Claims for Patent: 5,801,154

Summary for Patent: 5,801,154

Title:	Antisense oligonucleotide modulation of multidrug resistance-associated protein
Abstract:	Compositions and methods are provided for the treatment and diagnosis of diseases or conditions amenable to treatment through modulation of the synthesis or metabolism of multidrug resistance-associated protein (MRP). In accordance with referred embodiments, oligonucleotides are provided which are specifically hybridizable with nucleic acids encoding MRP. In a preferred embodiment, the oligonucleotide has at least one 2\'-methoxyethoxy modification. Methods of preventing the development of multidrug resistance and of improving the efficacy of chemotherapy are also disclosed.
Inventor(s):	Baracchini; Edgardo (San Diego, CA), Bennett; C. Frank (Carlsbad, CA), Dean; Nicholas M. (Encinitas, CA)
Assignee:	Isis Pharmaceuticals, Inc. (Carlsbad, CA)
Application Number:	08/835,770
Patent Claims:	1. An oligonucleotide comprising 8 to 30 nucleotides specifically hybridizable with a nucleic acid encoding multidrug resistance-associated protein and capable of inhibiting the expression of multidrug resistance-associated protein. 2. The oligonucleotide of claim 1 which is specifically hybridizable with mRNA encoding multidrug resistance-associated protein. 3. The oligonucleotide of claim 1 which specifically hybridizes with DNA encoding multidrug resistance-associated protein to form a triple stranded structure. 4. The oligonucleotide of claim 2 specifically hybridizable with a transcription initiation site, a translation initiation site, 5'-untranslated sequence, 3' untranslated sequence, coding sequence or an intron/exon junction of an mRNA encoding multidrug resistance-associated protein. 5. A pharmaceutical composition comprising an oligonucleotide of claim 1 and a pharmaceutically acceptable carrier. 6. The oligonucleotide of claim 1 wherein at least one of the intersugar linkages between nucleotides of the oligonucleotide is a phosphorothioate linkage. 7. The oligonucleotide of claim 1 wherein at least one of the nucleotides is modified at the 2' position. 8. The oligonucleotide of claim 7 wherein the nucleotide modification is 2'-O-methyl, 2'-O-propyl, 2'-methoxyethoxy or 2'-fluoro. 9. The oligonucleotide of claim 8 which is a chimeric oligonucleotide. 10. The oligonucleotide of claim 9 which is a gapped oligonucleotide. 11. The oligonucleotide of claim 1 comprising SEQ ID NO: 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28. 12. An oligonucleotide comprising 8 to 30 nucleotides specifically hybridizable with a nucleic acid encoding multidrug resistance-associated protein and capable of inhibiting the expression of multidrug resistance-associated protein, wherein said oligonucleotide comprises at least one 2'-methoxyethoxy modification. 13. The oligonucleotide of claim 12 which is a chimeric oligonucleotide. 14. The oligonucleotide of claim 13 which is a gapped oligonucleotide. 15. An oligonucleotide of claim 12 specifically hybridizable with a transcription initiation site, a translation initiation site, 5'-untranslated sequence, 3' untranslated sequence, coding sequence or an intron/exon junction of an mRNA encoding multidrug resistance-associated protein. 16. A pharmaceutical composition comprising an oligonucleotide of claim 12 and a pharmaceutically acceptable carrier. 17. An oligonucleotide of claim 12 wherein at least one of the intersugar linkages between nucleotides of the oligonucleotide is a phosphorothioate linkage. 18. An oligonucleotide of claim 12 comprising SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28. 19. An oligonucleotide comprising SEQ ID NO: 8 and at least one 2' methoxyethoxy modification. 20. The oligonucleotide of claim 19 which is a chimeric oligonucleotide. 21. The oligonucleotide of claim 20 which is a gapped oligonucleotide. 22. A method of inhibiting the synthesis of multidrug resistance-associated protein in a cell or tissue comprising contacting a cell or tissue with an oligonucleotide comprising 8 to 30 nucleotides specifically hybridizable with a nucleic acid encoding multidrug resistance-associated protein and capable of modulating the expression of multidrug resistance-associated protein. 23. A method of inhibiting the synthesis of multidrug resistance-associated protein in a cell or tissue comprising contacting a cell or tissue with an oligonucleotide comprising an oligonucleotide comprising SEQ ID NO: 8 and at least one 2' methoxyethoxy modification. 24. The method of claim 23 wherein the oligonucleotide is a chimeric oligonucleotide. 25. The method of claim 23 wherein the oligonucleotide is a gapped oligonucleotide. 26. A method of treating an animal suspected of having a condition which is characterized by overexpression of multidrug resistance-associated protein comprising administering to said animal a therapeutically effective amount of an oligonucleotide having 8 to 30 nucleotides specifically hybridizable with a nucleic acid encoding multidrug resistance-associated protein and capable of inhibiting the expression of multidrug resistance-associated protein. 27. The method of claim 26 wherein the oligonucleotide is administered in conjunction with a chemotherapeutic drug treatment for cancer. 28. The method of claim 27 wherein the condition is a multidrug-resistant cancer. 29. The method of claim 27 wherein the multidrug-resistant cancer is small-cell lung cancer. 30. A method for improving the efficacy of a chemotherapeutic drug treatment of a disease, said method comprising administering in conjunction with a chemotherapeutic drug treatment an oligonucleotide comprising 8 to 30 nucleotides specifically hybridizable with a nucleic acid encoding multidrug resistance-associated protein and capable of inhibiting the expression of multidrug resistance-associated protein. 31. The method of claim 30 wherein the disease is cancer. 32. A method for preventing the development of multidrug resistance during a chemotherapeutic drug treatment of a disease, said method comprising administering in conjunction with a chemotherapeutic drug treatment an oligonucleotide comprising 8 to 30 nucleotides specifically hybridizable with a nucleic acid encoding multidrug resistance-associated protein and capable of inhibiting the expression of multidrug resistance-associated protein. 33. The method of claim 32 wherein the disease is cancer. 34. A method of treating an animal suspected of having a condition which is characterized by leukotriene production comprising administering to said animal a therapeutically effective amount of an oligonucleotide having 8 to 30 nucleotides specifically hybridizable with a nucleic acid encoding multidrug resistance-associated protein and capable of inhibiting the expression of multidrug resistance-associated protein. 35. The method of claim 34 wherein the condition is an inflammatory condition.

Details for Patent 5,801,154

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2013-10-18
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2013-10-18
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2013-10-18