IP Library › Granted Patent US 12,221,607
Granted Patent B2
US 12,221,607 · App. 17/181,870 · Granted Feb 11, 2025

Multi-targeted single entity conjugates

Inventors: Vasant Jadhav (Cambridge, MA); Martin Maier (Cambridge, MA); Ivan Zlatev (Cambridge, MA); Akin Akinc (Cambridge, MA); Kallanthottathil G. Rajeev (Cambridge, MA); Jayaprakash K. Nair (Cambridge, MA); Pachamuthu Kandasamy (Cambridge, MA); Muthiah Manoharan (Cambridge, MA)
Assignee: ALNYLAM PHARMACEUTICALS, INC.
C12N15/113A61K47/549A61K47/55C07H21/00C12N15/111C12N2310/14C12N2310/20C12N2310/351C12N2310/3519C12N2310/51C12N2320/31
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Quick Facts
Patent No.
US 12,221,607
App. No.
17/181,870
Granted
Feb 11, 2025
Kind
B2
Abstract

The present invention relates, in general to, compounds, compositions and methods useful for modulating gene expression of multiple target nucleic acids by a single chemical entity.

Claims (26)

1. A multi-targeted molecule comprising a first double-stranded siRNA molecule and a second double-stranded siRNA molecule, wherein a sense or antisense strand of the first siRNA is covalently linked to a sense or antisense strand of the second siRNA via a linker, wherein at least one ligand is conjugated with the multi-targeted molecule, and wherein the linker comprises:

where n is 1 to 12; and m is 1 to 12.

2. The multi-targeted molecule of claim 1 , wherein the sense strand of the first siRNA molecule is covalently linked to the sense strand of the second siRNA molecule.

3. The multi-targeted molecule of claim 1 , wherein the sense strand of the first siRNA molecule is covalently linked to the antisense strand of the second siRNA molecule.

4. The multi-targeted molecule of claim 1 , wherein the antisense strand of the first siRNA molecule is covalently linked to the antisense strand of the second siRNA molecule.

5. The multi-targeted molecule of claim 1 wherein the first siRNA modulate gene expression of a first target nucleic acid and the second siRNA modulates gene expression of a second nucleic acid.

6. The multi-targeted molecule of claim 5 , wherein the first target nucleic acid and the second target nucleic acid are the same.

7. The multi-targeted molecule of claim 6 , wherein the first siRNA and the second siRNA target the same nucleic acid sequence.

8. The multi-targeted molecule of claim 1 , wherein the ligand is conjugated with one of the sense strands.

9. The multi-targeted molecule of claim 8 , wherein the ligand is conjugated at the 3′-end of one of the sense strands.

10. The multi-targeted molecule of claim 8 , wherein the ligand is conjugated at the 5′-end of one of the sense strands.

11. The multi-targeted molecule of claim 8 , wherein the ligand is conjugated at the 3′-end of one of the antisense strands.

12. The multi-targeted molecule of claim 8 , wherein the ligand is conjugated at the 5′-end of one of the antisense strands.

13. The multi-targeted molecule of claim 1 , wherein the first siRNA molecule and the second siRNA molecule are connected to each other via a nucleotide-based linker.

14. The multi-targeted molecule of claim 13 , wherein the linker is single-stranded.

15. The multi-targeted molecule of claim 13 , wherein the linker is double-stranded.

16. The multi-targeted molecule of claim 15 , wherein the double-stranded linker comprises a single-stranded region.

17. The multi-targeted molecule of claim 1 , wherein the first siRNA molecule and the second siRNA molecule are connected to each other via a non-nucleotide based linker.

18. The multi-targeted molecule of claim 13 , wherein the linker linking the two sense strands is a cleavable linker.

19. The multi-targeted molecule of claim 13 , wherein the ligand is conjugated to the linker.

20. The multi-targeted molecule of claim 1 , wherein the multi-targeted molecule comprises at least one modification selected from the group consisting of modified internucleoside linkage, modified nucleobase, modified sugar, and any combinations thereof.

21. The multi-targeted molecule of claim 20 , wherein said at least one modification is comprised in a sense strand, an antisense strand or the linker connecting said at least two siRNA molecules.

22. The multi-targeted molecule of claim 20 , wherein the linker comprises at least one nucleic acid modification is selected from the group consisting of locked nucleic acids, 2′-O-alkyl nucleosides, 2′-halo nucleosides, 2′-amino nucleosides, 2′-S-alkyl nucleosides, abasic nucleosides, 2′-cyano nucleosides, 2′-mercapto nucleosides; 2′-MOE nucleosides, acyclic nucleosides, S-cEt nucleosides, and any combinations thereof.

23. The multi-targeted molecule of claim 1 , wherein the linker comprises at least one modified internucleotide linkages selected from the group consisting of phosphodiesters, phosphotriesters, hydrogen phosphonates, alkyl or aryl phosphonates, phosphoramidates, phosphorothioates, methylenemethylimino, thiodiester, thionocarbamate, N,N′-dimethylhydrazine, phosphoroselenates, borano phosphates, borano phosphate esters, amides, hydroxylamino, siloxane, dialkylsiloxane, carboxamide, carbonate, carboxymethyl, carbamate, carboxylate ester, thioether, ethylene oxide linker, sulfide, sulfonate, sulfonamide, sulfonate ester, thioformacetal, formacetal, oxime, methyleneimino, methykenecarbonylamino, methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo, methyleneoxymethylimino, ethers, thioethers, thioacetamido, and any combinations thereof.

24. The multi-targeted molecule of claim 1 , wherein the linker comprises:

where n is 1 to 12; and m is 1 to 12.

Assignments (2)
SECURITY INTEREST Recorded Oct 1, 2025
From: ALNYLAM PHARMACEUTICALS, INC.; SIRNA THERAPEUTICS, INC.
To: BANK OF AMERICA, N.A.
Reel/Frame 072996/0337 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2024
From: JADHAV, VASANT; MAIER, MARTIN; ZLATEV, IVAN; AKINC, AKIN; RAJEEV, KALLANTHOTTATHIL G.; NAIR, JAYAPRAKASH K.; KANDASAMY, PACHAMUTHU; MANOHARAN, MUTHIAH
To: ALNYLAM PHARMACEUTICALS, INC
Reel/Frame 068951/0473 →
Continuity (3)
Division 15745591
Provisional Application 62194003 · Jul 17, 2015
Related Publication 20220106593A1 · Apr 7, 2022
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