Claims for Patent: 10,294,474

Summary for Patent: 10,294,474

Title:	Targeting ligands
Abstract:	Described are novel targeting ligands that may be linked to compounds, such therapeutic compounds that are useful in directing the compounds to the in vivo target. The targeting ligands disclosed herein can serve to target expression-inhibiting oligomeric compounds, such as RNAi agents, to liver cells to modulate gene expression. The targeting ligands disclosed herein, when conjugated to a therapeutic compound, may be used in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Compositions including the targeting ligands disclosed herein when linked to expression-inhibiting oligomeric compounds are capable of mediating expression of target nucleic acid sequences in liver cells, such as hepatocytes, which may be useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.
Inventor(s):	Zhen Li, Tao Pei, Agnieszka Glebocka, Michael Lawler, Fred Fleitz, Erich Altenhofer, Pankaj Kumar
Assignee:	Arrowhead Pharmaceuticals Inc
Application Number:	US15/452,324
Patent Claims:	1. A targeting ligand comprising a structure selected from the group consisting of: wherein the targeting ligand is linked to an RNAi agent. 2. The targeting ligand of claim 1, wherein the RNAi agent is double-stranded. 3. The targeting ligand of claim 2, wherein the RNAi agent includes one or more modified nucleotides. 4. The targeting ligand of claim 1, wherein the structure is selected from the group consisting of: 5. The targeting ligand of claim 2, wherein the double-stranded RNAi agent is linked to the targeting ligand at the 5′ terminal end of the sense strand of the RNAi agent. 6. The targeting ligand of claim 5, wherein the RNAi agent is linked to the linker of the targeting ligand via a phosphate group, phosphorothioate group, or a phosphonate group. 7. A composition comprising a targeting ligand linked to an expression-inhibiting oligomeric compound, wherein the structure of the targeting ligand and expression-inhibiting oligomeric compound is represented by the structure selected from the group consisting of: wherein R in each structure comprises the expression-inhibiting oligomeric compound, wherein the expression-inhibiting oligomeric compound comprises an RNAi agent, and wherein the targeting ligand is linked to the RNAi agent via a phosphate group, phosphorothioate group, or a phosphonate group. 8. The composition of claim 7, wherein the RNAi agent is a double-stranded RNAi agent. 9. The composition of claim 8, wherein the targeting ligand is linked to the 5′ terminal end of the sense strand of the RNAi agent. 10. A compound having the structure selected from the group consisting of: 11. A targeting ligand comprising a structure selected from the group consisting of: wherein the targeting ligand is linked to an RNAi agent. 12. The targeting ligand of claim 11, wherein the targeting ligand linked to the RNAi agent has the following structure: wherein R comprises the RNAi agent (Structure 1027a). 13. The targeting ligand of claim 11, wherein the RNAi agent is double stranded. 14. The targeting ligand of claim 13, wherein the RNAi agent includes one or more modified nucleotides. 15. A method of inhibiting expression of a target nucleic acid in a subject, the method comprising administering to the subject a therapeutic amount of the targeting ligand of claim 1. 16. A method of inhibiting expression of a target nucleic acid in a subject, the method comprising administering to the subject a therapeutic amount of the targeting ligand of claim 11. 17. A method of introducing a therapeutic agent into a mammalian cell, the method comprising contacting a mammalian cell with the targeting ligand of claim 1, wherein the therapeutic agent comprises the RNAi agent. 18. The method of claim 17, wherein the cell is present in a subject. 19. The method of claim 18, wherein the subject is a human. 20. The method of claim 19, wherein the therapeutic agent is a double-stranded RNAi agent. 21. A method of introducing a therapeutic agent into a mammalian cell, the method comprising contacting a mammalian cell with the targeting ligand of claim 11, wherein the therapeutic agent comprises the RNAi agent. 22. The method of claim 21, wherein the cell is present in a subject. 23. The method of claim 22, wherein the subject is a human. 24. The method of claim 23, wherein the therapeutic agent is a double-stranded RNAi agent. 25. A method of treating a disease or disorder that would benefit from administration of a therapeutic compound, the method comprising administering a therapeutic amount of the targeting ligand of claim 1 to a subject in need of treatment thereof. 26. A method of treating a disease or disorder that would benefit from administration of a therapeutic compound, the method comprising administering a therapeutic amount of the targeting ligand of claim 11 to a subject in need of treatment thereof. 27. A method of treating a disease or disorder that would benefit from administration of a therapeutic compound, the method comprising administering a therapeutic amount of the composition of claim 7 to a subject in need of treatment thereof. 28. A method of manufacturing a phosphoramidite compound including a compound of claim 10, the method comprising: (i) covalently linking the carboxylic acid moiety, or its activated ester, of the linker to a terminal amine located on the branch point group, and (ii) linking the linker to a phosphorus atom of a phosphoramidite through a phosphitylation reaction with a phosphoramidite forming reagent; thereby forming a phosphoramidite compound that includes a targeting ligand. 29. The method of claim 28, wherein the phosphoramidite reagent is selected from the group consisting of: 30. The targeting ligand of claim 2, comprising Structure 1003. 31. The targeting ligand of claim 2, comprising Structure 1008. 32. The targeting ligand of claim 2, comprising Structure 1023. 33. The targeting ligand of claim 5, comprising Structure 1003. 34. The targeting ligand of claim 5, comprising Structure 1008. 35. The targeting ligand of claim 5, comprising Structure 1023. 36. The targeting ligand of claim 6, comprising Structure 1003. 37. The targeting ligand of claim 6, comprising Structure 1008. 38. The targeting ligand of claim 6, comprising Structure 1023. 39. The composition of claim 7, comprising Structure 1003a. 40. The composition of claim 7, comprising Structure 1008a. 41. The composition of claim 7, comprising Structure 1023a. 42. The composition of claim 8, comprising Structure 1003a. 43. The composition of claim 8, comprising Structure 1008a. 44. The composition of claim 8, comprising Structure 1023a. 45. The composition of claim 9, comprising Structure 1003a. 46. The composition of claim 9, comprising Structure 1008a. 47. The composition of claim 9, comprising Structure 1023a. 48. The compound of claim 10, comprising Structure 1003b. 49. The compound of claim 10, comprising Structure 1008b. 50. The compound of claim 10, comprising Structure 1023b.