Oligomer-conjugate complexes and their use

• US 10,023,861 B2
• Filed: 08/29/2012
• Issued: 07/17/2018
• Est. Priority Date: 08/29/2011
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Prakash, Thazha P., Swayze, Eric E., Lima, Walter F., Kinberger, Garth A.
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US14/342,196
• Publication Number:
  US 20150018540A1
• Time in Patent Office: 2,148 Days
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/51 modulating the chemical stability, e.g. nuclease-resistance

Abstract

Oligonucleotides, chemically-modified oligonucleotides, and oligonucleotide-conjugate complexes for use in research, diagnostics, and/or therapeutics are described herein. In some embodiments, oligonucleotides comprising a stabilized phosphate moiety covalently attached to the 5′-terminal nucleoside are provided.

Claims

1. A compound comprising an oligonucleotide consisting of 10-30 linked nucleosides and at least one conjugate group, wherein the 5′

-terminal nucleoside of the oligonucleotide has Formula IV;

2. The compound of claim 1, wherein the conjugate group is covalently attached to the oligonucleotide at a nucleoside at position 1, 2, 3, 4, 6, 7, 8, 9, 18, 19, 20, or 21 from the 5′

-end of the oligonucleotide or at position 1, 2, 3, 12, 13, 4, 15, 17, 18, 19, 20, or 21 from the 3′

-end of the oligonucleotide.

3. The compound of claim 2, wherein the conjugate group is covalently attached to any of the 1 to 4 5′

-most terminal nucleosides of the oligonucleotide.

4. The compound of claim 2, wherein the conjugate group is covalently attached to the 5′

-terminal nucleoside of the oligonucleotide.

5. The compound of claim 2, wherein the conjugate group is covalently attached to the 8^th nucleoside from the 5′

-terminal end of the oligonucleotide.

6. The compound of claim 2, wherein the conjugate group is covalently attached to the 6^th nucleoside from the 5′

-terminal end of the oligonucleotide.

7. The compound of claim 2, wherein the conjugate group comprises C₂₀ alkyl.

8. The compound of claim 2, wherein the conjugate group comprises C₁₆ alkyl.

9. The compound of claim 2, wherein the conjugate group comprises C₁₀ alkyl.

10. The compound of claim 2, wherein the conjugate group comprises a steroid.

11. The compound of claim 2, wherein the conjugate group comprises cholesterol.

12. The compound of claim 2, wherein the conjugate group comprises a carbohydrate.

13. The compound of claim 2, wherein the conjugate group comprises N-acetylgalactosamine.

14. The compound of claim 2, wherein each nucleoside is a modified nucleoside.

15. The compound of claim 2, comprising at least one 2′

-substituted nucleoside.

16. The compound of claim 2, wherein the compound is single-stranded.

17. The compound of claim 2, wherein each of the 6 to 9 3′

-most terminal internucleoside linkages is a phosphorothioate linkage and each of the other internucleoside linkages is a phosphodiester linkage.

18. The compound of claim 2, wherein each of the 6 to 9 3′

-most terminal internucleoside linkages is a phosphorothioate linkage and each of the other internucleoside linkages is a phosphodiester or a phosphorothioate linkage.

19. The compound of claim 2, wherein the conjugate group comprises C₁₀ to C₂₂ alkyl.

20. The compound of claim 2, wherein the conjugate group comprises C₁₀ to C₂₂ alkenyl.

21. The compound of claim 2, wherein the conjugate group comprises C₂₂ alkyl.