Claims for Patent: 9,850,488

Summary for Patent: 9,850,488

Title:	Complement component C5 iRNA compositions and methods of use thereof
Abstract:	The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the complement component C5 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of C5 and to treat subjects having a complement component C5-associated disease, e.g., paroxysmal nocturnal hemoglobinuria.
Inventor(s):	Fitzgerald; Kevin (Brookline, MA), Butler; James (Lynnfield, MA), Bettencourt; Brian (Groton, MA), Borodovsky; Anna (Melrose, MA), Kuchimanchi; Satyanarayana (Acton, MA), Charisse; Klaus (Acton, MA), Manoharan; Muthiah (Weston, MA), Maier; Martin (Belmont, MA), Rajeev; Kallanthottathil G. (Wayland, MA), Foster; Donald (Attleboro, MA)
Assignee:	Alnylam Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	14/976,261
Patent Claims:	1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein said antisense strand comprises a region of complementarity which comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 780-802 of SEQ ID NO:1, wherein each strand is independently about 15-30 nucleotides in length, wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand are modified nucleotides, and wherein said sense strand is conjugated to a ligand attached at the 3'-terminus. 2. The dsRNA agent of claim 1, wherein at least one strand comprises a 3' overhang of at least 1 nucleotide. 3. A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of complement component C5 in a cell, wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein said antisense strand comprises a region of complementarity which comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 780-802 of SEQ ID NO:1, wherein each strand is independently about 14 to about 30 nucleotides in length, wherein said dsRNA agent is represented by formula (III): TABLE-US-00047 (III) sense: 5' n.sub.p-N.sub.a-(X X X).sub.i-N.sub.b-Y Y Y-N.sub.b-(Z Z Z).sub.j-N.sub.a-n.sub.q 3' antisense: 3' n.sub.p'-N.sub.a'-(X'X'X').sub.k-N.sub.b'-Y'Y'Y'-N.sub.b'-(Z'Z'Z').sub.- l-N.sub.a'- n.sub.q' 5' wherein: i, j, k, and l are each independently 0 or 1; p, p', q, and q' are each independently 0-6; each N.sub.a and N.sub.a' independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are modified, each sequence comprising at least two differently modified nucleotides; each N.sub.b and N.sub.b' independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are modified; each n.sub.p, n.sub.p', n.sub.q, and n.sub.q', each of which may or may not be present, independently represents an overhang nucleotide; XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent one motif of three identical modifications on three consecutive nucleotides; modifications on N.sub.b differ from the modification on Y and modifications on N.sub.b' differ from the modification on Y'; and wherein the sense strand is conjugated to at least one ligand. 4. The dsRNA agent of claim 1, wherein the modifications on the nucleotides are 2'-O-methyl or 2'-fluoro modifications. 5. The dsRNA agent of claim 1 or 3, wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 6. The dsRNA agent of claim 1, wherein said agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage. 7. A cell containing the dsRNA agent of claim 1 or 3. 8. A pharmaceutical composition for inhibiting expression of a complement component C5 gene comprising the dsRNA agent of claim 1. 9. A pharmaceutical composition for inhibiting expression of a complement component C5 gene comprising the dsRNA agent of claim 3. 10. A method of inhibiting complement component C5 expression in a cell, the method comprising: (a) contacting the cell with the dsRNA agent of claim 1 or 3 or a pharmaceutical composition of claim 8 or 9; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a complement component C5 gene, thereby inhibiting expression of the complement component C5 gene in the cell. 11. The method of claim 9, wherein said cell is within a subject. 12. The method of claim 10, wherein the subject is a human. 13. A method of treating a subject having a disease or disorder that would benefit from reduction in complement component C5 expression, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 or 3 or a pharmaceutical composition of claim 8 or 9, thereby treating said subject. 14. A method of preventing at least one symptom in a subject having a disease or disorder that would benefit from reduction in complement component C5 expression, the method comprising administering to the subject a prophylactically effective amount of the dsRNA agent of claim 1 or 3 or a pharmaceutical composition of claim 8 or 9, thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in C5 expression. 15. The method of claim 12, wherein the disorder is a complement component C5-associated disease. 16. The method of claim 14 wherein the disorder is a complement component C5-associated disease. 17. The dsRNA agent of claim 1 or 3, wherein the region of complementarity is between 19 and 25 nucleotides in length. 18. The dsRNA agent of claim 1, wherein all the nucleotides of said sense strand and all of the nucleotides of said antisense strand are modified nucleotides. 19. The dsRNA agent of claim 1, wherein the modifications on the nucleotides are independently selected from the group consisting of a 3'-terminal deoxy-thymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2'-aminot-modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a nucleotide comprising a 5'-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group. 20. The dsRNA agent of claim 1, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 21. The dsRNA agent of claim 20, wherein the ligand is ##STR00021## 22. The dsRNA agent of claim 21, wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic ##STR00022## and, wherein X is O or S. 23. The dsRNA agent of claim 22, wherein the X is O. 24. The dsRNA agent of claim 1, wherein the region of complementarity comprises the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO:113). 25. The dsRNA agent of claim 1, wherein the agent comprises a sense strand comprising the nucleotide sequence of 5'-AAGCAAGAUAUUUUUAUAAUA-3' (SEQ ID NO:62), and an antisense strand comprising the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO:113). 26. The dsRNA agent of claim 25, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO:2876) and the antisense strand comprises 5'- usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2889), wherein a, g, c and u are 2'-O-methyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage. 27. The dsRNA agent of claim 3, wherein i is 0; j is 0; i is 1; j is 1; both i and j are 0; or both i and j are 1. 28. The dsRNA agent of claim 3, wherein k is 0; l is 0; k is 1; l is 1; both k and l are 0; or both k and l are 1. 29. The dsRNA agent of claim 3, wherein the YYY motif occurs at or near the cleavage site of the sense strand. 30. The dsRNA agent of claim 3, wherein the Y'Y'Y' motif occurs at the 11, 12 and 13 positions of the antisense strand from the 5'-end. 31. The dsRNA agent of claim 3, wherein the double stranded region is 17-15 nucleotide pairs in length. 32. The dsRNA agent of claim 3, wherein the double stranded region is 21-23 nucleotide pairs in length. 33. The dsRNA agent of claim 3, wherein the modifications on the nucleotide are selected from the group consisting of a locked nucleic acid (LNA) LAN, HNA, CeNA, 2'-methoxyethyl, 2'O-alkyl, 2'O-allyl, 2'-C-allyl, 2'-fluoro, 2'-deoxy, 2'-hydroxyl, and combinations thereof. 34. The dsRNA agent of claim 3, wherein the modifications on the nucleotide are 2'-O-methyl or 2'-fluoro modifications. 35. The dsRNA agent of claim 3, wherein said dsRNA agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage. 36. The dsRNA agent of claim 35, wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3'-terminus of one strand. 37. The dsRNA agent of claim 36, wherein said strand is the antisense strand. 38. The dsRNA agent of claim 36, wherein said strand is the sense strand. 39. The dsRNA agent of claim 35, wherein the phosphorothioate or methylphosphonate internucleotde linkage is at the 5'-terminus of one strand. 40. The dsRNA agent of claim 39, wherein said strand is the antisense strand. 41. The dsRNA agent of claim 39, wherein said strand is the sense strand. 42. The dsRNA agent of claim 35, wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the both the 5'- and 3'-terminus of one strand. 43. The dsRNA agent of claim 42, wherein said strand is the antisense strand. 44. The dsRNA agent of claim 3, wherein the Y nucleotides contain a 2'-fluoro modification. 45. The dsRNA agent of claim 3, wherein the Y' nucleotides contain a 2'-O-methyl modification. 46. The dsRNA agent of claim 3, wherein p'>0; or p'=2. 47. The dsRNA agent of claim 46, wherein q'=0, p=0, q=0, and p' overhang nucleotides are complementary to the target mRNA. 48. The dsRNA agent of claim 46, wherein q'=0, p=0, q=0, and p' overhang nucleotides are non-complementary to the target mRNA. 49. The dsRNA agent of claim 3, wherein the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides. 50. The dsRNA agent of claim 3, wherein at least one np' is linked to a neighboring nucleotide via a phosphorothioate linkage. 51. The dsRNA agent of claim 3, wherein all np' are linked to neighboring nucleotides via phosphorothioate linkages. 52. The dsRNA agent of claim 3, wherein the region of complementarity comprises the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO:113). 53. The dsRNA agent of claim 3, wherein said dsRNA comprises a sense strand comprising the nucleotide sequence of 5'-AAGCAAGAUAUUUUUAUAAUA-3' (SEQ ID NO:62), and an antisense strand comprising the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO:113). 54. The dsRNA agent of claim 53, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO:2876) and the antisense strand comprises 5'- usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2889), wherein a, g, c and u are 2'-O-methyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothiate linkage. 55. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, wherein said dsRNA agent comprises a sense strand and an antisense strand each independently 15-30 nucleotides in length forming a double stranded region, the antisense strand comprising a region of complementarity comprising at least 17 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 780-802 of SEQ ID NO:1, wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand are modified nucleotides and the modifications are independently selected from the group consisting of a 2'-O-methyl modification and a 2'-fluoro modification, wherein said sense strand comprises two phosphorothioate internucleotide linkage at the 5'-terminus, and the antisense strand comprises two phosphorothioate internucleotide linkages at the 5'-terminus and two phosphorothioate internucleotide linkages at the 3'-terminus, and wherein said sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3'-terminus. 56. The dsRNA of claim 1, wherein the sense and antisense strands comprise the nucleotide sequences selected from the group consisting of 5'-AfaGfcAfaGfaUfAfUfuUfuUfaUfaAfuAf-3' (SEQ ID NO:122) and 5'- uAfuUfaUfaAfaAfauaUfcUfuGfcUfusUfsu-3' (SEQ ID NO:173); 5'-AfsasGfcAfaGfaUfAfUfuUfuUfaUfaAfuAf-3' (SEQ ID NO:164) and 5'-usAfsuUfaUfaAfaAfauaUfcUfuGfcUfususu-3' (SEQ ID NO:215); 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO:2875) and 5'-usAfsUfuAfuAfAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2888); 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 2876) and 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2889); 5'-asasGfcAfaGfaUfAfUfuUfuuAfuaAfua-3' (SEQ ID NO:2878) and 5'-usAfsUfuAfuAfAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2891); 5'-asasGfcAfaGfaUfAfUfuUfuuAfuaAfua-3' (SEQ ID NO:2879) and 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2892); 5'-asasgcaagaUfaUfuuuuauaaua-3' (SEQ ID NO:2884) and 5'-usAfsUfuAfuAfAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2897); and 5'-asasgcaagaUfaUfuuuuauaaua-3' (SEQ ID NO:2885) and 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO:2898), wherein a, g, c and u are 2'-O-methyl (2'OMe) A,G, C, and U, respectively; Af, Gg, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage. 57. The method of claim 10, further comprising contracting the cell with an anti-complement component C5 antibody, or antigen-binding fragment thereof. 58. The method of claim 13, further comprising administering to the subject an anti-complement component C5 antibody, or antigen-binding fragment thereof. 59. The method of claim 14, further comprising administering to the subject an anti-complement component C5 antibody, or antigen-binding fragment thereof. 60. The method of claim 57, wherein the anti-complement component C5 antibody, or antigen-binding fragment thereof, is eculizumab. 61. The method of claim 58, wherein the anti-complement component C5 antibody, or antigen-binding fragment thereof, is eculizumab. 62. The method of claim 59, wherein the anti-complement component C5 antibody, or antigen-binding fragment thereof, is eculizumab.

Details for Patent 9,850,488

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Alexion Pharmaceuticals, Inc.	SOLIRIS	eculizumab	Injection	125166	03/16/2007		2033-03-14