Unoprostone Exclusive Manufacturing and Supply Agreement

Exhibit 10.1

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

Unoprostone

Exclusive Manufacturing and Supply

Agreement

(also, Exhibit B to Unoprostone NDA Transfer, Data-Sharing and License Agreement )

Effective Date:

April 23, 2009

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

Table of Contents

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

Unoprostone Exclusive Manufacturing & Supply Agreement

THIS UNOPROSTONE EXCLUSIVE MANUFACTURING AND SUPPY AGREEMENT (“Agreement”) is made this 23 day of April, 2009 (the “Effective Date”), by and among Sucampo Pharma Americas, Inc., (“SPA”) a corporation organized and existing under the laws of the State of Delaware, U.S.A., (and a wholly-owned subsidiary of Sucampo Pharmaceuticals, Inc., a corporation organized and existing under the laws of the State of Delaware, U.S.A.), and having its principal office at 4520 East West Highway, Third Floor, Bethesda, Maryland 20814, and R Tech Ueno, Ltd., (“RTU”) a corporation organized and existing under the laws of Japan and having its registered office at Uchisaiwai-cho 1-1-7, Chiyoda-ku, Tokyo, Japan, 100-0011 (each referred to herein as a “Party” and collectively as the “Parties”).

WHEREAS, SPA is a United States based pharmaceutical company that seeks a supply source for Drug Substance and Drug Product (defined below) for SPA clinical evaluation and commercial sale in the SPA Territory (defined below);

WHEREAS, RTU is a Japan based pharmaceutical company and RTU holds an NDA with respect to the manufacture, promotion, use and sale of UNOPROSTONE (also known as Rescula ^® ) in Japan as a pharmaceutical product, and Unoprostone has been manufactured for preclinical and clinical development and commercial use as a human pharmaceutical by RTU;

WHEREAS, SPA seeks to have RTU supply Drug Substance and Drug Product as further defined herein for use in SPA clinical development and for future commercial sale in the SPA Territory and desires to have RTU operate as SPA’s exclusive supplier of Drug Substance and Drug Product for importation, use and sale in the SPA Territory.

NOW, THEREFORE, in consideration of the mutual promises exchanged herein, and in consideration of the conclusion of the Unoprostone NDA Transfer, Patent and Know-How Licensing and Data-Sharing Agreement ( “Unoprostone License Agreement” ) to be executed between the Parties contemporaneously with this Agreement, the Parties agree as follows:

Article 1. Definitions

1.1 “Additional Materials” means all raw materials, resins, chemical intermediates, consumables, components, excipients, packaging, labeling and other ingredients needed to manufacture the Drug Substance and/or Drug Product, including costs for relevant in-bound freight for the foregoing items.

1.2 “Adverse Event” means any untoward medical occurrence in any patient use of a Licensed Product or clinical investigation subject administered a Licensed Product and which does not necessarily have to have a causal relationship with this pharmaceutical treatment. An adverse event (AE) can

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product, including but not limited to those events that must or may be reported in accordance with the pre-clinical testing, clinical trial testing or in market pharmaco-vigilance or other reporting requirements as may be required by any Regulatory Agency incident to the prosecution or maintenance of an IND or an NDA or similar regulatory filing with respect to the testing, registration, manufacture use or sale of a product as a pharmaceutical for human use “Affiliate” means, with the respect to either Party, any Person that, directly or through one or more Affiliates, controls, or is controlled by, or is under common control with, such Party. For purposes of this definition, “control” means (i) ownership of more than fifty percent (50%) of the shares of stock entitled to vote for the election of directors, in the case of a corporation, or more than fifty percent (50%) of the equity or management voting interests in the case of any other type of legal entity, (ii) status as a general partner in any partnership, or (iii) any other arrangement whereby a Person controls or has the right to control, directly or indirectly, the commercial operations, the Board of Directors or the equivalent governing body of a corporation or other entity. Notwithstanding the foregoing, in no event at any time during the Term of this Agreement shall SPA be considered Affiliate of RTU nor RTU be considered Affiliate of SPA for the purpose of this Agreement.

1.3 “Annual Maintenance” means annual stability testing, sample storage, annual audit and annual updating of the e Drug Master File/ Chemistry, Manufacturing and Controls (“DMF/CMC”) elements of the NDA as required in accordance with Applicable Law shall remain with and be maintained by RTU.

1.4 “Applicable Law” means all federal, state, local, national and supra-national treaties, conventions laws or statutes statutes, and any implementing orders, rules and/or regulations, including any rules, regulations, orders, judgments, determinations, guidance, or requirements of Regulatory Authorities, courts of competent jurisdiction and any non-governmental agencies that control any aspect of the pharmaceutical, medical, commercial or financial activities contemplated by the parties in utilizing the rights granted or received incident to this Agreement, including but not limited to development of pharmaceutical products in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) standards, listing of securities on stock exchanges governed by major national securities exchanges or major securities listing organizations or compliance with financial and accounting standards as promulgated by the Financial Accounting Standards Board or its foreign equivalent for IFRF reporting standards, that may be in effect from time to time during the Term and applicable to a particular activity hereunder.

1.5 “Business Day” means a day, other than a Saturday or Sunday, on which banking institutions in Washington, DC, USA, or Tokyo, Japan, are open for business, such that a bank holiday in the United States which is not a banking holiday in Japan is nevertheless a Business Day under the terms of this Agreement.

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

1.6 “Certificate of Analysis” means a certificate provided by RTU to SPA with each shipment of the Drug Substance and Drug Product, which sets forth: (i) the results of any quality assurance testing; and (ii) the manufacturing date and the compliance of the report with relevant cGLP, cGMP and Applicable Law as may apply to the issuance and intended use of such certificate of analysis.

1.7 “cGLP” means quality systems, testing and current good laboratory practices applicable to the manufacture, labeling, packaging, handling, storage, and transport of active pharmaceutical ingredient, bulk dosage forms and packaged dosage forms, as set forth in the Food, Drug and Cosmetic Act (FDCA), including any regulations found in Title 21 of the U.S. Code of Federal Regulations (including Parts 11, 210 and 211), any update thereto and any other laws, regulations, policies, or guidelines applicable to the testing, manufacture, labeling, packaging, handling, storage, and transport of testing or pre-clinical pharmaceutical products, and/or any foreign equivalents thereof and any updates thereto.

1.8 “cGMP” means quality systems and current good manufacturing practices applicable to the manufacture, labeling, packaging, handling, storage, and transport of active pharmaceutical ingredient, bulk dosage forms and packaged dosage forms, as set forth in the Food, Drug and Cosmetic Act (FDCA), including any regulations found in Title 21 of the U.S. Code of Federal Regulations (including Parts 11, 210 and 211), any update thereto and any other laws, regulations, policies, or guidelines applicable to the manufacture, labeling, packaging, handling, storage, and transport of pharmaceutical products, and/or any foreign equivalents thereof and any updates thereto.

1.9 “Clinical Study(ies)” means a human clinical study, or other test or study in humans, with respect to a Drug Substance or a Drug Product performed incident to an open IND , including, but not limited to Phase I study, Phase II study, Phase III Study, Phase IV study, early access programs, compassionate use and single patient INDs, epidemiological studies, modeling and pharmacoeconomic studies, post-marketing studies, investigator sponsored studies, and health economics studies.

1.10 “Clinical Supply” means cGMP compliant Drug Product specifically produced and packaged for Clinical Studies for indications that are the subject of Regulatory Filings within the SPA Territory.

1.11 “Commercial” or “Commercialize” means any and all activities (whether before or after Regulatory Approval) directed to the commercialization of the Drug Product, including pre-launch and post-launch marketing, Promoting, distributing, offering to sell and selling the Drug Product, and importing or exporting the Drug Product for sale. When used as a verb, “Commercializing” means to engage in Commercialization and “Commercialized” has a corresponding meaning.

1.12 “Commercial Product” means Drug Product specifically produced and packaged for Commercial use and sale for indications with Regulatory Approval within the SPA Territory in final labeling and packaging as approved incident to the NDA.

1.13 “Confidential Information” means all information that is not in the public domain and is protectable by a Disclosing Party as a trade secret under Applicable Law (including, without limitation, Regulatory Data and Information, as defined below) provided to a Party by another Party, whether oral,

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

in writing or otherwise, including, without limitation, any information on the research, development, markets, customers, suppliers, patent applications, inventions, products, procedures, designs, formulas, business plans, financial projections, organizations, employees, consultants or any other similar aspects of a Party’s present or future business.

1.14 “Data Exclusivity” means any data or market exclusivity granted to a Drug Substance or Drug Product in the SPA Territory by any Regulatory Authority as of the Effective Date or at any time during the Term.

1.15 “Drug Approval Application” means, on a Drug Product-by-Drug Product basis in SPA Territory, an application submitted to a Regulatory Authority for Regulatory Approval for the Drug Product, and all supplements and amendments that may be filed with respect to the foregoing.

1.16 “DMF/CMC Package” means a collection of all necessary data and information relating to a Drug Substance documenting Drug Substance’s and RTU’s compliance with the Regulatory Authority standards in SPA Territory (including but not limited to the US Food & Drug Administration, the US Environmental Protection Agency, and US Pharmacopoeia and corresponding regulations promulgated by Applicable Law in other countries in SPA Territory).

1.17 “Drug Product” means a final galenic formulation of UNOPROSTONE Drug Substance supported as a cGMP formulation under an IND for the purposes of Clinical Trials or under as an approved and support formulation under an issued NDA in the SPA Territory for the purposes of commercial manufacture and sale of such specific formulations of Drug Substance as SPA may elect to register as a Drug Product in the SPA Territory from time to time. Drug Product shall be complete PRIOR to packaging for clinical use or commercial sale, as appropriate. Drug Product shall also mean Commercial Product and/or Promotional Sample, where applicable.

1.18 “Drug Substance” means bulk NDA and cGMP compliant UNOPROSTONE active pharmaceutical ingredient, prior to formulation as a final Drug Product. Drug Substance shall also mean non-formulated Clinical Supply and/or Commercial Product, where applicable.

1.19 “IND” means an application filed with a Regulatory Authority for authorization to commence human clinical trials of Unoprostone or prosecute a Drug Approval Application for Unoprostone, including, but not limited to (i) an Investigational New Drug Application as defined in the Food, Drug and Cosmetic Act (FDCA) or any update thereto or any successor application or procedure filed with the Food and Drug Administration (FDA), (ii) any foreign equivalent of a United States IND, and (iii) all supplements and amendments that may be filed with respect to the foregoing.

1.20 “Latent Defect” means Drug Substance or Drug Product not conforming to RTU’s warranty for pursuant to Section 9.7 such that the related non-conformance of Drug Substance or Drug Product is not readily discoverable based on SPA’s (or SPA designee’s) normal incoming-goods inspections.

1.21 Need to insert the definition of “Licensed Product” (from the IP agreement)

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

1.22 “Licensed Patents” means all patent and patent applications related to Unoprostone that are hereunder licensed to SPA and/or enable SPA activities in SPA Territory (i) that are owned by or licensed (with the right of sublicense) to RTU on before the Effective Date of this Agreement or (ii) which derive from inventions that are acquired, made, created, developed, conceived or reduced to practice by RTU during the Term of this Agreement, to the extent that such patents or patent applications relate to Unoprostone (including, without limitation, its composition of matter, its method of use, its formulation(s) (either alone or in combination with other agents), its dosing regimens, its manufacture, its synthesis, its metabolism, its safety and/or its utility ) or necessary, used, or useful for the development, manufacture or commercialization of Unoprostone, or (iii) which derive from an invention that is made, created, developed, conceived or reduced to practice by SPA after the Effective Date of this Agreement the practice of which would in the absence of a license, infringe on a claim of any unexpired patent described in (i) or (ii). Licensed Patents include all reissues, continuations, continuations-in-part, extensions, reexaminations, and foreign counterparts of any of the foregoing. Licensed Patents include listing set forth in Exhibit C ( Licensed Patents ), which may be amended from time-to-time to add additional patents and patent applications.

1.23 NDA” means a New Drug Application, as defined by laws for such application within the SPA Territories (as defined below) and applicable regulations promulgated in the countries or territories there under, or other appropriate marketing authorization in Japan, or any counterpart application or marketing authorization in any country of the SPA Territory. For the avoidance of doubt, maintenance of the NDA with respect to compliance of the Drug Substance or the Drug Product with the Drug Master File/Chemistry, Manufacturing and Controls (“DMF/CMC”) elements of the NDA shall remain with and be maintained by RTU .

1.24 “Order” means, with respect to Clinical Supply, Drug Substance, Drug Product Commercial Product, and/or Promotional Sample, a written communication from SPA to RTU of SPA’s order for purchase of a specified amount of need for Unoprostone or Licensed Product at a delivery date, delivery price and delivery location set forth in such written purchase order communication.

1.25 “Order Year” means each twelve-month period commencing from the date of the first Order placed by SPA for the Drug Product.

1.26 “Person” means any individual, trust (or any of its beneficiaries), estate, partnership, limited partnership, association, limited liability company, corporation, any other enterprise engaged in the conduct of business or operating as a non-profit entity, however formed or wherever organized, or any governmental body, agency or unit or formal non-governmental organization.

1.27 “Product Valid Claims” means, with respect to the Drug Substance or Drug Product, a claim of any issued and unexpired patent included within the Licensed Patents, the enforceability of which has not been subject to one or more of any of the following: (i) irretrievable lapse, revocation or abandonment; (ii) holding of unenforceability or invalidity by a decision of a court or other appropriate body of competent jurisdiction, that is unappealable or unappealed within the time allowed for appeal;

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

and/or (iii) disclaimer or admission of invalidity or unenforceability through reissue or re-examination or opposition, nullity action or invalidation suit response, terminal disclaimer or otherwise. The foregoing notwithstanding, in the event a claim of a patent within the Licensed Patent(s) has been held to be invalid or unenforceable, and an appeal is pending, such claim shall not be considered a Product Valid Claim until reinstated by a final decision of a court or governmental agency of competent jurisdiction.

1.28 “Promote” or “Promotion” means those activities normally undertaken by a pharmaceutical company’s sales force and marketing team to implement marketing plans and strategies aimed at encouraging the appropriate use of a particular prescription or other pharmaceutical product, including detailing. When used as a verb, “Promote” means to engage in such activities.

1.29 “Promotional Sample” means Drug Product specifically produced and packaged to Promote the Drug Product for indications with Regulatory Approval within the SPA Territory.

1.30 “Product Defect” means Drug Substance or Drug Product not conforming to RTU’s warranty for pursuant to Section 9.7 such that the related non-conformance of Drug Substance or Drug Product may be readily discovered based on SPA’s (or SPA designee’s) normal incoming-goods inspections procedures.

1.31 “Regulatory Approval” means, in the SPA Territory, any and all approvals, licenses (including product and establishment licenses), registrations, or authorizations of any Regulatory Authority necessary to Develop (as defined in the Unoprostone Licensing Agreement), manufacture, Commercialize (as defined in the Unoprostone Licensing Agreement), promote, distribute, transport, store, use, sell or market the Drug Product, including, where applicable, pricing or reimbursement approval, or pre- and post-approval marketing authorizations, labeling approvals, import and export licenses, technical, medical and scientific licenses.

1.32 “Regulatory Authority” means any national, supra-national, regional, federal, state, provincial or local regulatory agency, department, bureau, commission, council or other governmental entity regulating or otherwise exercising authority over the distribution, importation, exportation, manufacture, use, storage, transport, clinical testing, Commercialization, or sale of the Drug Substance, unpackaged Drug Product and/or Drug Product in final NDA approved labeling and packaging.

1.33 “Regulatory Data and Information” consists of data and information relating to a Drug Product that is derived from any or several of the following business activities undertaken by any of the Parties at any time: (i) market and business research and intelligence; (ii) research and development of pharmaceutical and medicinal products; (iii) obtaining marketing approval for pharmaceutical and medicinal products; and (iv) consultation with respect to any or several of the above activities.

1.34 “Regulatory Filings” means, collectively: all INDs, Drug Approval Applications, diagnostic product device approval applications, establishment license applications, Drug Master Files, and any product approvals under Section 505 (a) and (b) of the Food, Drug and Cosmetic Act (FDCA) (21 U.S.C. § 355(b)(4)(B)) or any update thereto or all other similar filings (including, without limitation, any

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

counterparts of any of the foregoing in SPA Territory) as may be required by any Regulatory Authority for the development, manufacture or commercialization of the Drug Substance or the Drug Product; and (b) all supplements and amendments to any of the foregoing.

1.35 “Specifications” mean the manufacturing, formulation, quality control, packaging, labeling, shipping and storage specifications as separately set out for Drug Substance or Drug Product in Exhibit B and as updated from time to time on mutual agreement in writing by the Parties as reflected in the relevant formulae edition and Regulatory Approvals.

1.36 “SPA Territory” means the United States of America and Canada, and their territories and possessions.

1.37 “Term” means the definition provided in Section 11.1.

1.38 “Third Party” means any Person other than RTU and SPA and their respective Affiliates.

1.39 “UNOPROSTONE” (also known by the USAN name of Unoprostone isopropyl) is the composition of matter defined chemically as [*] as described in more detail in Exhibit A and its salts, metabolites, as well as any active pro-drugs, isomers, tautomers, hydrates, chelates, complexes and polymorphs and all other pharmaceutically acceptable modifications as may be projected in the public domain as motivation to an medicinal chemistry expert in the drug development field.

Article 2. General Terms of Manufacturing and Supply

2.1 Supply. Subject to the terms and conditions of this Agreement, (i) SPA shall exclusively engage RTU to manufacture (or have manufactured), in compliance with the Specifications, cGMP standards and the NDA, test and deliver the Drug Substance and/or Drug Product for SPA and/or its Affiliates, sublicensees or distributors for the SPA Territory, in the specific formulations, quantities and at times as provided herein, and (ii) RTU shall exclusively provide the same in the SPA Territory to SPA in accordance with orders issued by SPA and received by RTU. All such Drug Substance and Drug Products manufactured and supplied by RTU shall:

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

2.4 Clinical Order; Supply. During the Term of this Agreement, RTU shall have the exclusive right to manufacture and supply Clinical Supply upon Order for SPA for clinical development purposes. During the Term of this Agreement, RTU and SPA shall from time to time confer and agree on SPA’s drug supply needs for SPA’s ongoing clinical development program and the projected costs of such supply. SPA shall inform RTU of its final requirements in advance of needing clinical supply in such timing as RTU shall reasonably need to duly perform its obligations hereunder, which shall constitute SPA’s Order to RTU and which, subject to the terms and conditions of this Agreement, RTU agrees to supply. The minimum of Clinical Product units per Order is [*] bottles.

2.5 Promotional Sample Supply. In the year prior to SPA’s first commercial sale of Commercial Product, RTU shall provide [*] Promotional Samples at no cost to SPA. Thereafter, SPA shall be entitled to purchase a commercially reasonable number of units of Promotional Samples at US$[*] per unit being a sample including 5 mL of 0.15% formulation of the Drug Product (payable in Japanese Yen, converted at the spot rate at the close of Business Day in which Order invoice is paid), provided that (excepting the first re-launch year) the total number of Promotional Samples purchased does not exceed [*] percent [*] of the Commercial Product.

2.6 Commercial Supply; Exclusivity; Forecasting; Order. During the Term of this Agreement, RTU shall have the exclusive right to manufacture and supply Commercial Product upon Order for SPA for commercial purposes subject to appropriate Regulatory Approval in any country of the SPA Territory in respect of the Commercial Product. SPA shall provide to RTU in writing a twenty-four (24) month forecast of its requirements for Commercial Product which forecast will be updated quarterly and the first 90 days shall constitute SPA’s supply Order to RTU, which, subject to the terms and conditions of this Agreement, RTU agrees to supply. The minimum number of Commercial Product units per Order is [*] bottles.

2.7 Placement and Acceptance of an Order.

2.8 Delivery and Acceptance; Risk of Loss. Any and all Clinical Supply, Commercial Product, or Promotional Sample supplied hereunder to SPA shall be shipped from RTU’s manufacturing facility in Sanda (Hyogo, Japan) or its contract manufacturer and delivered to a common carrier to be transported

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

for importation into the SPA Territory. The identity of the common carrier and the port of entry shall be mutually determined by the Parties in writing. Title and risk of loss shall pass to SPA at the time the goods are delivered to SPA or its designee, and SPA shall assume all responsibility for and costs associated with the goods upon such acceptance.

2.9 Inventory. RTU agrees to at all times maintain commercially reasonable inventory levels of Additional Materials required to manufacture the Drug Substance and Drug Products commensurate with orders received or reasonably anticipated.

2.10. Non-Exclusivity. Nothing in this Agreement shall prohibit RTU, either clinically or commercially, from manufacturing or supplying, either on its behalf or for any Third Party, drug products containing the Drug Substance, or drug products containing different active ingredients which require the same reagents as the production of UNOPROSTONE, outside of SPA Territory, provide, however, that RTU shall be prohibited from supplying the Drug Substance or the Drug Products in the SPA Territory or to those doing business either in the SPA Territory or outside the SPA Territory resulting in inducing or facilitating sale in the SPA Territory of the Drug Substance or the Drug Products to or by any party other than SPA.

2.11. Performance Issue; Safety Reporting. If either party becomes aware of any issue that may materially impact RTU’s ability to fulfill its obligations under this Agreement, it shall immediately notify the other party and both parties shall confer in good faith in order to address such issue. The parties shall be responsible for filing annual safety reports with the Regulatory Authority in accordance with a separate safety data exchange protocol to be mutually agreed by SPA and RTU.

2.12. Product Liability. Liability for defects to Drug Product determined to have been caused by or during the production process and the damage to Drug Product or packaging caused prior to acceptance of Drug Product by SPA will be assumed by RTU. All liability for non-defective Drug Product or damage to Drug Product after acceptance of Drug Product by SPA will be assumed by SPA.

Article 3. Additional Services

3.1 Laboratory and Regulatory Consulting Services. Laboratory services, including without limitation formulation services regarding Drug Substance and Drug Product, and regulatory consulting provided by RTU to SPA shall be transacted under a separate Laboratory and Consulting Services Agreement.

Article 4. Pricing and Payment

4.1 Clinical Supply Price. Clinical Supply shall be supplied pursuant to an Order issued in accordance with Section 2.4 ( Clinical Order; Supply) at the cost of US$ [*] per bottle (payable in Japanese Yen, converted at the spot rate at the close of Business Day in which Order invoice is paid). The bottle will be supplied in bulk packaged condition from R-Tech, and SPA assures clinical labeling and kitting.

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

4.2 Promotional Sample Price. Promotional Samples shall be supplied and priced pursuant to an Order issued in accordance with Section 2.5 ( Promotional Sample Supply).

4.3 Commercial Product Price; Cost of Goods; Royalty; Annual Maintenance.

For Glaucoma and/or Ocular Hypertension Use:

For Other Indication Use:

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

4.4 Withholding Taxes. All payments made under this Agreement shall be free and clear of any and all taxes, duties, levies, fees or other charges, except for withholding taxes. Where any sum due to be paid to a Party hereunder is subject to any withholding tax, the Parties shall use commercially reasonable efforts to do all such acts and things and to sign all such documents as will enable them to take advantage of any applicable double taxation agreement or treaty. In the event there is no applicable double taxation agreement or treaty, or if an applicable double taxation agreement or treaty reduces but does not eliminate such withholding or similar tax, the paying Party shall deduct any withholding taxes from payment and pay such withholding or similar tax to the appropriate government authority, deduct the amount paid from the amount due to the receiving Party and secure and send to the receiving Party the best available evidence of such payment.

4.5 Terms of Payment. All payments due under this Agreement shall be payable in Japanese Yen, converted at the spot rate at the close of the business day in which each such payment becomes payable. Unless specified otherwise herein, RTU will invoice SPA for Clinical Supply, Commercial Product and/or Promotional Sample upon RTU’s delivery thereof to SPA’s carrier and payments shall be due within thirty (30) days from the date of receipt of invoice. All payments under this Agreement shall be by appropriate electronic funds transfer in immediately available funds to such bank account as RTU shall designate. Each payment shall reference this Agreement and identify the obligation under this Agreement that the payment satisfies. If at any time legal restrictions prevent the remittance of part or all of payments owed by a Party hereunder, the Parties shall promptly negotiate in good faith the terms for repayment under lawful means or methods.

4.6 No Other Compensation. Unless otherwise agreed to by the Parties and set forth in writing, RTU and SPA hereby agree that the terms of this Agreement and all ancillary agreements hereto (including, without limitation, the Unoprostone License Agreement attached hereto) shall fully define all consideration, compensation and benefits, monetary or otherwise, to be paid, granted or delivered by

[*] = Certain confidential information contained in this document, marked by brackets, is filed
with the Securities and Exchange Commission pursuant to Rule 24b-2 of
The Securities Exchange Act of 1934, as amended.

each Party to the other in connection with the transactions contemplated herein. Neither Party has previously paid or entered into any other commitment to pay, whether orally or in writing, any employee of the other Party, directly or indirectly, any consideration, compensation or benefits, monetary or otherwise, in connection with the transactions contemplated herein.

4.7 Shipping Terms. All payments under this Agreement are inclusive of all cost, insurance and freight (CIF by Airfreight) necessary for delivery to SPA as described in Section 2.8, except that title and risk of loss shall pass to SPA upon delivery to SPA or its designee not upon delivery of shipping documents.

Article 5. Confidentiality and Non-Disclosure

5.1 Confidentiality.