IP Library › Granted Patent US 12,453,776
Granted Patent B2
US 12,453,776 · App. 18/736,363 · Granted Oct 28, 2025

Lipids and compositions for the delivery of therapeutics

Inventors: Muthiah Manoharan (Cambridge, MA); Muthusamy Jayaraman (Cambridge, MA); Kallanthottathil G. Rajeev (Cambridge, MA); Laxman Eltepu (Cambridge, MA); Steven Ansell (Cambridge, MA); Jianxin Chen (Cambridge, MA)
Assignee: ARBUTUS BIOPHARMA CORPORATION
A61K47/44A61K9/1272A61K31/7088A61K31/713A61K39/00A61K39/39A61K47/10A61K47/18A61K47/20A61K47/28C07C229/08C07C229/30C07C237/16C07C251/38C07C251/78C07C271/12C07C271/20C07C323/25C07D203/10C07D317/28C07D317/44C07D317/46C07D317/72C07D319/06C07D405/12C07D491/056C07D491/113C12N15/111C12N15/113A61K2039/55555A61K2039/55561C12N2310/14C12N2310/3515C12N2320/32Y02A50/30
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Quick Facts
Patent No.
US 12,453,776
App. No.
18/736,363
Granted
Oct 28, 2025
Kind
B2
Abstract

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure wherein: R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkyl, optionally substituted C 10 -C 30 alkenyl, optionally substituted C 10 -C 30 alkynyl, optionally substituted C 10 -C 30 acyl, or -linker-ligand; R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

Claims (52)

1. A cationic lipid having the structure

or a salt or isomer thereof,

wherein

E is C (O) O or OC (O);

R 1 and R 2 and R x are each independently for each occurrence H, optionally substituted C 1 -C 10 alkyl, or optionally substituted C 10 -C 30 acyl, provided that at least one of R 1 , R 2 and R x is not H;

R 3 is di(alkyl) aminoalkyl substituted with one or more halo, alkyl, alkenyl, alkylthio, alkoxy, alkoxycarbonyl, amino, alkylamino, and hydroxy, wherein alkoxy is optionally substituted with one or more alkyl and oxo; and

n is 0, 1, 2, or 3.

2. The cationic lipid of claim 1 , wherein at least two of R 1 , R 2 and R x are not H.

3. The cationic lipid of claim 2 , wherein R 1 and R 2 are each independently C 1 -C 10 alkyl and R x is H.

4. The cationic lipid of claim 3 , wherein n is 0.

5. A lipid particle comprising a cationic lipid of claim 1 , or a salt or isomer thereof.

6. The lipid particle of claim 5 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

7. The lipid particle of claim 5 , wherein the cationic lipid has a pKa of about 4 to about 7.

8. The lipid particle of claim 5 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

9. The lipid particle of claim 8 , wherein the neutral lipid is a phospholipid.

10. The lipid particle of claim 8 , wherein the lipid capable of reducing aggregation is a PEG-lipid.

11. The lipid particle of claim 10 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

12. The lipid particle of claim 8 , wherein the particle further comprises a sterol.

13. The lipid particle of claim 12 , wherein the sterol is cholesterol.

14. The lipid particle of claim 5 , further comprising a therapeutic agent.

15. The lipid particle of claim 14 , wherein the therapeutic agent is a nucleic acid.

16. The lipid particle of claim 15 , wherein the nucleic acid is selected from the group consisting of an siRNA and an antisense oligonucleotide.

17. The lipid particle of claim 15 , wherein the nucleic acid is an siRNA.

18. The lipid particle of claim 15 , wherein the nucleic acid is an mRNA.

19. The lipid particle of claim 12 , further comprising a therapeutic agent.

20. The lipid particle of claim 19 , wherein the therapeutic agent is a nucleic acid.

21. The lipid particle of claim 20 , wherein the nucleic acid is an mRNA.

22. A lipid particle comprising a cationic lipid of claim 4 , or a salt or isomer thereof.

23. The lipid particle of claim 22 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

24. The lipid particle of claim 22 , wherein the cationic lipid has a pKa of about 4 to about 7.

25. The lipid particle of claim 22 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

26. The lipid particle of claim 25 , wherein the neutral lipid is a phospholipid.

27. The lipid particle of claim 25 , wherein the lipid capable of reducing aggregation is a PEG-lipid.

28. The lipid particle of claim 27 , wherein the particle comprises about 40-60 mol % of the cationic lipid.

29. The lipid particle of claim 25 , wherein the particle further comprises a sterol.

30. The lipid particle of claim 29 , wherein the sterol is cholesterol.

31. The lipid particle of claim 22 , further comprising a therapeutic agent.

32. The lipid particle of claim 31 , wherein the therapeutic agent is a nucleic acid.

33. The lipid particle of claim 32 , wherein the nucleic acid is selected from the group consisting of an siRNA and an antisense oligonucleotide.

34. The lipid particle of claim 32 , wherein the nucleic acid is an siRNA.

35. The lipid particle of claim 32 , wherein the nucleic acid is an mRNA.

36. The lipid particle of claim 29 , further comprising a therapeutic agent.

37. The lipid particle of claim 36 , wherein the therapeutic agent is a nucleic acid.

38. The lipid particle of claim 37 , wherein the nucleic acid is an mRNA.

39. A pharmaceutical composition comprising a lipid particle of claim 14 and a pharmaceutically acceptable excipient, carrier, or diluent.

40. A pharmaceutical composition comprising a lipid particle of claim 21 and a pharmaceutically acceptable excipient, carrier, or diluent.

41. A pharmaceutical composition comprising a lipid particle of claim 31 and a pharmaceutically acceptable excipient, carrier, or diluent.

42. A pharmaceutical composition comprising a lipid particle of claim 38 and a pharmaceutically acceptable excipient, carrier, or diluent.

43. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 14 .

44. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 21 .

45. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 31 .

46. A method of modulating the expression of a target gene in a cell, comprising providing to the cell the lipid particle of claim 38 .

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 17, 2024
From: MANOHARAN, MUTHIAH; JAYARAMAN, MUTHUSAMY; RAJEEV, KALLANTHOTTATHIL G.; ELTEPU, LAXMAN; ANSELL, STEVEN; CHEN, JIANXIN
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 067749/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 17, 2024
From: ALNYLAM PHARMACEUTICALS, INC.
To: TEKMIRA PHARMACEUTICALS CORPORATION
Reel/Frame 067749/0173 →
CHANGE OF NAME Recorded Jun 17, 2024
From: TEKMIRA PHARMACEUTICALS CORPORATION
To: ARBUTUS BIOPHARMA CORPORATION
Reel/Frame 067749/0293 →
Continuity (12)
Continuation 18194540 · Mar 31, 2023
Continuation 17357122 · Jun 24, 2021
Continuation 15617520 · Jun 8, 2017
Continuation 14884489 · Oct 15, 2015
Continuation 13128283
Provisional Application 61234098 · Aug 14, 2009
Provisional Application 61225898 · Jul 15, 2009
Provisional Application 61185438 · Jun 9, 2009
Provisional Application 61171439 · Apr 21, 2009
Provisional Application 61154350 · Feb 20, 2009
Provisional Application 61113179 · Nov 10, 2008
Related Publication 20240424105A1 · Dec 26, 2024
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