RGN-259 LICENSE Agreement
Exhibit 10.6
*** text ommitted and filed seperately
confidential treatment requested
under 17 c.f.r.§§200.80(b)(4) and 240.24b-2
RGN-259 LICENSE Agreement
This License Agreement (this “Agreement” or this “License Agreement”) is effective as of March 7, 2014 (the “Effective Date”) by and between RegeneRx Biopharmaceuticals, Inc., a company organized and existing under the laws of the state of Delaware, with offices at 00000 Xxxxx Xxxxx Xxxx, Xxxxx 000, Xxxxxxxxx, Xxxxxxxx, X.X.X. (hereinafter “Licensor”), and Digital Aria Co., Ltd. with offices at 22nd FL, Parkview Tower, 248 Jungjail-ro, Bundang-gu, Seongnam-si, Xxxxxxxx-xx 000-000, Xxxxxxxx of Korea (hereinafter “Licensee”), each a “Party” and, collectively, the “Parties.”
Section 1. Definitions
As used in this Agreement, the following capitalized terms shall have the following meanings:
“Affiliate” shall mean, with respect to a Person, any Person that Controls, is Controlled by or is under common Control with such first Person. For purposes of this definition only, “Control” means (a) to possess, directly or indirectly, the power to direct the management or policies of a Person, whether through ownership of voting securities, or by contract relating to voting rights or corporate governance, or (b) to own, directly or indirectly, at least fifty percent (50%) of the outstanding voting securities or other ownership interest of such Person.
“Agreement” shall have the meaning given such term in the preamble.
“API” shall mean Tβ4 in the form of an active ingredient to be utilized as a component in the Licensed Product.
“Challenge” shall have the meaning given such term in Section 8.8(b).
“Change of Control” shall mean, with respect to a Party, the occurrence of any of the following:
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(a) any consolidation, merger, recapitalization or reorganization of a Party with or into any Third Party, or any other corporate reorganization involving a Third Party (“Merger”), as long as the stockholders of such Party immediately prior to the Merger own less than fifty percent (50%) of the surviving entity’s voting power immediately after the Merger;
(b) a change in the beneficial ownership of more than fifty percent (50%) of the voting securities of any Party (whether in a single transaction or series of related transactions) where, immediately after giving effect to such change, the legal or beneficial owner of more than fifty percent (50%) of the voting securities of such Party is a Third Party.
(c) the sale, transfer, lease, license or other disposition to a Third Party of all or substantially all of a Party’s assets, to which this Agreement relates, in one or a series of related transactions.
“Commercialization Plan” shall have the meaning given such term in Section 4.1.
“Commercially Diligent Efforts” shall mean, with respect to the development and commercialization by Licensee of at least one Licensed Product, the level of efforts and resources generally used by similarly situated pharmaceutical companies marketing compounds or products throughout the Territory (including internally developed, acquired and in-licensed compounds or products) with similar commercial potential at a similar stage in their lifecycle (assuming continuing development of such product).
“Confidential Information” shall mean any and all information, data, results, Inventions, trade secrets, techniques, material, or compositions of matter of any type or kind, including without limitation all Know-How and all other scientific, pre-clinical, clinical, regulatory, manufacturing, marketing, personnel, financial, legal and commercial information or data, whether communicated in writing, orally or by any other method, that a Party treats or identifies as confidential and, in each case, is disclosed by one Party to the other Party under this Agreement.
“Control”, “Controls” and “Controlled” shall mean, with respect to a particular item of information or intellectual property right, that the applicable Party or any Affiliate of such Party owns or has a license to such item or right and has the ability to grant to the other Party access to and a license or sublicense (as applicable) under such item or rights as provided for herein without violating the terms of any agreement or other arrangement with any Third Party existing as of the Effective Date or thereafter.
“Development Plan” shall have the meaning given such term in Section 3.1.
“Disclosing Party” shall have the meaning given such term in Section 9.1.
“Distributor” shall mean any Third Party appointed by Licensee to distribute, market and sell Licensed Product purchased from Licensee or any of its Affiliates (regardless of whether such Third Party has the right or obligation to provide packaging or labeling services with respect to such Licensed Product).
“Effective Date” shall have the meaning given such term in the preamble.
“FDA” shall mean the United States Food and Drug Administration or any successor U.S. governmental agency performing similar functions.
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“Field” shall mean the treatment of all human ophthalmic diseases and conditions in the Territory using Tβ4 in any formulation delivered topically to the eye, provided, however, that “Field” shall not include any use of the Licensed Product incorporated into the form of any type of cosmetic or food product.
“First Commercial Sale” shall mean the initial sale of Licensed Product by or on behalf of Licensee, its Affiliates, Sublicensees or Distributors in exchange for cash or some equivalent to which value can be assigned for the purpose of determining Net Sales in the Territory following Regulatory Approval of the Licensed Product in the Territory. For clarity, First Commercial Sale shall not include transfers of Licensed Product at below cost by or on behalf of Licensee, its Affiliates, Sublicensees or Distributors in connection with compassionate use, emergency use, treatment INDs, or the like authorized by the FDA or any corresponding Governmental Authorities in the Territory.
“GAAP” shall mean, in the case of the Licensor, Generally Accepted Accounting Principles recognized in the United States, and in the case of the Licensee, Generally Accepted Accounting Principles recognized in the Republic of Korea.
“Generic or Branded Generic” shall mean a drug product containing the same active ingredients as Licensed Products and is subject to the regulations of the governments of countries where they are dispensed and is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use.
“GCP” shall mean the then current good clinical practices as defined in U.S. Regulations 21 C.F.R. §§ 50, 54, 56, 312 and 314, the International Conference of Harmonization (ICH) E6 “Good Clinical Practice: Consolidated Guidance,” and in any successor regulation or any official guidance documents issued by a Governmental Authority.
“GLP” shall mean the then current good laboratory practice standards as defined by the FDA pursuant to 21 C.F.R. Part 58, and in any successor regulation or any official guidance documents issued by a Governmental Authority.
“GMP” shall mean the then current good manufacturing practices as defined by the FDA pursuant to 21 C.F.R. §§ 210 and 211 and in any successor regulation or any official guidance documents issued by a Governmental Authority.
“Governmental Action” shall have the meaning given such term in Section 13.2(b).
“Governmental Authority” shall mean: (i) any national, federal, provincial, state, municipal or other governmental body in any jurisdiction in the Territory, the United States or elsewhere, (ii) any international or multi-lateral body, (iii) any subdivision, ministry, department, secretariat, bureau, agency, commission, board, instrumentality or authority of any of the foregoing governments or bodies, (iv) any quasi-governmental or private body exercising any regulatory, expropriation or taxing authority under or for any of the foregoing governments or bodies, or (v) any international, multi-lateral, or multi-national judicial, quasi-judicial, arbitration or administrative court, grand jury, tribunal, commission, board or panel, in each case having jurisdiction over the United States or any jurisdiction in the Territory.
“ICC Rules” shall have the meaning given such term in Section 14.814.8(c).
“IND” shall mean an investigational new drug application filed with the FDA, or the equivalent in any jurisdiction in the Territory.
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“Indemnified Party” shall have the meaning given such term in Section 11.3.
“Indemnifying Party” shall have the meaning given such term in Section 11.3.
“Intellectual Property” shall mean any Inventions, Patents, patent rights, utility models, copyrights, trade secrets, Trademarks, service marks, Know-How, technical information and all other intellectual property rights.
“Invention” shall mean any process, method, use, composition of matter, article of manufacture, discovery, finding or invention, whether or not patentable.
“Joint Development Committee” shall have the meaning given such term in Section 3.4.
“Joint Inventions” shall have the meaning given such term in Section 8.2(c).
“Know-How” shall mean all tangible and intangible (i) techniques, technology, practices, trade secrets, methods, knowledge, know-how, skill, experience, test data and results (including pharmacological, toxicological and clinical test data and results), analytical and quality control data, results or descriptions, software and algorithms, and (ii) compounds, compositions of matter, and physical, biological or chemical material.
“Laws” shall mean (i) all constitutions, treaties, laws, statutes, codes, ordinances, guidance, orders, decrees, rules, regulations, and municipal by-laws, whether domestic or international, anywhere in the Territory or as may otherwise be agreed in writing between the Parties, (ii) all judgments, orders, writs, injunctions, decisions, rulings, decrees and awards of any Governmental Authority, and (iii) all policies, practices and guidelines of any Governmental Authority.
“Licensed Know-How” shall mean Know-How owned or Controlled by Licensor that exists as of the Effective Date or at any time thereafter during the Term, in each case that is necessary or useful for the development, registration, manufacture, promotion, marketing, distribution, or sale of the Licensed Product in the Field in the Territory.
“Licensed Patents” shall mean the Patents owned or Controlled by Licensor as of the Effective Date (as listed in Exhibit A hereto), to the extent that such Patents disclose or claim the Licensed Product as well as any future Patents owned or Controlled by Licensor or its Affiliates during the Term, to the extent that such future Patents disclose or claim the Licensed Product.
“Licensed Product” shall mean the Licensor’s drug candidate referred to as RGN-259 that utilizes Tβ4 as at least one of the biologically active ingredients and/or improvements thereto developed or acquired by or on behalf of Licensor for the Field in the Territory, in each case to the extent such improvements are owned or Controlled by Licensor. The term “Licensed Product” shall include both clinical and commercial applications of any such product.
“Licensee” shall have the meaning given such term in the preamble.
“Licensee Inventions” shall have the meaning given such term in Section 8.2(a).
“Licensee Product Data” shall have the meaning given such term in Section 13.313.3(b)(i).
“Licensor” shall have the meaning given such term in the preamble.
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“Licensor Inventions” shall have the meaning given such term in Section 8.2(b).
“Losses” shall have the meaning given such term in Section 11.1.
“Marketing Approval” shall mean all approvals, licenses, registrations, or authorizations of a Regulatory Authority in any jurisdiction of the Territory necessary for the manufacture, use, storage, marketing, importation or sale of the Licensed Product in such jurisdiction.
“Marketing Year” shall mean the period commencing on the date of the first Marketing Approval in any country in the Territory and ending on December 31 of the same year. Thereafter, and for the duration of this Agreement, each subsequent Marketing Year will correspond to a calendar year period (i.e., from January 1 to December 31).
“Net Sales” shall mean the gross receipts for sales made by Licensee, its Affiliates, Sublicensees and Distributors of the Licensed Product to other independent buyer(s) in bona fide arm’s length transactions, less the following deductions with respect to such sale, to the extent applicable to the Licensed Product and to the extent actually allowed and taken: (i) quantity and/or cash discounts actually allowed or taken to the extent customary; (ii) customs, duties, excise taxes, if any, directly related to the sale of the Licensed Product and actually paid; (iii) amounts allowed by reason of rejections and return of goods; (iv) Third-Party rebates related to the sale of the Licensed Product; and (v) import tax, value-added tax and other similar sales taxes related to the sale of the Licensed Product, all to the extent in accordance with GAAP as consistently applied across all products of Licensee. No deductions shall be made for commissions paid to individuals, whether with independent sales agencies or regularly employed by Licensee, its Affiliates, Sublicensees or Distributors, and on its payroll, or for the cost of collections. On sales made in other than in arm’s length transaction, the value of Net Sales attributed to such a transaction shall be that which would have been received in an arm’s length transaction, based on sales of like quantity and quality products on or about the time of such transaction.
“Panel” shall have the meaning given such term in Section 14.814.8(c)(i).
“Parties” and “Party” shall have the meanings given such terms in the preamble.
“Patents” shall mean any and all patents and/or patent applications, and any patents issuing on such patent applications, as well as any continuations, divisions, reissues and re-examinations of any of the foregoing.
“Person” shall mean an individual, sole proprietorship, partnership, limited partnership, limited liability partnership, corporation, limited liability company, business trust, joint stock company, trust, unincorporated association, joint venture or other similar entity or organization, including a government or political subdivision, department or agency of a government.
“PHS” shall mean the National Institutes of Health, the Centers for Disease Control, and/or the FDA, agencies of the United States Public Health Service within the Department of Health and Human Services.
“PHS License” shall mean the Patent License Agreement, dated as of February 6, 2001, between PHS and Licensor, attached hereto as Exhibit B.
“Product Liability Claim” shall mean any Third Party proceedings involving any actual or alleged death or bodily injury arising out of or resulting from the use of the Licensed Product sold by Licensee or its Sublicensees.
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“Prohibited List” shall mean (a) the HHS/OIG List of Excluded Individuals/Entities (available through the Internet at xxxx://xxx.xxx.xxx.xxx); (b) the General Services Administration’s List of Parties Excluded from Federal Programs (available through the Internet at xxxx://xxx.xxxx.xxx); and (c) the FDA Debarment List (available through the Internet at xxxx://xxx.xxx.xxx/xxx/xxxxxxxxxx_xxx/xxxxx/).
“Prosecute” shall have the meaning given such term in Section 8.5(a).
“Receiving Party” shall have the meaning given such term in Section 9.1.
“Regulatory Approval” shall mean any and all approvals (including, to the extent necessary, pricing approvals), licenses, registrations or authorizations of any Governmental Authority, necessary for the promotion, development (including without limitation the conduct of clinical trials), marketing, distribution, manufacture, sale or importation of a Licensed Product.
“Regulatory Authority” shall mean any applicable Governmental Authority in any jurisdiction in the Territory from which Regulatory Approval is required to be obtained.
“Regulatory Laws” shall mean all applicable Laws governing (i) marketing approval or clearance, import, export, testing, investigation, development, manufacture, packaging, labeling, handling, storage, distribution, installation, servicing, marketing, or sale, (ii) recordkeeping and reporting obligations, (iii) recalls, or (iv) similar regulatory matters, with respect to the Licensed Product.
“Relevant Period” shall mean, on a Licensed Product-by-Licensed Product basis and on a country-by-country basis, the period starting from the Effective Date and ending on (i) the expiration of the last-to-expire valid and applicable Licensed Patent within the given country of the Territory or (ii) the fifteenth (15th) anniversary of the First Commercial Sale of each Licensed Product in such country, whichever is later.
“RGN-137 Agreement” shall mean that certain RGN-137 License Agreement dated as of even date herewith and executed concurrently herewith between the Parties.
“Royalty Term” shall mean the period commencing on the First Commercial Sale and ending at the expiration of or the effective date of termination of this Agreement.
“Semi-exclusive” shall mean the license granted by Licensor to Licensee in a given country to manufacture, offer to sell, sell and import the Licensed Product in the Field in the Territory, pursuant to which Licensor may simultaneously, directly or through its Affiliate, manufacture, offer to sell, sell and import Licensed Product in that same country.
“Sublicensee” shall mean any Affiliate or Third Party to whom Licensee sublicenses any rights as permitted by Section 2.1(e).
“Tβ4” shall mean the 43 amino acid peptide commonly referred to as Thymosin Beta 4.
“Territory” or “Territories” shall mean the following countries: Japan, Australia, New Zealand, Brunei, Cambodia, East Timor, Indonesia, Korea, Laos, Malaysia, Mongolia, Myanmar (Burma), Philippines, Singapore, Thailand and Vietnam, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, Sri Lanka, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan.
“Third Party” shall mean any Person other than Licensor, Licensee, and Affiliates of either Party.
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“Trademark” shall mean any trademark, trade dress, brand xxxx, trade name, brand name, logo, business symbol or other similar indicia of origin.
“Valid Claim” shall mean a claim of an issued and unexpired Licensed Patent, that has not been revoked or held unenforceable or invalid by a decision of a court or other Governmental Authority of competent jurisdiction, and that is not appealable or has not been appealed within the time allowed for appeal, and that has not been abandoned, disclaimed, denied or admitted to be invalid or unenforceable through reissue, re-examination, disclaimer or otherwise.
Section 2. License Grant and Other Rights
2.1 License Grants to Licensee
(i) Licensee shall be entitled to sublicense any or all of the rights granted to Licensee pursuant to Section 2.1(a), 2.1(b) or 2.1(c) to any of its Affiliates or Third Party upon thirty (30) days’ prior written notice to Licensor (subject to Licensor’s approval, which approval shall not be unreasonably withheld), which notice shall include the identity of such Affiliate or Third Party.
(ii) All sublicenses granted to Affiliates or Third Parties pursuant to Section 2.1(e)(i) above shall be subject to all terms, conditions, obligations and covenants of this Agreement and all applicable provisions of the PHS License. No sublicense shall relieve Licensee of any of its obligations hereunder.
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(i) conduct or have conducted clinical trials and other studies involving the Licensed Product in the Territory for the generation of data in support of regulatory submissions to the Regulatory Authorities outside the countries of the Territory where the exclusive license is granted to Licensee as per Section 2.1(b) above; or
(ii) conduct activities in the Territory with respect to the manufacture, formulation and processing of the Licensed Product for use and commercialization outside the countries of the Territory where the exclusive license is granted to the Licensee as per Section 2.1(b) above.
(a) acknowledges that PHS has retained certain rights and interests in the Licensed Patents pursuant to the PHS License;
(b) agrees that the provisions of the PHS License contained in Exhibit C shall be binding on Licensee and its successors as if Licensee or its successors were the licensee under the PHS License; and
(c) shall assist Licensor in complying with Licensor’s obligations under the PHS License.
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Section 3. Development
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3.8 Clinical Supply of Licensed Product.
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Section 4. Commercialization of Licensed Product
4.2 Content of Commercialization Plan.
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Section 5. Manufacture and Supply of Licensed Product
Section 6. Royalties, License Fees and Equity Investments
(a) During the Royalty Term, on a semi-annual basis, Licensee shall pay Licensor royalties equal to [***] and [***] percent [***]% of aggregate annual Net Sales. Each such payment shall be due and payable no later than sixty (60) days after the end of the semi-annual period ending on December 31st and June 30th, in which the applicable Net Sales were made. In case any Generic/Branded Generic of any Licensed Product by any Third Party becomes commercially available in a country within the Territory without a direct or indirect agreement with the Licensee, its Affiliates or their Sublicensees or Distributors and such Generic/Branded Generic taken in the aggregate have according to IMS or similar data source a market share (in terms of unit quantity) in such country of at least 30% (thirty percent), then the royalties’ rate applicable and payable by Licensee on the Net Sales in such country will be reduced by fifty percent (50%).
(b) If it is necessary for Licensee to obtain a license from a Third Party under any Patent in a particular country in the Territory in order to use, make, or sell a Licensed Product and Licensee obtains such a license, Licensee may deduct, from the royalty payment that would otherwise have been due pursuant to Section 6.1(a) with respect to Net Sales of the applicable Licensed Product in such country in a particular applicable semi-annual period an amount equal to fifty percent (50%) of the royalties paid by Licensee to such Third Party pursuant to such license on account of the sale of such Licensed Product in such country during such applicable semi-annual period.
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6.2 License Fee and Equity Investment.
(a) On February 10, 2014, Licensee paid Licensor US$150,000 as a license fee ($100,000 of which is to be allocated to this RGN-259 license) pursuant to the terms set forth in the Binding Term Sheet that was executed between the Parties on February 7, 2014, the receipt of which is hereby acknowledged by Licensor.
(b) Licensee shall purchase US$1.35 million of Licensor common stock by March 28, 2014 at a price of US$0.12 per share.
(c) Licensee shall purchase US$1.0 million of Licensor common stock by August 31, 2014 at a price of US$0.12 per share.
(d) A failure of Licensee to make payments pursuant to Sections 6.2(b) and 6.2(c) by the deadlines set forth herein shall constitute a breach of material obligation under Section 13.1(a) and give Licensor the right to terminate this Agreement as provided in Section 13. For the avoidance of doubt, the equity investments provided in the foregoing subsections (b) and (c) of this Section 6.2 refer to the same equity investments provided in the Section 6.2 of the RGN-137 Agreement.
6.4 Commercial Milestone Payments.
(a) Licensee shall promptly pay to Licensor a non-refundable sum of US$[***] upon the First Commercial Sale of Licensed Product in Korea.
(b) Licensee shall promptly pay to Licensor a non-refundable sum of US$[***] upon obtaining US$[***] of aggregate, cumulative commercial Net Sales of Licensed Product in Japan.
(c) Licensee shall promptly pay to Licensor a non-refundable sum of US$[***] million upon obtaining US$[***] million of aggregate, cumulative commercial Net Sales of Licensed Product in the Territory (one time only), and Licensee shall pay to Licensor such US$[***] million in three equal installments of US$[***] million per year for three (3) consecutive years with the first payment due by the thirtieth (30th) day from obtaining the Net Sales defined hereunder and the two (2) subsequent payments due on the first and second anniversary of such first due date.
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6.7 Exchange Rate. When converting any amount in another currency into United States Dollars, Licensee shall use an exchange rate equal to New York foreign exchange rate quoted in the Wall Street Journal on the business day that is five (5) days prior to the date a payment under this Agreement is due.
(i) Licensor or its representative shall have the right to annually audit Licensee’s, its Affiliates’, its Sublicensees’ and its Distributors’ records as set forth in this Section 6.8. Licensee shall permit Licensor or its representative to have access during normal business hours to such records of Licensee, its Affiliates and its Sublicensees as may be reasonably necessary to verify the accuracy of the royalty reports hereunder for any Marketing Year ending not more than five (5) years prior to the date of such request. Annual audits can take place no more often than once per each calendar year. Notice of Licensor’s intent to conduct an audit must be provided within thirty (30) days of the later of: (i) Licensor’s receipt of the periodic royalty report reflecting full yearly sales of Licensed Product or (ii) Licensee’s filing of its official report in accordance with the Korean Stock Exchange regulations. Except as otherwise provided in Section 6.9(b)(ii), Licensor shall be responsible for its own costs and expenses relating to any audit conducted under this Section 6.9(b)(i). Licensee shall cause its Affiliates and Sublicensees to agree to make their records available for audit by Licensor or its representative as set forth in this Section 6.9.
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(ii) If any audit conducted by Licensor or its representative shows an underpayment of royalties to Licensor, Licensee shall remit to Licensor the amount of such underpayment within thirty (30) days after its receipt of Licensor’s request therefor. If an underpayment in royalties exceeds five percent (5%) of the total amount owed for the period then being audited, Licensee shall be responsible, and promptly shall reimburse Licensor, for Licensor’s reasonable out-of-pocket costs for conducting the audit. If any audit conducted by Licensor or its representative shows an overpayment of royalties to Licensor, such overpayment shall be refunded to Licensee promptly.
Section 7. Regulatory Matters
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7.6 Unknown Side Effects; Adverse Reactions.
Section 8. Intellectual Property
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8.3 Licenses to Certain Inventions.
8.5 Prosecution and Maintenance of Licensed Patents in the Territory.
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8.6 Infringement by Third Parties.
(b) Right to Bring Suit in the Territory.
(i) As between Licensor and Licensee, Licensor shall have the right, but not the obligation, to bring and control any legal action or proceeding with respect to any infringement of Licensed Patents or any misappropriation or misuse of Licensed Know-How by Third Parties in the Territory, at its own expense and using counsel of its own choice.
(ii) In the event that Licensor declines to take legal action with respect to any infringement of the Licensed Patents, Licensee shall have the right, after giving Licensor ten (10) working days’ prior notice of its intent to do so, to take such legal action at its own expense, with the concomitant right to choose legal counsel reasonably acceptable to Licensor and to determine legal strategy. Licensor shall have the right to participate in any such legal action using its own counsel, at its own expense. Licensee may not settle or compromise any such controversy with any Third Party without the prior written approval of Licensor, which shall not be unreasonably withheld or delayed.
(iii) For any action or proceeding brought by Licensor pursuant to this Section 8.6, if Licensor is unable to initiate or prosecute such action solely in its own name, then Licensee shall join such action voluntarily and shall execute all documents necessary to initiate litigation to prosecute and maintain such action.
(iv) In connection with any action or proceeding brought by Licensor pursuant to this Section 8.6, Licensee shall cooperate fully and will provide Licensor with any information or assistance that Licensor reasonably requests.
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8.8 Defense of Third Party Claims.
(i) For the defense of any Challenge pursuant to this Section 8.8, if Licensor is unable to initiate or prosecute such defense solely in its own name, then Licensee (subject to any necessary approval of the relevant court) shall join such action voluntarily and shall execute all documents necessary to initiate litigation to prosecute and maintain such action.
(ii) In connection with the defense of any Challenge brought by Licensor pursuant to this Section 8.8, Licensee shall cooperate fully and will provide Licensor with any information or assistance that Licensor reasonably requests.
(a) such recovery shall first be allocated to Licensor for reimbursement in respect of its respective out-of-pocket costs and expenses incurred in connection with such action; and
(b) any remaining amounts after such reimbursement shall be split equally by the Parties.
Section 9. Confidentiality and Press Releases
(a) was already legally in the possession of the Receiving Party, other than under an obligation of confidentiality, at the time of disclosure by the Disclosing Party;
(b) was generally available to the public or otherwise part of the public domain at the time of its disclosure to the Receiving Party;
(c) became generally available to the public or was otherwise part of the public domain after its disclosure and other than through any act or omission of the Receiving Party in breach of this Agreement;
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(d) was disclosed to the Receiving Party, other than under an obligation of confidentiality, by a Third Party who had no obligation to the Disclosing Party not to disclose such information to others; or
(e) is independently discovered or developed by the Receiving Party without the use of Confidential Information provided by the Disclosing Party.
9.2 Exceptions. The obligations of this Section 9 shall not apply to Confidential Information that:
(a) is submitted to Governmental Authorities by the Receiving Party to facilitate the issuance of any Regulatory Approval for the Licensed Product, or to obtain, maintain, enforce or defend Patents (in each case only to the extent permitted by this Agreement; provided that (A) such disclosure may be only to the extent reasonably necessary to obtain Regulatory Approvals or Patents, as applicable, and (B) the Receiving Party shall take reasonable measures to assure confidential treatment of such information to the extent applicable;
(b) is provided by the Receiving Party to Third Parties (including, in the case of Licensee, to its Affiliates, Sublicensees or Distributors) under written confidentiality agreements having provisions at least as stringent as those in this Agreement, for consulting, development, external testing, marketing trials and other similar activities to the extent that such Receiving Party is permitted to conduct such activities pursuant to this Agreement; or
(c) is otherwise required to be disclosed by the Receiving Party in compliance with Laws (including, without limitation and for the avoidance of doubt, the requirements of the U.S. Securities and Exchange Commission, the American Stock Exchange, the Korean Stock Exchange, and any other stock exchange on which securities issued by a Party are traded) or order by a court or other Governmental Authority having competent jurisdiction; provided, however, that the Receiving Party shall first give written notice to the Disclosing Party in order to allow the Disclosing Party the opportunity to seek confidential treatment of the Confidential Information. Confidential Information that is disclosed pursuant to Law or an order by a court or other Governmental Authority shall remain otherwise subject to the confidentiality and non-use provisions of this Section 9, and the Party disclosing Confidential Information pursuant to a Law or order by a court or other Governmental Authority shall take all reasonable steps necessary, including without limitation obtaining an order of confidentiality, to ensure the continued confidential treatment of such Confidential Information.
20 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
Section 10. Representations, Warranties and Covenants
(a) the execution, delivery and performance by Licensor of this Agreement and the consummation of the transactions contemplated hereby are within Licensor’s corporate powers and have been duly authorized by all necessary corporate action on the part of Licensor. This Agreement constitutes the legal, valid and binding obligation of Licensor, enforceable against Licensor in accordance with its terms;
(b) the execution, delivery and performance of this Agreement by Licensor will not violate any Law or any order of any Governmental Authority;
(c) except as may be required to permit the sale or exportation of Licensed Product into the Territory from time to time during the Term, the execution, delivery or performance of this Agreement by Licensor will not require Licensor to obtain any permits, authorizations or consents from any Governmental Authority, and such execution, delivery and performance will not result in a material breach of or give rise to any termination of any agreement or contract to which Licensor is a Party;
(d) Licensor has the right and authority to grant the licenses granted in Section 2 of this Agreement;
(e) to the best of our knowledge, without any investigation or due inquiry, all issued Licensed Patents are valid;
(f) Licensor has not received any written communication from a third party alleging that Licensor’s practice of the Licensed Patents infringes the right of such third party; and
21 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
(g) Licensor, its Affiliates, and its and their respective employees, agents, contractors and consultants have never been (i) debarred or (ii) convicted of a crime for which a person can be debarred, under Section 306(a) of the Generic Drug Enforcement Act of 1992 (Section 306 (a) or (b)) or similar Laws of any foreign jurisdiction. Licensor, its Affiliates, and its and their respective employees, agents, contractors and consultants have never been (i) threatened to be debarred or (ii) indicted for a crime or otherwise engaged in conduct for which a person can be debarred, under Section 306(a) or (b) of the Generic Drug Enforcement Act of 1992 or similar Laws of any other jurisdiction. Licensor shall promptly notify Licensee upon learning of any such debarment, conviction, threat or indictment.
(a) the execution, delivery and performance by Licensee of this Agreement and the consummation of the transactions contemplated hereby are within Licensee’s corporate powers and have been duly authorized by all necessary corporate action on the part of Licensee. This Agreement constitutes the legal, valid and binding obligation of Licensee, enforceable against Licensee in accordance with its terms;
(b) Licensee will be at all times properly registered, licensed and qualified, and have all requisite power and authority under its organizational documents and in accordance with the Laws of the Territory to develop (including without limitation the conduct of clinical trials), promote, market, distribute, import, export and sell the Licensed Product in the Territory, and to conduct its business and perform its obligations hereunder and, during the Term, it shall take all action as may be required and necessary to obtain and keep current any governmental licenses, permits, registrations and approvals (including without limitation Regulatory Approvals) that are necessary or advisable for it to carry out its activities hereunder;
(c) the execution, delivery and performance of this Agreement by Licensee will not violate any Law or any order of any Governmental Authority;
(d) except for Regulatory Approvals and as may be required to permit the sale or importation of Licensed Product from time to time into the Territory during the Term, the execution, delivery or performance of this Agreement by Licensee will not require Licensee to obtain any permits, authorizations or consents from any Governmental Authority, and such execution, delivery and performance will not result in a material breach of or give rise to any termination of any agreement or contract to which Licensee is a Party;
(e) Licensee, its Affiliates, and its and their respective employees, agents, contractors and consultants have never been (i) debarred or (ii) convicted of a crime for which a person can be debarred, under Section 306(a) of the Generic Drug Enforcement Act of 1992 (Section 306 (a) or (b)) or similar Laws of any foreign jurisdiction. Licensee, its Affiliates, and its and their respective employees, agents, contractors and consultants have never been (i) threatened to be debarred or (ii) indicted for a crime or otherwise engaged in conduct for which a person can be debarred, under Section 306(a) or (b) of the Generic Drug Enforcement Act of 1992 or similar Laws of any other jurisdiction. Licensee shall promptly notify Licensor upon learning of any such debarment, conviction, threat or indictment;
(f) Licensee and its Affiliates and its and their respective employees, agents, contractors and consultants shall not use any Person on a Prohibited List in connection with the performance of any of its obligations or activities under this Agreement;
22 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
(g) Licensee shall carry out its obligations and activities under this Agreement, including the development, promotion, marketing, distribution and sale of Licensed Products, in accordance with: (i) the terms hereof, (ii) all applicable Laws and Regulatory Laws, and any subsidiary legislation thereunder; and (iii) GCP, GLP, and, to the extent Licensee manufactures or has manufactured any Licensed Products pursuant to Section 5.1, GMP;
(h) As of the Effective Date, Licensee believes in good faith that it will have sufficient financial resources available to carry out, or to have carried out, all of its obligations and activities contemplated under this Agreement;
(i) Licensee and its Affiliates shall not develop, promote, market, distribute, or sell during the Term any product in the Field that utilizes or otherwise contains Tβ4 or any derivatives, analogs or fragments thereof without Licensor’s prior written approval. and
(j) Licensee shall not reverse engineer or otherwise deconstruct any API or component part of finished Licensed Product for the purpose of developing a product that would compete with the Licensed Product in the Field.
Section 11. Indemnification
23 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
24 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
Section 12. Information and Reporting
12.1 After the completion of equity investment as provided in Section 6.2, Licensee may examine, upon reasonable prior written request having been made to Licensor, but not more than twice per year, the books, records and accounts of Licensor. Licensee shall be entitled to receive reasonable information, including management accounts and operating statistics and other business and financial information, which exist at the time of request, to keep it properly informed about the business and affairs of Licensor and relevant to its interest as a shareholder.
12.2 Licensor shall provide reasonable access to Licensee’s personnel, upon reasonable notice and during normal business hours, but not more than twice per year, to access such books, records, accounts and other information relating to Licensor, which exist at the time of request, as may be necessary for them to review the information provided to Licensee pursuant to Sections 12.1.
12.3 Any information or documents provided to or made available for review by Licensee shall constitute Confidential Information and shall be protected accordingly as provided under Section 9 above.
Section 13. Term and Termination
13.2 Term and Rules Post Termination:
(a) In the event either Party is in breach of any material obligation hereunder or under the RGN-137 License Agreement (the “Breaching Party”), the non-breaching Party may give written notice to the Breaching Party specifying the claimed particulars of such breach, and in the event such material breach is not cured, within sixty (60) days following the date of such written notification, without prejudice to any other rights and remedies available at any time to the non-breaching Party, the non-breaching Party shall have the right thereafter to terminate this Agreement by giving thirty (30) days prior written notice to the Breaching Party to such effect.
25 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
(i) terminate this Agreement; or
(ii) convert this Agreement to a license between Licensee, on the one hand, and Licensor and PHS, on the other hand, with such conversion subject to the approval of PHS, which shall not be unreasonably withheld, and contingent upon Licensee’s acceptance of all of the provisions of the PHS License.
(b) Transfer of Materials. In the event of early termination of this Agreement for any reason:
(i) to the extent not transferred pursuant to Section 13.3(a), Licensee shall provide to Licensor a copy of any and all documentation and data owned by Licensee and in tangible form at the time of termination of the Agreement that has been generated with respect to the Licensed Product and is necessary to enable Licensor to continue development of a Licensed Product and the commercialization thereof in the Territory (collectively, the “Licensee Product Data”), and Licensor may use such Licensee Product Data at its discretion on an exclusive basis, to the extent necessary to enable Licensor, its Affiliates and Third Parties on behalf of Licensor or its Affiliates to continue to develop and commercialize a Licensed Product in the Territory; and
26 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
| A-2 |
(ii) if such termination occurs after a Licensed Product has received Regulatory Approval, Licensee shall, if permitted under applicable Law, promptly transfer and deliver to Licensor original copies of any and all Regulatory Approvals obtained in connection with the Licensed Product in the Territory (including any and all official registrations, licenses, permits, certificates, and/or importation documents issued by Regulatory Authorities in the Territory), as well as any and all regulatory documentation and applications for Regulatory Approval submitted to Regulatory Authorities in the Territory in connection with the Licensed Product; Licensor shall pay Licensee’s direct, out-of-pocket costs for compliance with this Section 13.3(b)(ii);
(iii) to the extent that any Regulatory Approval is issued in the name of Licensee, its Affiliates, Sublicensees or other designee, Licensee shall, to the extent permitted by applicable Law, promptly assign or procure the assignment to Licensor (or its designee) such Regulatory Approvals, and in the event assignment is not permitted under applicable Law or cannot be carried out for any other reason, the Licensee shall take all steps that are necessary and/or desirable to assist Licensor to obtain such Regulatory Approvals in the name of Licensor (or its designee) in the Territory, with such actions including without limitation coordinating with the applicable Regulatory Authority, furnishing all necessary information and documents in respect thereof, and promptly cancelling and terminating (as necessary) all Regulatory Approvals held by the Licensee, its Affiliate(s), Sublicensee(s) and/or other designee(s) which are not otherwise assignable or transferable to the Licensor (or its designee); Licensor shall pay Licensee’s direct, out-of-pocket costs for compliance with this Section 13.3(b)(iii); and
(iv) Licensee shall assign (or cause its Affiliates to assign) to Licensor all agreements with any Third Party with respect to the conduct of clinical trials for the Licensed Product, including agreements with contract research organizations, clinical sites and investigators, unless expressly prohibited by any such agreement or unless such agreement covers clinical trials for products in addition to the Licensed Products (in which case Licensee shall cooperate with Licensor in all reasonable respects to secure the consent of such Third Party to such assignment or to the conclusion of a new agreement between the Licensor and the Third Party on terms substantially similar to the agreement between Licensee and the Third Party), and Licensor shall assume all obligations under all such agreements.
27 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
Section 14. Miscellaneous
28 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
(i) The arbitration shall be conducted by a panel of three neutral arbitrators (the “Panel”) appointed in accordance with the ICC Rules.
(ii) The arbitration proceedings shall take place in New York, NY, USA. The arbitral proceedings and all pleadings shall be in the English language.
(iii) The Panel shall have the power to decide all questions of arbitrability.
(iv) At the request of either Party, the Panel will enter an appropriate protective order to maintain the confidentiality of information produced or exchanged in the course of the arbitration proceedings.
(v) The Panel is empowered to award any remedy allowed by law, including monetary damages, prejudgment interest and punitive damages, and to grant final, complete, interim or interlocutory relief, including injunctive relief.
(vi) The Parties may apply to a court of competent jurisdiction within the United States for a temporary restraining order, preliminary injunction, or other interim or conservatory relief, as necessary, without breach of this arbitration agreement and without any abridgment of the powers of the arbitrators. Judgment on the award rendered by the Panel may be entered in any court having jurisdiction thereof. Each Party hereby waives any defenses it may have to the personal jurisdiction and venue of such courts to resolve such disputes, including without limitation the defense of forum non conveniens, and each Party agrees not to file any motion to seek any relief under any forum non conveniens defense.
(vii) Each Party shall bear its own legal fees arising in connection with the dispute. The Panel may assess costs, fees and expenses of the ICC and the Panel to the Parties in the manner the Panel deems appropriate under the circumstances.
29 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
| If to Licensor: | RegeneRx Biopharmaceuticals, Inc. |
| 00000 Xxxxx Xxxxx Xxxx | |
| Xxxxx 000 | |
| Xxxxxxxxx, Xxxxxxxx 00000 | |
| U.S.A. | |
| Attn: President and CEO | |
| Phone: 000.000.0000 | |
| Fax: 000.000.0000 | |
| With a copy to: | Xxx Xxxxxx, Esq. |
| Xxxxxx LLP | |
| One Freedom Square | |
| Reston Town Center | |
| 00000 Xxxxxxx Xxxxx | |
| Xxxxxx, XX 00000-0000 | |
| Direct: (000) 000-0000 | |
| Fax: (000) 000-0000 | |
| If to Licensee: | Digital Aria Co., Ltd. |
| 22nd FL, Parkview Tower | |
| 248 Jungjail-ro, Bundang-gu | |
| Seongnam-si, Gyeonggi-do 000-000 | |
| Xxxxxxxx xx Xxxxx | |
| Attn: CEO | |
| Phone: x00 00 000 0000 | |
| Fax.: x00 00 000 0000 |
All such notices shall be effective upon receipt.
14.10 Governing Law. This Agreement shall be governed and construed in accordance with the laws of New York, USA without regard to its principles of conflict of laws. The Parties agree to exclude the application to this Agreement of the United Nations Convention on Contracts for the International Sale of Goods.
30 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
end
of page
[signatures appear on following page]
31 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
| RegeneRx Biopharmaceuticals, Inc. | ||
| By: | /s/X.X. Xxxxxxxxxxx | |
| Name: X.X. Xxxxxxxxxxx | ||
| Title: President & CEO | ||
| Digital Aria Co., Ltd. | ||
| By: | /s/Ill Park | |
| Name: Ill Park | ||
| Title: CEO | ||
32 | Page*** Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended.
Exhibit A - Licensed Patents: to be filled by RegeneRx
Exhibit B - PHS License Terms Applicable to Licensee
33 | Page
Exhibit A
Summary of OPHTHALMIC Patents and Patent Applications with Relevant Claims in Pan Asia
[Rest of Page Intentionally Left Blank]
| A-1 |
| 2600- | Country | Serial No. or Patent No. |
Filing Date |
Status | Representative Claims | |||||
| 109 | Australia | 766826 | 7-29-1999 | Issued | 1. A method for promoting wound healing in a subject in need of such treatment comprising administering to the subject a wound-healing effective amount of a composition containing a wound healing polypeptide said polypeptide comprising properties of having actin sequestering or actin binding activity said polypeptide comprising the amino acid sequence LKKTET. 13. A method for promoting wound healing in a subject in need of such treatment comprising administration to the subject of a wound-healing effective amount of a composition containing a polypeptide, said polypeptide comprising properties of having actin sequestering or actin binding capability, said polypeptide comprising amino acid sequence LKKTET; wherein said administration is selected from the group consisting of topical delivery, inhalation, systemic administration, oral administration, intranasal administration, aerosol administration, intravenous administration, intraperitoneal administration, intramuscular administration, intracavity administration, and transdermal administration. 24. A method for reducing inflammation in tissue of a subject comprising administering to a subject a therapeutically effective amount of a composition containing an inflammation-reducing polypeptide said polypeptide comprising properties of having actin sequestering or actin binding capability, said polypeptide comprising amino acid sequence LKKTET. 42. A method of inhibiting wound healing in a subject, comprising administering to the subject an effective amount of a composition containing an agent which decreases thymosin β4 activity. 46. A method of diagnosing a pathological state in a subject suspected of having pathology characterized by a wound healing disorder associated with thymosin β4, comprising: obtaining a sample suspected of containing thymosin β4 from the subject; detecting a level of thymosin β4 in the sample; and comparing the level of thymosin β4 in the sample to the level of thymosin β4 in a normal standard sample. 48. A method for ameliorating a wound healing disorder associated with thymosin β4, comprising treating a subject having the disorder, at the site of the disorder, with an effective amount of an agent which regulates thymosin β4 or the activity of a thymosin β4 isoform. 51. A method for identifying a compound which modulates wound healing, angiogenesis or cell migration activity, comprising contacting thymosin β4 or an isoform of thymosin β4 with a compound suspected of having thymosin β4 modulating activity and detecting an effect on thymosin β4 or thymosin β4 isoform activity. 54. A method of promoting epithelial cell migration in a subject, comprising contacting an epithelial cell with an effective amount of a composition including a polypeptide comprising properties of having actin sequestering or actin binding capability, said polypeptide comprising thymosin β4 or an isoform of thymosin β4. 63. A pharmaceutical composition comprising a fragment of a polypeptide, said fragment including amino acid sequence LKKTET, said fragment comprising properties of having actin sequestering or actin binding capability, said fragment having wound-healing or inflammation-reducing activity, said composition further including a pharmaceutically acceptable carrier when used to modulate wound healing or reduce inflammation. 69. A method for promoting wound healing in a subject in need of such treatment comprising administering to the subject a wound-healing effective amount of a composition containing a wound healing polypeptide other than thymosin β4, said polypeptide comprising properties of having actin sequestering or actin binding capability, said polypeptide having wound healing activity, and said polypeptide comprising the amino acid sequence LKKTET. |
| A-2 |
| 190 | Australia | 2006261156 | 6-19-2006 | Issued | 1. Use of a peptide agent comprising amino acid sequence LKKTET or a conservative variant thereof, LKKTNT or a conservative variant thereof, KLKKTET, XXXXXXX, Xxxxxxxx x0 (Tβ4), a Tβ4 isoform, analogue or derivative, Tβ4 sulfoxide, an N-terminal variant of Tβ4, a C-terminal variant of Xx0, Xx0xxx, Xx0, Xx00, Xx00, Tβ12, Tβ13, Tβ14, Tβ15, gelsolin, vitamin D binding protein (DBP), profilin, cofilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, or a stimulating agent that stimulates production of said peptide agent, in the manufacture of a medicament for treating elevated intraocular pressure in a subject, wherein said medicament is formulated as an ophthalmically acceptable composition. 2. A method of treating elevated intraocular pressure in a subject, comprising administering to the subject an ophthalmically acceptable composition comprising a peptide agent comprising amino acid sequence LKKTET or a conservative variant thereof, LKKTNT or a conservative variant thereof, KLKKTET, XXXXXXX, Xxxxxxxx x0 (Tβ4), a Tβ4 isoform, analogue or derivative, Tβ4 sulfoxide, an N-terminal variant of Tβ4, a C-terminal variant of Xx0, Xx0xxx, Xx0, Xx00, Xx00, Tβ12, Tβ13, Tβ14, Tβ15, gelsolin, vitamin D binding protein (DBP), profilin, cofilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, or a stimulating agent that stimulates production of said peptide agent. 9. A method of treating dry eye syndrome in a subject, comprising administering to the subject an ophthalmically acceptable composition having a pH of about 6.8 to 8.1 and comprising a peptide agent comprising amino acid sequence LKKTET, or a conservative variant thereof, LKKTNT or a conservative variant thereof. KLKKTET, XXXXXXX, Xxxxxxxx x0 (Tβ4), a Tβ4 isoform, analogue or derivative, Tβ4 sulfoxide, an N-terminal variant of Tβ4, a C-terminal variant of 1134, Tβ4ala, Tβ9, Tβ10, Tβ11, Tβ12, Tβ13, Tβ14, Tβ15, gelsolin, vitamin D binding protein (DBP), profiling, cofilin, depactin, Dnasel, vilin, fragmin, severin, capping protein, p-actinin, or acumentin, or a stimulating agent that stimulates production of said peptide agent. |
| X-0 |
| 000 | Xxxxxxxxx | 2009258034 | 3-13-2009 | Pending | 1. A peptide fragment having an amino acid sequence corresponding to a portion of at least one of a thymosin beta 4, a thymosin beta 10 or a thymosin beta 15 amino acid sequence, said fragment comprising amino acid sequence H-Leu-I_ys-I_ys-Thr-Glu-Thr-OH, Ac-Leu-Lys-Lys-Thr-Glu- Thr-OH, H-Ser-Asp-Lys-Pro-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle- Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle- Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, Ac- Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, H-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys- Glu-Thr-OH, Ac-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, H-IIe-GIu- Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser-OH, Ac-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly- Glu-Ser-OH, H-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr-Glu-Thr, Ac-Leu- Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro, H-Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu- Ile-Glu-Lys-Phe-Asp-Lys-Ser, H-Leu-Lys-Lys-Thr-Glu-Thr-Gln, Ac-Leu-Lys- Lys-Thr-Glu-Thr-Gln, H-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, Ac-GIu- Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, H-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly- Glu-Ser, Ac-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser, H-Met-Ala-Glu-lle- Glu-Lys-Phe-Asp-Lys-Ser, Ac-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Leu-Lys-Lys-Thr-Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu- Lys-Phe-Asp-Lys-Ser-OH, Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, Glu-Lys-Asn- Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, Ile-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu- Ser-OH, Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr- Glu-Thr-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp- Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-OH, H-Ser-Asp-Lys-Pro-Asp-Met- Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln- OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser- Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu- Lys-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys- Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu-Lys-OH, H-Leu-Lys-Lys-Thr-Glu- Thr-Gln-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys- Gln-Ala-Gly-Glu-Ser-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn- Pro-Leu-Pro-Ser-Lys-GIu-Thr-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys- Leu-Lys-Lys-Thr-Glu-Thr, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu- Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro- Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu- Thr-Gln, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys- Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln, H-Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu- Lys, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser- Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys, H-Leu-Lys-Lys-Thr-Glu-Thr-GIn- Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala- Gly-Glu-Ser, Ac-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro-Leu-Pro- Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser, Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr- Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys- Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu- Lys-OH, Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys- Glu-Thr-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, a methionine- containing variant of said fragment in which said methionine is oxidized or superoxidized, a variant of said fragment which normally is methionine- containing but which has an amino acid substituent substituted for at least one methionine of the normally methionine-containing fragment, an isolated R-enantiomer of said fragment, an isolated S-enantiomer of said fragment, or a combination thereof. 22. A method of at least one of suppressing inflammation in tissue of a subject, stimulating cell migration in tissue of a subject, protecting tissue from cytotoxicity in tissue of a subject, inhibiting apoptosis in tissue of a subject, stimulating collagen in tissue of a subject, inhibiting collagen in tissue of a subject, stimulating collagen IV in tissue of a subject, stimulating elastin in tissue of a subject, inhibiting NFkB translocation in tissue of a subject, inhibiting tissue damage caused by ultraviolet (UV) radiation, protecting tissue from ultraviolet (UV) radiation damage, promoting neurite outgrowth, promoting neuron survival, stimulating production of L1 , inhibiting IKBa phosphorylation, or restoring impaired T-lymphocyte blastogenic response comprising administering to said subject a peptide fragment having an amino acid sequence corresponding to a portion of a thymosin beta 4, a thymosin beta 10 or a thymosin beta 15 amino acid sequence, said fragment comprising amino acid sequence H-Leu-Lys-Lys-Thr-Glu-Thr-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-OH, H-Ser-Asp-Lys-Pro-OH, H-Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr- Glu-Thr-Gln-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, H-Glu-Lys-Asn-Pro- Leu-Pro-Ser-Lys-Glu-Thr-OH, Ac-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, H-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, Ac-IIe-GIu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, H-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr-Glu-Thr, Ac-Leu-Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, H-Leu-Lys-Lys-Thr-Glu-Thr-Gln, Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln, H-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, Ac-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, H-IIe-GIu-Gln-Glu-Lys-GIn-Ala-Gly-Glu-Ser, Ac-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser, H-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Ac-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Leu-Lys-Lys-Thr-Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, He-GIu-GIn-GIu-Lys-GIn-Ala-Gly-Glu-Ser-OH, Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-OH, H-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-Ile-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu- Thr-GIn-Glu-Lys, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe- Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-GIu-Thr-GIn-Glu-Lys, H-Leu-Lys-Lys- Thr-Glu-Thr-Gln-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln- Glu-Lys-GIn-Ala-Gly-Glu-Ser, Ac-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys- Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu- Ser, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys- Leu-Lys-Lys-Thr-Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu- Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr- Glu-Thr-GIn-Glu-Lys-OH, Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro- Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, a methionine-containing variant of said fragment in which said methionine is oxidized or superoxidized, a variant of said fragment which normally is methionine-containing but which has an amino acid substituent substituted for at least one methionine of the normally methionine-containing fragment, an isolated R-enantiomer of said fragment, an isolated S-enantiomer of said fragment, or a combination thereof. |
| X-0 |
| 000 | Xxxxx | 500875/2011
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3-13-2009 | Pending | 1. A peptide fragment having an amino acid sequence corresponding to a portion of at least one of a thymosin beta 4, a thymosin beta 10 or a thymosin beta 15 amino acid sequence, said fragment comprising amino acid sequence H-Leu-I_ys-I_ys-Thr-Glu-Thr-OH, Ac-Leu-Lys-Lys-Thr-Glu- Thr-OH, H-Ser-Asp-Lys-Pro-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle- Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle- Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, Ac- Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, H-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys- Glu-Thr-OH, Ac-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, H-IIe-GIu- Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser-OH, Ac-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly- Glu-Ser-OH, H-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr-Glu-Thr, Ac-Leu- Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro, H-Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu- Ile-Glu-Lys-Phe-Asp-Lys-Ser, H-Leu-Lys-Lys-Thr-Glu-Thr-Gln, Ac-Leu-Lys- Lys-Thr-Glu-Thr-Gln, H-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, Ac-GIu- Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, H-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly- Glu-Ser, Ac-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser, H-Met-Ala-Glu-lle- Glu-Lys-Phe-Asp-Lys-Ser, Ac-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Leu-Lys-Lys-Thr-Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu- Lys-Phe-Asp-Lys-Ser-OH, Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, Glu-Lys-Asn- Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, Ile-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu- Ser-OH, Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr- Glu-Thr-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp- Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-OH, H-Ser-Asp-Lys-Pro-Asp-Met- Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln- OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser- Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu- Lys-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys- Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu-Lys-OH, H-Leu-Lys-Lys-Thr-Glu- Thr-Gln-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys- Gln-Ala-Gly-Glu-Ser-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn- Pro-Leu-Pro-Ser-Lys-GIu-Thr-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys- Leu-Lys-Lys-Thr-Glu-Thr, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu- Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro- Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu- Thr-Gln, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys- Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln, H-Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu- Lys, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser- Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys, H-Leu-Lys-Lys-Thr-Glu-Thr-GIn- Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala- Gly-Glu-Ser, Ac-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro-Leu-Pro- Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser, Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr- Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys- Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala- Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu- Lys-OH, Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys- Glu-Thr-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, a methionine- containing variant of said fragment in which said methionine is oxidized or superoxidized, a variant of said fragment which normally is methionine- containing but which has an amino acid substituent substituted for at least one methionine of the normally methionine-containing fragment, an isolated R-enantiomer of said fragment, an isolated S-enantiomer of said fragment, or a combination thereof.
22. Use of a peptide fragment having an amino acid sequence corresponding to a portion of a thymosin beta 4, a thymosin beta 10 or a thymosin beta 15 amino acid sequence in the preparation of a medicament for at least one of suppressing inflammation in tissue of a subject, stimulating cell migration in tissue of a subject, protecting tissue from cytotoxicity in tissue of a subject, inhibiting apoptosis in tissue of a subject, stimulating collagen in tissue of a subject, inhibiting collagen in tissue of a subject, stimulating collagen IV in tissue of a subject, stimulating elastin in tissue of a subject, inhibiting NFkB translocation in tissue of a subject, inhibiting tissue damage caused by ultraviolet (UV) radiation, protecting tissue from ultraviolet (UV) radiation damage, promoting neurite outgrowth, promoting neuron survival, stimulating production of L1 , inhibiting IKBa phosphorylation, or restoring impaired T-lymphocyte blastogenic response, said fragment comprising amino acid sequence H-Leu-Lys-Lys-Thr-Glu-Thr-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-OH, H-Ser-Asp-Lys-Pro-OH, H-Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr- Glu-Thr-Gln-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH, H-Glu-Lys-Asn-Pro- Leu-Pro-Ser-Lys-Glu-Thr-OH, Ac-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, H-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, Ac-IIe-GIu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, H-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Ac-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Leu-Lys-Lys-Thr-Glu-Thr, Ac-Leu-Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, H-Leu-Lys-Lys-Thr-Glu-Thr-Gln, Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln, H-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, Ac-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr, H-IIe-GIu-Gln-Glu-Lys-GIn-Ala-Gly-Glu-Ser, Ac-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser, H-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Ac-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser, Leu-Lys-Lys-Thr-Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-OH, He-GIu-GIn-GIu-Lys-GIn-Ala-Gly-Glu-Ser-OH, Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-OH, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-OH, H-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-Ile-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu-Ser-OH, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-Gln, H-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu- Thr-GIn-Glu-Lys, Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe- Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-GIu-Thr-GIn-Glu-Lys, H-Leu-Lys-Lys- Thr-Glu-Thr-Gln-Glu-Lys-Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln- Glu-Lys-GIn-Ala-Gly-Glu-Ser, Ac-Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys- Asn-Pro-Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-Gln-Glu-Lys-Gln-Ala-Gly-Glu- Ser, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys- Leu-Lys-Lys-Thr-Glu-Thr-OH, Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-lle-Glu- Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr-Glu-Thr-GIn-OH, Ser-Asp-Lys- Pro-Asp-Met-Ala-Glu-lle-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr- Glu-Thr-GIn-Glu-Lys-OH, Leu-Lys-Lys-Thr-Glu-Thr-GIn-Glu-Lys-Asn-Pro- Leu-Pro-Ser-Lys-Glu-Thr-lle-Glu-GIn-Glu-Lys-GIn-Ala-Gly-Glu-Ser-OH, a methionine-containing variant of said fragment in which said methionine is oxidized or superoxidized, a variant of said fragment which normally is methionine-containing but which has an amino acid substituent substituted for at least one methionine of the normally methionine-containing fragment, an isolated R-enantiomer of said fragment, an isolated S-enantiomer of said fragment, or a combination thereof. |
| A-5 |
Exhibit B
For the purposes of this Exhibit C only, terms in bold have the meanings given such terms in the PHS License.
| 5.01 | PHS reserves on behalf of the Government an irrevocable, nonexclusive, non-transferable, royalty-free license for the practice of all inventions licensed under the Licensed Patent Rights throughout the world by or on behalf of the Government and on behalf of any foreign government or international organization pursuant to any existing or future treaty or agreement to which the Government is a signatory. Prior to the First Commercial Sale, Licensee agrees to provide PHS reasonable quantities of Licensed Products or materials made through the Licensed Processes solely for PHS research use and not for purposes of commercial development, manufacture or distribution, at a price equal to Licensee’s cost of such. |
| 5.02 | Licensee agrees that products used or sold in the United States embodying Licensed Products or produced through use of Licensed Processes shall be manufactured substantially in the United States, unless a written waiver is obtained in advance from PHS. |
| 5.03 | Licensee acknowledges that PHS may enter into future Cooperative Research and Development Agreements (CRADAs) under the Federal Technology Transfer Act of 1986 that relate to the subject matter of this Agreement. PHS agrees to notify Licensee, as soon as is practical of any proposed CRADA that relates to the subject matter of this Agreement. Licensee agrees not to unreasonably deny requests for a Research License from such future collaborators with PHS when acquiring such rights is necessary in order to make a Cooperative Research and Development Agreement (CRADA) project feasible. As of the effective date of this Agreement, Licensee requests that Licensee have an opportunity to join as a party to any proposed Cooperative Research and Development Agreement (CRADA). |
| 5.04 | In addition to the reserved license of Paragraph 5.01 above, PHS reserves the right to grant such nonexclusive Research Licenses directly or to require Licensee to grant nonexclusive Research Licenses on commercially reasonable terms. The purpose of this Research License is to encourage basic research, whether conducted at an academic or corporate facility. In order to safeguard the Licensed Patent Rights, however, PHS shall consult with Licensee before granting to commercial entities a Research License or providing to them research samples of Licensed Products or materials made through the Licensed Processes, provided however that PHS will not provide materials obtained from Licensee under Paragraph 5.01 above to third parties, except with Licensee’s prior written consent, which shall not be unreasonably withheld. |
| 8.01 | Licensee agrees to keep accurate and correct records of Licensed Products made, used, sold, or imported and Licensed Processes practiced under this Agreement appropriate to determine the amount of royalties due PHS. Such records shall be retained for at least five (5) years following a given reporting period and shall be available during normal business hours upon five (5) business days prior written notice from PHS to Licensee for inspection at the expense of PHS by an accountant or other designated auditor selected by PHS for the sole purpose of verifying reports and payments hereunder. The accountant or auditor shall only disclose to PHS information relating to the accuracy of reports and payments made under this Agreement. If an inspection shows an under reporting or underpayment in excess of five percent (5%) for any twelve (12) month period, then Licensee shall reimburse PHS for the cost of the inspection at the time Licensee pays the unreported royalties, including any late charges as required by Paragraph 9.08 of this Agreement. All payments required under this Paragraph shall be due within thirty (30) days of the date PHS provides Licensee notice of the payment due. |
| B-1 |
| 10.01 | Licensee shall use its reasonable best efforts to bring the Licensed Products and Licensed Processes to Practical Application. “Reasonable best efforts” for the purposes of this provision shall include substantial adherence to the Commercial Development Plan at Appendix F and substantial performance of the Benchmarks at Appendix E as may be amended from time to time by mutual written consent. The efforts of sublicensees and Affiliates shall be considered the efforts of Licensee. To the extent that the Benchmarks or development obligations set forth in Appendix E differ from or conflict with those set forth in the Commercial Development Plan in Appendix F, Appendix E shall be considered to supersede Appendix F and the Commercial Development Plan in Appendix F shall be amended to be consistent with Appendix E. |
| 12.05 | Licensee shall indemnify and hold PHS, its employees, students, fellows, agents, and consultants (the “Indemnified Parties”) harmless from and against all liability, demands, damages, expenses, and losses, including but not limited to death, personal injury, illness, or property damage (the “Indemnified Losses”) suffered by an Indemnified Party in connection with or arising out of a) the use by or on behalf of Licensee, its sublicensees, directors, employees, or third parties of any Licensed Patent Rights, or b) the design, manufacture, distribution, or use of any Licensed Products, Licensed Processes or materials by Licensee, or other products or processes developed in connection with or arising out of the Licensed Patent Rights. Licensee agrees to maintain a liability insurance program consistent with sound business practice. Notwithstanding any other provision to the contrary, Licensee shall have no obligation to indemnify an Indemnified Party from an Indemnified Loss in connection with or arising out of the design, manufacture, distribution or use of any Licensed Product or Licensed Process by or on behalf of the Indemnified Party. |
| 13.05 | PHS shall specifically have the right to terminate or, with Licensee’s consent, modify, at its option, this Agreement, if PHS determines that the Licensee: 1) is not using its reasonable best efforts to effectuate the Commercial Development Plan submitted with its request for a license and the Licensee cannot otherwise demonstrate to PHS’s satisfaction that the Licensee has taken, or can be expected to take within a reasonable time, effective steps to achieve Practical Application of the Licensed Products or Licensed Processes; 2) has not used its reasonable best efforts to achieve the Benchmarks as my be modified under Paragraph 9.02; 3) has willfully made a false statement of, or willfully omitted, a material fact in the license application or in any report required by this Agreement; 4) has committed a material breach of a covenant or agreement contained in the license; 5) is not keeping Licensed Products or Licensed Processes reasonably available to the public after commercial use commences; 6) cannot reasonably satisfy unmet health and safety needs; or 7) cannot reasonably justify a failure to comply with the domestic production requirement of Paragraph 5.02 unless waived. In making this determination, PHS will take into account the normal course of commercial development programs conduct with sound and reasonable business practices and judgment and the annual reports submitted by Licensee under Paragraph 9.02. Prior to invoking this right, PHS shall give written notice to Licensee providing Licensee specific notice of, and a ninety (90) day opportunity to respond to, PHS’s concerns as to the previous items 1) to 7). If Licensee fails to alleviate PHS’s concerns as to the previous items 1) to 7) or fails to initiate corrective action to PHS’s reasonable satisfaction, PHS may terminate this Agreement. |
| B-2 |
| 13.07 | PHS reserves the right according to 35 U.S.C. § 209(1)(4) to terminate or modify this Agreement if it is determined that such action is necessary to meet requirements for public use specified by federal regulations issued after the date of the license and such requirements are not reasonably satisfied by Licensee. |
| 13.08 | Within thirty (30) days of receipt of written notice of PHS’s unilateral decision to modify or terminate this Agreement, Licensee may, consistent with the provisions of 37 C.F.R. 404.11, appeal the decision by written submission to the designated PHS official. The decision of the designated PHS official shall be the final agency decision. Licensee may thereafter exercise any and all administrative or judicial remedies that may be available. |
| 13.09 | Within ninety (90) days of expiration or termination of this Agreement under this Article 13, a final report shall be submitted by Licensee. Any royalty payments, including those incurred but not yet paid (such as the full minimum annual royalty), and those related to patent expense, due to PHS shall become immediately due and payable upon termination or expiration. If terminated under this Article 13, sublicensees may elect to convert their sublicenses to direct licenses with PHS and Licensee pursuant to Paragraph 4.03. |
| B-3 |