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Generated: August 23, 2019

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Claims for Patent: 9,701,963

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Summary for Patent: 9,701,963
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:15/151,568
Patent Claims:1. A method of inhibiting complement component C5 expression in a cell, the method comprising: contacting the cell with a double stranded ribonucleic acid (dsRNA) agent that inhibits expression of a complement component C5 gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region 15-30 nucleotide pairs in length, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 769-821 of SEQ ID NO:1; and contacting the cell with an anti-complement component C5 antibody, or antigen-binding fragment thereof, thereby inhibiting expression of the complement component C5 gene in the cell.

2. The method of claim 1, wherein the cell is within a subject.

3. The method of claim 2, wherein the subject is a human.

4. The method of claim 3, wherein the human subject has a disease or disorder that would benefit from reduction in complement component C5 expression.

5. The method of claim 4, wherein the disorder is a complement component C5-associated disease.

6. The method of claim 4, wherein the dsRNA agent is administered to the subject before the anti-complement component C5 antibody, or antigen-binding fragment thereof, is administered to the subject.

7. The method of claim 6, wherein the dsRNA agent is administered to the subject first for a period of time sufficient to reduce the levels of complement component C5 in the subject.

8. The method of claim 1, wherein the antibody is eculizumab.

9. The method of claim 8, wherein the complement component C5 expression is decreased for an extended duration.

10. The method of claim 5, wherein the complement component C5-associated disease is selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); neuromyelitis optica (NMO); multiple sclerosis (MS); myasthenia gravis; and membranous nephropathy.

11. The method of claim 10, wherein the complement component C5-associated disease is paroxysmal nocturnal hemoglobinuria (PNH).

12. The method of claim 10, wherein the complement component C5-associated disease is atypical hemolytic uremic syndrome (aHUS).

13. The method of claim 2, wherein C5 levels in a tissue or a fluid of the subject are reduced by at least 10%.

14. The method of claim 1, wherein the dsRNA agent comprises at least one modified nucleotide.

15. The method of claim 1, wherein at least one strand of the dsRNA agent comprises a 3' overhang of at least 1 nucleotide.

16. The method of claim 1, wherein the dsRNA agent further comprises a ligand.

17. The method of claim 1, wherein the dsRNA agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

18. The method of claim 1, wherein the antisense strand comprises a region of complementarity which comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO:113), and wherein the dsRNA agent comprises at least one modified nucleotide.

19. The method 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).

20. The method of claim 19, 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.

21. 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 a double stranded ribonucleic acid (dsRNA) agent that inhibits expression of a complement component C5 gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region 15-30 nucleotide pairs in length, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 769-821 of SEQ ID NO:1; and administering to the subject a therapeutically effective amount of an anti-complement component C5 antibody, or antigen-binding fragment thereof, thereby treating the subject.

22. The method of claim 21, wherein the antibody is eculizumab.

23. 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 a double stranded ribonucleic acid (dsRNA) agent that inhibits expression of a complement component C5 gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region 15-30 nucleotide pairs in length, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 769-821 of SEQ ID NO:1; and administering to the subject a prophylactically effective amount of an anti-complement component C5 antibody, or antigen-binding fragment thereof, thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in C5 expression.

24. The method of claim 1, wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 780-802 of SEQ ID NO:1.

25. A method of inhibiting complement component C5 expression in a cell, the method comprising: contacting the cell with a double stranded ribonucleic acid (dsRNA) agent that inhibits expression of a complement component C5 gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region 15-30 nucleotide pairs in length, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 780-802 of SEQ ID NO:1; and contacting the cell with an anti-complement component C5 antibody, or antigen-binding fragment thereof, thereby inhibiting expression of the complement component C5 gene in the cell.

26. The method of claim 25, wherein the cell is within a human subject.

27. The method of claim 26, wherein the antisense strand comprises a region of complementarity which comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO:113), and wherein the dsRNA agent comprises at least one modified nucleotide.

28. The method of claim 22, wherein the effective amount of eculizumab to treat the subject is reduced as compared to the effective amount of eculizumab required to treat the subject in the absence of administration of the effective amount of the dsRNA agent.

29. The method of claim 28, wherein eculizumab is administered to the subject at a dose of less than about 600 mg.

30. The method of claim 29, wherein the dsRNA agent is administered to the subject at a dose of about 0.5 mg/kg to about 50 mg/kg.

31. The method of claim 28, wherein eculizumab is administered to the subject at a dose of about 100-500 mg.

32. The method of claim 31, wherein the dsRNA agent is administered to the subject at a dose of about 0.5 mg/kg to about 50 mg/kg.

Details for Patent 9,701,963

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Alexion Pharm SOLIRIS eculizumab INJECTABLE; IV (INFUSION) 125166 001 2007-03-16   Try a Free Trial Alnylam Pharmaceuticals, Inc. (Cambridge, MA) 2033-03-14 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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International Patent Family for US Patent 9,701,963

Country Patent Number Publication Date
World Intellectual Property Organization (WIPO) 2014160129 Dec 04, 2014
World Intellectual Property Organization (WIPO) 2014160129 Oct 02, 2014
Uruguay 35442 Oct 31, 2014
United States of America 2015247143 Sep 03, 2015
United States of America 2016108401 Apr 21, 2016
United States of America 2016244763 Aug 25, 2016
United States of America 2017268005 Sep 21, 2017
>Country >Patent Number >Publication Date

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