Claims for Patent: 9,127,274

Summary for Patent: 9,127,274

Title:	Serpinc1 iRNA compositions and methods of use thereof
Abstract:	The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the Serpinc1 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of Serpinc1 and methods of treating subjects having a bleeding disorder, such as a hemophilia.
Inventor(s):	Akin Akinc, Alfica Sehgal, Ivanka Toudjarska, Donald Foster, Stuart Milstein, Brian Bettencourt, Martin A. Maier, Klaus Charisse, Satyanarayana KUCHIMANCHI, Kallanthottathil G. Rajeev, Muthiah Monaharan
Assignee:	Genzyme Corp
Application Number:	US13/837,129
Patent Claims:	1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of Serpinc1, wherein said dsRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence of 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:941) and the antisense strand comprises the nucleotide sequence of 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:960), wherein a, g, c and u are 2′-O-methyl(2′-OMe) A, U, C, or G; Af, Cf, Gf or Uf are 2′-fluoro A, G, C or U; and s is a phosphorothioate linkage. 2. The dsRNA of claim 1, further comprising a ligand. 3. The dsRNA of claim 2, wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA. 4. The dsRNA of claim 2, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 5. The dsRNA of claim 4, wherein the ligand is 6. The dsRNA of claim 4, wherein the dsRNA is conjugated to the ligand as shown in the following schematic and, wherein X is O or S. 7. The dsRNA of claim 6, wherein the X is O. 8. A cell containing the dsRNA of claim 1. 9. A pharmaceutical composition for inhibiting expression of a Serpinc1 gene comprising the dsRNA of claim 1. 10. A method of inhibiting Serpinc1 expression in a cell, the method comprising: (a) contacting the cell with the dsRNA of claim 1; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a Serpinc1 gene, thereby inhibiting expression of the Serpinc1 gene in the cell. 11. The method of claim 10, wherein said cell is within a subject. 12. The method of claim 11, wherein the subject is a human. 13. The method of claim 12, wherein the human subject suffers from a bleeding disorder. 14. The method of claim 13, wherein the bleeding disorder is a hemophilia. 15. The method of any one of claims 10-14, wherein the Serpinc1 expression is inhibited by at least about 30%. 16. A method of treating a subject having a disorder that would benefit from reduction in Serpinc1 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA of claim 1, thereby treating said subject. 17. A method of preventing at least one symptom in a subject having a disorder that would benefit from reduction in Serpinc1 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA of claim 1, thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in Serpinc1 expression. 18. The method of claim 16, wherein the disorder is a bleeding disorder. 19. The method of claim 18, wherein the bleeding disorder is a hemophilia. 20. The method of claim 16, wherein the administration of the dsRNA to the subject causes an increase in blood clotting and/or a decrease in Serpinc1 protein accumulation. 21. The method of claim 16, wherein the dsRNA is conjugated to a ligand. 22. The method of claim 21, wherein the ligand is conjugated to the 3′-end of the sense strand of the dsRNA. 23. The method of claim 22, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 24. The method of claim 17, wherein the dsRNA is administered at a dose of about 0.01 mg/kg to about 50 mg/kg. 25. The method of claim 24, wherein the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg. 26. The method of claim 24, wherein the dsRNA is administered at a dose selected from the group consisting of 0.3 mg/kg 0.5 mg/kg 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg. 27. The method of claim 25 or 26, wherein the dsRNA is administered to the subject once a week. 28. The method of claim 25 or 26, wherein the dsRNA is administered to the subject twice a month. 29. The method of claim 16, further comprising measuring thrombin levels in said subject. 30. The method of claim 17, wherein the dsRNA is administered to the subject subcutaneously at a cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg. 31. A method of inhibiting the expression of Serpinc1 in a subject, the method comprising administering to said subject a therapeutically effective amount of the dsRNA of claim 1, thereby inhibiting the expression of Serpinc1 in said subject. 32. The method of claim 31, wherein the dsRNA is conjugated to a ligand. 33. The method of claim 32, wherein the ligand is conjugated to the 3′-end of the sense strand of the dsRNA. 34. The method of claim 33, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 35. The method of claim 31, wherein the dsRNA is administered at a dose of about 0.01 mg/kg to about 50 mg/kg. 36. The method of claim 35, wherein the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg. 37. The method of claim 35, wherein the dsRNA is administered at a dose selected from the group consisting of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg. 38. The method of claim 37, wherein the dsRNA is administered to the subject once a week. 39. The method of claim 37, wherein the dsRNA is administered to the subject twice a month. 40. The method of claim 31, wherein the dsRNA is administered to the subject subcutaneously at a cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg. 41. The method of claim 31, further comprising measuring thrombin levels in said subject. 42. The method of claim 21, wherein the ligand is 43. The method of claim 21, wherein the dsRNA is conjugated to the ligand as shown in the following schematic and, wherein X is O or S. 44. The dsRNA of claim 43, wherein the X is O. 45. The method of claim 16, wherein the dsRNA is administered at a dose of about 0.01 mg/kg to about 50 mg/kg. 46. The method of claim 45, wherein the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg. 47. The method of claim 45, wherein the dsRNA is administered at a dose selected from the group consisting of 0.3 mg/kg 0.5 mg/kg 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg. 48. The method of claim 46 or 47, wherein the dsRNA is administered to the subject once a week. 49. The method of claim 46 or 47, wherein the dsRNA is administered to the subject twice a month. 50. The method of claim 17, wherein the disorder is a bleeding disorder. 51. The method of claim 50, wherein the bleeding disorder is a hemophilia. 52. The method of claim 17, wherein the administration of the dsRNA to the subject causes an increase in blood clotting and/or a decrease in Serpinc1 protein accumulation. 53. The method of claim 17, wherein the dsRNA is conjugated to a ligand. 54. The method of claim 53, wherein the ligand is conjugated to the 3′-end of the sense strand of the dsRNA. 55. The method of claim 54, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 56. The method of claim 55, wherein the ligand is 57. The method of claim 55, wherein the dsRNA is conjugated to the ligand as shown in the following schematic and, wherein X is O or S. 58. The method of claim 57, wherein the X is O. 59. The method of claim 17, further comprising measuring thrombin levels in said subject. 60. The method of claim 34, wherein the ligand is 61. The method of claim 34, wherein the dsRNA is conjugated to the ligand as shown in the following schematic and, wherein X is O or S. 62. The method of claim 61, wherein the X is O.