Exhibit 10.12

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RESTATED

DEVELOPMENT AND COMMERCIALIZATION

COLLABORATION AGREEMENT

between

OTSUKA PHARMACEUTICAL CO., LTD.

and

BRISTOL-MYERS SQUIBB COMPANY

TABLE OF CONTENTS

 

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APPENDICES:

 

 

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RESTATED

DEVELOPMENT AND COMMERCIALIZATION

COLLABORATION AGREEMENT

This Restated Development and Commercialization Collaboration Agreement (this “Agreement”) is made and entered into as of October 23, 2001 (the “Restated Agreement Date”), by and between OTSUKA PHARMACEUTICAL CO., LTD. (“Otsuka”), a corporation organized and existing under the laws of Japan, having a principal place of business at 2-9, Kanda Tsukasa-cho, Chiyoda-ku, Tokyo, Japan, and BRISTOL-MYERS SQUIBB COMPANY (“BMS”), a corporation organized and existing under the laws of Delaware, having a principal place of business at Route 206 and Province Line Road, Princeton, New Jersey 08540, USA. This Agreement amends and restates that certain Development and Commercialization Collaboration Agreement between Otsuka and BMS dated September 20, 1999. The Effective Date of the Agreement, as amended and restated here, remains September 20, 1999.

RECITALS

A. Otsuka has developed a compound known as Aripiprazole (the “Compound”) and possesses certain patent rights, know-how, data and information related to such Compound;

B. BMS has considerable experience developing, obtaining regulatory approval of, and commercializing prescription drugs worldwide;

C. In order to complete the development of the Compound into an approved prescription drug and to bring the product to market at the earliest appropriate time, Otsuka has decided that it is necessary to contract with BMS for drug development and commercialization services on Otsuka’s behalf, and BMS agrees to provide such services, on the terms and conditions set forth in this Agreement; and

D. The parties believe this collaboration is essential to complete the development of the Compound and to optimize its commercial potential, to their financial benefit and to the benefit of human health worldwide.

AGREEMENT

NOW, THEREFORE, Otsuka and BMS agree as follows:

 

 

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1. DEFINITIONS

1.1. “Affiliate” of a party shall mean any corporation, firm, association, joint venture, partnership or other entity that directly or indirectly owns or controls, is owned, or controlled by or is under common ownership or control with such party. “Control” of an entity shall mean beneficial ownership of at least fifty percent (50%) of the voting equity or other ownership interests of the entity in question, conferring on the entity who holds such interests the power directly or indirectly to elect a majority of the board of directors or other managing authority of the entity or otherwise to direct the affairs of such corporation, firm, association, joint venture, partnership or other entity.

1.2. “Attributable Bulk” shall have the meaning set forth in Section 5.11.2.

1.3. “BMSLC” shall mean Bristol-Myers Squibb Laboratories Company, a wholly-owned subsidiary of BMS.

1.4. “BMS-OAPI Product Supply Agreement” shall mean, collectively, those certain agreements by which BMS supplies Product for sale in the United States, as described in Section 5.11.6.

1.5. “Bulk Tablets” shall mean the Product containing Compound in tablet form, supplied in bulk (not packaged) quantities, the formulation and specification of such tablets to be as used in the Ongoing Clinical Studies or in such other form(s) as the PDC deems appropriate. For the avoidance of doubt, the Bulk Tablets formulation excludes, and is different from, the Product in the “flash-melt” formulation.

1.6. “Business Days” shall mean the work days (exclusive of weekends and holidays) at the principal place of business of the party burdened with the obligation or undertaking under this Agreement to respond or act within a specified number of Business Days.

1.7. “Call” shall mean a visit by a professional sales representative to a physician or other health care professional licensed to prescribe, dispense or administer prescription drugs, or to an authorized representative of a prospective organizational purchaser of Product, which visit is for the purpose of promoting the sale of Product.

1.8. “Carcinogenicity Study” shall mean that certain two-year carcinogenicity study in rats being conducted by BMS pursuant to a Memorandum of Agreement between BMS and Otsuka effective as of March 29, 1999.

1.9. “Commercialization” shall mean advertising, marketing, promotion, sale and distribution of a product, and activities related thereto, including without limitation those specified in Section 5.3.2(b). When used as a verb, “Commercialize” means to engage in such activities.

 

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1.10. “Competitive Product” shall have the meaning set forth in Section 7.2.

1.1 1. “Compound” shall mean the chemical compound with the following formula: 7-{4- [4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1 H)-quinolinone, in the chemical form as used in the Ongoing Clinical Studies, known as Aripiprazole.

1.12. “Compound Form” shall mean any of the salts, esters, amides, hydrates, solvates and metabolites of the Compound.

1.13. “Co-Promotion” shall mean promotion of the Product by BMS and Otsuka (and their Affiliates) under a single regulatory approval, registration and Trademark. When used as a verb, “Co-Promote” shall mean to engage in such activities.

1.14. “Co-Promotion Countries” shall mean the United States of America and its territories and possessions, France, Spain, Germany and the United Kingdom, and Italy if it becomes legally permissible to Co-Promote in Italy.

1.15. “Distributor” shall have the meaning set forth in Section 5.3.12.

1.16. “Effective Date” shall mean September 20, 1999.

1.17. “EMEA” shall mean the European Agency for the Evaluation of Medicinal Products.

1.18. “European Union” shall mean (i) the member countries of the European Union (i.e., as of the Restated Agreement Date, Belgium, Denmark, Germany, Greece, Spain, France, Ireland, Italy, Luxemburg, Netherlands, Austria, Portugal, Finland, Sweden and the United Kingdom); (ii) those additional countries that here after become members of the European Union; and (iii) for purposes of this Agreement (except to the extent expressly provided otherwise), Norway, Switzerland and Iceland.

1.19. “FDA” shall mean the United States Food and Drug Administration, or the successor thereto.

1.20. “Field” shall mean, in the case of Product containing Compound or a Compound Form, prescription pharmaceutical agents for all uses and indications in humans; in the case of Product containing a Related Compound, “Field” shall mean prescription pharmaceutical agents for all Neuroscience Indications in humans. For the sake of clarification, “Field” excludes, and the scope of the Commercialization rights granted by Otsuka to BMS in this Agreement does not include, any products containing a Related Compound for any uses or indications other than Neuroscience Indications in humans.

 

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1.21. “First Commercial Sale” shall mean, in each country of the Territory, the date that Product (or a Competitive Product, as applicable in Section 7) is first sold pursuant to an approved NDA or MAA in a commercial transaction intending that Product (or Competitive Product, as the case may be) be used by an end user. For the sake of clarification, Product (or Competitive Product, as the case may be) sold, distributed or used only for clinical trials or experimental purposes shall not establish the date of First Commercial Sale.

1.22. “Global Floor Price-Based Adjustment” shall have the meaning set forth in Section 5.11.3.

1.23. “Improvements” shall have the meaning set forth in Section 4.5.5.

1.24. “IND” shall mean Investigational New Drug Application fled with the FDA.

1.25. “JCC” shall mean the Joint Commercialization Committee described in Section 5.1.

1.26. “Launch Date” shall mean the first date on which the Product is actively detailed in a country in the Territory.

1.27. “MAA” shall mean a Marketing Authorization Application or other application fled with the regulatory authorities of a country, or with an agency representing a group of countries, including the EMEA, outside the United States to obtain marketing authorization for a pharmaceutical product in such country or countries. “MA” shall mean the Marketing Authorization resulting from the approval of an MAA.

1.28. “Marketing Plan(s)” shall have the meaning set forth in Section 5.2.

1.29. “NDA” shall mean a New Drug Application fled with the FDA.

1.30. “Net Sales” in a country or region shall mean, with respect to Product, the gross amount invoiced by Otsuka, BMS or their respective Affiliates (or by BMS’s Sublicenses in the Rest of Territory) to non-Affiliate third-party purchasers for the sale or distribution of Product in such country or region, as the case may be, in the Territory, less the following amounts, but only to the extent included in the invoiced amount:

(i) customary trade, quantity and cash discounts actually allowed (exclusive of discounts given to promote sales of product other than Product); (ii) customary rebates, allowances, chargebacks, credits, refunds and other price adjustments actually granted and made to customers for rejected, returned or recalled goods, or price reductions; (iii) rebates, credits, charge-back and prime vendor rebates, fees, reimbursements or similar payments or credits granted or given to wholesalers and other distributors, buying groups, health care insurance carriers, pharmacy benefit management companies, health maintenance

 

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organizations or other institutions or health care organizations, and price reductions/adjustments required by law, regulations or contract, including, without limitation, those paid in connection with sale of Product to governmental or regulatory authorities or programs; (iv) transportation and insurance costs incidental to the sale of Product; and (v) any tax, tariff customs duties, excise or other duties or other governmental charge (other than an income tax) levied on the sale, transportation or delivery of Product and borne by the seller thereof. Such deductions shall in each case be related specifically to the Product (except to the extent this is not practicable, in which event such deductions shall be allocated in the ratio of gross sales of the Product to the total gross sales of all products to which such deductions apply) and shall be actually allowed to or taken by non-Affiliate third-party purchasers and not otherwise recovered by or reimbursed from the third-party purchasers to BMS, Otsuka or their Affiliates or Sublicensees. For the sake of clarification, no sales to BMS’s, Otsuka’s or their Affiliates’ or Sublicensees’ distributors or agents shall, unless they are non-Affiliate third-party purchasers, be considered as sales for the purpose of this definition, and only sales (and all sales) to non-Affiliate third-party purchasers shall be the basis for determining the amount of Net Sales; provided that, if BMS, Otsuka or their Affiliates or Sublicensees furnish Product directly or indirectly to an end user in a commercial transaction for which BMS, Otsuka or their Affiliates or Sublicensees receive consideration other than in the form of cash, or if BMS, Otsuka or their Affiliates or Sublicensees are the ultimate commercial end users of Product, the value of Product so furnished or used shall be included in Net Sales; in such case, Net Sales of Product so furnished or used by BMS, Otsuka or their Affiliates or Sublicensees shall be determined by multiplying the quantity of Product so furnished or used during a given calendar quarter by the average selling price of Product to non-Affiliate third-party purchasers in the same country during the same calendar quarter. In the case of a Product containing the Compound, a Compound Form or a Related Compound in combination with other active therapeutic ingredients, Net Sales of such combination product shall be determined as follows: Net Sales as defined above shall be multiplied by a fraction, the numerator of which shall be the average selling price of such quantity of Product as contains one (1) gram of the Compound, the Compound Form or the Related Compound as the sole active therapeutic ingredient, and the denominator of which shall be the average selling price of such quantity of combination Product as contains one (1) gram of the Compound, the Compound Form or the Related Compound.

1.31. “Neuroscience Indication” shall mean any indication for the treatment in humans of schizophrenia, schizo-affective disorder, psychotic disorder, anxiety, panic disorder, attention deficit disorder, Alzheimer’s dementia, bipolar disorder, obsessive-compulsive disorder, Huntington’s Chorea, Tourette syndrome and any other indication that rises from the pharmacological action of Compound, a Compound Form or a Related Compound on the central nervous system.

 

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1.32. “Non-Commercial Compound Price” shall have the meaning set forth in Section 5.11.2(a)(5).

1.33. “Non-Patent Country” shall mean any country in the Rest of Territory in which no Patent Rights exist on the date of First Commercial Sale of Product in such country covering the Product being sold.

1.34. “OAPI” shall mean Otsuka America Pharmaceutical, Inc., an Affiliate of Otsuka in the United States.

1.35. “Ongoing Clinical Studies” shall mean those clinical studies identified as such in Appendix C. Ongoing Clinical Studies are a subset of Otsuka Clinical Studies.

1.36. “Otsuka-BMS Compound Supply Agreement” shall mean, collectively, those certain agreements by which Otsuka supplies Compound to BMS for formulation into Product for sale in the United States and the Rest of Territory, as described in Section 5.11.5.

1.37. “Otsuka Clinical Studies” are those clinical studies identified in Appendix C, comprised of the Ongoing Clinical Studies listed in Part A of Appendix C and eight (8) additional specified studies listed in Part B of Appendix C.

1.38. “Patent Country” shall mean any country in the Rest of Territory in which a Patent Right exists on the date of First Commercial Sale of Product in such country covering the Product being sold.

1.39. “Patent Rights” shall mean the patents listed in Appendix A and all other patents and patent applications (and patents issuing from such applications) that become owned, solely or jointly, by Otsuka or any of its Affiliates during the term of this Agreement or to which Otsuka or any of its Affiliates otherwise have or acquire the right to grant licenses or sublicenses in the Territory, and which generically or specifically relate to the Compound, Compound Form(s), Related Compound(s) or Product; in each case including all divisionals, continuations, continuations-in-part, reissues, renewals, reexaminations, extensions and substitutions, and all applications therefor, and all counterparts thereof throughout the Territory.

1.40. “PDC” shall mean the Product Development Committee described in Section 4.1.

1.41. “Primary Position” shall mean a product presentation in a Call in which the sales representative promotes a particular product first in the Call and emphasizes and promotes that product more than any other product in the Call.

 

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1.42. “Product” shall mean any prescription, finished, human pharmaceutical product, in any formulation, in the Field containing Compound, a Compound Form or a Related Compound.

1.43. “Product Development Plan” shall mean that Full Development and Commercialization Plan described in Section 4.2 developed and approved by the PDC, and modifications and updates thereto approved by the PDC from time to time.

1.44. “Purchase Price” shall have the meaning set forth in Section 5.11.2.

1.45. “Quarterly Adjustment” shall have the meaning set forth in Section 5.11.2.

1.46. “Related Agreements” shall mean the Otsuka-BMS Compound Supply Agreement, the BMS-OAPI Product Supply Agreement, and the other agreements described in Section 15.5.

1.47. “Related Compound” shall mean any compound, other than the Compound and Compound Forms, that is covered by U.S. Patent Rights or which, if included in and made, used or sold as products in the United States prior to expiration of the U.S. Patent Rights, would infringe the U.S. Patent Rights.

1.48. “Reserved Territory” shall mean Japan, People’s Republic of China, Republic of China (Taiwan), North Korea, South Korea, The Philippines, Thailand, Indonesia, Pakistan and Egypt, subject to any removal of one or more countries from the Reserved Territory as provided in Section 5.4.2(a).

1.49. “Rest of Territory” shall mean the countries in the Territory outside of the European Union and the United States.

1.50. “Royalty Term” shall mean, with respect to each of the Patent Countries, the period beginning on the date of the First Commercial Sale of Product in such Patent Country and ending either (i) for all Patent Countries taken as a group, and not on a country-by-country basis, on the date when there is no longer any Valid Claim under the Patent Rights covering the Product being sold in any country within the group of Patent Countries, or (ii) on a country-by-country basis within the group of Patent Countries, on the date that is ten (10) years after the last day of the month in which the First Commercial Sale of Product in such country occurred, whichever date occurs later. With respect to each of the Non-Patent Countries, “Royalty Term” shall mean the period beginning on the date of the First Commercial Sale of Product in such Non-Patent Country and ending, on a country-by-country basis within the group of Non-Patent Countries, on the date that is ten (10) years after the last day of the month in which the First Commercial Sale of Product in such country occurred. For purposes of this Section 1.50, “Valid Claim” shall mean a Valid Claim in a Patent Right which would be infringed by the manufacture, use or sale of the Product being sold absent a license under

 

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such Patent Right. The foregoing applies to royalties due on Net Sales in the Rest of Territory, in accordance with Section 5.9.2(a). Royalties due on Net Sales in the United States shall be paid in accordance with Section 5.11.7.

1.51. “Secondary Position” shall mean a product presentation in a Call in which the sales representative promotes a particular product second in the Call and emphasizes and promotes that product more than any other product in the Call except for the product in the Primary Position.

1.52. “Sublicensee” shall mean any person or entity to which BMS sublicenses any of the rights granted in Section 5.4 of this Agreement pursuant to Sections 5.4.1(b) or 5.4.2.

1.53. “Target Product Profile” shall be as set forth in Appendix B hereto.

1.54. “Tentative Price” shall have the meaning set forth in Section 5.11.2(b).

1.55. “Territory” shall mean the entire world except for the Reserved Territory; provided that hereafter countries may be removed from and added to the Territory in accordance with the provisions of this Agreement.

1.56. “Trademark” shall mean any trademark, trade name, domain name, brand name, logo and design, whether registered or not, used during the term of this Agreement in connection with the identification, promotion, marketing or sale of Product in the Territory.

1.57. “U.S. Patent Rights” shall mean U.S. Patent No. 4,734,416 (including, for the sake of clarification, its divisional: U.S. Patent No. 4,824,840) and U.S. Patent No. 5,006,528, and all divisionals, continuations, continuations-in-part, reissues, renewals, reexaminations, extensions and substitutions, and all applications therefor.

1.58. “Valid Claim” shall mean a claim in a Patent Right which has not expired, lapsed, been canceled or become abandoned and has not been finally found to be invalid or unenforceable by an unreversed or an unappealable final decision or judgment of a court of other governmental authority of competent jurisdiction.

2. BACKGROUND AND SCOPE OF COLLABORATION

Through years of extensive and costly research and development, Otsuka has developed the Compound, which it believes can be developed into Product having considerable worldwide commercial and therapeutic potential. Recognizing the high cost and complexity of necessary further development, and the significant accompanying commercial risks, Otsuka has concluded that, in order to achieve the full potential of the Compound and Product, it is necessary to collaborate with another company. BMS has

 

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considerable experience developing, obtaining regulatory approval of and commercializing prescription drugs worldwide, and BMS shares Otsuka’s views as to the commercial and therapeutic potential of the Compound and Product.

Accordingly, as provided in this Agreement, Otsuka and BMS agree to collaborate on the continued development and Commercialization of Product. The parties believe this collaboration, on the terms and conditions set forth in this Agreement, is essential to achieve the goal of completing the development of Product and making it available to customers throughout the Territory at the earliest possible time. The parties hope to achieve commercial success through this collaboration, and they also believe that this collaboration will be to the benefit of human health worldwide.

As described in detail in this Agreement, Otsuka hereby retains BMS, as a contract service provider on behalf of Otsuka in the United States and the European Union, to continue the development of Product in collaboration with Otsuka and to Commercialize the Product in collaboration with Otsuka. Otsuka or its Affiliates will be the holder of the Product NDA in the United States and the MA(s) in the European Union, and, to the maximum extent permissible, BMS will Commercialize Product in the United States and the European Union on behalf of Otsuka, under Otsuka Trademark(s), recording Product sales in the name of Otsuka or its Affiliates. Otsuka retains the option to Co-Promote Product in the United States and the other Co-Promotion Countries in the European Union. Otsuka also retains the Reserved Territory for its Commercialization.

As provided below, BMS has an exclusive license to Commercialize Product in the Rest of Territory (countries in the Territory outside the United States and the European Union).

3. MILESTONE PAYMENTS

3.1. Milestone Payments .

In partial consideration of the commercialization rights granted to it in this Agreement, BMS shall pay the following amounts to Otsuka, in accordance with Section 5.9.6, at the times indicated:

3.1.1 Execution of the Agreement .

[*] within ten (10) Business Days of the Effective Date of this Agreement;

3.1.2 NDA .

[*] within thirty (30) days of the filing of the first NDA for Product in the United States.

 

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3.1.3 MAA .

[*] within thirty (30) days of the fling of the first MAA for Product in the European Union or any country thereof.

3.1.4 NDA Approval .

[*] within thirty (30) days of the first NDA approval for Product in the United States.

3.1.5 MAA Approval .

[*] within thirty (30) days of the first MAA approval for Product in the European Union or any country thereof.

3.2. No Refunds; Other Payments .

Except only as provided in Section 12.2(b) (referring to the refund of certain milestone payments in the event of termination due to QTc problem), under no circumstances are the payments under Section 3.1 refundable to BMS, or creditable against royalties or any other payments due from BMS to Otsuka, or subject to setoff against amounts due from Otsuka to BMS. The payments described in Section 3.1 are in addition to other payments to be made by BMS to Otsuka, and by Otsuka to BMS, as provided elsewhere in this Agreement. Otsuka shall have the right to retain all milestone and other payments received from BMS prior to any early termination of this Agreement, except as provided in Section 12.2(b).

4. PRODUCT DEVELOPMENT; REGULATORY MATTERS

4.1. Product Development Committee .

4.1.1 Formation of the PDC .

Immediately after the Effective Date, BMS and Otsuka formed a Product Development Committee (the “PDC”), which committee shall coordinate, oversee and direct the development efforts and related regulatory matters for Product throughout the Territory and the parties’ efforts and activities in connection therewith. It is intended that each party have equal status, representation and decisionmaking power with respect to all PDC matters.

4.1.2 PDC Composition and Governance .

Each party shall have equal representation and participation on the PDC. Each party shall have (in its discretion) up to seven (7) members on the PDC, shall designate members on the PDC in writing, and shall promptly advise the other party if it substitutes

 

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any of its members. If one or more members of the PDC are unable to attend by a meeting, the party that appointed the non-attending member or members may designate a substitute or substitutes, as the case may be, to serve in place of the absent member or members. The parties shall each be entitled to cause such other representatives as they may deem necessary or appropriate to attend and participate in PDC meetings from time to time.

The PDC shall be co-chaired by an Otsuka member and a BMS member (each a “Co-Chair”) designated by the respective parties. All decisions of the PDC shall be approved in writing by both Co-Chairs. All decisions shall require the unanimous, affirmative vote of the parties, with each party entitled to one vote on the PDC regardless of the number of members attending the meeting. Each party’s vote shall be cast by its Co-Chair or the Co-Chair’s designee. In the event that the parties fail to reach a unanimous decision on any issue before the PDC, the issue shall be referred to and resolved as quickly as reasonably possible by the joint decision of the respective heads of the parties’ research and development divisions (currently Mr. Kazuhiro Tomita in the case of Otsuka, and Dr. Peter S. Ringrose in the case of BMS); disagreements not resolved at that level shall be referred to and resolved in accordance with Section 14.

The PDC shall establish such PDC subcommittees as it deems appropriate to address the issues falling within its purview, such subcommittees to have equal representation and participation by both parties, with the same governance as described above (each party to appoint a Co-Chair; each Co-Chair to have one vote; decisions to be unanimous, failing which they shall be referred up to the PDC). The PDC shall coordinate closely with the JCC, including (without limitation) with respect to studies to be conducted under the authority of the PDC deemed by the JCC to be advisable to optimize the commercialization of Product.

4.1.3 Meetings .

The PDC shall meet as frequently as either party may reasonably request and at such times and places as they select but, in any event, at least twice yearly throughout the term of this Agreement (unless the parties mutually agree that no further meetings are necessary). Unless the Co-Chairs agree otherwise in writing, the location of meetings of the PDC shall alternate between the offices of BMS and the offices of Otsuka, with the first meeting to be held at BMS’s offices. All costs of participation by each member in the activities of the PDC shall be borne by the party appointing such member. The Co-Chairs shall appoint a secretary who shall maintain the records of the PDC and shall keep minutes of the meetings of the PDC. The records and minutes shall be subject to written ratification by the Co-Chairs, and the secretary shall distribute minutes to all members of the PDC. Any PDC matter may be decided by the Co-Chairs jointly without submission for review by all PDC members.

 

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4.1.4 Responsibilities of the PDC .

As provided in Section 4.2, the PDC shall meet promptly after the Effective Date in order to approve a plan (the Product Development Plan) for the rapid and orderly continuation of the development of Product in conformity with all applicable regulatory requirements and for the carrying out of clinical studies to be sponsored by BMS and Otsuka, respectively. The PDC shall be an ongoing, operational committee (and not merely an advisory body) responsible for both decisionmaking and supervision of the implementation of all phases of the development process, including post-marketing development, and all related regulatory matters. The PDC shall have final authority regarding necessary or advisable clinical studies to be conducted in order to optimize the Commercialization of Product, shall review the implementation of the Product Development Plan, and shall discuss and agree upon any additions or modifications to the Product Development Plan. In addition (and without limitation), the PDC shall discuss and agree upon the regulatory approval, including product labeling, for Product in the Territory, related strategies, and any issues or questions raised by any governmental agency or regulatory body in the Territory regarding Product or its development or regulation. Further, the PDC shall discuss and approve plans for, and the status of efforts in connection with, the development of new Product indications and formulations. Without limiting the above, the PDC shall have responsibility for decisionmaking regarding, and supervision of the implementation of new indications and formulations; all pre-launch and post-launch clinical studies (including, without limitation, Phase IIIb and Phase IV studies); pharmacoeconomic studies; registration and ongoing regulatory matters (FDA, DDMAC, EMEA or otherwise); product labeling; and chemistry, manufacture and control (CMC; including specifcations for Compound and Product); but excluding government reimbursement pricing, which shall be the responsibility of the JCC.

4.2. Product Development Plan .

After the Effective Date, BMS developed a proposed overall, continuing plan for the development, regulatory approval and continuing study of Product in the Territory. BMS submitted a draft of the plan (the Full Development and Commercialization Plan) to the PDC for its consideration, modification as it deemed appropriate, finalization and approval. After such consideration and modification, the PDC approved the plan (as indicated by the written approval of the Co-Chairs of the PDC). The Full Development and Commercialization Plan approved by the PDC is set forth or incorporated by reference in Appendix D and is hereby incorporated into this Agreement (such plan, as it is approved and as it may hereafter be modified and updated by the PDC, is referred to as the “Product Development Plan”). Each party shall use all commercially reasonable efforts to carry out its respective obligations under the Product Development Plan. The Product Development Plan sets forth, and shall continue to set forth, the detailed outlines and timelines of the scientific, medical, clinical, regulatory and other activities to be

 

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undertaken for the purpose of obtaining, as soon as reasonably practicable, initial and subsequent marketing approvals, providing market support, and developing any and all indications, formulations, dosage and dosing regimes for Product, all of which activities shall be undertaken by BMS and Otsuka at their respective risk and expense in accordance with the delineation of obligations set forth in Sections 4.3.2 and 4.3.3 (unless the parties mutually agree otherwise in writing). Such timelines shall include, without limitation, projected fling dates for the NDA in the United States and an MAA in the European Union. In developing and modifying the proposed Product Development Plan, and during the course of its implementation, BMS shall take into consideration such of Otsuka’s clinical, regulatory, commercial and scheduling requirements for the development, regulatory approval and marketing of Product in the Reserved Territory as Otsuka communicates to the PDC from time to time. Without limiting the above, BMS recognizes that there will be certain clinica