IP Library › Granted Patent US 9,428,534
Granted Patent B2
US 9,428,534 · App. 13/797,913 · Granted Aug 30, 2016

Antisense design

Inventors: Signe M. Christensen (Copenhagen, DK); Nikolaj Dam Mikkelsen (Bronshoj, DK); Miriam Frieden (Copenhagen, DK); Henrik Frydenlund Hansen (Rodovre, DK); Troels Koch (Copenhagen S, DK); Daniel Sejer Pedersen (Valby, DK); Christoph Rosenbohm (Hoersholm, DK); Charlotte Albaek Thrue (Hoersholm, DK); Majken Westergaard (Birkerod, DK)
Assignee: Roche Innovation Center Copenhagen A/S
C07H19/16A61K31/7088C07H19/04C07H19/06C07H21/00C07H21/02C12N15/111C12N15/113C12N2310/11C12N2310/315C12N2310/3231C12N2310/341C12N2320/51
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Quick Facts
Patent No.
US 9,428,534
App. No.
13/797,913
Granted
Aug 30, 2016
Kind
B2
Abstract

A novel class of pharmaceuticals which comprises a Locked Nucleic Acid (LNA) which can be used in antisense therapy. These novel oligonucleotides have improved antisense properties. The novel oligonucleotides are composed of at least one LNA selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides.

Claims (116)

1. A gapmer oligomer having 10-15 nucleotide units wherein a segment of 8-10 DNA nucleotides is flanked by locked nucleotides, and wherein at least one or all of the internucleotide linkages is a phosphorothioate linkage.

2. The gapmer oligomer according to claim 1 , wherein the locked nucleotides have the formula

wherein

X represents O, S, or N—R;

R is selected from the group consisting of H and C 1 -C 6 alkyl, and C 1 -C 6 alkyl substituted with one or more substituents selected from the group consisting of halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy;

n is 1;

(CH 2 ) n is optionally substituted with methyl; and

Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

3. The gapmer oligomer of claim 1 wherein the flanks independently have 1-4 locked nucleotides.

4. The gapmer oligomer of claim 2 , wherein the flanks independently have 1-4 locked nucleotides.

5. The gapmer oligomer of claim 1 , wherein the flanks independently have 2-3 locked nucleotides.

6. The gapmer oligomer of claim 2 , wherein the flanks independently have 2-3 locked nucleotides.

7. The gapmer oligomer according to claim 3 , wherein the oligomer has 12-14 nucleotide units.

8. The gapmer oligomer according to claim 4 , wherein the oligomer has 12-14 nucleotide units.

9. The gapmer oligomer according to claim 5 , wherein the oligomer has 12-14 nucleotide units.

10. The gapmer oligomer according to claim 6 , wherein the oligomer has 12-14 nucleotide units.

11. The gapmer oligomer according to claim 1 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 1-4 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

12. The gapmer oligomer according to claim 1 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 2-3 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

13. The gapmer oligomer according to claim 11 , wherein the oligomer has 12-14 nucleotide units.

14. The gapmer oligomer according to claim 12 , wherein the oligomer has 12-14 nucleotide units.

15. The gapmer oligomer according to claim 14 , wherein the locked nucleotides have the formula

wherein

X represents O, S, or N—R;

R is selected from the group consisting of H and C 1 -C 6 alkyl, and C 1 -C 6 alkyl substituted with one or more substituents selected from the group consisting of halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy;

n is 1;

(CH 2 ) n is optionally substituted with methyl; and

Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

16. The gapmer oligomer of any of claims 1 wherein (CH 2 )n is substituted with methyl.

17. The gapmer oligomer of claim 2 wherein (CH 2 )n is substituted with methyl.

18. The gapmer oligomer of claim 3 wherein (CH 2 )n is substituted with methyl.

19. The gapmer oligomer of claim 4 wherein (CH 2 )n is substituted with methyl.

20. The gapmer oligomer of claim 5 wherein (CH 2 )n is substituted with methyl.

21. The gapmer oligomer of claim 6 wherein (CH 2 )n is substituted with methyl.

22. The gapmer oligomer of claim 7 wherein (CH 2 )n is substituted with methyl.

23. The gapmer oligomer of claim 8 wherein (CH 2 )n is substituted with methyl.

24. The gapmer oligomer of claim 9 wherein (CH 2 )n is substituted with methyl.

25. The gapmer oligomer of claim 10 wherein (CH 2 )n is substituted with methyl.

26. The gapmer oligomer of claim 11 wherein (CH 2 )n is substituted with methyl.

27. The gapmer oligomer of claim 12 wherein (CH 2 )n is substituted with methyl.

28. The gapmer oligomer of claim 13 wherein (CH 2 )n is substituted with methyl.

29. The gapmer oligomer of claim 14 wherein (CH 2 )n is substituted with methyl.

30. The gapmer oligomer of claim 15 wherein (CH 2 )n is substituted with methyl.

31. The gapmer oligomer of claim 1 wherein (CH 2 )n is unsubstituted.

32. The gapmer oligomer of claim 2 wherein (CH 2 )n is unsubstituted.

33. The gapmer oligomer of claim 3 wherein (CH 2 )n is unsubstituted.

34. The gapmer oligomer of claim 4 wherein (CH 2 )n is unsubstituted.

35. The gapmer oligomer of claim 5 wherein (CH 2 )n is unsubstituted.

36. The gapmer oligomer of claim 6 wherein (CH 2 )n is unsubstituted.

37. The gapmer oligomer of claim 7 wherein (CH 2 )n is unsubstituted.

38. The gapmer oligomer of claim 8 wherein (CH 2 )n is unsubstituted.

39. The gapmer oligomer of claim 9 wherein (CH 2 )n is unsubstituted.

40. The gapmer oligomer of claim 10 wherein (CH 2 )n is unsubstituted.

41. The gapmer oligomer of claim 11 wherein (CH 2 )n is unsubstituted.

42. The gapmer oligomer of claim 12 wherein (CH 2 )n is unsubstituted.

43. The gapmer oligomer of claim 13 wherein (CH 2 )n is unsubstituted.

44. The gapmer oligomer of claim 14 wherein (CH 2 )n is unsubstituted.

45. The gapmer oligomer of claim 15 wherein (CH 2 )n is unsubstituted.

46. The gapmer oligomer of claim 1 wherein the locked nucleotides have the formula:

wherein

X represents O;

n is 1;

(CH 2 )n is substituted with methyl; and

Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

47. The gapmer oligomer of claim 46 , wherein the flanks independently have 1-4 locked nucleotides.

48. The gapmer oligomer of claim 46 , wherein the flanks independently have 2-3 locked nucleotides.

49. The gapmer oligomer according to claim 46 , wherein the oligomer has 12-14 nucleotide units.

50. The gapmer oligomer according to claim 47 , wherein the oligomer has 12-14 nucleotide units.

51. The gapmer oligomer according to claim 48 , wherein the oligomer has 12-14 nucleotide units.

52. The gapmer oligomer according to claim 46 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 1-4 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

53. The gapmer oligomer according to claim 46 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 2-3 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

54. The gapmer oligomer of claim 1 wherein the locked nucleotides have the formula:

wherein

X represents O;

n is 1;

(CH 2 )n is not substituted; and

Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

55. The gapmer oligomer of claim 54 , wherein the flanks independently have 1-4 locked nucleotides.

56. The gapmer oligomer of claim 54 , wherein the flanks independently have 2-3 locked nucleotides.

57. The gapmer oligomer according to claim 54 , wherein the oligomer has 12-14 nucleotide units.

58. The gapmer oligomer according to claim 55 , wherein the oligomer has 12-14 nucleotide units.

59. The gapmer oligomer according to claim 56 , wherein the oligomer has 12-14 nucleotide units.

60. The gapmer oligomer according to claim 54 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 1-4 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

61. The gapmer oligomer according to claim 54 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 2-3 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

62. The gapmer oligomer of claim 1 wherein the locked nucleotides have the formula:

wherein

X represents O;

n is 1;

(CH 2 )n is substituted with methyl; and

Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

63. The gapmer oligomer of claim 62 , wherein the flanks independently have 1-4 locked nucleotides.

64. The gapmer oligomer of claim 62 , wherein the flanks independently have 2-3 locked nucleotides.

65. The gapmer oligomer according to claim 62 , wherein the oligomer has 12-14 nucleotide units.

66. The gapmer oligomer according to claim 63 , wherein the oligomer has 12-14 nucleotide units.

67. The gapmer oligomer according to claim 64 , wherein the oligomer has 12-14 nucleotide units.

68. The gapmer oligomer according to claim 62 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 1-4 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

69. The gapmer oligomer according to claim 62 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 2-3 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

70. The gapmer oligomer of claim 1 wherein the locked nucleotides have the formula:

wherein

X represents O;

n is 1;

(CH 2 )n is not substituted; and

Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

71. The gapmer oligomer of claim 70 , wherein the flanks independently have 1-4 locked nucleotides.

72. The gapmer oligomer of claim 70 , wherein the flanks independently have 2-3 locked nucleotides.

73. The gapmer oligomer according to claim 70 , wherein the oligomer has 12-14 nucleotide units.

74. The gapmer oligomer according to claim 71 , wherein the oligomer has 12-14 nucleotide units.

75. The gapmer oligomer according to claim 72 , wherein the oligomer has 12-14 nucleotide units.

76. The gapmer oligomer according to claim 70 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 1-4 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

77. The gapmer oligomer according to claim 70 , wherein the central region is 8-10 DNA nucleotides and the flanks are both independently 2-3 locked nucleotides, and wherein all of the internucleotide linkages is a phosphorothioate linkage.

78. The gapmer oligomer according to claim 13 , wherein the locked nucleotides have the formula

wherein

X represents O, S, or N—R;

R is selected from the group consisting of H and C 1 -C 6 alkyl, and C 1 -C 6 alkyl substituted with one or more substituents selected from the group consisting of halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy;

n is 1;

(CH 2 )n is optionally substituted with methyl; and

Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

Assignments (2)
CHANGE OF NAME Recorded May 22, 2015
From: SANTARIS PHARMA A/S
To: ROCHE INNOVATION CENTER COPENHAGEN A/S
Reel/Frame 035761/0266 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 5, 2014
From: CHRISTENSEN, SIGNE M.; MIKKELSEN, NIKOLAJ DAM; FRIEDEN, MIRIAM; HANSEN, HENRIK FRYDENLUND; KOCH, TROELS; PEDERSEN, DANIEL SEJER; ROSENBOHM, CHRISTOPH; THRUE, CHARLOTTE ALBAEK; WESTERGAARD, MAJKEN
To: SANTARIS PHARMA A/S
Reel/Frame 032358/0764 →
Priority Claims (3)
DK 2002 01774 · Nov 18, 2002 · national
DK 2003 01540 · Oct 20, 2003 · national
WO PCT/DK03/00788 · Nov 18, 2003 · international
Continuity (2)
Continuation 10535472 · Dec 19, 2005
Related Publication 20140296502A1 · Oct 2, 2014