

1.106 Patent Rights ” means the rights and interests in and to (a) all patents and patent applications (including provisional applications), including all divisionals, continuations, substitutions, continuations-in-part, re-examinations, re-issues, additions, renewals, extensions, confirmations, registrations, any other pre- or post-grant forms of any of the foregoing, (b) any confirmation patent or registration patent or patent of addition, utility models, patent term extensions, and supplemental protection certificates or requests for continued examinations,

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foreign counterparts, and the like of any of the foregoing, (c) any and all patents that have issued or in the future issue from the foregoing patent applications, including author certificates, utility models, petty patents, innovation patents and design patents and certificates of invention.  

1.107 Person ” means any natural person, corporation, general partnership, limited partnership, joint venture, proprietorship or other business organization or a Governmental Authority.

1.108 Phase II Clinical Study ” means a clinical study in humans of the safety, dose ranging and efficacy of a pharmaceutical Product, as described in federal regulation 21 C.F.R. § 312.21(b) and its foreign equivalents.

1.109 Phase IIa Clinical Study ” means a Phase II Clinical Study specifically designed to assess dosing range and requirements.

1.110 Phase III Clinical Study ” means a controlled clinical study, or a portion of a controlled study, in humans of the efficacy and safety of a Product, which study (in its entirety or portion, as applicable), is prospectively designed to demonstrate statistically whether such Product is effective and safe for use in a particular indication in a manner sufficient to file an BLA, MAA or other Regulatory Approval Application to obtain Regulatory Approval, as further defined in federal regulation 21 C.F.R. § 312.21(c) and its foreign equivalents.  For clarity, with respect to what is commonly called a phase 2/3 study, the Phase III Clinical Study definition is met upon the first patient, first visit in the portion of such study that is prospectively designed to demonstrate statistically whether such pharmaceutical Product is effective and safe for use in a particular indication in a manner sufficient to file a BLA, MAA or other Regulatory Approval Application to obtain Regulatory Approval, as further defined in federal regulation 21 C.F.R. § 312.21(c) and its foreign equivalents.

1.111 POC Development Plan ” means the written plan for CANbridge’s Development efforts in connection with the conduct of the POC Study (including a description of the POC Study itself), prepared and finalized by CANbridge in accordance with Section 4.2 (Development Authorities), as amended from time to time in accordance with this Agreement.

1.112 POC Study Data Package ” means a package of information regarding the results of the POC Study containing the information and data described in Schedule 1.112 .

1.113 POC Study ” means, with respect to a Product, a Phase IIa Clinical Study that is appropriately designed (a) to demonstrate efficacy in Esophageal Squamous Cell Carcinoma (“ ESCC ”) through relevant primary and/or secondary efficacy endpoints as described in the POC Development Plan and (b) to support generation of efficacy data that would allow movement of such Product into a Phase IIa Clinical Study or Phase III Clinical Study that would support the regulatory strategy of seeking Regulatory Approval for ESCC in the Territory.

1.114 POC Study ROFN ” has the meaning set forth in Section 4.4 (POC Study ROFN).

1.115 POC Study ROFN Period ” has the meaning set forth in Section 4.4 (POC Study ROFN).

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1.116 Pricing and Reimbursement Approval ” means, with respect to a Product, the governmental approval, agreement, determination or decision establishing the price or level of reimbursement for such Product, in a given jurisdiction prior to sale of such Product in such jurisdiction.  

1.117 Prior CDA ” means the Confidential Disclosure Agreement between AVEO and CANbridge, dated 4th February 2015 (the “ Prior CDA Effective Date ”).

1.118 Prior CDA Effective Date ” has the meaning set forth in Section 1.117 (Prior CDA).

1.119 Product ” means any product that contains, incorporates, comprises or is derived from any ERBB3 Antibody (a) that is discovered, Developed or Controlled by or on behalf of AVEO or any of its Affiliates prior to or during the Term or (b) the Development, Manufacture or Commercialization of which is Covered by a Licensed Patent.

1.120 “Profit Share Payments ” means any payments made by a Profit Share Sublicensee to CANbridge or its Affiliates with respect to any Product that are calculated based on a percentage of a Profit Share Sublicensee’s markup or profit on its resale of such Product.

1.121 Profit Share Sublicensee ” means a Sublicensee in any country in the Territory other than in Europe and Japan that (a) purchases Products from CANbridge or its Affiliate in consideration for a transfer price and (b) pays AVEO or its Affiliate a percentage of its markup or profit on the resale of such Products.

1.122 Qualified Person ” or “ QP ” means a qualified person as defined the Clinical Trial Directive 2001/20/EC and Annex 13 to the European GMP Guide.

1.123 Recall ” means a Party’s removal or correction of a Product following (a) notice or request of any Regulatory Authority or (b) the good faith determination by such Party that an event, incident or circumstance has occurred that required such a recall of such Product.  A Recall does not include a market withdrawal or a stock recovery.

1.124 Regulatory Approval Application ” means a BLA, an MAA or other equivalent application to seek Regulatory Approval of a Product for sale or marketing in any country(ies) outside the United States, as defined in the applicable Laws and filed with the Regulatory Authority of such country(ies).

1.125 Regulatory Approval ” means the approval of the applicable Regulatory Authority necessary for the marketing and sale of a Product in the Field in a country(ies), excluding separate Pricing and Reimbursement Approval that may be required.

1.126 Regulatory Authority ” means any multinational, federal, national, state, provincial or local regulatory agency, department, bureau or other governmental entity with authority over the clinical development, manufacture, marketing and sale of a Product in a country, including FDA in the United States and EMA in the EU.

1.127 Regulatory Documentation ” means the documents set forth on Exhibit C .

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1.128 Regulatory Filing ” means any documentation comprising or relating to or supporting any filing or application with any Regulatory Authority with respect to a Product, including any documents submitted to any Regulatory Authority, including INDs, Regulatory Approval Applications, and all correspondence with any Regulatory Authority with respect to any Product (including minutes of any meetings, telephone conferences or discussions with any Regulatory Authority).  

1.129 ROFN ” has the meaning set forth in Section 4.4.3 (Right of First Negotiation).

1.130 ROFN Opportunity ” has the meaning set forth in Section 4.4.1 (POC Study ROFN).

1.131 ROFN Period ” has the meaning set forth in Section 4.4.3 (Right of First Negotiation).

1.132 Royalty Term ” has the meaning set forth in Section 6.3.2 (Royalty Term).

1.133 Rules ” has the meaning set forth in Section 13.1 (Arbitration).

1.134 Safety Data ” means any Adverse Event information from human trials and all results from non-clinical safety studies, including, but not limited to, toxicology and carcinogenity data (if any), with respect to a Product required by one or more Regulatory Authorities to be collected or to be reported to such Regulatory Authorities under applicable Laws, but excluding any information related to the efficacy of the Product.

1.135 Sales Milestone Event ” has the meaning set forth in Section 6.1.4 (Sales Milestone Payments).

1.136 Sales Milestone Payment ” has the meaning set forth in Section 6.1.4 (Sales Milestone Payments).

1.137 Serious Adverse Event ” or “ SAE ” has the meaning set forth in 21 C.F.R. § 312.32, and generally means any Adverse Event that (a) results in death, (b) is life-threatening, (c) requires inpatient hospitalization or prolongation of existing hospitalization, (d) results in persistent or significant disability or incapacity or (e) is a congenital anomaly or birth defect.  

1.138 Severed Clause ” has the meaning set forth in Section 14.4 (Severability).

1.139 Significant Development Event ” means any of the following Development events: (a) any material interaction and/or written correspondence between a Party and any Regulatory Authority with respect to any Product; (b) any material event with respect to any Clinical Study involving any Product; and (c) any material result obtained in the conduct of any Clinical Study involving any Product during the period covered by the Development Report.

1.140 Sublicense ” has the meaning set forth in Section 3.3.3 (Sublicense Requirements).

1.141 Sublicense Payment ” has the meaning set forth in Section 6.2.1 (Sublicense Payments).

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1.142 Sublicense Revenue Percentage ” has the meaning set forth in Section 6.2.1 (Sublicense Payments).  

1.143 Sublicense Revenue ” means all payments received by CANbridge or its Affiliates from a Sublicensee in consideration for a Sublicense, including upfront payments, maintenance fees and development milestone payments, but excluding payments received based on sales of Products, such as royalty payments, sales milestone payments or profit share payments (including Profit Share Payments). For the avoidance of doubt, Sublicense Revenue will not include (a) amounts paid to CANbridge by a Sublicensee (i) in respect of future Development costs or in consideration of services performed by CANbridge, to the extent such Development costs or services represent a transaction for fair market value, or (ii) as a loan or equity investment in CANbridge, provided , however , that any portion of such loan or equity investment that does not represent a transaction for fair market value would be included as a Sublicense Revenue and (b) any transfer price payments and/or Profit Share Payments paid to CANbridge by a Profit Share Sublicensee.

1.144 Sublicensee ” means, with respect to a Party, a Third Party sublicensee of rights granted to such Party under this Agreement or a Third Party licensee of rights with respect to a Product which rights are retained by such Party under this Agreement with respect to such Product.

1.145 Supply Agreement ” has the meaning set forth in Section 5.1.5 (Supply Terms).

1.146 Technology Transfer ” has the meaning set forth in Section 5.1.1 (Transfer of Licensed Know-How).

1.147 Technology Transfer Plan ” has the meaning set forth in Section 5.1.1 (Transfer of Manufacturing Know-How).

1.148 Term ” has the meaning set forth in Section 12.1 (Term).

1.149 Territory ” means the Licensed Territory for CANbridge and the North America Territory for AVEO, as applicable.

1.150 Third Party ” means any Person other than a Party or any of its Affiliates.

1.151 Third Party Claim ” has the meaning set forth in Section 10.3.1 (Notice).

1.152 Third Party Collaboration Agreement ” has the meaning set forth in Section 4.6.1 (Unblocking Rights).

1.153 Third Party Partner ” has the meaning set forth in Section 4.6.1 (Unblocking Rights).

1.154 Trademark ” means any trademark, trade name, service mark, service name, brand, domain name, trade dress, logo, slogan or other indicia of origin or ownership, including the goodwill and activities associated with each of the foregoing.

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1.155 United States ,” “ U.S. ” “ US ” or “ US Territory ” means the United States of America and its territories and possessions.  

1.156 UPC ” has the meaning set forth in Section 7.6 (EU Unitary Patent System).

1.157 USPTO ” has the meaning set forth in Section 7.2.2 (In the North America Territory).

1.158 Valid Claim ” means a claim (including a process, use, or composition of matter claim) of (a) an issued and unexpired patent that has not (i) irretrievably lapsed or been abandoned, revoked, dedicated to the public or disclaimed or (ii) been held invalid, unenforceable or not patentable by a court, governmental agency, national or regional patent office or other appropriate body that has competent jurisdiction, which holding, finding or decision is final and unappealable or unappealed within the time allowed for appeal or (b) a pending patent application, which claim has not been abandoned or finally disallowed without the possibility of appeal; provided, that, if a pending patent application has been pending for longer than seven years from the date of filing of the initial priority application, then such corresponding claim in such pending patent application will not be deemed to be a Valid Claim.

1.159 Validation of Manufacturing Development ” means the validation, to CANbridge’s reasonable satisfaction, of the Manufacturing development activities conducted by AVEO prior to the Effective Date, which in any event will occur upon the completion by CANbridge or its designated CMO of an engineering run of Product drug substance using the manufacturing process used by AVEO to manufacture Product drug substance prior to the Effective Date, which engineering run enables CANbridge to perform its planned preclinical studies with respect to the Product.  

1.160 Withholding Party ” has the meaning set forth in Section 6.9.2 (Tax Withholding).

ARTICLE 2
GOVERNANCE; JOINT STEERING COMMITTEE

2.1 Formation; Purposes and Principles .  Promptly following the Effective Date, but in no event later than [**] days thereafter, AVEO and CANbridge will form a joint steering committee (the “ JSC ”) to provide oversight and to facilitate information sharing between the Parties with respect to the activities of the Parties under this Agreement.  

2.2 Specific Responsibilities .  In addition to its overall responsibility to provide oversight and to facilitate information sharing between the Parties with respect to the activities of the Parties under this Agreement, the JSC will:

(a) review and approve changes to the POC Development Plan proposed by CANbridge on an as-needed basis;

(b) review and discuss, as necessary, the Parties’ Development and Manufacturing activities related to the Products, including the performance of each Party, or a Party’s Affiliate or Sublicensee, as applicable, in performing the activities under the POC Development Plan;

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(c) coordinate and share information with respect to the Development and Commercialization of Products;  

(d) keep each Party reasonably informed of the other Party’s Development and Manufacturing activities and Commercialization activities and interactions with Regulatory Authorities, by receiving updates from the Party conducting such activities;

(e) attempt to resolve in the first instance all matters between the Parties that are in dispute; and

(f) perform such other functions as are assigned to it in this Agreement or as appropriate to further the purposes of this Agreement to the extent agreed to in writing by the Parties.

2.3 Membership .  The JSC will be composed of an equal number of representatives appointed by each of AVEO and CANbridge.  Each individual appointed by a Party as a representative to the JSC will be an employee or contractor of such Party, or an employee or contractor of such Party’s Affiliate.  Each Party may replace any of its JSC representatives at any time upon written notice to the other Party, which notice may be given by e-mail, sent to the other Party’s co-chairperson.  The JSC will be co-chaired by one designated representative of each Party.  The co-chairperson of the JSC will cast its Party’s vote on the JSC and such designee will have the authority to make decisions on behalf of such Party.  The co-chairpersons will be responsible for (a) calling meetings, (b) preparing and circulating an agenda in advance of each meeting; provided , however , that the co-chairpersons will include any agenda items proposed by either Party on such agenda, and (c) preparing and issuing minutes of each meeting promptly thereafter.  Each JSC representative will be subject to confidentiality obligations no less stringent than those in ARTICLE 8 (Confidentiality and Publicity).

2.4 Meetings; Reports .  The JSC will hold meetings [**] during the Term for so long as the JSC exists; provided , however , that, in the event the Parties enter into a Collaboration Agreement or an Expanded License pursuant to Section 4.4.2 (North America Territory ROFN), the JSC will meet no less frequently than [**]. At least [**] Business Days prior to each meeting of the JSC, each Party will provide a reasonably detailed report describing its Development and Manufacturing activities under the POC Development Plan and this Agreement conducted to date.  The JSC may meet in person or by audio or video conference as its representatives may mutually agree.  Other representatives of the Parties, their Affiliates and Third Parties involved in the Development, Manufacture or Commercialization of the Products may be invited by the members of the JSC to attend meetings as non-voting observers; provided , however , that such representatives are subject to confidentiality obligations no less stringent than those in ARTICLE 8 (Confidentiality and Publicity); provided , further , that each representative appointed by a Party to take action at a meeting will have sufficient authority to execute such action on behalf of such Party.  No action taken at a meeting will be effective unless at least one representative of each Party is present or participating.  Neither Party will unreasonably withhold attendance of at least one representative of such Party at any meeting of the JSC for which reasonable advance notice was provided.

2.5 Decision-Making ; Escalation to Executive Officers .  The Parties will endeavor in good faith to reach unanimous agreement with respect to all matters within the JSC’s authority.

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Should the JSC not be able to reach agreement with respect to such matter at a duly called meeting of the JSC, either Party may refer such matter to the Executive Officers for resolution, and the Executive Officers will attempt to resolve the matter in good faith.  If the Executive Officers fail to resolve such matter within [**] Business Days after the date on which the matter is referred to the Executive Officers (unless a longer period is agreed to by the Parties), then decisions regarding such matter may be finally determined by CANbridge; provided , however , that CANbridge will only exercise such final decision-making authority after the good faith consideration of AVEO’s position; and provided , further , that CANbridge will not be entitled to use such final decision-making authority, and any decision must be unanimous in the event of any disagreement or deadlock at the JSC, with respect to the following matters:  

2.5.1 any amendment of the POC Development Plan in a manner that fails to satisfy the minimum requirements set forth in Section 4.2 (Development Authorities), unless such amendment is the result of AVEO’s failure to comply with its obligations under this Agreement;

2.5.2 the negation of any consent right or other rights specifically allocated to AVEO under this Agreement or any obligation of CANbridge set forth in this Agreement; or

2.5.3 the expansion or narrowing of the responsibilities of the JSC.

For clarity, AVEO will have the sole right to make any final decisions related to the Development, Manufacture and/or Commercialization by AVEO of the Product in the North America Territory.

2.6 Alliance Managers .  

2.6.1 Appointment .  Each Party will have the right, but not the obligation, to appoint a person to oversee interactions between the Parties for all matters related to the Development and Commercialization of Products between meetings of the JSC (each, an “ Alliance Manager ”).  The Alliance Managers will have the right to attend all meetings of the committees as non-voting participants and may bring to the attention of the JSC any matters or issues either Alliance Manager reasonably believes should be discussed and will have such other responsibilities as the Parties may mutually agree in writing.  Each Party may replace its Alliance Manager at any time or may designate different Alliance Managers with respect to Development and Commercialization matters, respectively, by notice in writing to the other Party.

2.6.2 Responsibility .  The Alliance Managers, if appointed, will have the responsibility of creating and maintaining a constructive work environment within the JSC and between the Parties for all matters related to this Agreement.  Without limiting the generality of the foregoing, each Alliance Manager will:

(a) provide a single point of communication within the Parties’ respective organizations and between the Parties with respect to this Agreement; coordinate cooperative efforts, internal communications and external communications between the Parties with respect to this Agreement; and

(b) take such other steps as may be required to ensure that meetings of the committees occur as set forth in this Agreement, that procedures are followed with respect to such meetings (including the giving of proper notice and the preparation and approval of minutes)

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and that relevant action items resulting from such meetings are appropriately carried out or otherwise addressed.  

ARTICLE 3
LICENSE GRANTS

3.1 AVEO License Grant; Right of Reference .  

3.1.1 Exclusive License Grant .  Subject to the terms and conditions of this Agreement, including the provisions of Section 4.4.2(b) (Failure to Reach Agreement), AVEO hereby grants to CANbridge an exclusive (even with respect to AVEO and its Affiliates), sublicenseable (subject to Section 3.3.1 (CANbridge Right to Sublicense)), royalty-bearing right and license under the Licensed Patents and Licensed Know-How to (a) Develop, Manufacture, Commercialize and otherwise Exploit the Product in the Field in the Licensed Territory, and (b) Develop and Manufacture Products outside the Licensed Territory solely for the purpose of Commercializing such Products inside the Licensed Territory.

3.1.2 CANbridge Right of Reference .  Subject to the terms of this Agreement, AVEO hereby grants to CANbridge access to, and a right of reference with respect to, (a) its Regulatory Filings and corresponding documentation to the extent Controlled by AVEO as of the Effective Date, and (b) Safety Data and CMC Data contained or referenced in any Regulatory Filings and corresponding documentation Controlled by AVEO at any time during the Term, in each case ((i) and (ii)), for the sole purpose of Developing and Manufacturing the Product in the Licensed Territory.  For clarity, the foregoing will not obligate AVEO to maintain an active IND or Regulatory Approval Application with respect to any Product.

3.2 CANbridge License Grant; Right of Reference .  

3.2.1 License Grant . Subject to the terms and conditions of this Agreement, CANbridge hereby grants to AVEO a non-exclusive, royalty-free, sublicenseable (subject to Section 3.3.2 (AVEO Right to Sublicense)), right and license under the CANbridge Program Patents and CANbridge Program Know-How (a) to Develop, Manufacture, Commercialize, use and otherwise Exploit the Product in the Field in the North America Territory and (b) to Develop Products outside the North America Territory solely for the purpose of Commercializing such Products inside the North America Territory.  

3.2.2 AVEO Right of Reference .  Subject to the terms of this Agreement, CANbridge hereby grants to AVEO access to, and a right of reference with respect to, Safety Data and CMC Data contained or referenced in any Regulatory Filing and corresponding documentation Controlled by CANbridge during the Term for the sole purpose of Developing and Manufacturing the Product in the North America Territory. For clarity, the foregoing will not obligate CANbridge to maintain an active IND or Regulatory Approval Application with respect to any Product.

3.3 Sublicensing and Subcontracting .  

3.3.1 CANbridge Right to Sublicense .  CANbridge will have the right to grant Sublicenses (through multiple tiers) to its Affiliates or Third Parties of any and all rights granted to CANbridge by AVEO pursuant to Section 3.1 ( AVEO License Grant; Right of Reference ), provided , however , that CANbridge will provide AVEO with written notice of its intent to grant

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any such Sublicense (or an option to receive a Sublicense) of rights to Commercialize the Product pursuant to this Section 3.3.1 ( CANbridge Right to Sublicense ) at least [**] days, with respect to any country in Europe, and at least [**] days, with respect to any country in the Licensed Territory outside of Europe, before it enters into any agreement containing any such Sublicense (or option to receive a Sublicense), and CANbridge will consider in good faith any AVEO proposal for such Sublicense (or option to receive a Sublicense) to be granted to it.  In the event that CANbridge grants a Sublicense pursuant to this Section 3.3.1 ( CANbridge Right to Sublicense ), CANbridge will remain responsible for its obligations under this Agreement and will ensure that each of its Sublicensees complies with all relevant provisions of this Agreement.  

3.3.2 AVEO Right to Sublicense .  AVEO will have the right to grant Sublicenses (through multiple tiers) to its Affiliates or Third Parties of any and all rights granted to AVEO by CANbridge pursuant to Section 3.2 ( CANbridge License Grant ; Right of Reference), provided , however , that in the event that AVEO grants a sublicense pursuant to this Section 3.3.2 (AVEO Right to Sublicense), AVEO will remain responsible for its obligations under this Agreement and will ensure that each of its Sublicensees complies with all relevant provisions of this Agreement.

3.3.3 Sublicense Requirements .  Each license or Sublicense granted by a Party to an Affiliate or a Third Party (including any subcontractor) pursuant to Section 3.3.1 (CANbridge Right to Sublicense) or 3.3.2 (AVEO Right to Sublicense) (a “ Sublicense ”) will be in writing and will be consistent with the relevant restrictions and limitations set forth in this Agreement.  No Sublicense or subcontract will diminish, reduce or eliminate any obligation of either Party under this Agreement.

3.3.4 Performance by CANbridge Sublicensees .   CANbridge will promptly provide AVEO with a copy of any fully executed Sublicense agreement covering any Sublicense granted hereunder.  Any such Sublicense agreement entered into by CANbridge will contain the following provisions:  (a) a requirement that such Sublicensee submit applicable sales or other reports to AVEO to the extent necessary or relevant to the reports required to be made or records required to be maintained under this Agreement; (b) an audit requirement consistent with that set forth in Section 6.8 (Financial Audits); (c) a requirement that such Sublicensee comply with the confidentiality provisions and restrictions on use of Confidential Information contained in Section 8.1 (Confidential Information) with respect to AVEO’s Confidential Information; and (d) those provisions required by the Existing Third Party License Agreements that are listed on Schedule 3.3.4 attached hereto.

3.4 Exclusivity Covenant .  During the Term, neither AVEO and its Affiliates nor CANbridge and its Affiliates will directly or indirectly conduct, have conducted, engage in or fund any activity that involves the Development or Commercialization of any ErbB3 inhibitory Antibody product other than the Product pursuant to the terms and conditions set forth in this Agreement.  

3.5 Acquisition Transactions .  

3.5.1 Effect of Acquisition Transaction . Notwithstanding anything to the contrary in this Agreement, in the event of an acquisition of a Party or its business (an “ Acquired Party ”) by a Third Party (an “ Acquirer ”) after the Effective Date, directly or indirectly, whether by merger, asset purchase or otherwise (each, an “ Acquisition Transaction ”), then, as to any such

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Acquirer, (a) any Patent Rights, Know-How, or Regulatory Approvals that are held at the time of such acquisition by the Acquirer, or any Affiliate of the Acquirer that becomes an Affiliate of the Acquired Party as a result of such acquisition, will be deemed not to be Controlled by the Acquired Party, and (b) subject to Section 3.5.2 (Protective Procedures), such Acquirer will not be obligated to comply with the covenants in Section 3.4 (Exclusivity Covenant), as applicable, with respect to any program involving the research, development or commercialization of any ErbB3 inhibitory Antibody product conducted by such Acquirer immediately prior to such acquisition (a “ Competitive Program ”).  

3.5.2 Protective Procedures . Notwithstanding the foregoing, concurrently with the consummation of the Acquisition Transaction, the Acquired Party will prepare, present to the other Party (the “ Non-Acquired Party ”) for its review, and implement a plan that outlines the  procedures to be implemented to establish an ethical wall to ensure that (a) any information with respect to this Agreement or any Product that is disclosed to the Acquiring Party during due diligence is returned to the other Party or destroyed, (b) subject to subsection (a), all Confidential Information, in both hard and electronic copy, of AVEO and CANbridge that relates to this Agreement or the Product will be kept separate from the Acquirer, (c) the Acquirer will not use any Know-How or Patent Rights Controlled by the Acquired Party immediately prior to the Acquisition Transaction at any time during the Term to research, develop and/or commercialize any Competitive Program, (d) no employees of the Acquired Party or its Affiliates work on any product that is the subject of the Competitive Program for a period of at least one year following such employee’s conclusion of work on the Development or Commercialization of a Product, and (e) no employees of such Acquirer or its Affiliates as of the date of consummation of the Acquisition Transaction will thereafter conduct any activities that involve the Development or Commercialization of any Product. In addition, the resources devoted by the Acquired Party to, and the efforts of the Acquired Party required for, the conduct of the Competitive Program will not be factored into, or otherwise affect, CANbridge’s obligations under Sections 4.3.1 (Development Diligence) or 5.2.3 (Commercialization Diligence). The procedures set forth in this Section 3.5.2 (Protective Procedures) will remain in place during the Term of this Agreement.

3.6 Reservation of Rights .  No rights, other than those expressly set forth in this Agreement, are granted to either Party under this Agreement, and no additional rights will be deemed granted to either Party by implication, estoppel or otherwise, with respect to any intellectual property rights.  All rights not expressly granted by either Party or its Affiliates to the other under this Agreement are reserved. Without limiting the generality of the foregoing, AVEO hereby retains the right under the Licensed Patents and Licensed Know-How (a) to Develop, Commercialize and Manufacture all products that do not comprise or contain an ERBB3 Antibody, (b) to perform its obligations under this Agreement, (c) to Develop Products for Commercialization in the North America Territory and (d) to Develop Products outside the North America Territory solely for the purpose of Commercializing such Products inside the North America Territory.

3.7 Bankruptcy Code § 365(n) Election .  All rights and licenses now or hereafter granted under or pursuant to this Agreement, including pursuant to Section 3.1 (AVEO License Grant; Right of Reference) and Section 3.2 (CANbridge License Grant; Right of Reference), are rights to “ intellectual property ” (as defined in Section 101(35A) of Title 11 of the United States Code, as amended (such Title 11, the “ Bankruptcy Code ”)).  Each Party, as licensee of such rights

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under this Agreement, will retain and may fully exercise all of its rights and elections under the United States Bankruptcy Code.  In the event of the commencement of a bankruptcy proceeding by or against a Party under the Bankruptcy Code (the “ Insolvent Party ”), the other Party will be entitled to a complete duplicate of (or complete access to, as appropriate) any intellectual property licensed to it under this Agreement and all embodiments of such intellectual property (including all information related to such intellectual property and rights of reference with respect to Regulatory Approvals), and same, if not already in its possession, will be promptly delivered to it (a) upon any such commencement of a bankruptcy proceeding upon its written request therefore, unless the Insolvent Party continues to perform all of its obligations under this Agreement, or (b) if not delivered or granted under (a) above, following the rejection of this Agreement by or on behalf of the Insolvent Party upon written request therefore by the other Party. The Parties hereto acknowledge and agree that all payments by CANbridge to AVEO under this Agreement, other than royalty payments pursuant to Section 6.3 (Royalties), do not constitute royalties within the meaning of Bankruptcy Code §365(n) or relate to licenses of intellectual property under this Agreement.  

3.8 No Inconsistent Third Party Agreements .  During the Term, neither AVEO nor any of its Affiliates will enter into any license of intellectual property pursuant to which AVEO or any of its Affiliates grants to a Third Party rights under or to Know-How and Patent Rights, or otherwise enters into any agreement, that would contravene or be inconsistent or in conflict with the rights of CANbridge or the obligations of AVEO under this Agreement.  During the Term, neither AVEO nor any of its Affiliates will amend, modify or terminate any in-license of Third Party intellectual property (including, without limitation, any such in-license that is in effect as of the Effective Date) without the prior written consent of CANbridge (which may be granted or withheld by CANbridge in its absolute discretion) if such amendment, modification or termination would materially adversely affect any of the rights that CANbridge or any of its Affiliates has under this Agreement.

 

ARTICLE 4
DEVELOPMENT

4.1 Development Responsibilities .  Subject to the terms and conditions of this Agreement, including this ARTICLE 4 (Development):

(a) CANbridge will be solely responsible, at its own expense, for Developing Products for the purpose of obtaining Regulatory Approval and Commercializing Products in the Licensed Territory; provided , however , that, AVEO will have the right, at its sole cost and expense, to file an IND and conduct Clinical Studies for the Product in any country in the Licensed Territory in any indication in which CANbridge or its Affiliates or Sublicensees does not have an active IND for the same indication in such country, for the sole purpose of obtaining Marketing Authorization and Commercializing the Product in the North America Territory; provided further , that such IND and such Clinical Studies for the Product would not reasonably be expected to materially and adversely affect the Development or Commercialization of the Product in the Licensed Territory.

(b) AVEO will be solely responsible, at its own expense, for Developing Products for the purpose of obtaining Regulatory Approval and Commercializing

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Products in the North America Territory; provided , however , that CANbridge will have the right, at its sole cost and expense, to file an IND and conduct Clinical Studies for the Product in any country in the North America Territory in any indication in which AVEO or its Affiliates or Sublicensees does not have an active IND for the same indication in such country, for the sole purpose of obtaining Marketing Authorization and Commercializing the Product in the Licensed Territory; provided , that , such IND and such Clinical Studies for the Product would not reasonably be expected to materially and adversely affect the Development or Commercialization of the Product in the North America Territory.  

4.2 Development Authorities .  

4.2.1 POC Development Plan .  The Development of the Products under this Agreement will be governed by the POC Development Plan. The initial approved POC Development Plan is attached hereto as Exhibit A .  The POC Development Plan will include, with respect to the Product, the strategy for pre-clinical and clinical studies necessary to demonstrate proof-of-concept for the Product for the treatment of squamous cell esophagus cancer, including a POC Study meeting the requirements set forth in Schedule 4.2.1 .  The activities set forth in the POC Development Plan will at all times be designed to be in compliance with all applicable Laws.

4.2.2 Post-POC Development .  Within [**] days after the date of delivery of the POC Study Data Package CANbridge will prepare and provide to the JSC a post-POC development plan that will include (a) the proposed Development strategy to be used in order to receive Marketing Authorization for the Product in the Field in the Licensed Territory through the date on which such Marketing Authorization is received in any Major Market Country and (b) the expected timelines applicable to the conduct of all Clinical Studies involving the Product.  In addition, if AVEO determines to Develop the Product for the North America Territory, AVEO will prepare and provide to the JSC a forward-looking plan summarizing its Development strategy for the Product in the North America Territory for purposes of coordination and information sharing. Notwithstanding the foregoing, if either Party is Developing or Commercializing a product for the same indication as the Product, then the other Party will not be required to provide such Party or the JSC with its post-POC development plan. To the extent there are any material updates to CANbridge’s post-POC development plan, from time to time CANbridge will promptly provide such updates to AVEO through the JSC.  

4.2.3 Development Principles . The Parties will each conduct the Development of Products both pursuant to and outside of the scope of the POC Development Plan in accordance with the following principles, except to the extent (if any) otherwise expressly provided in the POC Development Plan or this Agreement, and the JSC will take into account and attempt to implement the following principles in its decision-making, including preparation, review and approval of any updates to and amendments of the POC Development Plan:

(a) Regardless of the specific division of responsibility between the Parties for particular activities at any particular time, the JSC will serve as a conduit for sharing information, knowledge and expertise relating to the Development and Commercialization of the Product.

(b) CANbridge will not conduct, or authorize or cause its Affiliates or any Sublicensees to conduct, any Development activity with respect to the Product if such activity

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would reasonably be likely to have a material adverse impact on the Development of the Product in the North America Territory.  

(c) AVEO will not conduct, or authorize or cause its Affiliates or any Sublicensees to conduct, any Development activity with respect to the Product if such activity would reasonably be likely to have a material adverse impact on the Development of the Product in the Licensed Territory.

(d) Neither Party will conduct any Development activity with respect to the Product without first notifying the other Party of its intent to do so and discussing and coordinating such Development with the other Party’s Development activities, provided , that , if a Party is Developing or Commercializing a product for the same indication as the Product as of the date of any such discussions or coordination activities with the other Party, that Party will implement procedures reasonably acceptable to the other Party to ensure that none of its employees who are actively participating in the Development or Commercialization of the product for the other indication participates in, or has access to the information disclosed in, such discussions or coordination activities.

4.3 Development Diligence; Manner of Performance; Reports .  

4.3.1 Development Diligence . CANbridge (directly and through its Affiliates and Sublicensees) will use Commercially Reasonable Efforts to: (a) Develop and Manufacture Products in accordance with the POC Development Plan; and (b) Develop, Manufacture, and obtain Regulatory Approval for the Product in each Major Market Country in the Licensed Territory.

4.3.2 Development Responsibility .  CANbridge will be responsible for the day-to-day implementation of the Development activities for which it (or any of its Affiliates) is assigned responsibility under this Agreement and the POC Development Plan, and will keep AVEO reasonably informed as to the progress of such activities.  CANbridge will perform its Development obligations under this Agreement in good scientific manner and in compliance with all applicable Laws (including with respect to each such activity that will or would reasonably be expected to be submitted to a Regulatory Authority in support of a regulatory filing or Regulatory Approval Application, then-current Good Laboratory Practice Standards and Good Clinical Practices).

4.3.3 Clinical Studies . Notwithstanding anything to the contrary in this Agreement, CANbridge may terminate or suspend any Clinical Study relating to the Products of which it or its Affiliate or Sublicensee is the sponsor, without the approval or consent of the JSC or AVEO, if (a) a Regulatory Authority, institutional review board or safety data review board for such Clinical Study has required or recommended such termination or suspension or (b) CANbridge believes in good faith that such termination or suspension is warranted because of observed safety risks to the study subjects or patients. In either case, CANbridge will promptly notify AVEO in writing of such termination or suspension.

4.3.4 Development Records; Reports .  Each Party will maintain complete and accurate records (in the form of technical notebooks or electronic files where appropriate) of all work conducted by it with respect to the Development of the Products and all information resulting

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from such Development work. Such records, including any electronic files where such information may also be contained, will fully and properly reflect all Development work done and results achieved in the Development of the Product in sufficient detail and in good scientific manner appropriate for patent and regulatory purposes.  Periodically, but no less frequently than [**] , to the extent that a Party has conducted any Development activities over such [**] , such Party will deliver to the JSC a report (each, a “ Development Report ”) containing reasonably detailed information regarding its progress with respect to the Development of the Product in such Party’s Territory, which will include a summary of (a) all Development activities conducted and results obtained with respect to each Product, (b) any Significant Development Events applicable to any Product, (c) a summary of all (i) Know-How conceived or reduced to practice over such period and (ii) Clinical Data, including Safety Data and CMC Data, generated by such Party over such period and (d) with respect to CANbridge, (i) reasonable evidence of its satisfaction of the minimum requirements set forth in   Section 12.2.3 (Termination by AVEO) and (ii) a non-binding estimate of the expected timing of any Development Milestone Event and Sales Milestone Event to be achieved with respect to each Product.  

4.3.5 POC Study Data Package . Within [**] days following the database lock of the POC Study, CANbridge will deliver the POC Study Data Package to AVEO.

4.3.6 Notice of Investigation or Inquiry .  If any Regulatory Authority (a) contacts a Party or its Affiliate with respect to the alleged improper Development, Manufacture or Commercialization of any Product, (b) conducts, or gives notice of its intent to conduct, an inspection at a Party’s or its Affiliate’s facilities used in the Development or Manufacturing of Product, or (c) takes, or gives notice of its intent to take, any other regulatory action with respect to any activity of a Party or its Affiliate that could reasonably be expected to adversely affect any Development, Manufacture or Commercialization activities with respect to a Product in the other Party’s Territory, then such Party will promptly notify the other Party of such contact, inspection or notice.  In addition, each Party will provide the other Party with at least [**] days’ advance notice of any meeting with any Regulatory Authority regarding any Regulatory Approval Application for any Product or any such audit or inspection conducted by any Regulatory Authority at any site at which such Product is being Manufactured or Clinical Studies with respect to such Product are being conducted. To the extent any such meeting is between CANbridge and any Regulatory Authority in Europe, then, to the extent that CANbridge reasonably determines that there is space sufficient for AVEO representatives to attend such meeting and such attendance by AVEO will not delay the proposed timing for the meeting, AVEO may elect to send representatives reasonably acceptable to CANbridge to participate in any such meeting at AVEO’s sole cost and expense.

4.4 Rights of First Negotiation .  

4.4.1 POC Study ROFN . Commencing on the Effective Date until the date of AVEO’s receipt of the POC Study Data Package (“ POC Study ROFN Period ”), AVEO will and hereby does grant to CANbridge a right of first negotiation with respect to any license or co-development agreement under which AVEO would grant to any Third Party any rights to Develop or Commercialize the Product in any country in the North America Territory (the “ ROFN Opportunity ”). If AVEO determines that it desires to enter into an agreement with a Third Party with respect to such rights during the POC Study ROFN Period, then AVEO will so notify CANbridge and CANbridge will have the option, within [**] days of receipt of such notice from

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AVEO, to notify AVEO of its desire to negotiate for such contemplated Third Party rights (the “ POC Study ROFN ”). Following AVEO’s receipt of such notice from CANbridge, the Parties will negotiate exclusively in good faith the terms and conditions of an agreement with respect to such contemplated rights for a reasonable period of time, such period not to exceed [**] days. If CANbridge exercises the POC Study ROFN and the Parties are unable to reach agreement during such [**] day period (or such longer period as the Parties may agree), then, (a) for the remainder of the POC Study ROFN Period, if any, AVEO will not enter into any agreement with a Third Party with respect to Development or Commercialization of the Product in the North America Territory on terms more favorable, in the aggregate, to the Third Party than the final offer proposed by AVEO to CANbridge during the POC Study ROFN Period and (b) subject to the foregoing, AVEO will thereafter have no obligation to CANbridge with respect to the ROFN Opportunity and will have the right to pursue itself, or to negotiate and execute an agreement with any Third Party with respect to, the ROFN Opportunity.  

4.4.2 North America Territory ROFN .  

(a) Exclusive Negotiation Period . During the period not to exceed [**] months following the date of AVEO’s receipt of the POC Study Data Package, AVEO and CANbridge will exclusively negotiate with each other in good faith (the “ Exclusive Negotiation Period ”) the terms and conditions under which (a) CANbridge and AVEO would enter into a collaboration agreement pursuant to which the Parties would co-Develop the Product in the squamous cell esophagus cancer therapeutic field, including the sharing of the Development costs thereof (the “ Collaboration Agreement ”), or (b) the North America Territory would become included within the Licensed Territory for all purposes under this Agreement (the Expanded License ”).

(b) Failure to Reach Agreement . In the event that the Parties are unable to reach agreement with respect to either a Collaboration Agreement or an Expanded License during the Exclusive Negotiation Period pursuant to Section 4.4.2(a) (Exclusive Negotiation Period), then, subject to Section 4.4.3 (Right of First Negotiation):

(i) each Party will have the right to continue the Development of the Product within their respective Territories in accordance with this Agreement;

(ii) except with respect to Safety Data and CMC Data, CANbridge would not grant to AVEO (i) any access to Clinical Data developed or obtained by CANbridge with respect to the Product in the Licensed Territory or (ii) a right of reference with respect to its Regulatory Filings owned or Controlled by CANbridge or its Affiliates in the Licensed Territory; and

(iii) except with respect to Safety Data and CMC Data, AVEO would not grant to CANbridge (i) any access to new Clinical Data developed or obtained by AVEO with respect to the Product in the North America Territory or (ii) a right of reference with respect to its new Regulatory Filings owned or Controlled by AVEO or its Affiliates and developed or filed after the Effective Date.

4.4.3 Right of First Negotiation .  Following any failure to reach agreement pursuant to Section 4.4.2(b) (Failure to Reach Agreement), AVEO will be free to pursue itself

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and/or to negotiate and grant rights to one or more Third Parties under intellectual property rights Controlled by AVEO with respect to Development and/or Commercialization of the Product in the North America Territory; provided , however , that, if during the [**] month period following the end of the Exclusive Negotiation Period (the “ ROFN Period ”), AVEO determines that it desires to enter into an agreement with a Third Party with respect to such rights, AVEO will so notify CANbridge and CANbridge will have the right, within [**] days of receipt of such notice from AVEO, to notify AVEO of its desire to negotiate for such contemplated Third Party rights (the “ ROFN ”). Following AVEO’s receipt of such notice from CANbridge, the Parties will negotiate in good faith the terms and conditions of an agreement with respect to such contemplated rights for a reasonable period of time, such period not to exceed [**] days. If CANbridge exercises the ROFN and the Parties are unable to reach agreement during such [**] day period (or such longer period as the Parties may agree), then, (a) for the remainder of the ROFN Period, if any, AVEO will not enter into any agreement with a Third Party with respect to Development or Commercialization of the Product in the North America Territory on terms more favorable, in the aggregate, to the Third Party than the final offer proposed by AVEO to CANbridge during the ROFN Period and (b) subject to the foregoing, AVEO will thereafter have no obligation under this Agreement to negotiate with CANbridge with respect to the Development or Commercialization of the Product in the North America Territory and will have the right to pursue itself, and/or to negotiate and execute an agreement with any Third Party with respect to, the Development or Commercialization of the Product in the North America Territory.  

4.5 Regulatory Submissions and Regulatory Approvals .  

4.5.1 Ownership of Regulatory Approvals .  CANbridge or its relevant Affiliates will have the sole right to file and hold all Regulatory Filings for the Products in the Field in the Licensed Territory and may file and hold Regulatory Filings in the North America Territory, in accordance with the POC Development Plan solely for the purpose of Developing Products for the Licensed Territory. AVEO or its relevant Affiliates will have the sole right to file and hold Regulatory Filings in the North America Territory related to the Products for the purpose of Developing and Commercializing the Products in the North America Territory. The Parties will file and hold all Regulatory Filings in eCTD format.

4.5.2 Regulatory Cooperation .

(a) CANbridge Responsibilities . Subject to applicable Law and this Section 4.5.2 (Regulatory Cooperation), CANbridge will oversee, monitor and manage all regulatory interactions, communications and filings with, and submissions to, Regulatory Authorities with respect to the Products in the Licensed Territory. CANbridge will have final decision making authority regarding all regulatory activities, including the labeling strategy and the content of submissions within such Licensed Territory, subject to the terms and conditions of this Agreement; provided , however , that, the foregoing will not apply to any Development activities conducted by AVEO in the Licensed Territory as permitted by this Agreement.

(b) AVEO Responsibilities . Subject to applicable Law and this Section 4.5.2 (Regulatory Cooperation), AVEO will oversee, monitor and manage all regulatory interactions, communications and filings with, and submissions to, Regulatory Authorities with respect to the Products in the North America Territory.  AVEO will have final decision making authority regarding all regulatory activities, including the labeling strategy and the content of

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submissions within such North America Territory, subject to the terms and conditions of this Agreement; provided , however , that, the foregoing will not apply to any Development activities conducted by CANbridge in the North America Territory as permitted by this Agreement. AVEO will also provide reasonable regulatory and administrative support and assistance to CANbridge in connection with the submission of its IND application for the Product in China, including but not limited to, (i) the provision of a notarized authorizat ion letter and business license and (ii) the provision of a notarized copy of the GLP certificate of AVEO’s contract research organization responsible for the performance of preclinical experiments on the Product.  

4.5.3 Regulatory Notification .  Solely to the extent that, and for so long as, AVEO has an active IND or Regulatory Approval Application with respect to any Product, the following will apply:

(a) Each Party will report to the other Party all Adverse Events or Serious Adverse Events with respect to any Product, as the case may be, in its respective territory, within timeframes consistent with its reporting obligations under applicable Laws and in any event no later than [**] hours following receipt of notification by the clinical site of a Serious Adverse Event, which report will, in each case, include the circumstances and nature of such Serious Adverse Event.  In addition, to the extent requested by a Party, the other Party will promptly provide to such Party any other information or materials that such Party may require to provide to any Regulatory Authority with respect to any such Serious Adverse Event.

(b) Each Party will promptly notify the other Party upon its determination that any event, incident or circumstance has occurred that may result in the need for a Recall, market withdrawal or stock recovery of a Product (but in no event later than [**] hours and in all cases prior to the execution of such Recall, market withdrawal or stock recovery).  For all Recalls, the Parties will reasonably consult with each other with respect to the actions to be taken to address such Recall.  Subject to the foregoing, (i) for all Recalls, market withdrawals and stock recoveries that are taken in the Licensed Territory, CANbridge will be responsible for execution, and AVEO will reasonably cooperate in all such efforts and (ii) for all Recalls, market withdrawals and stock recoveries that are taken in the North America Territory, AVEO will be responsible for execution, and CANbridge will reasonably cooperate in all such efforts.  All expenses incurred in connection with any Recall (including expenses for notification, destruction and return of the affected Product and any refund to customers of amounts paid for such Product) in the Licensed Territory will be the sole responsibility of CANbridge, and, subject to any allocation of responsibility to CANbridge as a manufacturer of Product that is set forth in the Supply Agreement, all expenses incurred in connection with any Recall in the North America Territory will be the sole responsibility of AVEO.

(c) The Parties will enter into a pharmacovigilance agreement on reasonable and customary terms that sets forth, among other things, guidelines and procedures for the receipt, investigation, recording, review, communication, reporting and exchange between the Parties of Adverse Event reports (which for the purposes of information exchange between the Parties will include Adverse Events as well as reports of pregnancy, claims of lack of efficacy, overdose, abuse, misuse, medication errors, occupational expose and off-label use), technical complaints, periodic safety update reports and any other information concerning the safety of the Products anywhere in the world and the maintenance of a global safety database with respect to the Products.  

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4.6 Third Party Partners .     

4.6.1 Unblocking Rights . If, at any time during the Term, either Party enters into an agreement (a “ Third Party Collaboration Agreement ”) with one or more Third Party(ies) (the “ Third Party Partner ”) to Develop and/or Commercialize a Product in the Field in the United States (with respect to AVEO) or a Major Market Country (with respect to CANbridge), respectively, such Party will use Commercially Reasonable Efforts to negotiate the terms of the Third Party Collaboration Agreement regarding intellectual property that are necessary to permit such Party to license or sublicense to the other Party any Patent Rights and Know-How developed in the course of activities pursuant to the Third Party Collaboration Agreement that are necessary or useful for the other Party to Develop, Manufacture and Commercialize Products in its respective territory in accordance with this Agreement.

4.6.2 Global Coordination . Each Party will use Commercially Reasonable Efforts to include in any Third Party Collaboration Agreement a good faith obligation on such Third Party Partner to participate in discussions with AVEO and CANbridge at least annually to facilitate information sharing and the global coordination of the Development, Manufacture and Commercialization of Products.

 

ARTICLE 5
MANUFACTURE AND COMMERCIALIZATION

5.1 Technology Transfer and Manufacture .  

5.1.1 Transfer of Licensed Know-How . Promptly after the Effective Date, AVEO will take such steps as may be reasonably necessary to transfer to CANbridge all Licensed Know-How (including all historical process or analytical development information ( i.e. all experimentally or literature-derived data used to Develop the Product through the completion of Technology Transfer)) that is necessary or useful to enable the Manufacture and Development of the Product, including the Regulatory Documentation set forth on Exhibit C , by providing copies or samples of relevant documentation, materials and other embodiments of such Know-How, including data within reports, notebooks and electronic files, and by making available its qualified technical personnel on a reasonable basis to consult with CANbridge with respect to such Know-How (“ Technology Transfer ”). Such Technology Transfer will be conducted in accordance with the technology transfer plan attached hereto as Exhibit C (the “ Technology Transfer Plan ”).   Each Party will bear its own internal costs incurred in the course of the Technology Transfer to the extent set forth in the Technology Transfer Plan; provided , that , any such costs and expenses incurred by either Party that are not included as part of the Technology Transfer Plan will be the sole responsibility of CANbridge.

5.1.2 Manufacturing Responsibility .  Subject to Section 5.1.3 (Right of AVEO to Manufacture) and Section 5.1.4 (Technology Transfer), CANbridge will have the obligation to Manufacture and supply AVEO with its requirements of Product in connection with the Development and Commercialization of Products by AVEO in the North America Territory pursuant to this Agreement, subject to agreement by the Parties of a commercially reasonable forecasting process to be defined in the Supply Agreement.  

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5.1.3 Right of AVEO to Manufacture.   Notwithstanding the foregoing, if at any time during the Term (a) the per unit price of any Product Manufactured by CANbridge (as opposed to being Manufactured by a Third Party CMO) quoted by CANbridge is higher by [**] % or more than the lowest binding commitment to supply submitted by a Third Party CMO to AVEO and shared with CANbridge or (b) CANbridge does not have the capacity, or is otherwise unable, to supply AVEO with its requirements of Product in a GMP-compliant manufacturing facility adequate for the Manufacture of such Product, then, in either such case, AVEO will have the right (but not the obligation) to Manufacture such Product itself or have such Product Manufactured by such Third Party CMO and in order to satisfy all of its requirements of such Product. AVEO may exercise its rights under this Section 5.1.3 (Right of AVEO to Manufacture) with respect to any Product by giving prior written notice to CANbridge.  

5.1.4 Technology Transfer . Upon receipt by CANbridge of written notice from AVEO under Section 5.1.3 (Right of AVEO to Manufacture), CANbridge will provide reasonable assistance to enable AVEO to Manufacture or have Manufactured such Product. Such assistance will include, without limitation, engaging in any technology transfer process required in order to enable AVEO or any Third Party CMO engaged by AVEO to Manufacture such Product. If such written notice is the result of a lower Third Party CMO supply price as set forth in Section 5.1.3(a) (Right of AVEO to Manufacture), then AVEO will be responsible for the costs and expenses of any such assistance provided by CANbridge under this Section 5.1.4 (Technology Transfer). If such written notice is the result of CANbridge’s inability to meet AVEO’s capacity requirements as set forth in Section 5.1.3(b) (Right of AVEO to Manufacture), then CANbridge will be responsible for the costs and expenses of any such assistance provided by CANbridge under this Section 5.1.4 (Technology Transfer).

5.1.5 Supply Terms .  Subject to Sections 5.1.3 (Right of AVEO to Manufacture) and 5.1.4 (Technology Transfer), AVEO hereby agrees to purchase any and all of its requirements of Product during the Term from CANbridge at a transfer price equal to CANbridge’s COGS (which amount will be no greater than CANbridge’s own COGS for the same Product in the Licensed Territory) plus [**]%, provided , however , that: CANbridge uses a CMO reasonably acceptable to AVEO for such Manufacture of Products that (a) is comparable in cost to other CMOs in the industry performing similar manufacturing work, and (b) has been inspected by the FDA and inspected by the applicable Regulatory Authority in the EU or by a Qualified Person in the EU authorized to sign the required certificate (as required by Clinical Directive 2001/20/EC and Annex 13 to the European GMP Guide) and, in any such case, found to be in material compliance with all applicable Laws. The Parties will execute a supply agreement containing supply and quality terms and conditions consistent with this Agreement and typical for such agreements (the “ Supply Agreement ”), including the right of AVEO to audit CANbridge’s records of COGS applicable to the Manufacture of Products and the requirement that all Products supplied by CANbridge hereunder be Manufactured in accordance with GMP and the applicable Product specifications.

5.2 Commercialization .  

5.2.1 Responsibilities of the Parties .

(a) In the Licensed Territory . CANbridge will be solely responsible, at its expense, for Commercializing the Product in the Licensed Territory.

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(b) In the North America Territory . AVEO will be solely responsible, at its expense, for Commercializing the Product in the North America Territory.  

(c) Commercialization Plan .  At any time prior to the first submission of a Regulatory Approval Application with respect to a Product in any country in the Licensed Territory, CANbridge will prepare and provide to the JSC, a Commercialization plan that will include (i) a launch plan for each Product in each of the Major Market Countries; (ii) the projected commercial infrastructure and sales force to be used with respect to such Product in each of the Major Market Countries; (iii) a [**]-year sales forecast for such Product in the Licensed Territory and for each of the Major Market Countries; and (iv) the projected pricing for the Product in each of the Major Market Countries, provided , however , that if AVEO is Developing or Commercializing a product (other than the Product) for the same indication as the Product, then CANbridge will not be required to provide AVEO or the JSC with a Commercialization plan for that Product.  At any time prior to the first submission of a Regulatory Approval Application with respect to a Product in any country in the North America Territory, AVEO will prepare and provide to the JSC its projected pricing for the Product in the North America Territory.

(d) Compliance by CANbridge .  CANbridge will perform its Commercialization obligations under this Agreement in good scientific manner and in compliance in all material respects with all applicable Laws, including, for purposes of clarity, applicable GLPs, GMPs or Good Clinical Practices (and, as appropriate, ICH guidance or other comparable regulation and guidance of any Regulatory Authority in any country or region in the Licensed Territory).

(e) Reports by CANbridge .  CANbridge will keep AVEO regularly informed of the progress of its efforts to Commercialize Products in the Licensed Territory through reports to the JSC not less than [**].

(f) Importation or Resale of Products .  The Parties recognize that it is possible that Products originally sold by a Party (or its Affiliates, Sublicensees or Distributors) in its territory may be imported and resold in the other Party’s territory.  Each Party will take reasonable measures to prevent any such imports and/or sales, to the full extent permitted by applicable Law. Without limiting the foregoing, each Party will, and will cause its Affiliates, Sublicensees and Distributors to, (a) label Products sold by it as being for sale in its territory (or a country thereof); and (b) refrain from selling Products to any entity that such Party or its Affiliates, Sublicensees or Distributors has reason to believe will resell quantities of Product in the other Party’s territory.

5.2.2 No Violation . Notwithstanding anything to the contrary contained herein, neither Party (including its Affiliates and Sublicensees) will be obligated to undertake or continue any Commercialization activities with respect to the Products if such Party reasonably determines that performance of such Commercialization activity would violate applicable Law or infringe any Third Party Patent Rights.

5.2.3 Commercialization Diligence . CANbridge will (directly and through its Affiliates and Sublicensees) use Commercially Reasonable Efforts and will cause its Affiliates and Sublicensees to use Commercially Reasonable Efforts to Commercialize the Product in each

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Major Market Country in the Licensed Territory in which such Product receives Regulatory Approval.  

ARTICLE 6
FINANCIAL PROVISIONS

6.1 Upfront Payment; Reimbursement of Manufacturing Development Costs; Milestone Payments .  

6.1.1 Upfront Payment .  Subject to the terms and conditions of this Agreement, CANbridge will pay AVEO a non-refundable, non-creditable payment in the amount of US $1,000,000, which upfront payment will be due and payable to AVEO within [**] Business Days following the Effective Date.

6.1.2 Reimbursement of Manufacturing Development Costs .  Subject to the terms and conditions of this Agreement, CANbridge will reimburse AVEO for the costs and expenses incurred by AVEO in connection with the conduct by AVEO of Manufacturing development activities with respect to the Product prior to the Effective Date in the aggregate amount of US $1,000,000, (a) US $500,000 of which will be due and payable to AVEO on the earlier of (i) the date of completion by CANbridge of the Validation of Manufacturing Development, or (ii) 12 months from the Effective Date and (b) the remaining US $500,000 of which will be due and payable to AVEO on the earlier of (i) the date of completion by CANbridge of the Validation of Manufacturing Development or (ii) 18 months from the Effective Date.

6.1.3 Development Milestone Payments .  Subject to the terms and conditions of this Agreement, CANbridge will pay to AVEO the following non-refundable, non-creditable one-time milestone payments (each, a “ Development Milestone Payment ”) within [**] days of CANbridge or its Affiliates achieving each of the following milestones in the relevant Territory (each a “ Development Milestone Event ”):

 

Development Milestone Event

Territory

Development Milestone Payment

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

 

Each Development Milestone Payment will be payable only upon the first achievement of the applicable Development Milestone Event, and no amounts would be due for subsequent or repeated achievements.  Notwithstanding the foregoing, in the event that CANbridge sublicenses all or any portion of the rights granted to it under Section 3.1 ( AVEO License Grant; Right of

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Reference ) in (a) the EU, (b) Japan, or (c) the entirety of China, Taiwan and South Korea, then, in lieu of paying the Development Milestone Payments to AVEO in any such country or countries, CANbridge will instead pay to AVEO the payment set forth in Section 6.2 (Sublicense Revenue) below.  For purposes of this Section 6.1.3 (Development Milestone Payments), the [**] .

6.1.4 Sales Milestone Payments .  Subject to the terms and conditions of this Agreement, CANbridge will pay to AVEO the following non-refundable, non-creditable one-time sales milestone payments (each, a “ Sales Milestone Payment ”) within [**] days following the end of the first Calendar Year during the Royalty Term in which the aggregate Net Sales of the Product by CANbridge and its Affiliates in the Licensed Territory achieves each of the following sales thresholds (each a “ Sales Milestone Event ”):

Sales Milestone Event

Sales Milestone Payment

Aggregate Net Sales Greater than or Equal to US $[**]

[**]

Aggregate Net Sales Greater than or Equal to US $[**]

[**]

Aggregate Net Sales Greater than or Equal to US $[**]

[**]

Aggregate Net Sales Greater than or Equal to US $[**]

[**]

 

Each Sales Milestone Payment will be payable only upon the first achievement of the applicable Sales Milestone Event, and no amounts would be due for subsequent or repeated achievements.

6.1.5 Milestone Event Notice .  Within [**] Business Days after a Party becomes aware that a Milestone Event was achieved, it will notify the other Party thereof in writing.  

6.2 Sublicense Revenue .  

6.2.1 Sublicense Payments . In the event that CANbridge sublicenses all or any portion of the rights granted to it under Section 3.1 ( AVEO License Grant; Right of Reference ) in (a) the EU, (b) Japan, or (c) the entirety of China, Taiwan and South Korea, then CANbridge will pay to AVEO a percentage of all Sublicense Revenue received by it from such Sublicensees within [**] days following the receipt of such Sublicense Revenue, at the percentages set forth below (such percentage, the “ Sublicense Revenue Percentage ” and such payment, the “ Sublicense Payment ”):

 

 

Timing of Sublicense Grant

Sublicense Revenue Percentage

Any Sublicense granted [**]

[**]

Any Sublicense granted [**]

[**]

Any Sublicense granted [**]

[**]

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Any Sublicense granted [**]

[**]

 

6.2.2 Adjustment to Certain Sublicense Revenue .  In the event that (a) any Sublicense Revenue received by CANbridge pursuant to Section 6.2.1 (Sublicense Payments) is in the form of a development milestone payment that is attributable to the receipt by the applicable Sublicensee of Regulatory Approval of a Product in any EU country and (b) the amount of the Sublicense Payment due and payable by CANbridge to AVEO pursuant to Section 6.2.1 (Sublicense Payments) as a result of such development milestone is less than $[**], CANbridge will pay AVEO, in addition to the applicable Sublicense Payment, an amount equal to the difference between such Sublicense Payment and $[**] (such difference, the “ Additional Payment ”); provided , however , that, CANbridge will have the right to credit the full amount of the Additional Payment against any other payments that are due and payable by CANbridge under this Agreement to AVEO on and after such date.   

6.3 Royalties .  

6.3.1 Royalty Rates . Subject to the terms and conditions in this Agreement, on a country-by-country and Product-by-Product basis during the applicable Royalty Term, CANbridge will pay to AVEO royalties on Net Sales of Products (whether by CANbridge, its Affiliates or Sublicensees) in the Licensed Territory, as calculated by multiplying the applicable royalty rates below by the corresponding amount of incremental Net Sales in the Licensed Territory of all Products in each Calendar Year:

Annual Net Sales of Products

Royalty Rate

For that portion of aggregate annual Net Sales less than US $[**]

[**]

For that portion of aggregate annual Net Sales greater than or equal to US $[**] and less than US $[**]

[**]

For that portion of aggregate annual Net Sales greater than or equal to US $[**] and less than US $[**]

[**]

For that portion of aggregate annual Net Sales greater than or equal to US $[**]

[**]

 

For example, if the Net Sales of the Product in the Licensed Territory in a given Calendar Year totaled $[**], CANbridge would pay to AVEO [**], for a total royalty payment [**] equal to $[**].

6.3.2 Royalty Term .  Royalties will be due under this Section 6.3.2 (Royalty Term) with respect to a Product and country in the Licensed Territory during the period commencing on the First Commercial Sale of such Product in such country and ending upon the later of (a) the expiration of the last Valid Claim within the Licensed Patents Covering the Product in such country, (b) the expiration of regulatory data exclusivity in such country, and (c) the 10 th anniversary of the First Commercial Sale in such country (such period, the “ Royalty Term ”). Notwithstanding the foregoing, and subject to Section 6.6.3 (Sales Prior to Receipt of Marketing Authorization), sales of Product prior to receipt of Marketing Authorization for a Product, such as

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so-called “ treatment IND sales, ” “ named patient sales, ” and “ compassionate use sales, ” will constitute Net Sales subject to the payment of royalties pursuant to this Section 6.3 (Royalties) if such sale is made at a price greater than the cost of goods for such Product.  

6.4 Royalty Payments and Reports .  CANbridge will pay to AVEO any amounts due pursuant to Section 6.3.1 (Royalty Rates) within [**] days after the end of each Calendar Quarter, and will provide to AVEO concurrently with such payment a statement setting forth (a) the amount of Net Sales of Products in each country in the Licensed Territory during such Calendar Quarter (including such amounts expressed in local currency and as converted to Dollars); (b) the type and amount of permitted deductions from gross sales to determine Net Sales and the total amount of such deductions; (c) the applicable royalty rates for all Products in each country in the Licensed Territory after applying any permitted deductions set forth above; and (d) a calculation of the amount of royalty due to AVEO.  Sublicense Payments will be made by CANbridge with respect to each Product that is the subject of a Sublicense agreement [**] days after the end of each Calendar Quarter in which CANbridge receives any Sublicense Revenue from a Sublicensee, and CANbridge will provide to AVEO concurrently with such payment a statement setting forth (y) the amount of Sublicense Revenue received in each country in the Licensed Territory during such Calendar Quarter (including such amounts expressed in local currency and as converted to Dollars) and (z) the total amount of exclusions from Sublicense Revenue to determine the applicable Sublicense Payments.  

6.5 Profit Share Payments .  In the event that CANbridge receives any Profit Share Payment from Profit Share Sublicensees in any Calendar Quarter during the Royalty Term in any country in the Licensed Territory other than in Europe and Japan, then CANbridge will pay to AVEO [**]% of such Profit Share Payment within [**] days following the end of such Calendar Quarter. CANbridge will provide to AVEO concurrently with such payment a statement setting forth the amount of Profit Share Payments received during such Calendar Quarter (including such amounts expressed in local currency and as converted to Dollars).

6.6 Payment Reductions .  

6.6.1 Biosimilar Competition .  If at any time during the Royalty Term there is Biosimilar Competition for a Product in any country in the Licensed Territory in which such Product is then being sold by CANbridge or an Affiliate or Sublicensee, then the applicable royalties in effect with respect to such Product in such country as specified in Section 6.3.1 (Royalty Rates) will be reduced by [**]%.

6.6.2 Blocking Third Party Intellectual Property .  With respect to a particular country in the Licensed Territory, CANbridge will be entitled to deduct from royalty payments under Section 6.3 (Royalties) otherwise payable to AVEO in such country [**]% of any Blocking Third Party Intellectual Property Costs paid by CANbridge under a license to Blocking Third Party Patent Rights obtained by CANbridge and applicable to such country.

6.6.3 Sales Prior to Receipt of Marketing Authorization . With respect to sales of a Product in a country in the Licensed Territory prior to the receipt of Marketing Authorization (including, “ treatment IND sales, ” “ named patient sales, ” and “ compassionate use sales ”) that are at a price greater than the cost of goods for such Product, then if the actual price received for such Product is lower than the projected sale price in such country set forth in the Commercialization

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plan provided by CANbridge to the JSC pursuant to Section 5.2.1(c) (Commercialization Plan), then CANbridge will be entitled to reduce the royalty payments under Section 6.3 (Royalties) otherwise payable to AVEO with respect to such sale in such country by a percentage equal to the percentage difference between the actual price received for such Product and such projected sale price set forth in the CANbridge Commercialization plan until such time as Marketing Authorization is received. For example, if the projected sale price in a Commercialization plan for a Product prior to the receipt of Marketing Authorization is $ [**] but the actual price received for such Product is $ [**] , then the applicable royalty to AVEO for such Product will be reduced by [**] % until such time as Marketing Authorization is received.  

6.6.4 Maximum Annual Reduction .  In no event will the reductions in Sections 6.6.1 (Biosimilar Competition), 6.6.2 (Blocking Third Party Intellectual Property) and 6.6.3 (Sales Prior to Receipt of Marketing Authorization) reduce the royalty rates under Section 6.3 ( Royalties ) in any Calendar Year to less than the greater of (a) [**]% of the royalty rates set forth in Section 6.3.1 (Royalty Rates) or (b) a rate equal to the sum of the Aggregate AVEO Third Party Royalty Obligation and the Applicable Percentage (as defined below); provided , however , that CANbridge will be entitled to carry forward to future Calendar Years any amounts with respect to which CANbridge would have been entitled to make a deduction pursuant to this Section 6.6.4 (Maximum Annual Reduction) but for such maximum annual reduction.  As used herein, the “ Applicable Percentage ” means (i) [**]% if any portion of the reduction in the royalty rate is pursuant to Section 6.6.1 (Biosimilar Competition) and (ii) [**]% if no portion of the reduction in royalty rate is pursuant to Section 6.6.1 (Biosimilar Competition).

6.7 Reimbursement of Third Party Expenses .   CANbridge will reimburse AVEO for the following milestone payments that AVEO is obligated to pay to Third Parties under the license agreements set forth on Schedule 1.60 (AVEO In-License Agreements) within [**] days of the first achievement of each milestone event set forth below:

Third Party Milestone Event

Milestone Payment

[**]

          [**]

[**]

[**]

[**]

[**]

[**]

[**]

 

Each Third Party milestone payment set forth in this Section 6.7 (Reimbursement of Third Party Expenses) will be due and payable (i) only upon the first achievement of the applicable milestone event, and no amounts would be due for subsequent or repeated achievements, and (ii) only if the achievement of such milestone results in AVEO being required to make a milestone payment no smaller than the corresponding amount set forth above to a Third Party pursuant to an agreement set forth on Schedule 1.60 (AVEO In-License Agreements).

6.8 Financial Audits .  

6.8.1 Record Keeping . CANbridge and its Affiliates will keep complete and accurate records in accordance with its Accounting Standards of the items underlying (a) the Sales

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Milestone Payments, (b) the Development Milestone Payments, (c) Net Sales, (d) royalty payments, (e) Sublicense Revenue, (f) Profit Share Payments, (g) its satisfaction of the minimum requirements set forth in Section 12.2.3 (Termination by AVEO), (h) any other elements thereof required to prepare the reports or calculate payments required under this Agreement (including any payments made under Section 6.6.3 ), and (i) any other payments under this Agreement. AVEO will have the right [**] , at its own expense, to have an independent, certified public accountant, selected by AVEO and reasonably acceptable to CANbridge, review any such records of CANbridge in the location(s) where such records are maintained by CANbridge upon reasonable prior written notice, during regular business hours and under obligations of confidentiality, for the sole purpose of verifying the basis and accuracy of payments made under this Agreement, within the prior [**] Calendar Year period.  The records for any Calendar Year may be audited no more than once.  

6.8.2 Audit Period . Upon the expiration of [**] years following the end of any Calendar Year, the calculation of amounts payable with respect to such Calendar Year will be binding and conclusive.

6.8.3 Audit Report . The report prepared by the independent certified public accounting firm, a copy of which will be sent or otherwise provided to each Party by such independent public accountant at the same time, will contain the conclusions of such accounting firm regarding the audit and will specify that the amounts paid pursuant thereto were correct or, if incorrect, the amount of any underpayment or overpayment, and the specific details regarding any discrepancies.  No other information will be provided to AVEO without the prior consent of CANbridge unless disclosure is required by Law, regulation or judicial order, and if so determined by AVEO, it will, if permitted, give CANbridge prior notice thereof reasonably sufficient for CANbridge to seek a protective order against or limiting such disclosure.  If such report shows any underpayment, CANbridge will remit to AVEO, within [**] days after receipt of such report, (a) the amount of such underpayment and (b) if such underpayment exceeds [**]% of the total amount owed for the period then being audited, the reasonable out-of-pocket costs incurred in conducting such review.  Any overpayments will be refunded by AVEO within [**] days of receipt of the audit report or will be deducted from future payments owed to AVEO, in the sole discretion of AVEO.  The Parties mutually agree that all information subject to review under this Section is Confidential Information of CANbridge and that AVEO will retain and cause the accountant to retain all such information in confidence in accordance with ARTICLE 8 (Confidentiality and Publicity).

6.9 Tax Matters .  

6.9.1 Tax Responsibility . Each Party will be solely responsible for the payment of all taxes imposed on its share of income arising directly or indirectly from the activities of the Parties under this Agreement, except as expressly set forth in this Section 6.9 ( Tax Matters ).

6.9.2 Tax Withholding . A Party will withhold and deduct from all payments made (or to be made) pursuant to this Agreement by such Party (the “ Withholding Party ”), any tax required to be withheld and deducted from such payments under applicable Law and in accordance with this Section 6.9 ( Tax Matters ).  Any amounts so withheld and deducted will be remitted by the Withholding Party on a timely basis to the appropriate Governmental Authority for the account of the other Party and the Withholding Party will provide the other Party reasonable evidence of

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the remittance within [**] days thereof. To the extent that amounts are so withheld by the Withholding Party and duly paid over to the appropriate Governmental Authority, such withheld amounts will be treated for all purposes of this Agreement as having been paid to the other Party, in respect of which such deduction and withholding was made.  Each Party will furnish to the Withholding Party such forms, certificates and documentation as may be necessary or appropriate, and that are legally required, to obtain any reduction of, credit for, or exemption from the withholding of any tax.  

6.9.3 Retroactive Payments . In the event that a taxing authority retroactively determines that a payment made by a Withholding Party to the other Party pursuant to this Agreement should have been subject to withholding or to additional withholding of taxes, and the Withholding Party remits such taxes to the taxing authority, the Withholding Party will have the right (a) to offset such amount, including any interest and penalties that may be imposed thereon (except to the extent any such interest or penalties result from the gross negligence of the Withholding Party), against future payment obligations of the Withholding Party under this Agreement, (b) to invoice the other Party for such amount (which will be payable by the other Party within [**] days of its receipt of such invoice) or (c) to pursue reimbursement by any other available remedy.

6.10 Currency of Payments .  All payments under this Agreement will be paid in U.S. Dollars by wire transfer to an account designated by the receiving Party (which account the receiving Party may update from time to time in writing ) .

 

ARTICLE 7
INTELLECTUAL PROPERTY OWNERSHIP,
PROTECTION AND RELATED MATTERS

7.1 Ownership of Inventions .  

7.1.1 Inventorship .  Ownership of inventions, improvements, developments or discoveries, whether patentable or non-patentable, invented or otherwise developed or generated by either Party or its Affiliates, or any of its or their employees, sublicensees (where permitted), independent contractors or agents during the Term, in the course of Developing, Manufacturing or Commercializing any Product under this Agreement (“ Inventions ”), and any and all intellectual property rights therein, will be determined based on the principles of inventorship in accordance with United States patent Laws.

7.1.2 Ownership .  Any Invention made, conceived, reduced to practice, or otherwise discovered solely by the employees, independent contractors, or agents of AVEO (“ AVEO Inventions ”), and all Patent Rights claiming such Invention, will be solely owned by AVEO.  Subject to Schedule 7.1.2, any Invention made, conceived, reduced to practice or otherwise discovered by the employees, independent contractors or agents of CANbridge (“ CANbridge Inventions ”), and all Patent Rights claiming such Invention, will be solely owned by CANbridge.  

7.1.3 Assignment Obligation . Each Party will cause all employees of such Party who perform activities for such Party under this Agreement to be under an obligation to assign their rights in any Patent Rights and Know-How, whether or not patentable, resulting therefrom to

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such Party. With respect to any activities of a Party under this Agreement that are subcontracted to a Person that is not an employee, the Party retaining such subcontractor will include in the applicable subcontract an assignment to such Party of all rights in Patent Rights and Know-How made by such subcontractor resulting from such activities, and in any event will include in the applicable subcontract a license to such Party that is sublicensable to the other Party under this Agreement, of any Patent Rights and Know-How made by such contractor resulting from such activities.    

7.1.4 Right to Practice Joint Patent Rights and Joint Know-How .  The Parties will jointly own any Joint Know-How and Joint Patent Rights.  Subject to the rights and licenses granted to, and the obligations (including payment obligations) of each Party under this Agreement, either Party is entitled to practice the Joint Patent Rights and Joint Know-How for all purposes on a worldwide basis and license the Joint Patent Rights and Joint Know-How without the consent of and without a duty of accounting to the other Party.  Each Party will grant and hereby does grant all permissions, consents and waivers with respect to, and all licenses under, the Joint Patent Rights and Joint Know-How, throughout the world, necessary to provide the other Party with such rights of use and Exploitation of the Joint Patent Rights and Joint Know-How, and will execute documents as reasonably necessary to accomplish the foregoing.

7.2 Prosecution and Maintenance of the Licensed Patents .  

7.2.1 In the Licensed Territory . CANbridge will have the sole right, at its expense, to prepare, file, prosecute and maintain the Licensed Patents (including any Joint Patent Rights) in all countries in the Licensed Territory.  CANbridge will keep AVEO reasonably informed of all steps with regard to and the status of such preparation, filing, prosecution, and maintenance of such Patent Rights, including by providing AVEO with (i) copies of all correspondence and material communications it sends to or receives from the European Patent Office (“ EPO ”) and equivalent patent offices in other jurisdictions in the Licensed Territory, relating to the Licensed Patents, (ii) a draft copy of all applications sufficiently in advance of filing to permit reasonable review and comment by AVEO, and (iii) a copy of applications as filed, together with notice of its filing date and serial number. Before CANbridge submits any material filing, including a new patent application, or response to such patent authorities with respect to the Licensed Patents, CANbridge will provide AVEO with a reasonable opportunity to review and comment on such filing or response and will take into account and consider in good faith AVEO’s reasonable and timely requests and suggestions regarding the filing, prosecution and maintenance of the Licensed Patents under this Section 7.2.1 (In the Licensed Territory).  Without limiting the foregoing, within [**] Business Days following the Effective Date, CANbridge will reimburse AVEO for the costs and expenses incurred by AVEO in connection with the filing and maintenance of the Licensed Patents in March of 2016 in the Licensed Territory.

7.2.2 In the North America Territory .  AVEO will have the sole right, at its expense, to prepare, file, prosecute and maintain the Licensed Patents (including the Joint Patent Rights) in all countries in the North America Territory.  AVEO will keep CANbridge reasonably informed of all steps with regard to and the status of such preparation, filing, prosecution, and maintenance of such Patent Rights, including by providing CANbridge with (i) copies of all correspondence and material communications it sends to or receives from the US Patent and Trademark Office (the “ USPTO ”) and equivalent patent offices in other jurisdictions in the North America Territory, relating to the Licensed Patents, (ii) a draft copy of all applications sufficiently

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in advance of filing to permit reasonable review and comment by CANbridge, and (iii) a copy of applications as filed, together with notice of its filing date and serial number. Before AVEO submits any material filing, including a new patent application, or response to such patent authorities with respect to the Licensed Patents, AVEO will provide CANbridge with a reasonable opportunity to review and comment on such filing or response and will take into account and consider in good faith CANbridge’s reasonable and timely requests and suggestions regarding the filing, prosecution and maintenance of the Licensed Patents under this Section 7.2.2 ( In the North America Territory ); provided , however , that, CANbridge’s rights under this Section 7.2.2 (In the North America Territory) will terminate upon the expiration of CANbridge’s rights of first negotiation pursuant to Section 4.4 (Rights of First Negotiation).     

7.2.3 Step-In Right .  If either Party (the “ Filing Party”) elects not to continue to prosecute or maintain a Patent Right within the Licensed Patents in its respective Territory pursuant to Sections 7.2.1 (In the Licensed Territory) and 7.2.2 (In the North America Territory) above, the Filing Party will give the other Party notice thereof within a reasonable period (but not less than [**] days) prior to allowing such Patent Rights to lapse or become abandoned or unenforceable, and the other Party (the “ Assuming Party ”) will have the right to prosecute or maintain such Patent Right in the name of the Filing Party.  Subject to any rights granted by a Filing Party to a Sublicensee under this Agreement, the Assuming Party will have the right, but not the obligation, to assume responsibility for continuing the prosecution of such Patent Rights in such country or region and paying any required fees to maintain such Patent Rights in such country or region or defending such Patent Rights, all at the Assuming Party’s sole expense, through patent counsel or agents of its choice.  The Assuming Party will not become an assignee of any such Patent Rights as a result of its assumption of any such responsibility.  Upon transfer of the Filing Party’s responsibility for filing, prosecuting and maintaining any of the Patent Rights to the Assuming Party under this Section 7.2.3 (Step-In Right), the Filing Party will promptly deliver to the Assuming Party copies of all necessary files related to the Patent Rights with respect to which responsibility has been transferred and will take all actions and execute all documents reasonably necessary for the Assuming Party to assume such prosecution, maintenance and defense); provided , however , that, CANbridge’s rights under this Section 7.2.3 (Step-In Right) will terminate upon the expiration of CANbridge’s rights of first negotiation pursuant to Section 4.4 (Rights of First Negotiation).

7.2.4 Cooperation .  Each Party will, and will cause its Affiliates to, reasonably cooperate, with the other with respect to the preparation, filing, prosecution and maintenance of Licensed Patents pursuant to this Section 7.2 ( Prosecution and Maintenance of the Licensed Patents ).

7.3 Prosecution and Maintenance of the CANbridge Program Patents .  CANbridge will have the sole right, at its expense, to prepare, file, prosecute and maintain the CANbridge Program Patents worldwide.  CANbridge will keep AVEO reasonably informed of all steps with regard to and the status of such preparation, filing, prosecution, and maintenance of such CANbridge Program Patents in the North America Territory, including by providing AVEO with (a) copies of all correspondence and material communications it sends to or receives from the USPTO and equivalent patent offices in other jurisdictions in the North America Territory relating to the CANbridge Program Patents, (b) a draft copy of all applications sufficiently in advance of filing to permit reasonable review and comment by AVEO, and (c) a copy of applications as filed, together

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with notice of its filing date and serial number. Before CANbridge submits any material filing, including a new patent application, or response to such patent authorities with respect to the CANbridge Program Patents in the North America Territory, CANbridge will provide AVEO with a reasonable opportunity to review and comment on such filing or response and will take into account and consider in good faith AVEO’s reasonable and timely requests and suggestions regarding the filing, prosecution and maintenance of the CANbridge Program Patents under this Section 7.2.1 (Prosecution and Maintenance of the CANbridge Program Patents).  

7.4 Third Party Infringement .  

7.4.1 Notice .  Each Party will promptly notify the other in writing of any (a) apparent, threatened or actual infringement by a Third Party of any Licensed Patent, including receipt of any notice filed pursuant to the Biologics Price Competition and Innovation Act of 2009, including notices pursuant to a §351(k) application under the BPCIA, or any analogous law outside the United States, or (b) unauthorized use or misappropriation of any Licensed Know-How by a Third Party of which it becomes aware, and, in each case, will provide the other Party with all available evidence supporting such infringement or unauthorized use or misappropriation (each, an “ Infringement ”).

7.4.2 Enforcement of Licensed Patents in the Licensed Territory . CANbridge will have the sole right, using counsel of its choosing and at its sole expense, to institute any Action alleging Infringement of the Licensed Patents (including the Joint Patent Rights) in the Licensed Territory (a “ Licensed Territory Infringement Action ”).  CANbridge will notify and keep AVEO apprised in writing of any such Licensed Territory Infringement Action and will consider AVEO’s reasonable interests and requests regarding such Licensed Territory Infringement Action; provided , that, if CANbridge does not intend to prosecute a Licensed Territory Infringement Action, or ceases to diligently pursue a Licensed Territory Infringement Action, (a) it will promptly inform AVEO in writing and (b) the Parties will discuss in good faith the possibility of AVEO, at its own expense, initiating such Licensed Territory Infringement Action against the applicable Third Party infringer(s) in CANbridge’s sole discretion.  If in connection with such good faith discussions, AVEO informs CANbridge that it wishes to prosecute any such Licensed Territory Infringement Action against the applicable Third Party infringer(s) and CANbridge determines in its discretion that AVEO may not prosecute such Licensed Territory Infringement Action against any such Third Party infringer(s), then, sales of Biosimilar Products by such Third Party will not be counted to determine whether the market share test in the definition of “Biosimilar Competition” has been achieved.

7.4.3 Enforcement of Licensed Patents in the North America Territory . AVEO will have the sole right, using counsel of its choosing and at its sole expense, to institute any Action alleging Infringement of the Licensed Patents (including the Joint Patent Rights) in the North America Territory (a “ North America Infringement Action ” and, collectively with a Licensed Territory Infringement Action, an “ Infringement Action ”).  AVEO will notify and keep CANbridge apprised in writing of any such North America Infringement Action and will consider CANbridge’s reasonable interests and requests regarding such North America Infringement Action. AVEO will have the right to settle or compromise any North America Infringement Action brought pursuant to this Sections 7.4.23 (Enforcement of Licensed Patents in the North America Territory) without the consent of CANbridge.

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7.4.4 Enforcement of the CANbridge Program Patents . CANbridge will have the sole right, using counsel of its choosing and at its sole expense, to institute any Infringement Action under the CANbridge Program Patents worldwide in its sole discretion.  

7.4.5 Cooperation .  In any Infringement Action brought under the Licensed Patents pursuant to Sections 7.4.2 (Enforcement of Licensed Patents in the Licensed Territory), or 7.4.3 (Enforcement of Licensed Patents in the North America Territory) each Party will, and will cause its Affiliates to, reasonably cooperate with each other, in good faith, relative to the other Party’s efforts to protect the Licensed Patents and will join such suit as a party, if requested by the other Party. Furthermore, the Party initiating any Infringement Action pursuant to Sections 7.4.2 (Enforcement of Licensed Patents in the Licensed Territory) or 7.4.3 (Enforcement of Licensed Patents in the North America Territory) will consider in good faith all reasonable and timely comments from the other Party on any proposed arguments asserted or to be asserted in litigation related to the enforcement or defense of any such Patent Rights.

7.4.6 Allocation of Recoveries . Any settlements, damages or monetary awards recovered by either Party pursuant to any Licensed Territory Infringement Action with respect to the Licensed Patents will, after reimbursing the Parties for their reasonable out-of-pocket expenses in making such recovery (which amounts will be allocated pro rata if insufficient to cover the totality of such expenses), be allocated [**]% to CANbridge and [**]% to AVEO.  For clarity, any settlements, damages or monetary awards recovered by AVEO pursuant to any North America Infringement Action with respect to the Licensed Patents will be allocated 100% to AVEO.

7.5 Claimed Infringement .  Each Party will promptly notify the other Party if a Third Party brings any Action alleging patent infringement by CANbridge or AVEO or any of their respective Affiliates or Sublicensees with respect to the Development, Manufacture or Commercialization of any Product (any such Action, an “ Infringement Claim ”).  In the case of any Infringement Claim, CANbridge will have the right, but not the obligation to, control the defense and response to such Infringement Claim in the Licensed Territory, and AVEO will have the right, but not the obligation to, control the defense and response to such Infringement Claim in the North America Territory.  Upon the request of the Party controlling the response to the Infringement Claim, the other Party will reasonably cooperate with the controlling Party in the reasonable defense of such Infringement Claim.  The other Party will have the right to consult with the controlling Party concerning any Infringement Claim and to participate in and be represented by independent counsel in any associated litigation.  If the Infringement Claim is brought against both Parties, then each Party will have the right to defend against the Infringement Claim. The Party defending an Infringement Claim under this Section 7.5 (Claimed Infringement) will (a) consult with the other Party as to the strategy for the prosecution of such defense, (b) consider in good faith any comments from the other Party with respect thereto and (c) keep the other Party reasonably informed of any material steps taken and provide copies of all material documents filed, in connection with such defense.  The Party controlling the defense against an Infringement Claim will have the right to settle such Infringement Claim on terms deemed reasonably appropriate by such Party, provided , that , unless any such settlement includes a full and unconditional release from all liability of the other Party and does not adversely affect the rights of the other Party, any such settlement will be subject to the other Party’s prior written consent.

7.6 EU Unitary Patent System .  Without limiting CANbridge’s rights under this Section 7.4 (Third Party Infringement), CANbridge will have the exclusive right to opt-in and

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opt-out of any Licensed Patent from the jurisdiction of the EU Unified Patent Court, in accordance with the terms of Unified Patent Court Regulation (EU) No 1257/2012 and its applicable Annexes and Rules of Procedure, as amended from time to time and in effect (the “ UPC ”). Unless CANbridge has expressly opted-in to the EU Unitary Patent System with respect to a given Licensed Patent, AVEO will not initiate any action to enforce any such Licensed Patent under the EU Unitary Patent System without CANbridge’s prior written approval.  

7.7 Trademarks. CANbridge will own, and will be solely responsible for, the selection and registration of all Trademarks used exclusively for the Commercialization of the Products in the Licensed Territory. CANbridge will discuss with AVEO in good faith the selection of Trademarks in the Licensed Territory through the JSC and the Parties will coordinate a branding strategy with respect to such Trademarks, subject to CANbridge’s final decision-making authority in the Licensed Territory.  AVEO will discuss with CANbridge in good faith the selection of Trademarks in the North America Territory through the JSC and the Parties will coordinate a branding strategy with respect to such Trademarks, subject to AVEO’s final decision-making authority in the North America Territory.

ARTICLE 8
CONFIDENTIALITY AND PUBLICITY

8.1 Confidential Information .  

8.1.1 Confidentiality Obligation . During the Term and for a period of [**] years after any termination or expiration of this Agreement, each Party agrees to, and will cause its Affiliates to, keep in confidence and not to disclose to any Third Party, or use for any purpose, except to exercise its rights or perform its obligations under this Agreement, any Confidential Information of the other Party.

8.1.2 Permitted Disclosures . Each Party agrees that it and its Affiliates will provide or permit access to the other Party’s Confidential Information only to the receiving Party’s employees, consultants, advisors and Sublicensees, and to the employees, consultants and advisors of the receiving Party’s Affiliates, in each case on a need to know basis who are subject to obligations of confidentiality and non-use with respect to such Confidential Information no less stringent than the obligations of confidentiality and non-use of the receiving Party pursuant to this Section 8.1 ( Confidential Information ); provided , however , that each Party will remain responsible for any failure by its Affiliates and Sublicensees, and its and its Affiliates’ respective employees, consultants and advisors, to treat such Confidential Information as required under Section 8.1 ( Confidential Information ) as if such Affiliates, employees, consultants, advisors and Sublicensees were parties directly bound to the requirements of this Section 8.1 (Confidential Information).

8.1.3 Confidentiality Limitation . Notwithstanding anything to the contrary herein, each Party may use and disclose the other Party’s Confidential Information as follows:  (a) under appropriate written confidentiality obligations substantially equivalent to those in this Agreement, to its Affiliates, potential and actual permitted Sublicensees, contractors and any other Third Parties, to the extent such use or disclosure is reasonably necessary to perform its obligations or to exercise its rights under this Agreement, (b) to the extent such use or disclosure is consistent with this Agreement, is not prohibited by the Existing Third Party License Agreements and is reasonably necessary for filing or prosecuting the Licensed Patents, (c) to its advisors (including

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financial advisors, attorneys and accountants), actual or potential acquisition partners, financing sources or investors and underwriters on a need to know basis, in each case under appropriate confidentiality obligations (which may include professional ethical obligations) substantially equivalent to those in this Agreement; provided , however , that each Party will remain responsible for any failure by any of the foregoing individuals to treat such Confidential Information as required under Section 8.1 ( Confidential Information ) (as if such individuals were parties directly bound to the requirements of this Section 8.1 , or (d) as required by any court or other governmental body or as otherwise required by applicable L aw s; provided , that , notice is promptly given to the other Party and the disclosing Party cooperates with reasonable requests from the other Party to seek a protective order or other appropriate remedy to protect the Confidential Information .  

8.1.4 Secrecy of Licensed Know-How . AVEO will protect, will cause its Affiliates to protect and will use Commercially Reasonable Efforts to cause its Sublicensees and its and their respective officers, directors, employees, and agents to protect, the secrecy and confidentiality of the Licensed Know-How and AVEO’s interest in the Joint Know-How using at least the same degree of care as it uses to prevent the disclosure of its own other confidential information of like importance.

8.2 Publicity .  

8.2.1 Initial Press Releases .  Promptly following the Effective Date, the Parties will issue a mutually agreed upon press release regarding the subject matter of this Agreement, including a description of the financial terms, a high-level description of the overall scope of the transaction and the scope of planned Development and value of the Agreement in the form attached hereto as Exhibit B .  

8.2.2 Further Publicity; Publications .  The Parties acknowledge the importance of supporting each other’s efforts to publicly disclose results and significant developments regarding the Product in the Field, and each Party may make such disclosures from time to time, subject to this Section 8.2.2 (Further Publicity; Publications).  Such disclosures may include achievement of milestones, significant events in the Development process with respect to the Products, Commercialization activities with respect to the Products and the like.  Except for the initial press releases described in Section 8.2.1 (Initial Press Releases):

(a) Whenever either Party elects to make any such public disclosure, it will first notify the other Party of such planned press release or public announcement and provide a draft for review no less than [**] Business Days in advance of issuing such press release or making such public announcement (or, with respect to press releases and public announcements that are required by applicable Law, with as much advance notice as possible under the circumstances if it is not possible to provide notice no less than [**] Business Days in advance). Each Party will have the right to review and approve any such planned press release or public announcement proposed by the other Party, including any oral presentation or abstract, that contains clinical data or pertains to results of Clinical Studies or other studies with respect to the Product, or that includes Confidential Information of the other Party; provided , however , that (A) the reviewing Party will attempt to provide such approval as soon as reasonably possible and will not unreasonably withhold such approval; (B) the reviewing Party will provide explanations of its disapproval of such press release; and (C) a Party desiring to make such public disclosure may issue such press release or public announcement without such prior review by the other Party if (i)

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the entire contents of such press release or public announcement have previously been made public other than through a breach of this Agreement by such Party, and (ii) such press release or public announcement does not materially differ from a previously issued press release or other publicly available information; and provided , further , that the other Party will have the right to review, but not approve, any press release or public announcement that the proposing Party determines is required by applicable Law based on the advice of counsel, which public disclosures are subject to Section 8.2 ( Publicity ; Publications).  The Party reviewing a press release provided under this Section 8.2.2(a) (Further Publicity) will review and approve or disapprove such press release within [**] Business Days after its receipt thereof.  

(b) The principles to be observed in such disclosures will include accuracy, compliance with applicable Law and regulatory guidance documents, reasonable sensitivity to potential negative reactions of Regulatory Authorities and the need to keep investors informed regarding the business of the Party making such public disclosure.  Nothing in this Section 8.2 ( Publicity ) will restrict a Party from making a disclosure required by Law as reasonably determined by such Party’s counsel, including disclosures required by any laws or regulations relating to the public sale of securities; provided , however , that such disclosure will include the minimum amount of Confidential Information required by such applicable laws and regulations, and the Parties will seek confidential treatment of Confidential Information to be included in such disclosures to the greatest extent possible under such laws and regulations.  

(c) In the event that either Party proposes to publish or present the results of Development or Commercialization carried out on the Product, such publication or presentation will be subject to the prior review by the other Party for patentability and protection of such other Party’s Confidential Information.  Each Party will provide to the other Party the opportunity to review any proposed abstracts, manuscripts or summaries of presentations that cover the results of Development or Commercialization of the Product during the Term.  The other Party will respond in writing promptly and in no event later than [**] days after receipt of the proposed material with either approval of the proposed material or a specific statement of concern, based upon either the need to seek patent protection or concern regarding competitive disadvantage arising from the proposal.  In the event of any such concern, the submitting Party agrees not to submit such publication or to make such presentation that contains such information until the other Party is given a reasonable period of time to seek patent protection for any material in such publication or presentation that it believes is patentable or to resolve any other issues, and the submitting Party will remove from such proposed publication any Confidential Information of the other Party as requested by such other Party.

ARTICLE 9
REPRESENTATIONS AND WARRANTIES; CERTAIN COVENANTS

9.1 Mutual Representations and Warranties .  Each Party represents and warrants to the other Party that, as of the Effective Date:

9.1.1 Organization .  It is a corporation duly organized, validly existing, and in good standing under the laws of the jurisdiction of its organization, and has all requisite power and authority, corporate or otherwise, to execute, deliver, and perform this Agreement.

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9.1.2 Authority .  It has full right, power and authority to enter into this Agreement and to perform its respective obligations under this Agreement, it has the right to grant to the other the licenses and sublicenses granted pursuant to this Agreement, and this Agreement and the performance by such Party of this Agreement do not violate such Party’s charter documents, bylaws or other organizational documents.  

9.1.3 Consents .  Except for any Marketing Authorizations, Regulatory Filings, manufacturing approvals or similar approvals necessary for the Development, Manufacture or Commercialization of the Products, all necessary consents, approvals and authorizations of all Governmental Authorities and other Persons required to be obtained by it in connection with the execution, delivery and performance of this Agreement have been obtained.

9.1.4 No Conflict .  It is not under any obligation, contractual or otherwise, to any Person that would adversely affect the diligent and complete fulfillment of obligations under this Agreement and the execution and delivery of this Agreement by such Party, and the performance of such Party’s obligations under this Agreement (as contemplated as of the Effective Date) and the licenses and sublicenses to be granted by such Party pursuant to this Agreement (a) do not conflict with or violate any requirement of Laws applicable to such Party, (b) do not conflict with or violate any order, writ, judgment, injunction, decree, determination, or award of any court or governmental agency presently in effect applicable to such Party, and (c) do not conflict with, violate, breach or constitute a default under any contractual obligations of such Party or any of its Affiliates.

9.1.5 Enforceability .  This Agreement is a legal and valid obligation binding upon it and is enforceable against it in accordance with its terms, subject to the general principles of equity and subject to bankruptcy, insolvency, moratorium, judicial principles affecting the availability of specific performance and other similar Laws affecting the enforcement of creditors’ rights generally.

9.2 Additional Representations and Warranties of AVEO .  AVEO represents and warrants to CANbridge that, as of the Effective Date:

9.2.1 Licensed Patents .  All Licensed Patents as of the Effective Date are listed on Schedule 9.2.1 (Licensed Patents). Except as otherwise noted in Schedule 9.2.1 , AVEO is the sole and exclusive owner of the Licensed Patents. With respect to Licensed Patents not solely owned by AVEO, AVEO licenses such Licensed Patents in a manner that permits sublicenses as provided in this Agreement.  All Licensed Patents owned by AVEO and, to AVEO’s Knowledge, all other Licensed Patents, are (i) subsisting and in good standing and (ii) being diligently prosecuted in the respective patent offices in accordance with Law, and have been filed and maintained properly and correctly and all applicable fees have been paid on or before the due date for payment. To AVEO’s Knowledge, all issued Licensed Patents are valid and enforceable.

9.2.2 Licensed Know-How .  To AVEO’s Knowledge, the Development and Manufacture of the Product by or on behalf of AVEO prior to the Effective Date did not misappropriate the Know-How of any Third Party. AVEO has sufficient rights under such Licensed Know-How to transfer and license such Licensed Know-How to CANbridge as provided in Section 5.1.1 (Transfer of Licensed Know-How).

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9.2.3 Delivery of Documentation .  True, complete, and correct copies of: (a) all existing Regulatory Filings relating to the Product and (b) all material adverse information with respect to the safety and efficacy of the Product in AVEO’s possession and control, in each case ((a) and (b)) have been provided or made available to CANbridge prior to the Effective Date.  

9.2.4 Third Party Challenges .  There are no claims, judgments, or settlements against, or amounts with respect thereto, made against AVEO or any of its Affiliates relating to the Licensed Patents or the Licensed Know-How.  Except as otherwise disclosed in writing to CANbridge, no claim or litigation has been brought or, to AVEO’s Knowledge, threatened by any Person (a) alleging that the Licensed Patents are invalid or unenforceable, (b) asserting the misuse, or non-infringement of any of the Licensed Patents, (c) challenging AVEO’s Control of the Licensed Patents or (d) alleging misappropriation of the Know-How used in the Development and Manufacture of the Product by or on behalf of AVEO prior to the Effective Date.

9.2.5 Non-Infringement of Third Party IP .  To AVEO’s Knowledge, the Development and Manufacture of the Products, as conducted by AVEO prior to the Effective Date, did not infringe any Patent Right or misappropriate or otherwise violate any Know-How of any Person. To AVEO’s Knowledge, the Development and Manufacture of the Products as specifically described in this Agreement and the POC Development Plan in effect on the Effective Date will not infringe any Patent Right or misappropriate or otherwise violate any Know-How of any Person existing as of the Effective Date.  No written claim of infringement of the Patent Rights or misappropriation of the Know-How of any Third Party has been made, or to AVEO’s Knowledge, threatened, against AVEO or any of its Affiliates with respect to the Development, Manufacture or Commercialization of the Product.

9.2.6 Absence of Litigation .  There are no judgments or settlements against or owed by AVEO or, to AVEO’s Knowledge, pending litigation against AVEO or litigation threatened against AVEO in writing, in each case related to the Product, including any such litigation any relating to any Regulatory Filings Controlled by AVEO as of the Effective Date.

9.2.7 US Government Rights .  Except as otherwise disclosed by AVEO in writing to CANbridge, neither AVEO nor any of its Affiliates is or has been a party to any agreement with the U.S. federal government or an agency thereof pursuant to which the U.S. federal government or such agency provided funding for the Development of a Product, and the inventions claimed or covered by the Licensed Patents are not a “ subject invention ” as that term is described in 35 U.S.C. § 201(f).

9.2.8 Maintenance of Regulatory Filings, Good Laboratory and Clinical Practices .  AVEO and its Affiliates have generated, prepared, maintained, and retained all Regulatory Filings that are required to be maintained or retained pursuant to and in material compliance with applicable Law, and have conducted in material compliance with applicable Law, including GLP and GCP, (a) all Development of the Product in the Field conducted prior to the Effective Date and (b) all research activities that are material to the receipt of Regulatory Approval for the Product.

9.2.9 Confidentiality of Know-How .  To the Knowledge of AVEO, no material breach of confidentiality has been committed by any Third Party with respect to the Licensed Know-How and AVEO has used reasonable measures to protect the confidentiality thereof.

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9.2.10 Assignment of Third Party Rights; Third Party Consents .  

(a) AVEO has obtained from each of its employees and agents, and from the employees and agents of its Affiliates, who are participating in the Exploitation of the Product, rights to any and all Know-How created by such employees and agents in the course of his or her employment by or engagement with AVEO that relates to the Product, such that CANbridge will, by virtue of this Agreement, receive from AVEO, without payments beyond those required by ARTICLE 6 (Financial Provisions), the licenses and other rights granted to CANbridge under this Agreement.

(b) Each Person who has or has had any ownership rights in or to any Licensed Patents purported to be owned solely by AVEO, has assigned and has executed an agreement assigning its entire right, title, and interest in and to such Licensed Patents to AVEO; to AVEO’s Knowledge, no current officer, employee, agent, or consultant of AVEO or any of its Affiliates is in violation of any term of any assignment or other agreement, in each case, regarding the protection of patents or other intellectual property or proprietary information of AVEO or such Affiliate.

(c) AVEO and its Affiliates have employed Persons with appropriate education, knowledge and experience to conduct and to oversee the conduct of the pre-clinical and clinical studies with respect to the Product conducted prior to the Effective Date.

(d) Prior to the Effective Date hereof, AVEO has obtained all assignments and consents from Third Parties necessary to perform its obligations under this Agreement, including, but not limited to, the consent by Patheon to assign the Patheon manufacturing contract to CANbridge, as set forth in Exhibit C hereto.

9.2.11 Statements to FDA and Other Regulatory Authorities . Neither AVEO nor any of its Affiliates, nor, to AVEO’s Knowledge, any of its or their respective officers, employees, or agents has made an untrue statement of material fact or fraudulent statement to the FDA or any other Regulatory Authority with respect to the Development of the Product, failed to disclose a material fact required to be disclosed to the FDA or any other Regulatory Authority with respect to the Development of the Product, or committed an act, made a statement, or failed to make a statement with respect to the Development of the Product that could reasonably be expected to provide a basis for the FDA to invoke its policy respecting “ Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities ”, set forth in 56 Fed. Reg. 46191 (September 10, 1991) and any amendments thereto or any analogous laws or policies in the applicable Territory.

9.2.12 Compliance with Law . To AVEO’s Knowledge, all of the studies, tests and pre-clinical and clinical trials of the Product conducted prior to, or being conducted as of, the Effective Date by or on behalf of AVEO have been and are being conducted in all material respects in accordance with applicable Laws.

9.2.13 In-licenses . Except as set forth in Schedule 1.60 , there are no agreements between AVEO or any of its Affiliates, on the one hand, and any Third Party, on the other hand, pursuant to which AVEO has (i) in-licensed any Patent Rights or Know-how owned or Controlled by such Third Party that are included as part of the Licensed Patents or Licensed Know-How, or (ii) agreed to make any payments (including royalties) to any Third Party or agreed to undertake or

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observe any restrictions or obligations with respect to the Development, Manufacture or Commercialization of the Product.  

9.3 No Debarment .  Each Party represents and warrants that neither it nor any of its or its Affiliates’ employees or agents performing under this Agreement has ever been, or is currently: (a) debarred under 21 U.S.C. § 335a; (b) excluded, debarred, suspended, or otherwise ineligible to participate in federal health care programs or in federal procurement or non-procurement programs; (c) listed on the FDA’s Disqualified and Restricted Lists for clinical investigators; or (d) convicted of a criminal offense that falls within the scope of 42 U.S.C. § 1320a-7(a), but has not yet been excluded, debarred, suspended, or otherwise declared ineligible.  Each Party further covenants that if, during the Term of this Agreement, it becomes aware that it or any of its or its Affiliates’ employees or agents performing under this Agreement is the subject of any investigation or proceeding that could lead to that Party becoming a debarred entity or individual, an excluded entity or individual or a convicted entity or individual, such Party will immediately notify the other Party. This provision will survive termination or expiration of this Agreement.

 

ARTICLE 10
INDEMNIFICATION; DAMAGES

10.1 Indemnification by AVEO .  AVEO will indemnify and hold harmless CANbridge, its Affiliates and their respective directors, officers, employees and agents (collectively, the “ CANbridge Indemnified Parties ”), from, against and in respect of any and all Losses incurred or suffered by any CANbridge Indemnified Party to the extent resulting from:  (a) any breach of any representation or warranty made by AVEO in this Agreement, or any breach by AVEO of any covenant or agreement in this Agreement; (b) the negligence or intentional misconduct of AVEO or any of its Affiliates or Sublicensees, or any of their respective directors, officers, employees and agents, in performing AVEO’s obligations or exercising AVEO’s rights under this Agreement; (c) activities conducted by AVEO or its Affiliates related to the Development, Manufacture, or other Exploitation of the Products anywhere in the world prior to the Effective Date; and (d) the Development, Commercialization, Manufacture, or other Exploitation of any Products in the North America Territory during the Term or anywhere in the world after the termination (but not the expiration) of this Agreement.

10.2 Indemnification by CANbridge .  CANbridge will indemnify and hold harmless AVEO, its Affiliates and their respective directors, officers, employees and agents (collectively, the “ AVEO Indemnified Parties ”), from, against and in respect of any and all Losses incurred or suffered by any AVEO Indemnified Party to the extent resulting from:  (a) any breach of any representation or warranty made by CANbridge in this Agreement, or any breach by CANbridge of any covenant or agreement in this Agreement, (b) the negligence or intentional misconduct of, or violation of Law by, CANbridge, any of its Affiliates or Sublicensees, or any of their respective directors, officers, employees and agents, in performing CANbridge’s obligations or exercising CANbridge’s rights under this Agreement, or (c) the Development, Commercialization, Manufacture or other Exploitation of any Product in the Licensed Territory during the Term.

10.3 Claims for Indemnification .  

10.3.1 Notice .  An Indemnified Party entitled to indemnification under Sections 10.1 ( Indemnification by AVEO ) or 10.2 ( Indemnification by CANbridge ) will give prompt

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written notification to the Indemnifying Party from whom indemnification is sought of the commencement of any Action by a Third Party for which indemnification may be sought (a “ Third Party Claim ”) or, if earlier, upon the assertion of such Third Party Claim by a Third Party; provided , however , that failure by an Indemnified Party to give notice of a Third Party Claim as provided in this Section 10.3.1 ( Notice ) will not relieve the Indemnifying Party of its indemnification obligation under this Agreement, except and only to the extent that such Indemnifying Party is actually prejudiced as a result of such failure to give notice.  

10.3.2 Defense .  Within [**] days after delivery of a notice of any Third Party Claim in accordance with Section 10.3.1 (Notice), the Indemnifying Party may, upon written notice thereof to the Indemnified Party, assume control of the defense of such Third Party Claim with counsel reasonably satisfactory to the Indemnified Party.  If the Indemnifying Party does not assume control of such defense, the Indemnified Party may control such defense.  The Party not controlling such defense may participate therein at its own expense.

10.3.3 Cooperation .  The Party controlling the defense of any Third Party Claim will keep the other Party advised of the status of such Third Party Claim and the defense thereof and will reasonably consider recommendations made by the other Party with respect thereto.  The other Party will reasonably cooperate with the Party controlling such defense and its Affiliates and agents in defense of the Third Party Claim, with all out-of-pocket costs of such cooperation to be borne by the Party controlling such defense.

10.3.4 Settlement .  The Indemnified Party will not agree to any settlement of such Third Party Claim without the prior written consent of the Indemnifying Party, which consent will not be unreasonably withheld.  The Indemnifying Party will not, without the prior written consent of the Indemnified Party, which will not be unreasonably withheld, agree to any settlement of such Third Party Claim or consent to any judgment in respect thereof that does not include a complete and unconditional release of the Indemnified Party from all liability with respect thereto or that imposes any liability or obligation on the Indemnified Party.

10.4 Insurance .  Each Party, at its own expense, will maintain liability insurance (or self-insure) with respect to its activities under this Agreement in an amount consistent with industry standards.  Each Party will provide a certificate of insurance (or evidence of self-insurance) evidencing such coverage to the other Party upon request.  Without limiting the foregoing, during the Term and thereafter for the period of time required below, each Party will maintain on an ongoing basis comprehensive general liability insurance in the minimum amount of $[**] per occurrence and $[**] annual aggregate combined single limit for bodily injury and property damage liability; and Products liability insurance (including contractual liability coverage on such Party’s indemnification obligations under this Agreement) in the amount of at least $[**] per occurrence and as an annual aggregate combined single limit for bodily injury and property damage liability; provided , however , that (a) prior to the initiation of any Clinical Study, the Party responsible for such Clinical Study will secure and maintain in full force and effect clinical trial insurance in compliance with applicable Law in those countries where such Clinical Study is conducted, and (b) commencing not later than [**] days prior to the reasonably anticipated First Commercial Sale of a Product, and thereafter for the period of time required below, each Party will obtain and maintain on an ongoing basis Products liability insurance (including contractual liability coverage on such Party’s indemnification obligations under this Agreement) in the amount of at least $[**] per occurrence and as an annual aggregate combined

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single limit for bodily injury and property damage liability.  All of such insurance coverage may be maintained through a self-insurance plan that substantially complies with the foregoing limits and requirements and may be satisfied through one or more policies, including an umbrella policy; provided , however , that such self-insurance is determined to be investment quality by a recognized rating agency such as Moody’s or Standard & Poor’s.  Not later than [**] days following receipt of written request from a Party, the other Party will provide to the requesting Party a letter(s) affirming appropriate self-insurance and/or a certificate of insurance evidencing such coverage in accordance with this Agreement.  Each Party will maintain such insurance or self-insurance coverage without interruption during the Term and for a period of six years thereafter, and, if applicable, will provide certificates and/or letters evidencing such insurance coverage without interruption as reasonably requested during the period of time for which such coverage must be maintained.  Each Party will be provided at least [**] days’ prior written notice of any cancellation or material decrease in the other Party’s insurance coverage limits described above.  Notwithstanding the foregoing, either Party’s failure to maintain adequate insurance will not relieve that Party of its obligations set forth in this Agreement.  

ARTICLE 11
LIMITATION OF LIABILITY

11.1 No Consequential or Punitive Damages.   EXCEPT AS SET FORTH IN SECTION 11.2 (Exclusion from Liability Limitation), NEITHER PARTY NOR ANY OF ITS AFFILIATES WILL BE LIABLE FOR INDIRECT, INCIDENTAL, CONSEQUENTIAL, SPECIAL, EXEMPLARY, PUNITIVE OR MULTIPLE DAMAGES OR FOR ANY LOST PROFITS ARISING OUT OF THIS AGREEMENT, IN EACH CASE HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, TORT, NEGLIGENCE, BREACH OF STATUTORY DUTY OR OTHERWISE, REGARDLESS OF ANY NOTICE OF SUCH DAMAGES.

11.2 Exclusion from Liability Limitation .  THE LIMITATIONS AND DISCLAIMER SET FORTH IN SECTION 11.1 (No Consequential or Punitive Damages) WILL NOT APPLY TO A CLAIM (A) FOR WILLFUL MISCONDUCT; (B) FOR A BREACH OF SECTION 3.4 (Exclusivity Covenant), OR (C) FOR AN INTENTIONAL BREACH BY AVEO OF SECTION 4.4 (Right of First Negotiation) OR (D) FOR A BREACH OF ARTICLE 8 (Confidentiality and Publicity); OR (E) FOR INDEMNIFIABLE LOSSES PURSUANT TO SECTION 10.1 ( Indemnification by AVEO ), OR SECTION 10.2 ( Indemnification by CANbridge ).

 

ARTICLE 12
TERM AND TERMINATION

12.1 Term .  Unless terminated earlier in accordance with this ARTICLE 12 (Term and Termination), this Agreement will become effective as of the Effective Date and will continue in full force until the last to expire Royalty Term in the Licensed Territory (the “ Term ”). Upon the expiration (but not termination) of this Agreement, the licenses granted pursuant to Section 3.1 ( AVEO License Grant; Right of Reference ) will become perpetual, irrevocable, and fully paid-up.

12.2 Early Termination .  

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12.2.1 Termination for Material Breach .    Upon (a) any material breach of this Agreement by AVEO or (b) any material breach of this Agreement by CANbridge (the Party so allegedly breaching being the “ Breaching Party ”), the other Party (the “ Non-Breaching Party ”) will have the right, but not the obligation, to terminate this Agreement in its entirety by providing 45 days written notice to the Breaching Party in the case of a material breach of a payment obligation and 90 days written notice to the Breaching Party in the case of any other material breach, which notice will, in each case (x) expressly reference this Section 12.2.1 ( Termination for Material Breach ), (y) reasonably describe the alleged breach which is the basis of such termination, and (z) clearly state the Non-Breaching Party’s intent to terminate this Agreement if the alleged breach is not cured within the applicable cure period. Notwithstanding the foregoing, (i) if the alleged material breach by CANbridge is that it has failed to use Commercially Reasonable Efforts to Develop or Commercialize the Product in a particular country in the Licensed Territory under Section 4.3.1 ( Development Diligence) or Section 5.2.3 (Commercialization Diligence) other than a Major Market Country in the EU, then AVEO will have the right to terminate this Agreement solely with respect to such country (and not in its entirety); (ii) if the alleged material breach by CANbridge is that it has failed to use Commercially Reasonable Efforts to Develop or Commercialize the Product in a Major Market Country in the EU, then AVEO will have the right to terminate this Agreement solely with respect to the EU; (iii) if such material breach (other than a payment breach), by its nature, is curable, but is not reasonably curable within the applicable cure period, then such cure period will be extended if the Breaching Party provides a written plan for curing such breach to the Non-Breaching Party and uses Commercially Reasonable Efforts to cure such breach in accordance with such written plan; provided , however , that no such extension will exceed 90 days without the consent of the Non-Breaching Party; and (iv) if the Breaching Party disputes that it has materially breached this Agreement, the dispute will be resolved pursuant to ARTICLE 13 (Dispute Resolution), and this Agreement may not be terminated during the pendency of such dispute resolution procedure. The termination will become effective at the end of the notice period unless the Breaching Party cures such breach during such notice period; provided , however , that the Non-Breaching Party may, by notice to the Breaching Party, designate a later date for such termination in order to facilitate an orderly transition of activities relating to the Product. If, as a result of the application of such dispute resolution procedures, the Breaching Party is determined to be in material breach of this Agreement (an “ Adverse Ruling ”), then if the Breaching Party fails to cure such material breach within 60 days after such ruling (whether or not such actions are specified by the Adverse Ruling) (or 10 days after such ruling in the case of a payment breach), then the Non-Breaching Party may terminate this Agreement upon written notice to the Breaching Party as provided in this Section 12.2.1 (Termination for Material Breach).  

12.2.2 Termination by CANbridge for Convenience . CANbridge may, upon 180 days prior written notice to AVEO, unilaterally terminate this Agreement for convenience and without cause.

12.2.3 Termination by AVEO .  Until the delivery of the POC Study Data Package to AVEO, AVEO may, upon 90 days prior written notice to CANbridge, unilaterally terminate this Agreement if CANbridge has failed to expend at least $[**] for or devote at least one FTE to (or any combination thereof, based on an FTE rate equal to $[**] per FTE) the conduct of Manufacturing and Development of any Product for use in the Field in the Licensed Territory in any Calendar Year prior to delivery of such POC Study Data package to AVEO. Such minimums

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will be prorated for any partial Calendar Years commencing upon the Effective Date and ending upon the date of delivery of the POC Study Data Package to AVEO. Notwithstanding the foregoing, AVEO will not have the right to terminate this Agreement if a failure to meet the minimums set forth in this Section 12.2.3 (Termination by AVEO) is a result of a regulatory delay not attributable to any act of or failure to act by CANbridge, a Force Majeure Event, a failure or early termination of any Clinical Study, or a determination by the JSC or an agreement by the Parties to halt Development activities for the Product in the Licensed Territory.       

12.2.4 Termination for Challenge . AVEO may terminate this Agreement in its entirety, effective upon 30 days’ notice to CANbridge, if CANbridge or any of its Sublicensees commences or conducts legal proceedings, or assists any Third Party in commencing or conducting legal proceedings, to challenge the validity, enforceability, or ownership of any Licensed Patents (other than to assert its own rights as an owner with respect to any Patent Rights), including by (a) filing a declaratory judgment action in which the applicable Licensed Patents is alleged to be invalid or unenforceable, (b) citing prior art pursuant to 35 U.S.C. §301, filing a request for re-examination of the applicable Licensed Patents, or provoking or becoming party to an interference with the applicable Licensed Patents pursuant to 35 U.S.C. §135 or (c) filing or commencing any re-examination, opposition, cancellation, nullity or similar proceedings against the applicable Licensed Patents, or petitioning for any form of administrative or judicial (or arbitration) review of the applicable Licensed Patents, including post-grant review, inter partes review, or opposition proceedings.

12.3 Effects of Termination .  

12.3.1 Effects of Termination Generally . Upon termination of this Agreement in its entirety pursuant to Section 12.2 (Early Termination), the Parties’ rights and obligations under this Agreement generally, including under the POC Development Plan, will terminate and neither Party will have any further rights or obligations under this Agreement from and after the effective date of termination, except as set forth in this Section 12.3 ( Effects of Termination ); provided , however , that, if this Agreement is terminated with respect to a particular country only (other than a Major Market Country), then such rights and obligations will terminate only to the extent they relate solely to the terminated country.

12.3.2 Accrued Obligations .  Expiration or termination of this Agreement for any reason will not release either Party from any obligation or liability which, on the effective date of such expiration or termination, has already accrued to the other Party or which is attributable to a period prior to such expiration or termination.

12.3.3 Survival .  This Section 12.3.3 (Survival), the provisions set forth in the following Sections, as well as, to the extent applicable, any other Sections or defined terms referred to in such Sections or Articles or necessary to give them effect, will survive any expiration or termination of this Agreement in its entirety: Section 3.7 (Bankruptcy Code §365(n) Election); Section 7.1 (Ownership of Inventions); Section 7.3 (Prosecution and Maintenance of the CANbridge Program Patents); ARTICLE 8 (Confidentiality and Publicity); ARTICLE 10 (Indemnification; Damages); ARTICLE 11 (Limitation of Liability); ARTICLE 12 (Term and Termination); ARTICLE 13 (Dispute Resolution); ARTICLE 14 (Miscellaneous), to the extent applicable; and, to the extent that any obligations have accrued prior to termination for any reason under this ARTICLE 12 (Term and Termination) or otherwise extend beyond the effective date of

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termination (as expressly set forth therein), the payment provisions in ARTICLE 6 (Financial Provisions). Furthermore, any other provisions required to interpret the Parties’ rights and obligations under this Agreement, including applicable definitions in ARTICLE 1 (Definitions), will survive to the extent required.  Except as otherwise expressly provided in this Agreement, all rights and obligations of the Parties under this Agreement, including any licenses granted under this Agreement, will terminate upon expiration or termination of this Agreement in its entirety or solely with respect to the terminated country, as the case may be, for any reason.  

12.3.4 Transfer of Regulatory Filings and Regulatory Approvals .  Promptly following the effectiveness of any termination by AVEO pursuant to Section 12.2.1 (Termination for Material Breach) or by CANbridge pursuant to Section 12.2.2 (Termination by CANbridge for Convenience), or by AVEO pursuant to Section 12.2.3 (Termination by AVEO) or Section 12.2.4 (Termination for Challenge) and upon AVEO’s written request, CANbridge will, at CANbridge’s sole cost and expense, assign and transfer to AVEO all Regulatory Filings, filings for Pricing and Reimbursement Approval and Marketing Authorizations for Products that are held by or under authority of CANbridge or its Affiliates or Sublicensees as of the effective date of termination, with respect to the terminated country or the Licensed Territory, as the case may be, and will take such actions and execute such other instruments, assignments and documents as may be necessary to effect the transfer of rights under such Regulatory Filings, filings for Pricing and Reimbursement Approval and Marketing Authorizations to AVEO.  If applicable Law prevents or delays the transfer of ownership of any such Regulatory Filing, filing for Pricing and Reimbursement Approval or Marketing Authorizations to AVEO, CANbridge will grant, and does hereby grant, to AVEO an exclusive and irrevocable right of access and right of reference to such Regulatory Filing, filing for Pricing and Reimbursement Approval and Marketing Authorizations for the Products in the Licensed Territory or the terminated country, as the case may be, and will reasonably cooperate to make the benefits of such Regulatory Filings, filings for Pricing and Reimbursement Approval and Marketing Authorizations available to AVEO or its designee(s).  AVEO will have the right to grant licenses or sublicenses (as applicable) under the rights granted to it under this Section 12.3.4 (Transfer of Regulatory Filings and Regulatory Approvals) to its Affiliates and Third Parties, through multiple tiers.

12.3.5 Transfer of Clinical Data . Promptly following the effectiveness of any termination by AVEO pursuant to Section 12.2.1 (Termination for Material Breach) or by CANbridge pursuant to Section 12.2.2 (Termination by CANbridge for Convenience), or by AVEO pursuant to Section 12.2.3 (Termination by AVEO) or Section 12.2.4 (Termination for Challenge) and upon AVEO’s written request, CANbridge will, at CANbridge’s sole cost and expense, transfer to AVEO its entire right, title, and interest in and to all preclinical and clinical data, Clinical Data, Safety Data and all other supporting data, including CMC Data and pharmacology, toxicology, chemistry and biology data, in CANbridge’s Control as of the effective date of such termination related to, and to the extent necessary or reasonably useful for AVEO to continue the Development, Manufacture and/or Commercialization of, Products.

12.3.6 Survival of Sublicenses .  In the event of a termination of this Agreement for any reason, the terms of this Section 12.3.6 (Survival of Sublicenses) will apply with respect to any CANbridge Sublicense existing as of the effective date of such termination in the terminated territory, but only if the applicable Sublicensee did not contribute to any material breach of this Agreement that was the cause of the termination by AVEO of this Agreement and is not otherwise

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in material breach of the applicable Sublicense agreement at such time: (a) all of such Sublicensee’s obligations under the applicable Sublicense agreement to CANbridge will remain in effect as obligations to AVEO and will be enforceable solely by AVEO as a third party beneficiary; (b) such Sublicensee’s rights under the Sublicense agreement that do not exceed and are consistent with AVEO’s obligations to CANbridge under this Agreement, whether in scope, duration, nature or otherwise, will survive termination; provided , however , that the foregoing will in no way be interpreted to increase the scope, duration, territory or other aspect of the rights sublicensed to such Sublicensee; and (c) all of CANbridge’s rights under such Sublicense agreement will remain in effect, may be exercised solely by AVEO and will inure to the exclusive benefit of AVEO .  

12.3.7 On-Going Trials .  In the event that any Clinical Study with respect to a Product has been Commenced and is on-going as of the effective date of the termination of this Agreement in its entirety (an “ On-Going Clinical Study ”) for any reason other than a termination by CANbridge pursuant to Section 12.2.1 (Termination for Material Breach), CANbridge will, at CANbridge’s sole cost and expense, as AVEO may request, (a) promptly transition to AVEO or its designee some or all of such On-Going Clinical Studies and the activities related to or supporting such trials including by, inter alia, requiring any Third Party with which CANbridge has an agreement with respect to the conduct of Clinical Studies for Products (including agreements with CMOs, contract research organizations, clinical sites and investigators), to cooperate with AVEO in order to accomplish the transfer to AVEO of similar rights as held by CANbridge under its agreements with such Third Parties, (b) continue to conduct such On-Going Clinical Studies for a period requested by AVEO up to a maximum of twelve months after the effective date of such termination, or (c) terminate such On-Going Clinical Studies in a manner consistent with applicable Laws; provided , however , that in the event that AVEO, CANbridge, an institutional review board or independent safety board reasonably determines that an On-Going Clinical Study being run by CANbridge or any of its Affiliates would pose an unacceptable safety risk for subjects or patients participating in such On-Going Clinical Study, CANbridge will not be obligated to continue such Clinical Study.

12.3.8 Return of Confidential Information .  Within [**] days after the effective date of termination of this Agreement in its entirety, each Party will, and cause its Affiliates to (a) destroy, all tangible items solely comprising, bearing or containing any Confidential Information of the other Party that are in such first Party’s or its Affiliates’ possession or Control, and provide written certification of such destruction, or (b) prepare such tangible items of the other Party’s Confidential Information for shipment to such other Party, as such other Party may direct, at the first Party’s expense; provided , however , that, in any event, (x) each Party may retain one copy of the Confidential Information of the other Party to the extent necessary to perform its obligations that survive expiration or termination of this Agreement; and (y) such first Party may retain one copy of such Confidential Information of the other Party for its legal archives.

12.3.9 Transition; Manufacturing; Inventory .  Following the effectiveness of any termination by AVEO pursuant to Section 12.2.1 (Termination for Material Breach), or by AVEO pursuant to Section 12.2.3 (Termination by AVEO) or Section 12.2.4 (Termination for Challenge) or by CANbridge pursuant to Section 12.2.2 (Termination by CANbridge for Convenience), CANbridge and its Affiliates will (a) continue to Manufacture and supply AVEO with its requirements of Product in accordance with ARTICLE 5 (Manufacture and Commercialization)

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and the Supply Agreement for period requested by AVEO (not to exceed [**] months after the Term; provided , however , that, to the extent AVEO requests a period of more than [**] months, the obligation of CANbridge to Manufacture and supply AVEO with its requirements of Product under this Section 12.3.9 (Transition; Manufacturing; Inventory) for such additional [**] month period will be subject to the Parties agreeing in good faith on a reasonable premium to the transfer price to be paid by AVEO for such Product) and (b) reasonably cooperate with AVEO and its designees to facilitate a smooth, orderly and prompt transition to AVEO or its designees of the activities with respect to Products, including any ongoing Development and Commercialization activities with respect to Products, for a period requested by AVEO (not to exceed [**] months after the Term; provided , however , that, to the extent AVEO requests a period of more than [**] months for such transition activities, the obligation of CANbridge to provide such activities under this Section 12.3.9 (Transition; Manufacturing; Inventory) for such additional [**] month period will be subject to the Parties agreeing in good faith on a reasonable payment to be made by AVEO for such activities). For the period that is [**] days following the effective date of the termination of this Agreement, CAN bridge will retain the right to sell, distribute or otherwise dispose of its Product inventory in its or its Affiliates or Sublicensees possession as of the effective date of termination, subject to CANbridge’s continuing obligation to make Sales Milestone Payments and royalty payments in accordance with ARTICLE 6 (Financial Provisions) with respect to Net Sales derived from such distribution, sale and disposition. Without limiting the foregoing, upon the written request of AVEO, CANbridge will promptly, and in any event within [**] days after such request (i) take such steps as may be reasonably necessary to assign to AVEO CANbridge’s rights under any Supply Agreement between CANbridge and any Third Party that relates to any Product (and not any other product) to the extent permitted by the terms of such Supply Agreement; (ii) consent to the supply by the Third Party manufacturer to AVEO of AVEO’s requirements of such Products, to the extent permitted under the terms of the Supply Agreement; or (iii) provide AVEO or its designee with reasonable assistance in order to facilitate (A) the transfer to AVEO of the Manufacturing processes (including CMC Data) for such Products and any related manufacturing technology, in each case used by CANbridge or such CANbridge Third Party manufacturer with respect such Products, and (B) the qualification of AVEO’s or its designee’s facility as required by any Regulatory Authority in order for AVEO or its designee to Manufacture quantities of such Products.     

12.3.10 Cooperation .  Each Party will cause its Affiliates and Sublicensees to comply with the obligations in this Section 12.3 ( Effects of Termination ).

 

ARTICLE 13
DISPUTE RESOLUTION

13.1 Dispute Resolution Escalation .  The Parties recognize that disputes as to certain matters arising out of or in connection with this Agreement may arise from time to time. It is the objective of the Parties to establish procedures to facilitate the resolution of disputes arising under this Agreement in an expedited manner by mutual cooperation. To accomplish this objective, any and all disputes between the Parties arising out of or in connection with this Agreement will first be referred to the JSC for resolution. Should the JSC not be able to reach agreement at a duly called meeting of the JSC within [**] after the date on which the matter is referred to the JSC, then either Party may refer such matter to the Executive Officers for resolution and the Executive Officers will attempt to resolve the matter in good faith.  If the Executive Officers fail to resolve such

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matter within [**] Business Days after the date on which the matter is referred to the Executive Officers (unless a longer period is agreed to by the Parties), then either Party may submit the dispute to the ICC for final resolution by binding arbitration in accordance with Section 13.2 (Arbitration).  

13.2 Arbitration .  Except as set forth in this Section 13.2 (Arbitration), each dispute, difference, controversy or claim arising in connection with or related or incidental to, or question occurring under, this Agreement or the subject matter hereof will be referred to and finally resolved by arbitration in accordance with the Rules of Arbitration (the “ Rules ”) of the International Chamber of Commerce (“ ICC ”), by an arbitral tribunal composed of three arbitrators, all of whom will have previous judicial experience, appointed by agreement of the Parties in accordance with said Rules.  If, at the time of the arbitration, the Parties agree in writing to submit the dispute to a single arbitrator, said single arbitrator will be appointed by agreement of the Parties, or, failing such agreement, by ICC in accordance with said Rules.  The foregoing arbitration proceedings may be commenced by either Party by notice to the other Party.  Unless otherwise agreed by the Parties hereto, all such arbitration proceedings will be held in New York, New York, U.S.A.; provided , however , that proceedings may be conducted by telephone conference call with the consent of the Parties and the arbitrator(s).  All arbitration proceedings will be conducted in the English language.  The arbitrator(s) will consider grants of equitable relief and orders for specific performance as co-equal remedies along with awards of monetary damages. The arbitrator(s) will have no authority to award punitive damages.  The allocation of expenses of the arbitration, including reasonable attorney’s fees, will be determined by the arbitrator(s), or, in the absence of such determination, each Party will pay its own expenses.  The Parties hereby agree that the arbitrator(s) has authority to issue rulings and orders regarding all procedural and evidentiary matters that the arbitrator(s) deem reasonable and necessary with or without petition therefore by the Parties as well as the final ruling and judgment. All rulings by the arbitrator(s) will be final.  Notwithstanding any contrary provision of this Agreement, any Party may seek equitable measures of protection in the form of attachment of assets or injunctive relief (including, without limitation, specific performance and injunctive relief) in any matter relating to the proprietary rights and interests of either Party from any court of competent jurisdiction, pending a decision by the arbitral tribunal in accordance with this Section 13.2 (Arbitration).  The Parties hereby exclude any right of appeal to any court on the merits of such matter.   The provisions of this Section 13.2 (Arbitration) may be enforced and judgment on the award (including without limitation equitable remedies) granted in any arbitration hereunder may be entered in any court having jurisdiction over the award or any of the Parties or any of their respective assets.

13.3 Jury Waiver .  EACH PARTY, TO THE EXTENT PERMITTED BY LAW, KNOWINGLY, VOLUNTARILY, AND INTENTIONALLY WAIVES ITS RIGHT TO A TRIAL BY JURY IN ANY ACTION OR OTHER LEGAL PROCEEDING ARISING OUT OF OR RELATING TO THIS AGREEMENT AND THE TRANSACTIONS IT CONTEMPLATES TO ARBITRATE AS SET FORTH IN SECTION 13.2 (Arbitration). THIS WAIVER APPLIES TO ANY ACTION OR LEGAL PROCEEDING, WHETHER SOUNDING IN CONTRACT, TORT OR OTHERWISE.

ARTICLE 14
MISCELLANEOUS

14.1 Assignment; Successors .  

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14.1.1 Assignment . This Agreement and the rights and obligations of each Party under this Agreement will not be assignable, delegable, transferable, pledged or otherwise disposed of by either Party without the prior written consent of the other Party; provided , however , that either Party may assign or transfer this Agreement, without such consent (but with written notice to the other Party), (a) to an Affiliate or (b) to a Third Party that acquires all or substantially all of the business or assets of such Party or at least 50% of the combined voting power of such Party, whether by merger, consolidation, reorganization, acquisition, sale or otherwise.  If this Agreement is assigned or transferred to an Affiliate, the assigning or transferring Party will remain responsible (jointly and severally) with such Affiliate for the performance of such assigned or transferred obligations. No assignment or transfer of this Agreement or a Party’s rights or obligations under this Agreement will be valid and effective unless and until the assignee agrees in writing to be bound by the terms and conditions of this Agreement.  

14.1.2 Successors . Any permitted assignment of the rights and obligations of a Party under this Agreement will be binding on, and inure to the benefit of and be enforceable by and against, the successors and permitted assigns of the assigning Party.  The permitted assignee or transferee will assume all obligations of its assignor or transferor under this Agreement.  Any assignment or attempted assignment by either Party in violation of the terms of this Section 14.1.2 (Successors) will be null, void and of no legal effect.

14.2 Choice of Law .  This Agreement will be governed by and interpreted under the laws of the State of New York, other than any principle of conflict or choice of laws that would cause the application of the laws of any other jurisdiction; provided , however , that all questions concerning (a) inventorship of Patent Rights under this Agreement will be determined in accordance with Section 7.1 ( Ownership of Inventions ) and (b) the construction or effect of Patent Rights will be determined in accordance with the laws of the country or other jurisdiction in which the particular patent has been filed or granted, as the case may be.  The Parties agree to exclude the application to this Agreement of the United Nations Conventions on Contracts for the International Sale of Goods.

14.3 Notices .  Any notice or report required or permitted to be given or made under this Agreement by one Party to the other will be in writing and will be deemed to have been delivered (a) upon personal delivery, (b) on the second Business Day (at the place of delivery) next following deposit with a reputable, internationally recognized overnight courier that maintains records of delivery and (c) in the case of notices provided by telecopy (which notice will be followed immediately by an additional notice pursuant to clause (a) or (b) above if the notice is of a default under this Agreement), upon completion of transmission, with transmission confirmed, to the addressee’s facsimile machine, as follows (or at such other addresses or facsimile numbers as may have been furnished in writing by a Party to the other as provided in this Section 14.3 ( Notices )). This Section 14.3 ( Notices ) is not intended to govern the day-to-day business communications necessary between the Parties in performing their obligations under the terms of this Agreement.

If to AVEO:

AVEO Pharmaceuticals, Inc.

 

One Broadway, 14th Floor

 

Cambridge, MA 02142

 

Attn : Michael Bailey, Chief Executive Officer

60


 

 

Fax:  [**]

 

 

With a copy to:

Mintz Levin Cohn Ferris Glovsky and Popeo, P.C.

 

One Financial Center

 

Boston, MA  02111

 

Attn :  John J. Cheney, Esq.

 

Fax:  [**]

 

 

 

 

If to CANbridge:

CANbridge Life Sciences Ltd.

303A, Building E

Wangjing Pioneer Park

No. 2 LizeZhongEr Road

Chaoyang District, Beijing, China

Attn : Chief Executive Officer

Fax: [**]

 

With a copy to:

Ropes & Gray LLP

800 Boylston Street

Prudential Tower

Boston, Massachusetts 02199-3600

Attn : David M. McIntosh

Fax: [**]

 

 

14.4 Severability .  If, under applicable Law, any provision of this Agreement is invalid or unenforceable, or otherwise directly or indirectly affects the validity of any other material provision of this Agreement and if the rights or obligations of either Party under this Agreement will not be materially and adversely affected thereby, (such invalid or unenforceable provision, a “ Severed Clause ”), it is mutually agreed that (a) this Agreement will endure except for the Severed Clause, (b) this Agreement will be construed and enforced as if such Severed Clause had never comprised a part hereof, (c) the remaining provisions of this Agreement will remain in full force and effect and will not be affected by the Severed Clause or by its severance herefrom, and (d) in lieu of such illegal, invalid, or unenforceable provision, there will be added automatically as a part of this Agreement a legal, valid, and enforceable provision as similar in terms to such illegal, invalid, or unenforceable provision as may be possible and reasonably acceptable to the Parties.  To the fullest extent permitted by applicable Law, each Party hereby waives any provision of law that would render any provision hereof illegal, invalid, or unenforceable in any respect.

14.5 Integration .  This Agreement, together with all schedules and exhibits attached hereto, constitutes the entire agreement between the Parties with respect to the subject matter of this Agreement and supersedes all previous arrangements between the Parties with respect to the subject matter hereof, whether written or oral, including the Prior CDA.  In the event of a conflict between the POC Development Plan or any schedules or attachments to this Agreement, on the one hand, and this Agreement, on the other hand, the terms of this Agreement will govern. Each

61


 

Party confirms that it is not relying on any representations or warranties of the other Party except as specifically set forth in this Agreement.  

14.6 Waivers and Amendments .  The failure of any Party to assert a right under this Agreement or to insist upon compliance with any term or condition of this Agreement will not constitute a waiver of that right or excuse a similar subsequent failure to perform any such term or condition by the other Party. Notwithstanding the authority granted to the JSC under this Agreement, (a) no waiver will be effective unless it has been given in writing and signed by the Party giving such waiver, and (b) no provision of this Agreement may be amended or modified other than by a written document signed by authorized representatives of each Party.

14.7 Independent Contractors; No Agency .  Neither Party will have any responsibility for the hiring, firing or compensation of the other Party’s or such other Party’s Affiliates’ employees or for any employee benefits with respect thereto.  No employee or representative of a Party or its Affiliates will have any authority to bind or obligate the other Party for any sum or in any manner whatsoever, or to create or impose any contractual or other liability on such other Party, without such other Party’s written approval.  For all purposes, and notwithstanding any other provision of this Agreement to the contrary, each Party’s legal relationship under this Agreement to the other Party will be that of independent contractor, and the relationship between the two Parties will not constitute a partnership, joint venture, or agency, including for all tax purposes.

14.8 Affiliates .  To the extent that this Agreement imposes obligations on Affiliates or Sublicensees of a Party, such Party will cause its Affiliates and its Sublicensees to perform such obligations.  Either Party may use one or more of its Affiliates to perform its obligations and duties or exercise its rights under this Agreement; provided , however , that each such Affiliate or Sublicensee will be bound by the corresponding obligations of the applicable Party and provided , further , that, subject to such Party’s assignment to an Affiliate pursuant to Section 14.1 ( Assignment; Successors ), such Party will remain liable under this Agreement for the prompt payment and performance of all of its obligations under this Agreement.

14.9 Force Majeure .  Neither Party will be responsible to the other for, or be deemed to have defaulted under or breached this Agreement for, any failure or delay in performing any of its obligations under this Agreement or for other nonperformance under this Agreement (excluding, in each case, the obligation to make payments when due) if such delay or nonperformance is caused by or results from events beyond the reasonable control of the non-performing Party, including strike, fire, flood, earthquake, hurricanes, accident, war, acts of war (whether war be declared or not), insurrections, riots, civil commotion, strikes, lockouts, or other labor disturbances (whether involving the workforce of the non-performing Party or of any other Person), act of terrorism, act of God or acts, omissions or delays in acting of the government of any country or of any local government, or by cause unavoidable or beyond the reasonable control of such Party (except to the extent such delay results from the breach by the non-performing Party or any of its Affiliates of any term or condition of this Agreement) (a “ Force Majeure Event ”).  In such event, the Party affected will promptly (and, in any event, within [**] days) notify the other Party in writing of such Force Majeure Event, stating the nature of the event, its anticipated duration, and any action being taken to avoid or minimize its effect.  The suspension of performance will be of no greater scope and no longer duration than is necessary and the non-performing Party and will use Commercially Reasonable Efforts to resume performance of its obligations.

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14.10 No Third Party Beneficiary Rights .  This Agreement is not intended to and will not be construed to give any Third Party any interest or rights (including any third party beneficiary rights) with respect to or in connection with any agreement or provision contained herein or contemplated hereby, other than, to the extent provided in ARTICLE 10 (Indemnification; Damages), the Indemnified Parties.  

14.11 Non-exclusive Remedy .  Except as expressly provided herein, the rights and remedies provided herein are cumulative and each Party retains all remedies at law or in equity, including the Parties’ ability to receive legal damages or equitable relief, with respect to any breach of this Agreement.  Neither Party will be required to terminate this Agreement due to a breach of this Agreement by the other Party.

14.12 Interpretation .  The Article and Section headings used herein are for reference and convenience only, and will not enter into the interpretation of this Agreement.  Except as otherwise explicitly specified to the contrary, (a) references to an Article, Section, Exhibit or Schedule means an Article or Section of, or a Schedule or Exhibit to this Agreement and all subsections thereof, unless another agreement is specified; (b) references in any Section to any clause are references to such clause of such Section; (c) references to any agreement, instrument, or other document in this Agreement refer to such agreement, instrument, or other document as originally executed or, if subsequently amended, replaced, or supplemented from time to time, as so amended, replaced, or supplemented and in effect at the relevant time of reference thereto; (d) references to a particular Law mean such Law as in effect as of the relevant time, including all rules and regulations thereunder and any successor Law in effect as of the relevant time, and including the then-current amendments thereto; (e) words in the singular or plural form include the plural and singular form, respectively; (f) unless the context requires a different interpretation, the word “ or ” has the inclusive meaning that is typically associated with the phrase “ and/or ”; (g) the terms “ including, ” “ include(s), ” “ such as, ” “ e.g. ” and “ for example ” mean including the generality of any description preceding such term and will be deemed to be followed by “ without limitation ”; (h) whenever this Agreement refers to a number of days, such number will refer to calendar days unless Business Days are specified, and if a period of time is specified and dates from a given day or Business Day, or the day or Business Day of an act or event, it is to be calculated exclusive of that day or Business Day; (i) “ monthly ” means on a calendar month basis, (j) “ quarter ” or “ quarterly ” means on a Calendar Quarter basis; (k) “ annual ” or “ annually ” means on a Calendar Year basis; (l) “ year ” means a 365 day period unless Calendar Year is specified; (m) “ $ ” or “ dollars ” means U.S. Dollars; (n) references to a particular Person include such Person’s successors and assigns to the extent not prohibited by this Agreement; (o) all words used in this Agreement will be construed to be of such gender or number as the circumstances require; (p) a capitalized term not defined herein but reflecting a different part of speech than a capitalized term which is defined herein will be interpreted in a correlative manner; (q) any definition of or reference to any agreement, instrument or other document herein will be construed as referring to such agreement, instrument or other document as from time to time amended, supplemented or otherwise modified (subject to any restrictions on such amendments, supplements or modifications set forth herein); (r) the words “ hereof, ” “ herein, ” “ hereby ” and derivative or similar words refer to this Agreement (including any Exhibits or Schedules); (s) neither Party or its Affiliates will be deemed to be acting “ on behalf of ” the other Party under this Agreement, except to the extent expressly otherwise provided; (t) there will be no double-counting in calculating Development costs or any components thereof; and (u) provisions that require that a Party, or the JSC hereunder “ agree ”, “ consent ” or “ approve ” or

63


 

the like will be deemed to require that such agreement, consent or approval be specific and in writing in a written agreement, letter or approved minutes, but, except as expressly provided herein, excluding e-mail and instant messaging.  

14.13 Further Assurances .  Each Party will duly execute and deliver, or cause to be duly executed and delivered, such further instruments and do and cause to be done such further acts and things, including the filing of such assignments, agreements, documents, and instruments, as may be necessary or as the other Party may reasonably request in connection with this Agreement or to carry out more effectively the provisions and purposes hereof, or to better assure and confirm unto such other Party its rights and remedies under this Agreement.

14.14 Ambiguities; No Presumption .  Each of the Parties acknowledges and agrees that this Agreement has been diligently reviewed by and negotiated by and between them, that in such negotiations each of them has been represented by competent counsel and that the final agreement contained herein, including the language whereby it has been expressed, represents the joint efforts of the Parties hereto and their counsel.  Accordingly, in interpreting this Agreement or any provision hereof, no presumption will apply against any Party as being responsible for the wording or drafting of this Agreement or any such provision, and ambiguities, if any, in this Agreement will not be construed against any Party, irrespective of which Party may be deemed to have authored the ambiguous provision.

14.15 Execution in Counterparts; Facsimile Signatures .  This Agreement may be executed in counterparts, each of which counterparts, when so executed and delivered, will be deemed to be an original, and all of which counterparts, taken together, will constitute one and the same instrument even if both Parties have not executed the same counterpart.  Signatures provided by facsimile transmission or in Adobe™ Portable Document Format (PDF) sent by electronic mail will be deemed to be original signatures.

[Remainder of this page intentionally blank.]

 


64


 

IN WITNESS WHEREOF, each Party has caused this Agreement to be duly executed by its authorized representative under seal, in duplicate on the Effective Date.

AVEO PHARMACEUTICALS, INC.

 

/s/ Michael Bailey ______________________

Name: Michael Bailey

Title:  President and CEO

 

CANBRIDGE LIFE SCIENCES, LTD.

____ /s/ James Xue ______________________

Name:  James Xue

Title: President and CEO

65


 

Schedule 1.60 – Existing Third Party License Agreements

 

1.

Research and Commercialization License Agreement between EvoGenix PTY Limited and AVEO Pharmaceuticals, Inc., Dated September 25, 2007

 

 

o

First Amendment to Research and Commercialization License Agreement between EvoGenix Pty Limited and AVEO Pharmaceuticals, Inc., between AVEO Pharmaceuticals, Inc. and Cephalon (formerly EvoGenix), dated September 26, 2012

 

 

o

Second Amendment to the Research and Commercialization License Agreement between AVEO Pharmaceuticals, Inc. and Cephalon Australia, dated September 26, 2013

 

 

2.

Option and License Agreement by and between AVEO Pharmaceuticals, Inc. and Biogen Idec International GMBH, Dated March 18, 2009.  

 

 

o

Amendment No. 1 to Option and License Agreement by and between AVEO Pharmaceuticals, Inc. and Biogen Idec International GMBH Dated March 18, 2014

 

 

3.

Services Agreement between AVEO Pharmaceuticals, Inc. and Selexis SA, Dated April 12, 2010

 

 

o

Amendment No. 1 to Services Agreement between AVEO Pharmaceuticals, Inc. and Selexis SA, Dated October 1, 2010

 

 

4.

Commercial License Agreement between Selexis SA and AVEO Pharmaceuticals, Inc., Dated May 31, 2011.

 

 

 

Schedule 1.60

 


 

Schedule 1.88 – List of AVEO Individuals for Purposes of Knowledge

 

·

President and Chief Executive Officer

 

·

Chief Financial Officer

 

·

Chief Medical Officer

 

·

Vice President of Corporate Development and Alliance Management

 

·

Senior Corporate Counsel

 

·

Vice President of Technical Operations

 

 

Schedule 1.88

 


 

Schedule 1.112 - Information to be Included in the POC Study Data Package

 

[**].

 

Schedule 1.112

 


 

Schedule 3.3.4 - Provisions Required by the Existing Third Party License Agreements to be Included in Sublicense Agreements

 

Option and License Agreement by and between AVEO Pharmaceuticals, Inc. and Biogen Idec International GMBH of March 18, 2009 and Amendment No. 1 thereto of March 18, 2014 (“ Biogen Agreement ”)

 

8.14. Blocked Payments . If, by reason of applicable laws or regulations in any country, it becomes impossible or illegal for CANbridge to transfer, or have transferred on its behalf, royalties or other payments to AVEO that would result in a payment to Biogen, then CANbridge will promptly notify AVEO of the conditions preventing such transfer and such royalties or other payments will be deposited in local currency in the relevant country to the credit of Biogen in a recognized banking institution designated by Biogen or, if none is designated by Biogen within a period of 30 days, in a recognized banking institution selected by CANbridge, and identified in a notice given to AVEO.

 

8.16. Records and Audits .

(a) Royalties . CANbridge will keep complete and accurate records of the underlying revenue and expense data relating to the calculations of Net Sales and payments required by ARTICLE 6 (Financial Provisions). Biogen will have the right, [**] at its own expense, to have a nationally recognized, independent, certified public accounting firm, selected by it and reasonably acceptable to CANbridge, review any such records of CANbridge in the location(s) where such records are maintained by CANbridge upon reasonable notice (which will be no less than [**] prior notice) and during regular business hours and under obligations of strict confidence, for the sole purpose of verifying the basis and accuracy of payments made under ARTICLE 6 (Financial Provisions) within the [**] period preceding the date of the request for review. CANbridge will receive a copy of each such report concurrently with receipt by Biogen. Should such inspection lead to the discovery of a discrepancy to Biogen’s detriment, CANbridge will pay the amount due within [**] after its receipt from the accounting firm of the certificate any undisputed amount of the discrepancy. Biogen will pay the full cost of the review unless the underpayment of royalties is greater than 5% of the amount due for the entire period being examined, in which case CANbridge will pay the reasonable cost charged by such accounting firm for such review. Any overpayment of royalties by CANbridge revealed by an examination will be paid back by Biogen to CANbridge within [**]. The records of CANbridge for any Calendar Year may be audited no more than once, whether by Biogen or AVEO, provided , that if AVEO is the auditing Party under Section 6.8.1 (Record Keeping), AVEO will have the right to share the applicable audit report with Biogen, and if Biogen is the auditing Party under this Schedule 3.3.4 (Performance by CANbridge Sublicensees), Biogen will have the right to share the applicable audit report with AVEO.

 

10.1. Confidential Information . CANbridge will keep in confidence and not disclose to any Third Party, or use for any purpose, except to exercise its rights or perform its obligations under this Agreement, any Confidential Information of Biogen in accordance with the terms and conditions of ARTICLE 8 (Confidentiality and Publicity).

 

 

Schedule 3.3.4

 


 

Services Agreement between AVEO Pharmaceuticals, Inc. and Selexis SA, of April 12, 2010 and Amendment No. 1 to Services Agreement between AVEO Pharmaceuticals, Inc. and Selexis SA, of April 12, 2010 (the “ Selexis Agreement ”)

 

9.1(b) In the event that AVEO discloses to CANbridge (i) sequence information pertaining to the Selexis Genetic Elements, (ii) Selexis Vector Maps, or (iii) Protocols associated with Selexis proprietary Gene Cloning or Selexis proprietary Transfection Methods, and CANbridge desires to  disclose such information to a CMO that has not been engaged to prepare portions of the CMC documentation to be filed with the applicable regulatory authorities where, in the reasonable opinion of CANbridge, the CMO requires access to such documentation, or if CANbridge desires to disclose any Confidential Information of Selexis (as defined in the Selexis Agreement) to a potential Collaboration Partner (as defined in the Selexis Agreement) then CANbridge will so notify AVEO and AVEO will promptly notify Selexis of the identity of the parties and confirm that they have been bound by obligations of confidentiality and nonuse with respect to such Confidential Information that are no less stringent than the obligations set forth in the Selexis Agreement.

 

Confidential Information . CANbridge will keep in confidence and not disclose to any Third Party, or use for any purpose, except to exercise its rights or perform its obligations under this Agreement, any Confidential Information of Selexis in accordance with the terms and conditions of ARTICLE 8 (Confidentiality and Publicity).

 

Commercial License Agreement between AVEO Pharmaceuticals, Inc. and Selexis SA, of May 31, 2011

 

Confidential Information . CANbridge will keep in confidence and not disclose to any Third Party, or use for any purpose, except to exercise its rights or perform its obligations under this Agreement, any Confidential Information of Selexis in accordance with the terms and conditions of ARTICLE 8 (Confidentiality and Publicity).

 

Research and Commercialization License Agreement between EvoGenix Pty Limited and AVEO Pharmaceuticals, Inc. Dated September 25, 2007, and the First Amendment thereto, between AVEO Pharmaceuticals, Inc. and Cephalon (formerly EvoGenix, dated September 26, 2012 (the “ EvoGenix Agreement ”)

 

4.4(c) All Improvements made by any sublicensee through the exercise of its rights under the EvoGenix Agreement will be the property of EvoGenix. For clarity, the Improvements will be licensed by EvoGenix to AVEO under the EvoGenix Agreement as Improvements to the Licensed Technology, as defined therein and provided below, licensed to CANbridge hereunder as Licensed Patents or Licensed Know-How, as defined in this Agreement and as applicable, and further sublicensed to the applicable sublicensee.  

 

AVEO Results ” means (a) any antibodies resulting from the Research, including the immunoglobulin molecule (such as IgG), whether in monospecific or any other form, any immunoglobulin fragment (such as Fv, Fab, F(ab') or F(ab') 2 ), any fusion protein of an immunoglobulin or immunoglobulin fragment and any single chain antibody (such as scFv), and

2


 

any derivative of any of the foregoing, (b) any nucleic acids encoding any of the foregoing, (c) cells expressing any of the foregoing, and (d) any uses of any of the foregoing. AVEO Results include Products.

 

Designated Target ” means each Target with respect to which AVEO elects to conduct Research pursuant to clause 2.2, but excluding any Restricted Target.

 

Improvement ” means any development, modification, adaptation, or improvement of the Licensed Technology (including the discovery of new uses of the Licensed Technology) that is made by or on behalf of AVEO during the Term. Notwithstanding the foregoing, "Improvement" shall not include any Target or AVEO Results or any development, modification, adaptation, or improvement or other Intellectual Property subsisting in, claiming or covering any Target or AVEO Results, but shall include Intellectual Property subsisting in, claiming or covering new, modified or improved applications of the Licensed Technology to Targets.

 

Know-How ” means drawings, specifications, designs, research and development results, test results and other technical information and Confidential Information that are (a) Controlled by EvoGenix at any time during the term of this Agreement and (b) provided by EvoGenix to AVEO hereunder or otherwise necessary or useful in connection with the Research or Commercialization of actual or potential Products, and any material form in which the above materials or information are contained or embodied, or from which they can be reproduced. For the avoidance of doubt, Know-How does not include the AVEO Results.

 

Licensed Technology ” means: (a) the Patent Rights and/or (b) the Know-How.

 

Target ” means a single human or non-human antigen and its isoforms.

 

Patent Rights ” means

 

(a) the patents and patent applications described in Part A of Schedule 1 of the EvoGenix Agreement;

 

(b) all patent applications that may be filed which are based on, or claim priority from, or are divided from or are continuations of, any patent application described in Schedule 1 of the EvoGenix Agreement;

 

(c) all patents which may be granted pursuant to any of the patent applications referred to in the foregoing paragraph (a) or (b); and

 

(d) all patents and patent applications covering Improvements licensed to AVEO under the EvoGenix Agreement.

 

Product ” means any product (a) that is directed to, inhibits or modulates the expression or activity of a Designated Target and (b) that is or includes:

 

3


 

(i) a protein that is engineered or produced by or on behalf of AVEO using the Licensed Technology, regardless of the intended use of such protein; and/or

 

(ii) any composition of matter, chemical entity or other substance based on, derived from or incorporating all or part of any such protein, including without limitation all analogs, homologs of and binding regions derived from any such protein.

 

Research ” means, with respect to any Designated Target, the research, manufacture and development of pharmaceuticals, including Products, utilizing all or part of the Licensed Technology, provided, however, that “Research" shall only include the humanisation of murine antibodies using the Licensed Technology to the extent conducted by AVEO 's Personnel at AVEO's premises or by a subcontractor appointed by AVEO).

 

Restricted Target ” means the Targets specifically set forth in Schedule 4 to the EvoGenix Agreement.

 

5.5(d) If by reason of applicable laws or regulations in any country, it becomes impossible or illegal for CANbridge to transfer, or have transferred on its behalf, milestones, sales-based or other payments to AVEO that result in a payment to EvoGenix, CANbridge will promptly notify AVEO of the conditions preventing such transfer and such payments shall be deposited in local currency in the relevant country to the credit of EvoGenix in a recognized banking institution designated by EvoGenix or, if none is designated by EvoGenix within a period of 30 days, in a recognized banking institution selected by CANbridge, and identified in a notice given to AVEO. If so deposited in a foreign country, CANbridge will provide reasonable cooperation to EvoGenix so as to allow EvoGenix to assume control over such deposit as promptly as practicable.  

 

Confidential Information . CANbridge will keep in confidence and not disclose to any Third Party, or use for any purpose, except to exercise its rights or perform its obligations under this Agreement, any Confidential Information of EvoGenix in accordance with the terms and conditions of ARTICLE 8 (Confidentiality and Publicity) and in accordance with Section 10 of the EvoGenix Agreement: regarding all documents and other materials in any medium in CANbridge’s possession, power or control which constitute Confidential Information (as defined in the EvoGenix Agreement) CANbridge will return to AVEO (i) any EvoGenix Confidential Information forming part of the Know-How as defined in the EvoGenix Agreement upon termination of this Agreement or the EvoGenix Agreement, and (ii) all other Confidential Information of EvoGenix upon demand by EvoGenix.

 

4


 

Schedule 4.2.1 - POC Study Requirements

 

The POC Study will meet the following criteria:

[**].

 

Schedule 4.2.1

 


 

Schedule 7.1.2- EvoGenix Improvements

 

Pursuant to Section 4.4(c) of the Research and Commercialization License Agreement between EvoGenix PTY Limited and AVEO Pharmaceuticals, Inc., dated September 25, 2007 (“EvoGenix Agreement”) any Inventions that are Improvements (as defined in the EvoGenix Agreement) made by CANbridge through exercise of its rights under that portion of the Licensed Patents or Licensed Know-How that are in-licensed by AVEO pursuant to the terms of the EvoGenix Agreement will be the property of EvoGenix. For clarity, any such Improvements that are owned by EvoGenix will be licensed by EvoGenix to AVEO under the EvoGenix Agreement and included as Licensed Patents and/or Licensed Technology under this Agreement and will be licensed to CANbridge hereunder.  

 

Improvement ” means any development, modification, adaptation, or improvement of the Licensed Technology (including the discovery of new uses of the Licensed Technology) that is made by or on behalf of AVEO during the Term. Notwithstanding the foregoing, "Improvement" shall not include any Target or AVEO Results or any development, modification, adaptation, or improvement or other Intellectual Property subsisting in, claiming or covering any Target or AVEO Results, but shall include Intellectual Property subsisting in, claiming or covering new, modified or improved applications of the Licensed Technology to Targets

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Schedule 7.1.2 - 1


 

Schedule 9.2.1 - Licensed Patents

 

AVEO Patents Relating to AV203

Schedule 9.2.1 - 1


 

AVEO No.

Jurisdiction

Filed

Application No.

Status

Publication or Patent No.

Expiration

[**]

 

 

 

 

 

 

 

[**]

[**]

[**]

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Schedule 9.2.1 - 2


 

 

Patents In-Licensed From EvoGenix

 

Docket No./ Country

Application or Patent Number

Title

Priority Date

Status

[**]

[**]

[**]

[**]

[**]

[**]

[**]

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[**]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Schedule 9.2.1 - 3


 

Patents In-Licensed From Selexis

Docket No./ Country

Application or Patent Number

Title

Priority Date

Status

[**]

[**]

[**]

[**]

[**]

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Exhibit A- 1

 


 

Exhibit A: POC Development Plan

 

 

 

 

 

Confidential Materials omitted and filed separately with the Securities and Exchange Commission.  A total of three pages were omitted. [**]

 

 

 

 

Exhibit A

 


 

Exhibit B: Initial Press Release

 

DRAFT – NOT FOR RELEASE

 

AVEO and CANbridge Life Sciences Announce Exclusive Licensing Agreement for AV-203 Outside of North America

 

CAMBRIDGE, Mass., USA and BEIJING, China – March XX, 2016 – AVEO Oncology (AVEO) and CANbridge Life Sciences, a biopharmaceutical company focused on developing Western drug candidates in China and North Asia, today announced an exclusive license agreement in which AVEO has granted CANbridge Life Sciences worldwide rights, excluding the United States, Canada, and Mexico, to AV-203, AVEO’s clinical-stage ErbB3 (HER3) inhibitory antibody candidate.

 

CANbridge plans to develop AV-203 first in esophageal squamous cell cancer (ESCC), the most prevalent form of esophageal cancer.  According to the World Health Organization, esophageal cancer is the eight most common cancer globally, with over 450,000 cases diagnosed each year. To date, AVEO has completed a Phase 1, open-label, dose-escalation study of AV-203 in patients with advanced solid tumors. In this study, AV-203 was found to be generally safe and well-tolerated, with an early signal of activity consistent with preclinical data showing the potential for heregulin, the only known ligand for ErbB3, to serve as a biomarker predictive of AV-203 anti-tumor activity.

 

Under the terms of the agreement, CANbridge Life Sciences will pay AVEO up to $134 million in upfront and potential reimbursement and milestone payments, assuming the successful achievement of specified development, regulatory and commercialization objectives.  AVEO is also eligible for a tiered royalty, ranging from a low double-digit up to a low-teen percent on net sales of AV-203 in the agreement’s territories.

 

CANbridge Life Sciences will be responsible for costs associated with the execution of a development plan that includes additional manufacturing requirements as well as pre-clinical and clinical studies necessary to demonstrate proof-of-concept for AV-203 as a treatment for squamous cell esophagus cancer, including a Phase IIa proof-of-concept study meeting mutually agreed upon criteria.  Following completion of the proof-of-concept studies, AVEO and CANbridge will negotiate a possible agreement under which they may co-develop AV-203, with each party bearing a percentage of the cost of global development activities based on respective geographic rights.  If the parties fail to reach such an agreement, CANbridge may continue the development of AV-203 on its own in markets outside of the United States, Canada and Mexico.

 

“With an exclusive license to AV-203 outside of North America, CANbridge will be expanding outside of Asia for the first time,” said James Xue, CANbridge Chairman and CEO. “Pre-clinical work shows that AV-203 has the potential to treat ESCC, the most common type of esophageal cancer in Asia, with fifty percent of worldwide diagnoses occurring in China. Esophageal cancer is also prevalent in other parts of the world, particularly developing countries. As part of our globalization strategy, we plan to develop AV-203 in Asia first, then bring it to other territories where patients with this form of disease have few treatment options.”

Exhibit B

54483985_21


 

There is a growing body of clinical data which suggests that heregulin-driven ErbB3 signaling drives resistance to standard therapy in a variety of tumors overexpressing HER3, ” said Michael Bailey, president and chief executive officer of AVEO. “ This agreement allows us to further advance AV-203 development in this setting together with a motivated partner in CANbridge that is led by a deeply experienced team hailing from Genzyme, Synageva and other life sciences innovators.  Importantly, it allows us to retain North American rights for future development, giving us the opportunity to explore a third late-stage drug candidate at a point where our lead development candidate, tivozanib, may be nearing the commercialization stage in North America .”

 

About CANbridge Life Sciences

 

CANbridge Life Sciences, Ltd. is a bio-pharmaceutical company accelerating development and commercialization of specialty healthcare products for serious and critical medical conditions in China and North Asia (Korea and Taiwan).  CANbridge develops partnerships with Western bio-pharmaceutical companies with clinical-stage pharmaceutical, medical device or diagnostic products that are either unavailable in China/North Asia or address medical needs that are underserved in the region. CANbridge also licenses, or obtains exclusive rights to commercialize, drug and device products that are approved in their home markets for commercialization in China and North Asia.  CANbridge has an agreement with EUSA Pharma, to commercialize Caphosol® in China for the prevention and treatment of oral mucositis caused by cancer treatments, and a license with Apogenix to develop, manufacture and commercialize immune-oncology therapy, APG101, for the treatment of glioblastoma multiforme in China, Macao, Hong Kong and Taiwan, where it will be developed as CAN008.

 

Led and backed by a highly-seasoned executive team, with extensive Chinese drug development experience, CANbridge has the capability to select, acquire, develop and commercialize future therapeutics and diagnostics targeting the unmet medical needs of Chinese and East Asian patients with serious or critical conditions.  

 

CANbridge is privately-held and headquartered in Beijing, China.  For more on CANbridge Life Sciences, please go to www.canbridgepharma.com .

 

About AVEO

 

AVEO Oncology (AVEO) is a biopharmaceutical company dedicated to advancing a broad portfolio of targeted therapeutics for oncology and other areas of unmet medical need. The company is focused on developing and commercializing its lead candidate tivozanib, a potent, selective, long half-life inhibitor of vascular endothelial growth factor 1, 2 and 3 receptors, in North America as a treatment for Renal Cell Carcinoma and other cancers. AVEO is leveraging multiple partnerships to develop and commercialize tivozanib in non-oncologic indications worldwide and oncology indications outside of North America, as well as to progress its pipeline of novel therapeutic candidates in cancer and cachexia (wasting syndrome). For more information, please visit the company’s website at www.aveooncology.com .

 

 

Exhibit A- 2

 


 

AVEO Cautionary Note Regarding Forward-Looking Statements

 

 

CANbridge Contact:

Company

James Xue                                                                    

CEO

+8610.8414.8018

  781.995.0074

 

Media:

Deanne Eagle

Planet Communications

917.837.5866

 

AVEO Contact:

David Pitts, Argot Partners

(212) 600-1902

aveo@argotpartners.com

 

 

 

###

 

Exhibit A- 3

 


 

Exhibit C: Technology Transfer Plan and Transfer of Regulatory Documents

Technology Transfer Plan

 

This plan describes the transfer to CANbridge of all historical process or analytical development information that is necessary or useful to enable the Manufacture of the Product.  The transfer consists of three parts: (1) providing access to electronic copies of relevant documentation listed below, (2) the physical transfer or assignment of technology inventory listed below, and (3) the assignment of the Patheon (formerly Laureate) manufacturing contract covering the ongoing drug product stability and reference standard stability program, which assignment is subject to the prior written consent of Patheon.  

 

AVEO will provide electronic copies of the following documents, which have been deemed necessary or useful to enable the Manufacture of Product:

 

[**]

 

 

Table: Current Technology Inventories

ITEM

LOCATION

INVENTORY

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

[**]

 

 

Transfer of Regulatory Documents

 

Importancy

Document

Prepared by

Check if provided

Notes

Number

Content

Clear

1.1

[**]

AVEO

 

[**]

Clear

1.1.1

[**]

AVEO

 

[**]

Clear

1.1.2

[**]

AVEO

 

[**]

Clear

1.1.4

[**]

AVEO

 

[**]

Exhibit C-1

 


 

Clear

1.1.5

[**]

AVEO

 

[**]

Clear

1.2

[**]

AVEO

 

[**]

Clear

1.3

[**]

AVEO

 

[**]

*All regulatory documents will be electronic since the submission was done electronically

 


Exhibit C-2

 


 

1

List of preclinical study reports in the IB, including source documents (see details in the list based on the IB Edition 3 dated on 29 July, 2013 )

 

Importancy

Document

Prepared by

Notes

No.

Original file number in I.B.

Content

Clear

4

4.1.1.1

[**]

AVEO

[**]

Clear

5

4.1.1.2

[**]

AVEO

[**]

Clear

6

4.1.1.3

[**]

AVEO

[**]

Clear

7

4.1.1.4

[**]

AVEO

[**]

Clear

8

4.1.1.5

[**]

AVEO

[**]

Clear

9

4.1.1.6

[**]

AVEO

[**]

Clear

10

4.1.1.7

[**]

AVEO

[**]

Clear

12

4.1.2.1

[**]

AVEO

[**]

Clear

13

4.1.2.2

[**]

AVEO

[**]

Clear

14

4.1.2.3

[**]

AVEO

[**]

Clear

15

4.1.2.4

[**]

AVEO

[**]

Clear

16

4.1.2.5

[**]

AVEO

[**]

Exhibit C-3

 


 

Clear

17

4.1.2.6

[**]

AVEO

[**]

Clear

18

4.1.2.7

[**]

AVEO

[**]

Clear

19

4.1.2.8

[**]

AVEO

[**]

Clear

22

4.2.1.1

[**]

AVEO

[**]

Clear

23

4.2.1.2

[**]

AVEO

[**]

Clear

24

4.2.1.3

[**]

AVEO

[**]

Clear

32

4.3.2

[**]

AVEO

[**]

Clear

35

4.3.4.1

[**]

AVEO

[**]

Clear

36

4.3.4.2

[**]

AVEO

[**]

Clear

38

4.3.5.1

[**]

AVEO

[**]

Check & get back

40

 

[**]

AVEO

[**]

 

 

 

 

 

 

2

Phase I clinical study related documents kept by the sponsor (see details in the list per FDA GCP guidance)  

 

 

2.1

Documents before the phase I study started

 

 

 

Importancy

Document

Prepared by

Notes

No.

Title of document

Purpose

Clear

1

[**]

[**]

AVEO

[**]

Exhibit C-4

 


 

Clear

2

[**]

[**]

AVEO

[**]

Clear

4

[**]

[**]

AVEO

[**]

 

 

 

 

Clear

5

[**]

[**]

AVEO

[**]

 

 

 

 

 

 

 

Clear

13

[**]

[**]

AVEO

[**]

Clear

14

[**]

[**]

AVEO

[**]

Clear

15

[**]

[**]

AVEO

[**]

Exhibit C-5

 


 

Clear

16

[**]

[**]

AVEO

[**]

 

 

 

 

 

[**]

2.2

Documents during the Clinical Conduct of the Trial

 

 

 

In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant information is documented as it becomes available.

 

 

 

Importancy

Document

Prepared by

Notes

No.

Title of document

Purpose

Clear

1

[**]

[**]

AVEO

[**]

Clear

2

[**]

[**]

AVEO

[**]

 

 

Exhibit C-6

 


 

Clear

3

[**]

[**]

AVEO

[**]

 

 

 

 

 

 

 

Clear

4

 

[**]

AVEO

[**]

[**]

Clear

7

[**]

[**]

AVEO

[**]

 

Clear

9

[**]

[**]

AVEO

[**]

Clear

10

[**]

[**]

AVEO

[**]

Clear

12

[**]

[**]

AVEO

[**]

Clear

14

[**]

[**]

AVEO

[**]

Exhibit C-7

 


 

Clear

16

[**]

[**]

AVEO

[**]

Clear

19

[**]

[**]

AVEO

[**]

Clear

20

[**]

[**]

AVEO

[**]

Clear

22

[**]

[**]

AVEO

[**]

Clear

23

[**]

[**]

AVEO

[**]

 

 

 

 

 

 

2.3

Documents after Completion of the Trial
After completion the trial, all of the documents identified in sections 2.2.1 and 2.2.2 should be in the file together with the following:

 

 

After completion the trial, all of the documents identified in sections 2.2.1 and 2.2.2 should be in the file together with the following:

 

 

Importancy

Document

Prepared by

Notes

No.

Title of document

Purpose

Clear

5

[**]

[**]

AVEO

[**]

Clear

7

[**]

[**]

AVEO

[**]

Exhibit C-8

 


 

Clear

8

[**]

[**]

AVEO

[**]

 

 

 

 

 

 

3

Other Clinical Related Documents
After completion the trial, all of the documents identified in sections 2.2.1 and 2.2.2 should be in the file together with the following:

 

Importancy

Document

Prepared by

Notes

No.

Content

Clear

1

[**]

 

AVEO

[**]

Clear

2

[**]

 

AVEO

[**]

 

 

Exhibit C-9

 

Exhibit 31.1

CERTIFICATION

I, Michael Bailey, certify that:

 

1.

I have reviewed this Quarterly Report on Form 10-Q of AVEO Pharmaceuticals, Inc.;

 

2.

Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this report;

 

3.

Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;

 

4.

The registrant’s other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have:

 

a.

Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those entities, particularly during the period in which this report is being prepared;

 

b.

Designed such internal control over financial reporting or caused such internal control over financial reporting to be designed under our supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles;

 

c.

Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and

 

d.

Disclosed in this report any change in the registrant’s internal control over financial reporting that occurred during the registrant’s most recent fiscal quarter (the registrant’s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to materially affect, the registrant’s internal control over financial reporting; and

 

5.

The registrant’s other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the registrant’s auditors and the audit committee of the registrant’s board of directors (or persons performing the equivalent functions):

 

a.

All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are reasonably likely to adversely affect the registrant’s ability to record, process, summarize and report financial information; and

 

b.

Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal control over financial reporting.

Date: May 10, 2016

 

/s/ Michael Bailey

Michael Bailey

President and Chief Executive Officer

(Principal Executive Officer)

 

Exhibit 31.2

CERTIFICATION

I, Keith Ehrlich, certify that:

 

1.

I have reviewed this Quarterly Report on Form 10-Q of AVEO Pharmaceuticals, Inc.;

 

2.

Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this report;

 

3.

Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;

 

4.

The registrant’s other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have:

 

a.

Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those entities, particularly during the period in which this report is being prepared;

 

b.

Designed such internal control over financial reporting or caused such internal control over financial reporting to be designed under our supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles;

 

c.

Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and

 

d.

Disclosed in this report any change in the registrant’s internal control over financial reporting that occurred during the registrant’s most recent fiscal quarter (the registrant’s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to materially affect, the registrant’s internal control over financial reporting; and

 

5.

The registrant’s other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the registrant’s auditors and the audit committee of the registrant’s board of directors (or persons performing the equivalent functions):

 

a.

All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are reasonably likely to adversely affect the registrant’s ability to record, process, summarize and report financial information; and

 

b.

Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal control over financial reporting.

Date: May 10, 2016

 

/s/ Keith S. Ehrlich 

Keith S. Ehrlich, C.P.A.

Chief Financial Officer

(Principal Financial Officer)

 

Exhibit 32.1

CERTIFICATION PURSUANT TO 18 U.S.C. SECTION 1350,

AS ADOPTED PURSUANT TO

SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002

In connection with the Quarterly Report on Form 10-Q of AVEO Pharmaceuticals, Inc. (the “Company”) for the fiscal quarter ended March 31, 2016 as filed with the Securities and Exchange Commission on the date hereof (the “Report”), the undersigned, Michael Bailey, President and Chief Executive Officer of the Company, hereby certifies, pursuant to 18 U.S.C. Section 1350, that, to his knowledge on the date hereof:

(1) The Report fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934; and

(2) The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.

Date: May 10, 2016

 

/s/ Michael Bailey 

Michael Bailey

President and Chief Executive Officer

(Principal Executive Officer)

 

 

Exhibit 32.2

CERTIFICATION PURSUANT TO 18 U.S.C. SECTION 1350,

AS ADOPTED PURSUANT TO

SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002

In connection with the Quarterly Report on Form 10-Q of AVEO Pharmaceuticals, Inc. (the “Company”) for the fiscal quarter ended March 31, 2016 as filed with the Securities and Exchange Commission on the date hereof (the “Report”), the undersigned, Keith Ehrlich, Chief Financial Officer of the Company, hereby certifies, pursuant to 18 U.S.C. Section 1350, that, to his knowledge on the date hereof:

(1) The Report fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934; and

(2) The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.

Date: May 10, 2016

 

/s/ Keith S. Ehrlich 

Keith S. Ehrlich, C.P.A.

Chief Financial Officer

(Principal Financial Officer)