RESEARCH COLLABORATION AND LICENSE AGREEMENT

RESEARCH COLLABORATION


AND LICENSE AGREEMENT


between


OXIGENE EUROPE AB


and


BRISTOL-MYERS SQUIBB COMPANY


Dated as of December 15, 1999


TABLE OF CONTENTS


Page


I


DEFINITIONS


II


REPRESENTATIONS AND WARRANTIES


2.1 Representations and Warranties of Both Parties...................6
2.2 Additional Representations and Warranties of OXiGENE.............7


III


ASU LICENSE AGREEMENT


3.1 Representations and Warranties of OXiGENE........................8
3.2 OXiGENE Obligations..............................................9
3.3 Rights of, and Obligations to, ASU..............................10


IV


JOINT DEVELOPMENT COMMITTEE


4.1 Members.........................................................10
4.2 Responsibilities................................................11
4.3 Meetings........................................................12
4.4 Decisions.......................................................12
4.5 Minutes.........................................................12
4.6 Term............................................................13
4.7 Expenses........................................................13


V


COLLABORATIVE RESEARCH PROGRAM


5.1 Scope of Research Program.......................................13
5.2 Funding of Research Program.....................................13
5.3 Conduct of Research Program.....................................14
5.4 Records.........................................................15
5.5 Material Transfer...............................................15
5.6 Liability.......................................................15
5.7 Term of Research Program........................................15
5.8 Termination of Research Program; Effect.........................16


VI


OWNERSHIP; PATENT PROTECTION


6.1 Ownership of BMS Collaboration Technology.......................17
6.2 Ownership of ASU Licensed Technology, OXiGENE Licensed Technology,
OXiGENE Collaboration Technology................................17
6.3 Ownership of Joint Collaboration Technology.....................17
6.4 Patent Filing, Prosecution and Maintenance......................17
6.5 Termination of Support by BMS...................................18


VII


GRANT OF LICENSES; RESERVATION OF RIGHTS


7.1 Mutual Research Licenses........................................18
7.2 BMS Commercialization License; Limited Partial Conversion to
Non-exclusivity.................................................19
7.3 Mutual Ex-Field Licenses........................................19
7.4 ******..........................................................19
7.5 ******..........................................................19
7.6 ******..........................................................19
7.7 ******..........................................................19


VIII


DEVELOPMENT AND COMMERCIALIZATION


8.1 Development Efforts by BMS......................................20
8.2 Transfer of INDs, etc...........................................20
8.3 Ownership of Regulatory Filings.................................20
8.4 Reporting; OXiGENE Liaison......................................20
8.5 Trademarks......................................................21
8.6 ******..........................................................21


IX


MONETARY OBLIGATIONS


9.1 BMS's Reimbursement of Certain Expenses.........................21
9.2 License Fee.....................................................22
9.3 Development Milestone Payments by BMS...........................22
9.4 Additional License Fee, Milestone Payment.......................23
9.5 Royalties.......................................................23
9.6 Third Party Royalties...........................................24
9.7 Additional Royalty Indemnification..............................25


X


PAYMENTS AND REPORTS


10.1 Payment.........................................................25
10.2 Mode of Payment.................................................25
10.3 Records Retention...............................................25
10.4 Audit Request...................................................25
10.5 Taxes...........................................................26
10.6 Blocked Currency................................................26
10.7 Late Payments...................................................26


XI


MANUFACTURING


11.1 Transfer of Manufacturing Responsibility........................26
11.2 Negotiation, Execution of Supply Agreement......................27
11.3 Terms of Supply Agreement.......................................27
11.4 Cost of Manufacturing and Related Activities....................28
11.5 Manufacturing Liaisons..........................................28
11.6 U.S. Manufacture................................................28


XII


CONFIDENTIALITY


12.1 Confidentiality; Exceptions.....................................28
12.2 Exclusions to Confidentiality...................................29
12.3 Injunctive Relief...............................................29


XIII


INTELLECTUAL PROPERTY


13.1 Patent Enforcement..............................................29
13.2 Infringement Actions by Third Parties...........................30
13.3 Superior Rights of ASU..........................................31


XIV


INDEMNIFICATION


14.1 By BMS..........................................................31
14.2 By OXiGENE......................................................32
14.3 Notice..........................................................32
14.4 Complete Indemnification........................................32
14.5 Insurance.......................................................32


XV


TERM; TERMINATION


15.1 Term............................................................33
15.2 Effect of Expiration............................................33
15.3 Termination by Either Party.....................................33
15.4 Termination by BMS..............................................34
15.5 Effect of Expiration or Termination.............................34
15.6 Right to Sell Stock on Hand.....................................35
15.7 Termination of Sublicenses......................................35
15.8 Accrued Rights, Surviving Obligations...........................35


XVI


FORCE MAJEURE


16.1 Events of Force Majeure.........................................35


XVII


MISCELLANEOUS


17.1 Non-solicitation................................................36
17.2 Standstill......................................................36
17.3 Relationship of Parties.........................................37
17.4 Guaranty........................................................37
17.5 Assignment......................................................37
17.6 Disclaimer of Warranties........................................37
17.7 Further Actions.................................................38
17.8 Notice..........................................................38
17.9 Use of Name.....................................................38
17.10 Public Announcements............................................39
17.11 Waiver..........................................................39
17.12 Compliance with Law.............................................39
17.13 Severability....................................................39
17.14 Amendment.......................................................40
17.15 Governing Law; English Original; Jurisdiction...................40
17.16 Arbitration.....................................................40
17.17 No Consequential Damages........................................40
17.18 Entire Agreement................................................41
17.19 Parties in Interest.............................................41
17.20 Descriptive Headings............................................41
17.21 Counterparts....................................................41


RESEARCH COLLABORATION
AND LICENSE AGREEMENT


THIS RESEARCH COLLABORATION AND LICENSE AGREEMENT (this "Agreement"), dated as of December 15, 1999, is between OXiGENE Europe AB, a company duly organized and existing under the laws of Sweden and having offices at Blasieholmsgatan 2c, S-111 48 Stockholm, Sweden, for and on behalf of itself and its Affiliates ("OXiGENE"), and Bristol-Myers Squibb Company, a company duly organized and existing under the laws of the State of Delaware and having offices at Route 206 and Province Line Road, Princeton, New Jersey, USA 08543-4000, for and on behalf of itself and its Affiliates ("BMS").


PRELIMINARY STATEMENTS


A. OXiGENE is a leading biotechnology company.


B. BMS is an international pharmaceutical company.


C. OXiGENE has entered into that certain License Agreement with the Arizona Board of Regents, acting on behalf of Arizona State University (collectively, "ASU"), pursuant to which OXiGENE has been granted a license, with the right to sublicense, certain patent rights and other know-how and technology owned by ASU.


D. OXiGENE wishes to grant a sublicense to BMS, and BMS wishes to take a sublicense from OXiGENE, under certain rights granted to OXiGENE under such License Agreement and under other relevant patent rights and know-how owned by OXiGENE, upon the terms and conditions set forth in this Agreement.


E. Furthermore, OXiGENE and BMS wish to collaborate in connection with the research, development and commercialization of products covered by such licensed technology, upon the terms and conditions set forth in this Agreement.


NOW, THEREFORE, in consideration of the foregoing preliminary statements and the mutual covenants and agreements of the Parties contained in this Agreement, the Parties hereby agree as follows:


I


DEFINITIONS


As used in this Agreement, the following terms shall have those meanings set forth in this Section 1 unless the context dictates otherwise.


1.1 "Affiliate" with respect to either Party, shall mean any Person controlling, controlled by, or under common control with, such Party. For these purposes, "control" shall refer to (i) the possession, directly or indirectly, of the power to direct the management or policies of a Person, whether through the ownership of voting securities, by contract or otherwise, or (ii) the beneficial ownership (as such term is defined in the 1934 Act) of at least 50% of the voting securities or other ownership interest of a Person.


1.2 "ASU Advisory Committee" shall have the meaning assigned thereto in Section 3.1(f).


1.3 "ASU License Agreement" shall mean that certain License Agreement No. 206-01.LIC, dated August 2, 1999, by and between OXiGENE and ASU, a redacted copy of which is attached hereto as Exhibit A.


1.4 "ASU Licensed Technology" shall mean ASU'S PATENT RIGHTS I, II, III and IV and all related TECHNOLOGY and KNOW-HOW to which OXiGENE has been granted a license under the ASU License Agreement, as such block capitalized terms are defined therein. A list of all such Patents in existence on the Effective Date is included in Exhibit B attached.


1.5 "BMS Collaboration Technology" shall mean all Inventions and Know-How first studied, developed, reduced to practice or shown to have utility solely by employees of BMS in connection with the performance of BMS's obligations under the Research Program, as well as any and all Patents covering same.


1.6 "CA4P" shall mean the chemical compound having the chemical name Combretastatin A4 phosphate.


1.7 "Collaboration Compound" shall mean any chemical compound, the composition of matter and/or method of use of which is, or under Section 9.4 is deemed to be, covered by the ASU Licensed Technology, the OXiGENE Licensed Technology and/or the OXiGENE Collaboration Technology, and that is the subject of any of the research, development, commercialization and/or marketing activities contemplated by this Agreement. While the Parties intend CA4P to be the initial Collaboration Compound, other compounds may be selected as Collaboration Compounds in addition to, or in lieu of, CA4P.


1.8 "Combretastatin" shall mean any cancer cell growth inhibitory substance derived from the bush willow Combretum caffrum.


1.9 "Confidential Information" shall have the meaning assigned to such term in Section 12.1.


1.10 "Covered Product" shall mean any pharmaceutical product the manufacture, sale or use of which in any country in the Territory is covered by a Valid Claim of any Patent included in the ASU Licensed Technology, the OXiGENE Licensed Technology, the OXiGENE Collaboration Technology, the BMS Collaboration Technology and/or the Joint Collaboration Technology.


1.11 "EEA" shall mean the countries in the European Economic Area, or any successor thereto, from time to time.


1.12 "Effective Date" shall mean the date first set forth above.


1.13 "FDA" shall mean the United States Food and Drug Administration, or any successor thereto.


1.14 "Field" shall mean the prevention, diagnosis, control or treatment of any human or animal disease or condition by the Systemic Use of a Covered Product(s), either as a single agent or in combination with any other therapy. The Field may be modified from time to time as provided in Section 7.7"


1.15 "First Commercial Sale" shall mean, with respect to any Covered Product, the first sale for use or consumption by the general public of such Covered Product in a country in the Territory after all required marketing and pricing approvals have been granted, or otherwise permitted, by the governing health authority of such country. "First Commercial Sale" shall not include the sale of any Covered Product for use in clinical trials or for compassionate use prior to the approval of an NDA; provided, however, that if and to the extent that BMS receives remuneration for any such compassionate use or named patient sales, BMS shall pay royalties thereon in accordance with Section 9.5.


1.16 "IND" shall mean an Investigational New Drug Application to be filed with the FDA, or the equivalent thereof in other countries or regulatory jurisdictions.


1.17 "Invention" shall mean any new or useful method, process, manufacture, compound or composition of matter, whether or not patentable or copyrightable, or any improvement thereof.


1.18 "Joint Collaboration Technology" shall mean all Inventions and Know-How first studied, developed, reduced to practice or shown to have utility jointly by one or more employees of BMS and one or more employees of OXiGENE during the performance of the Parties' respective obligations under the Research Program, as well as any and all Patents covering same.


1.19 "Joint Development Committee" shall mean the entity organized and acting pursuant to Section 4.


1.20 "Know-How" shall mean unpatented technical and other information which is not in the public domain including information comprising or relating to discoveries, inventions, data, designs, formulae, methods, models, assays, research plans, procedures, designs for experiments and tests and results of experimentation and testing (including results of research or development), processes (including manufacturing processes, specifications and techniques), laboratory records, chemical, pharmacological, toxicological, clinical, analytical and quality control data, trial data, case report forms, data analyses, reports or summaries and information contained in submissions to and information from ethical committees and regulatory authorities. Know-How includes rights protecting Know-How. The fact that an item is known to the public shall not be taken to exclude the possibility that a compilation including the item, and/or a development relating to the item, is (and remains) not known to the public.


1.21 "Licensed Product" shall mean any pharmaceutical product the manufacture, sale or use of which in any country in the Territory is covered by a Valid Claim of any Patent included in the ASU Licensed Technology. For purposes of clarification, all Licensed Products are Covered Products, but not all Covered Products are Licensed Products.


1.22 "NDA" shall mean a New Drug Application to be filed with the FDA, or the equivalent thereof in other countries or regulatory jurisdictions.


1.23 "Net Sales" shall mean, with respect to any Covered Product, the gross amount invoiced to Third Parties by BMS, its Affiliates or its Sublicensees, as the case may be, for such Covered Product, commencing with the First Commercial Sale of such Covered Product, less deductions for: (i) reasonable and customary trade, quantity and/or cash discounts actually granted; (ii) reasonable and customary credits, refunds and allowances (including, without limitation, cash, credit and free goods allowances) actually allowed or given for chargebacks, retroactive price reductions, billing errors and rebates (including, without limitation, government-mandated and managed healthcare negotiated rebates); (iii) credits and refunds for Covered Product that is rejected, spoiled, damaged, outdated or returned actually allowed or given; (iv) freight, postage, shipping insurance and other transportation costs actually incurred in transporting Covered Product to a Third Party; and (v) taxes, tariffs, customs duties, surcharges and other governmental charges incurred in connection with the sale, exportation or importation of Covered Product. Such amounts shall be determined from the books and records of BMS, its Affiliates or its Sublicensees, as the case may be, maintained in accordance with the generally accepted accounting principles, consistently applied.


Notwithstanding the foregoing, in the event a Covered Product is sold in conjunction with another proprietary active component so as to be a combination product (whether packaged together or in the same therapeutic formulation), Net Sales shall be calculated by multiplying the Net Sales of such combination product by a fraction, the numerator of which shall be the fair market value of the Covered Product as if sold separately (determined in accordance with generally accepted accounting principles), and the denominator of which shall be the aggregate fair market value of all the proprietary active components of such combination product, including the Covered Product, as if sold separately. In the event no such separate sales are made by BMS, its Affiliates or Sublicensees, Net Sales of the combination product shall be calculated in a manner to be negotiated and agreed upon by the Parties, reasonably and in good faith, prior to any sale of such combination product, which shall be based upon the respective estimated commercial values of the proprietary active components of such combination product.


Notwithstanding the foregoing, in connection with (X) any sale or other disposition of Covered Product that is not a bona fide, arms length transaction for money, or (Y) any other use of Covered Product that does not result in or give rise to sales revenue that is customary in the country in which such use takes place (except as provided in the next paragraph), Net Sales shall be calculated at the relevant open market price in the country in which such sale, disposition or use takes place, or, if such price is not reasonably ascertainable, at a reasonable price, assessed on an arms length basis, for the goods and/or services received in consideration of the sale, disposition or use of Covered Product.


BMS's or any of its Affiliate's transfer of Covered Product to another Affiliate or a Sublicensee shall not result in any Net Sales, unless such Covered Product is consumed by such Affiliate or Sublicensee in the course of its commercial activities. In such case, Net Sales shall occur upon such other Affiliate's or Sublicensee's sale of such Covered Product to a Third Party. Further, the disposition of Covered Product for, or the use of Covered Product in, pre-clinical or clinical (Phase I - III) trials or other market-focused (Phase IV or V) trials or free samples shall not result in any Net Sales.


1.24 "1934 Act" shall mean the Securities Exchange Act of 1934, as amended, and all regulations promulgated pursuant thereto from time to time.


1.25 "North America" shall mean the United States and Canada and their respective possessions.


1.26 "OXiGENE Collaboration Technology" shall mean all Inventions and Know-How first studied, developed, reduced to practice or shown to have utility solely by employees of OXiGENE, or of any Third Party working on behalf of for the benefit of OXiGENE and/or in whose Inventions and Know-How OXiGENE otherwise has rights, in connection with the performance of OXiGENE's obligations under the Research Program, as well as any and all Patents covering same.


1.27 "OXiGENE Licensed Technology" shall mean all Patents owned or controlled by, or licensed to, OXiGENE, and all Know-How and Inventions developed, owned or controlled by, or licensed to, OXiGENE, on or after the Effective Date, other than the ASU Licensed Technology, which, in the reasonable opinion of the Parties, is necessary for or may be useful in the development, manufacture, use or sale of Licensed Products in the Field in the Territory, all to the extent that OXiGENE has the right to license or otherwise make available such Patents, Know-How and Inventions to BMS hereunder. A list of all such Patents in existence on the Effective Date is included in Exhibit B attached.


1.28 "OXiGENE Pre-clinical Studies" shall have the meaning assigned thereto in Section 9.1(a).


1.29 "Party" shall mean OXiGENE or BMS and, when used in the plural, shall mean OXiGENE and BMS.


1.30 "Patents," as used in this Agreement, shall mean all of the subject letters patent and patent applications throughout the Territory, as well as any and all substitutions, extensions, renewals, continuations, continuations-in-part, divisions, patents-of-addition and/or reissues thereof.


1.31 "Person" shall mean any natural person, corporation, firm, business trust, joint venture, association, organization, company, partnership or other business entity, or any government or any agency or political subdivision thereof.


1.32 "Research Plan" shall have the meaning thereto in Section 5.1.


1.33 "Research Program" shall mean the research program that is conducted by OXiGENE in collaboration with BMS pursuant to Section 5.


1.34 "Royalty Term" shall mean, with respect to each Covered Product in a country in the Territory, the period of time commencing on the Effective Date and ending on the later of: (i) the ****** anniversary of the First Commercial Sale of such Covered Product in such country, or (ii) if, at the time of the First Commercial Sale of such Covered Product in such country, the sale of such Covered Product is covered by a Valid Claim of a Patent directed to the composition of matter or use in the Field of the compound contained in such Covered Product or a pharmaceutical preparation containing such compound that is included in the ASU Licensed Technology, the OXiGENE Licensed Technology and/or the OXiGENE Collaboration Technology, the date on which the last of such Patents expires.


1.35 "Sublicensee" shall mean a Third Party to which BMS has granted sublicense rights under the OXiGENE Licensed Technology, OXiGENE Collaboration Technology, BMS Collaboration Technology and Joint Collaboration Technology and further sublicense rights under the ASU Licensed Technology.


1.36 "Substances" shall have the meaning assigned thereto in Section 5.5.


1.37 "Supply Agreement" shall have the meaning assigned thereto in Section 11.2.


1.38 "Systemic Use" shall mean any use of a compound or product where the administration is by means other than topical.


1.39 "Territory" shall mean all of the countries in the entire world.


1.40 "Third Party" shall mean any Person who or which is neither a Party nor an Affiliate of a Party.


1.41 "Valid Claim" shall mean (i) a pending claim in any patent application that has not been pending for more than five years, which for purposes of Sections 1.10, 1.21 and 1.33 shall be treated as if such pending claim were issued in then-current form, or (ii) a claim of any issued letters patent that, in each case, has not been held invalid or unenforceable by final decision of a court or other governmental agency of competent jurisdiction, unappealable or unappealed within the time allowed for appeal, and that is not admitted to be invalid or unenforceable through reissue, disclaimer or otherwise.


II


REPRESENTATIONS AND WARRANTIES


2.1 Representations and Warranties of Both Parties. Each Party represents and warrants to the other Party that, as of the Effective Date:


(a) Such Party is duly organized and validly existing under the laws of the jurisdiction of its incorporation and has full corporate power and ...