Claims for Patent: 6,042,822

Summary for Patent: 6,042,822

Title:	Interferon polymer conjugates
Abstract:	Compositions containing alpha interferon conjugated to a substantially non-antigenic polymer are disclosed in which at least about 30% of the conjugates include covalent attachment of the alpha interferon to the substantially non-antigenic polymer at a histidine. Also disclosed is a process for preparing the conjugates. The process includes contacting an alpha interferon with a succinimidyl carbonate-activated substantially non-antigenic polymer at a pH which is sufficient to facilitate covalent attachment of the polymer on a histidine of the alpha interferon.
Inventor(s):	Gilbert; Carl W. (Powder Springs, GA), Park-Cho; Myung-ok (Seoul, KR)
Assignee:	Enzon, Inc. (Piscataway, NJ)
Application Number:	09/287,476
Patent Claims:	1. A pharmaceutical composition, comprising a mixture of alpha-interferon-conjugate positional isomers, wherein one of said positional isomers comprises an alpha-interferon covalently conjugated to a substantially non-antigenic alkyl terminated polyalkylene oxide at a histidine residue on said alpha interferon, so that said alpha interferon conjugates have a T.sub.max at least about 4 times greater than unmodified alpha-interferon measured under the same conditions. 2. The pharmaceutical composition of claim 1, wherein said alpha interferon conjugates have a T.sub.max at least about 8 times greater than unmodified alpha-interferon measured under the same conditions. 3. A pharmaceutical composition, comprising a mixture of alpha-interferon-conjugate positional isomers, wherein one of said positional isomers comprises an alpha-interferon covalently conjugated to a substantially non-antigenic alkyl terminated polyalkylene oxide at a histidine residue on said alpha interferon, so that said alpha interferon conjugates have an AUC at least about 10 times that of unmodified alpha-interferon measured under the same conditions. 4. The pharmaceutical composition of claim 1, wherein said polyalkylene oxide is polyethylene glycol. 5. The pharmaceutical composition of claim 1, wherein said alpha interferon conjugates have at least about 10% of the activity of unmodified alpha-interferon measured under the same conditions when said pharmaceutical composition is administered subcutaneously in a mammal. 6. The pharmaceutical composition of claim 3, wherein said alpha interferon conjugates have at least about 10% of the activity of unmodified alpha-interferon measured under the same conditions when said pharmaceutical composition is administered subcutaneously in a mammal. 7. The pharmaceutical composition of claim 1, wherein said alpha interferon conjugates have at least about 10% of the activity of unmodified alpha-interferon measured under the same conditions, and a T.sub.1/2, of about 5 hours alpha phase when said conjugate is administered subcutaneously in a mammal. 8. The pharmaceutical composition of claim 3, wherein said alpha-interferon-conjugates have at least about 10% of the activity of unmodified alpha-interferon measured under the same conditions, and a T.sub.1/2, of about 5 hours alpha phase when said pharmaceutical composition is administered subcutaneously in a mammal. 9. The pharmaceutical composition of claim 1, wherein said alpha interferon is interferon alpha 2b. 10. The pharmaceutical composition of claim 9, wherein said histidine residue is His34. 11. The pharmaceutical composition of claim 1, wherein said mixture of said alpha interferon conjugate positional isomers comprises at least about 3 positional isomers. 12. The pharmaceutical composition of claim 1 wherein said mixture of said alpha interferon positional isomers comprises at least about 6 positional isomers. 13. The pharmaceutical composition of claim 1, wherein said mixture of said alpha interferon conjugate positional isomers comprises at least about 8 positional isomers. 14. The pharmaceutical composition of claim 13, wherein said alpha interferon is alpha interferon 2b and said mixture of alpha interferon conjugate positional isomers comprises said polyalkylene oxide linked to said alpha interferon 2b, at an amino acid residue selected from the group consisting of Cys1, Lys31 His34, Lys49, Lys83, Lys121, Lys131, and Lys134. 15. The pharmaceutical composition of claim 4, wherein said polyalkylene oxide is a monomethoxy-polyethylene glycol, (mPEG). 16. The alpha-interferon-conjugate of claim 1 wherein said polyalkylene oxide is terminated with a C.sub.1-4 alkyl. 17. The pharmaceutical composition of claim 1, wherein said polyalkylene oxide has a molecular weight of from about 200 to about 35,000. 18. A pharmaceutical composition, comprising a mixture of alpha interferon polymer conjugate positional isomers, wherein one of said positional isomers comprises an alpha interferon covalently conjugated to a substantially non-antigenic polymer at a histidine residue on said alpha interferon, wherein said substantially non-antigenic polymer is selected from the group consisting of polypropylene glycol, dextran, polyvinyl pyrrolidones, polyacryl amides, polyvinyl alcohols and carbohydrate-based polymers, so that said interferon conjugates have a T.sub.max at least about 4 times greater than unmodified alpha-interferon measured under the same conditions. 19. An alpha interferon-containing composition, comprising a plurality of alpha interferon polymer conjugates, wherein at least about 15% of the conjugates include covalent attachment of a substantially non-antigenic alkyl terminated polyalkylene oxide at a histidine of said alpha interferon, so that said interferon conjugates have a T.sub.max at least about 4 times greater than unmodified alpha-interferon measured under the same conditions. 20. The alpha interferon-containing composition of claim 19, wherein the alpha interferon portion of said alpha interferon-containing composition is alpha interferon 2b and said histidine is His34. 21. The alpha interferon-containing composition of claim 19, wherein at least about 30% of said conjugates include covalent attachment of said alkyl terminated polyalkylene oxide at histidine-34 of said alpha interferon. 22. A pharmaceutical composition comprising a mixture of alpha interferon 2b-polymer positional isomers, wherein from about 30 to about 60% of the positional isomers include a substantially non-antigenic alkyl terminated polyalkylene oxide conjugated to the His34 of said alpha interferon, from about 7 to about 20% of the positional isomers include a substantially non-antigenic alkyl terminated polyalkylene oxide conjugated to the Cys1 of said alpha interferon and about 7 to about 15% of the positional isomers include a substantially non-antigenic alkyl terminated polyalkylene oxide conjugated to the Lys121 of said alpha interferon, so that said interferon conjugates have a T.sub.max at least about 4 times greater than unmodified alpha-interferon measured under the same conditions.

Details for Patent 6,042,822

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Llc	PEGINTRON	peginterferon alfa-2b	Injection	103949	January 19, 2001		2013-11-10
Merck Sharp & Dohme Llc	SYLATRON	peginterferon alfa-2b	For Injection	103949	March 29, 2011		2013-11-10

International Patent Family for US Patent 6,042,822

Country	Patent Number	Estimated Expiration
South Africa	9811590
South Africa	969557
World Intellectual Property Organization (WIPO)	9932139
World Intellectual Property Organization (WIPO)	9718832