License Agreement

TEXT OMITTED AND FILED SEPARATELY

CONFIDENTIAL TREATMENT REQUESTED

UNDER 17.C.F.R. Sections 200.80(B)(4),

200.83 AND 240.24B-2





LICENSE AGREEMENT



THIS Agreement, effective November 30, 1992 by and between STERITECH, INC., a California corporation, having a principal office at 2341 Stanwell Drive, Concord, California 94520 ("STERITECH") and MILES INC., an Indiana corporation, Mobay Road, Pittsburgh, Pennsylvania 15205 ("MILES"), and DIAMOND SCIENTIFIC CORPORATION, a ________ corporation, ("DIAMOND").



WITNESSETH THAT:



WHEREAS, United States Patent No. 4,545,987, entitled: "PSORALEN INACTIVATED DOUBLE-STRANDED RNA VIRAL VACCINES", was issued on October 8, 1985, a copy of which is attached hereto as Exhibit A;



WHEREAS, United States Patent No. 4,693,981, entitled: "PREPARATION OF INACTIVATED VIRAL VACCINES", was issued on September 15, 1987, a copy of which is attached hereto as Exhibit B;



WHEREAS, United States Patent No. 4,727,027, entitled: "PHOTOCHEMICAL DECONTAMINATION TREATMENT OF WHOLE BLOOD OR BLOOD COMPONENTS", was issued on February 23, 1988, a copy of which is attached hereto as Exhibit C;



WHEREAS, United States Patent No. 4,748,120, entitled: "PHOTOCHEMICAL DECONTAMINATION TREATMENT OF WHOLE BLOOD OR BLOOD COMPONENTS", was issued on May 31, 1988, a copy of which is attached hereto as Exhibit D;



WHEREAS, United States Patent No 4,791,062, entitled: "FVR VACCINE", was issued on December 13, 1988, a copy of which is attached hereto as Exhibit E;



WHEREAS, United States Patent No. 5,106,619, entitled: "PREPARATION OF INACTIVATED VIRAL VACCINES", was issued on April 21, 1992, a copy of which is attached hereto as Exhibit F;



WHEREAS, DIAMOND, which is a wholly owned subsidiary of MILES, is the owner by assignment of U.S. Patent Nos.: 4,545,987; 4,693,981; 4,727,027; 4,748,120; 4,791,062; and 5,106,619 and has the right to grant licenses under these patents;











WHEREAS, DIAMOND, which is a wholly owned subsidiary of MILES, is the owner of the foreign patents and patent applications that correspond to the above patents and are identified in Exhibit G and has the right to grant licenses under the foreign patents and patent applications.



WHEREAS, STERITECH desires to obtain [...***...] license to the inventions and discoveries embodied in U.S. Patent Nos.: 4,545,987; 4,693,981; 4,727,027; 4,748,120; 4,791,062; and 5,106,619 Related Patents and Patent Applications, and the Foreign Patents and Patent Applications (identified in Exhibit G) in the field of [...***...];



WHEREAS, MILES is willing to grant STERITECH such [...***...] in the field of [...***...], subject to rights reserved by the U.S. government, to U.S. Patent Nos.: 4,545,987; 4,693,981; 4,727,027; 4,748,120; 4,791,062; and 5,106,619; Related Patents and Patent Applications, and the Foreign Patents and Patent Applications (identified in Exhibit G);



WHEREAS, MILES is willing to grant STERITECH a license, subject to rights reserved by the U.S. government, to U.S. Serial No. 07/350,335, and its related foreign applications (identified in Exhibit H) which applications are jointly owned by DIAMOND and the Regents of the University of California at San Francisco.



NOW THEREFORE, the parties agree as follows:



1. DEFINITIONS



The following definitions will apply throughout this Agreement:



LICENSED PATENTS shall mean U.S. Patent Nos.: 4,545,987; 4,693,981; 4,727,027; 4,748,120; 4,791,062; and 5,106,619 as well as the Foreign Patents identified in Exhibits G and H;



RELATED PATENTS AND PATENT APPLICATIONS shall mean any continuation, reissue, reexamination, continuation-in-part, extension or divisional application of a Licensed Patent and/or any letters patent that issue thereon;



FOREIGN PATENT APPLICATIONS shall mean the foreign patent applications identified in Exhibits G and H or that may be filed in the future as foreign counterparts of the Licensed Patents and/or any letters patent that issue thereon;



LICENSED PRODUCT shall mean any product for use in the field of [...***...] that is covered by a claim of a Licensed Patent in the country in which it is sold and/or any product utilizing a process covered by a claim of a Licensed Patent in the country in which it is used; and



AFFILIATES OF STERITECH shall mean all organizations that are at least 50% owned or controlled by STERITECH or any organization owning at least 50% of or controlling STERITECH or subsidiaries of such organizations owning at least 50% of or controlling STERITECH.





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NET SALES shall mean the gross revenues received by STERITECH and its Affiliates from the sale of Licensed Products less sales, use and/or value added taxes actually paid, import and/or export duties, tariffs and other excise taxes actually paid, transportation prepaid or allowed, and amounts allowed or credited due to returns, rebates, discounts and the like (not to exceed the original billing or invoice amount). For cases in which the Licensed Product is a product covered by a claim of a Licensed Patent, Net Sales shall be computed on the revenues received by STERITECH and its Affiliates from sales of such product. For cases in which the process covered by the claim of a Licensed Patent is used (e.g., [...***...]), Net Sales shall be computed on the revenues received by STERITECH and its Affiliates from the sales of the materials that perform such process. Where such materials are sold as components of a system (e.g., [...***...]) the royalty base on which Net Sales will be computed shall be the [...***...] that permit performance of the licensed process, rather than [...***...].



2. GRANT



MILES and DIAMOND hereby grant to STERITECH, and its Affiliates, a [...***...] license in the field of [...***...], including [...***...], subject to rights reserved by the U.S. government, under the Licensed Patents, Related Patents and Patent Applications, and Foreign Patent Applications, for [...***...], with the right to make, have made, use, and sell products covered by a claim thereunder and practice any process covered by a claim thereunder, including the right to sub-license others to make, have made, use, or sell any such product or practice any such process.



This license is [...***...] with respect to U.S. Serial No. 07/350,335 only with respect to MILES' rights under this application, which application is jointly owned by DIAMOND and The Regents of the University of California at San Francisco.



3. CONSIDERATION AND ROYALTIES



3.1 PAYMENTS MADE IN CONSIDERATION OF THE EXECUTION OF THE LICENSE AGREEMENT. As consideration for the licenses granted herein, STERITECH will pay a non-refundable license fee, upon execution of this Agreement, of $[...***...].



3.2 ADVANCED ROYALTIES TO BE PAID DURING LICENSE. In addition to the fee specified in Paragraph 3.1, STERITECH will pay a non-refundable milestone payment of $[...***...] upon [...***...] for the [...***...] Licensed Product and a non-refundable milestone payment of $[...***...] upon [...***...] for the [...***...] Licensed Product. These milestone payments will be credited against royalties.



3.3 ROYALTY. STERITECH will pay MILES a royalty equal to [...***...] of Licensed Products. Only [...***...] shall be paid under this Agreement for each Licensed Product sold regardless of [...***...] of Licensed Patents that are applicable thereto. No royalty shall be payable on [...***...] is purchasing the Licensed Product for use in its own commercial activities,





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excluding use solely for [...***...]. Royalties shall otherwise be payable on the [...***...] of STERITECH.



3.4 CESSATION OF OBLIGATION TO PAY ROYALTY. STERITECH's obligation to pay a royalty for a Licensed Product which is made, used or sold in any given country shall cease:



(a) if every one of the claims directed to Licensed Product which would be infringed but for the license granted herein and all of the claims directed to the process(es) of making and using that Licensed Product which would be infringed but for the license granted herein are held invalid and unenforceable by a court of competent jurisdiction in a final, unappealable decision; or



(b) upon expiration of the last to expire of the Licensed Patents; or



(c) if no claim of any Licensed Patent covers Licensed Product in the country where the product is sold and no claim of any Licensed Patent covers Licensed Product in the country in which Licensed Product is produced or used.





3.5 MINIMUM ROYALTIES. STERITECH shall pay the following minimum royalties, inclusive of royalties payable under Section 3.3:



AMOUNT YEAR

$[...***...] [...***...]



$[...***...] [...***...]



$[...***...] [...***...]



$[...***...] [...***...]





The first year to which minimum royalty requirement shall apply shall be the earlier of [...***...] or the [...***...] for the first Licensed Product. Each twelve months period thereafter shall constitute a year for the purpose of calculating minimum royalties. In the event minimum royalties are not paid as provided above for any year, MILES may, by notice to STERITECH given within [...***...] of the end of the respective year:



(a) terminate this License Agreement, if STERITECH is not then exercising reasonable good faith efforts to develop and/or market Licensed Products, or



(b) [...***...].



4. PAYMENT





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4.1 ACCOUNTS. STERITECH shall keep a complete and correct account of the number of Licensed Products sold in sufficient detail to determine the amounts due to MILES. STERITECH shall keep such account for at least three years after making the royalty payment.



STERITECH's records shall be available upon written request for inspection at reasonable times during regular business hours by an independent certified public accountant selected by MILES to whom STERITECH has no reasonable objection for the purpose of verifying royalty statements and payments made by STERITECH under this Agreement. This accountant shall not disclose to MILES any information other than the quantities and payments required to be reported hereunder. MILES shall hold all such information in confidence.



4.2 PAYMENT. Within [...***...] after the end of each of STERITECH's operating quarters, STERITECH shall send MILES a written statement, setting forth all sales of Licensed Product and a computation of royalties on these sales to MILES in accordance with this Agreement. Such statements shall be accompanied by payment of the total amount of royalty due. To the extent no royalty is due because of credits for previous milestone payments, this shall be reported by STERITECH.



5. LITIGATION



5.1 NOTIFICATION. MILES agrees to notify STERITECH in writing if the validity, infringement, or priority of invention of any of the Licensed Patents is put in issue by any person not a party hereto.



5.2 INFRINGEMENT. MILES agrees to use all reasonable measures to enforce the Licensed Patents against infringers. Upon learning of infringement of a Licensed Patent, STERITECH shall promptly notify MILES of the infringement and provide MILES with such notice concerning such infringement. MILES shall have [...***...] from the date of STERITECH's notice to abate the infringement or to file suit against the infringer.



5.3 LAWSUITS. If MILES brings suit against an infringer of a Licensed Patent, it shall give notice of such suit to STERITECH and STERITECH shall have [...***...] in which to elect to join MILES in the prosecution of the suit. If STERITECH so elects, MILES and STERITECH shall share equally in the expenses, costs, attorneys fees, and proceeds of such suit for past infringement. If STERITECH elects not to join MILES, MILES shall be responsible for all expenses and shall take all proceeds for past infringement. If STERITECH elects not to join with MILES, MILES shall keep STERITECH reasonably informed of the status of any such litigation.



5.4 FAILURE TO SUE. If MILES fails to bring suit [...***...] after notice by STERITECH as specified by Section 5.2 above, STERITECH may elect to file suit on its own. STERITECH's obligation to continue paying royalties hereunder shall not be affected by the bringing of such suit. Proceeds from the litigation, if any, shall be divided between MILES and Steritech in proportion to their contribution to the cost of litigation.





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5.5 SETTLEMENT. For as long as this [...***...], MILES shall not have the power to accept any settlement that includes a license for future activities in that country without STERITECH's written consent, which consent shall not be unreasonably withheld.



5.6 INFRINGEMENT OF THIRD PARTY RIGHTS. In the event of any infringement or likely infringement by any of the licensed subject matter of any third party's intellectual property (collectively, "Infringing Rights"), MILES and STERITECH shall cooperate in good faith and on a mutual and reasonable basis, with each party responsible for its respective expenses:



(a) To negotiate and settle any dispute with any such third party concerning the Infringing Rights, and otherwise resolve any such infringement and secure STERITECH's continued rights to the Infringing Rights; and



(b) To make a reasonable and equitable adjustment, if any, to the royalties paid or otherwise due under this Agreement in respect of licenses or other rights obtained by STERITECH from third parties under such Infringing Rights in order for STERITECH to continue to exercise rights granted under this Agreement.



6. MISCELLANEOUS



6.1 NOTICE. Until such time as either party shall give notice to the other party of a change of address, reports, notices, and other communications to MILES shall be addressed to:



Divisional Controller

MILES INC.

Animal Health Products

12707 West 63rd

Shawnee Mission, KS 66216



and notices and other communications to STERITECH shall be addressed as follows:



STERITECH, INC.

2341 Stanwell Drive

Concord, California 94520

Attention: President



6.2 GOVERNING LAW. This Agreement shall be interpreted under the laws of California.



6.3 TERMINATION.



(a) MILES may terminate this License Agreement for noncompliance by STERITECH of any material provision by giving notice of its intention to do so [...***...]





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before termination. If STERITECH shall, within the [...***...] notice period correct the noncompliance, the notice shall have no further effect and the Agreement shall continue.



(b) STERITECH may terminate this License Agreement by giving notice of its intention to do so [...***...] before termination.



6.4 SOLE AGREEMENT. This Agreement constitutes the entire understanding between the parties and neither party shall be obligated by any condition or representation other than those expressly stated herein or as may be subsequently agreed to by the parties hereto in writing.



6.4 HEADINGS. The headings and subheading of the various Articles and Sections of this Agreement are inserted merely for the purpose of convenience and do not express or imply any limitation, definition, or extension of the specific terms of the Articles and Sections so designated.



6.6 WARRANTIES.



(a) MILES represents and warrants that it is the owner of DIAMOND which is the owner of the entire right, title and interest in and to the Licensed Patents, Related Patents and Patent Applications, and Foreign Patent Applications with the exception of U.S. Serial No. 07/350,335 and its corresponding Foreign Patent Applications which are jointly owned by DIAMOND and The Regents of the University of California at San Francisco and has the right to grant the licenses given hereunder.



(b) MILES warrants and represents that there are no known outstanding claims or licenses or other encumbrances upon Licensed Patents, Related Patents and Patent Applications, and Foreign Patent Applications with the exception of the limited rights reserved by the U.S. government and the joint ownership of U.S. Serial No. 07/350,335 and that MILES is not now in the possession of any information which would, in MILES' opinion, render any of the claims of any of the Licensed Patents invalid and/or unenforceable.



6.7 PATENT RELATED EXPENSES. MILES will pay all annuities, taxes, and other expenses due and owing to maintain any Licensed Patent, Related Patent and Patent Application, and Foreign Patent Application in full force and in effect for any year (i.e., calendar year or twelve-month period, as the case may be) in which royalties, license fees and milestone payments owed or paid by STERITECH equal or exceed such annuities, taxes and expenses. In the event STERITECH pays royalties, license fees and milestone payments less than the total annuities, taxes and expenses due in a given year, MILES shall advise STERITECH and provide STERITECH with the option to pay the excess expense so as to maintain the Licensed Patent, Related Patent or Patent Application, or Foreign Patent Application.





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6.8 FOREIGN PATENT PROSECUTION. In the event that STERITECH and MILES shall agree, each acting reasonably and in good faith, that it is desirable to obtain foreign patent protection of the licensed subject matter beyond the Foreign Patents and Foreign Patent Applications identified herein, MILES shall prepare, file and prosecute foreign applications with respect thereto. Expenses of obtaining and maintaining such patent protection shall be allocated as provided in Section 6.7. In the event MILES does not agree with STERITECH concerning the desirability of obtaining such protection, MILES shall execute such documents as shall permit STERITECH to undertake such preparation, filing and prosecution, in which case STERITECH shall bear the expenses thereof, but shall be entitled to credit such expenses against royalties payable hereunder.



6.9 LICENSE GRANTED BACK TO MILES. At any time during the term of this Agreement, MILES has the right to obtain a non-exclusive license under any Licensed Patent under reasonable conditions. It is expressly agreed that any license granted by STERITECH to MILES under this paragraph shall be limited to only those rights reasonable necessary for [...***...] thereof including but not limited to [...***...].















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IN WITNESS WHEREOF, the parties heretofore have affixed their authorized signatures as of the date given.





ATTEST: MILES, INC.



By: /s/ Thomas W. Roy By: /s/ Mark Yogman

--------------------------------- -------------------------------------

Title: Vice President,

Strategic Planning

Date: November 19, 1992





ATTEST: DIAMOND SCIENTIFIC CORPORATION



By: /s/ Kathryn L. Johns By: /s/ Spencer J. Nunley

--------------------------------- -------------------------------------

Title: Secretary

Date: November 20, 1992





ATTEST: STERITECH, INC.



By: /s/ D. Hall By: /s/ Stephen T. Isaacs

--------------------------------- -------------------------------------

Title: Chief Executive Officer

Date: November 30, 1992













EXHIBIT A



United States Patent [19] [11] Patent Number: 4,545,987 Giles et al. [45] Date on Patent: Oct. 8, 1985 - --------------------------------------------------------------------------------



[54] PSORALEN INACTIVATED DOUBLE-STRANDED RNA VIRAL VACCINES



[75] Inventors: Richard E. Giles, Alameda; David R. Stevens, Fremont; Gary P.

Wiesehahn, Alameda, all of Calif.



[73] Assignee: Advanced Genetics Research Institute, Oakland, Calif.



[21] Appl. No.: 563,939



[22] Filed: Dec. 20, 1983



[51] Int. CL4. . . . . . . . . . . . . . . . . A61K 39/12



[52] U.S. CL . . . . . . . . . . . . . . . . . 424/89; 435/235; 435/238



[58] Field of Search . . . . . . . . . . . . . 435/235, 238; 424/89



[56] References Cited





Theiler, Vet. J., (1980), 64:600-607. Kemeny and Drehle, Am. J. Vet. Res. (1961), 22:921-925. Alexander and Haig, Onderstepoort J. Vet. Res., (1951), 25:3-15. Parker et al., Vet. Rec., (1975), 96:284-287. Isaacs et al., Biochemistry, (1977), 16:1058-1064. Hearst and Thiry, Nucleic Acids Res., (1977), 4:1339-1347. Hanson et al., J. Gen. Virol., (1978), 40:345-358. Talib and Banerjee, Virology, (1982), 118:430-438. Hanson, Medical Virology II, Proceedings of the 1982 International Symposium on Medical Virology, de la Maza and Peterson, eds., New York: Elsevier Biomedical, 1983, pp. 45-75. J. Parker et al., (1975), Vet. Rec. 96:284-287. J. L. Stott, et al., (1979), Proc. Annu. Meet US Anim Health Assoc., 177:55-62. B. I. Osburn et al., and J. L. Stott et al., (1979), Fed. Proc. 38 (3 part 1) 1091 Coden: FEPRA.



Primary Examiner -- Shep K. Rose Attorney, Agent or Firm -- Townsend & Townsend



[57] ABSTRACT



Novel vaccines of double-stranded RNA viruses are prepared by psoralen inactivation under mild conditions in an inert atmosphere, optionally in the presence of a mild singlet oxygen scavenger. The resulting inactivated virus can be used as a vaccine for inoculation of hosts to provide for the stimulation of the immune system to the virus.



11 Claims, No Drawings



4,545,987





PSORALEN INACTIVATED DOUBLE-STRANDED RNA VIRAL VACCINES



BACKGROUND OF THE INVENTION



1. Field of the Invention



The disease Bluetongue is a systemic viral infection of ruminants, such as sheep and cattle. The Bluetongue virus (BTV) is transmitted by small biting flies and is known to occur in twenty serotypic variants that do not provide cross-protection immunologically.



The Bluetongue virus is the prototype orbivirus and is composed of ten double-stranded RNA genomic segments. Bluetongue virions have an inner capsid of five polypeptides and a diffuse non-enveloped outer layer containing two polypeptides. It is found that variable amino acid sequences in P2, the major surface polypeptide, are responsible for immunologic serotype specificity. A core protein, P7, is detected by the complement fixation assay and determines cross-reacting group specificity.



In the United States, the primary serotypes observed are 11 and 17, with serotypes 2, 10 and 13 being observed less frequently.



The first vaccine for BTV was an attenuated live virus vaccine, which has been utilized over forty years in South Africa. Other modified live virus Bluetongue vaccines have also been reported. These attenuated live virus vaccines induce teratogenic lesions in fetuses and may also result in the emergence of recombinant virus strains. There is, therefore, need for an effective vaccine against Bluetongue, which provides protection to an inoculated mammalian host, without the hazards observed with attenuated live Bluetongue virus.



2. Description of the Prior Art



Theiler, Vet. J. (1908) 64:600-607 describes an attenuated live Bluetongue virus vaccine. Kemeny and Drehle, Am. J. Vet. Res. (1961) 22:921-925 describe a tissue culture-propagated BTV for vaccine preparation. Alexander and Haig, Onderstepoort J. Vet. Res. (1951) 25:3-15 describe the use of attenuated BTV in the production of a polyvalent vaccine for sheep. Parker et al, Vet. Rec. (1975) 96:284-287 describe an inactivated vaccine against Bluetongue.



Isaacs et al, Biochemistry (1977) 16:1058-1064, describe the synthesis of several psoralen derivatives and their photoreactivity with double-stranded RNA. Hearst and Thiry, Nucleic Acids Research (1977) 4:1339-1347; Hanson et al, J. Gen. Virol. (1978) 40:345-358; and Talib and Banerjee, Virology (1982) 118:430-438, describe the photoreactivity of various psoralen derivatives with animal viruses. Hanson, in Medical Virology II, Proceedings of the 1982 International Symposium on Medical Virology, de la Maza and Peterson, eds., New York: Elsevier Biomedical, 1983, pp. 45-75, has cited unpublished data on the inactivation of Bluetongue virus utilizing psoralen photochemistry.





SUMMARY OF THE INVENTION





Vaccines are provided for inoculation against Bluetongue virus, which inactivated vaccines are prepared by irradiating the virus suspension with light in the presence of psoralen in an inert atmosphere for a time sufficient to completely inactivate the virus. The resulting inactivated virus suspension may then be stored for subsequent use.









DESCRIPTION OF THE SPECIFIC EMBODIMENTS





Vaccines are provided for inoculation of ruminants against Bluetongue. The vaccines are prepared by inactivation of one or more serotypes of Bluetongue virus (BTV), a multisegmented double-stranded RNA orbivirus. The BTV is inactivated by combining a suspension of the BTV in an appropriate medium with a sufficient amount of a psoralen to provide for complete inactivation of BTV upon irradiation with long wavelength ult ...