Claims for Patent: 9,181,549

Summary for Patent: 9,181,549

Title:	Conjugated antisense compounds and their use
Abstract:	Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
Inventor(s):	Thazha P. Prakash, Punit P. Seth, Eric E. Swayze
Assignee:	Ionis Pharmaceuticals Inc
Application Number:	US14/586,751
Patent Claims:	1. A compound having the formula (XXVI): wherein: T2 is a group comprising a conjugate linker, a cleavable moiety, and an oligomeric compound. 2. The compound of claim 1, wherein the conjugate linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, ethylene glycol, a polyamide, or a disulfide bond. 3. The compound of claim 1, wherein the conjugate linker has the formula: 4. The compound of claim 1, wherein T2 has the formula: wherein: CM is the cleavable moiety and T3 comprises the oligomeric compound. 5. The compound of claim 4, wherein T2 has the formula: wherein: T3 is the oligomeric compound. 6. The compound of claim 5, wherein the oligomeric compound is a modified oligonucleotide. 7. The compound of claim 6, wherein the modified oligonucleotide consists of 15 to 24 linked nucleosides wherein at least one nucleoside is a modified nucleoside. 8. The compound of claim 6, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among: a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a (4′-CH2—O-2′) bicyclic nucleoside, a (4′-(CH2)2-O-2′) bicyclic nucleoside, a (4′-C(CH3)H—O-2′) bicyclic nucleoside; and a morpholino. 9. The compound of claim 8, wherein the modified oligonucleotide has a gapmer sugar motif comprising: a 5′-region consisting of 2-8 linked 5′-region nucleosides, wherein each 5′-region nucleoside is a modified nucleoside; a 3′-region consisting of 2-8 linked 3′-region nucleosides, wherein each 3′-region nucleoside is a modified nucleoside; and a central region between the 5′-region and the 3′-region consisting of 5-10 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside. 10. The compound of claim 9, wherein the modified oligonucleotide has a chemical motif selected from among: MsMy(Ds)0-1(DsDs)(3-5)MsM MsMy(Ds)0-1(DsDs)(3-5)MyMsM MsMy(Ds)0-1(DsDs)(3-5)MyMyMsM MsMy(Ds)0-1(DsDs)(3-5)MyMyMyMsM MsMyMy(Ds)0-1(DsDs)(3-5)MsM MsMyMy(Ds)0-1(DsDs)(3-5)MyMsM MsMyMy(Ds)0-1(DsDs)(3-5)MyMyMsM MsMyMy(Ds)0-1(DsDs)(3-5)MyMyMyMsM MsMyMyMy(Ds)0-1(DsDs)(3-5)MsM MsMyMyMy(Ds)0-1(DsDs)(3-5)MyMsM MsMyMyMy(Ds)0-1(DsDs)(3-5)MyMyMsM MsMyMyMy(Ds)0-1(DsDs)(3-5)MyMyMyMsM MsMyMyMyMy(Ds)0-1(DsDs)(3-5)MsM MsMyMyMyMy(Ds)0-1(DsDs)(3-5)MyMsM MsMyMyMyMy(Ds)0-1(DsDs)(3-5)MyMyMsM; and MsMyMyMyMy(Ds)0-1(DsDs)(3-5)MyMyMyMsM; wherein each M is independently a modified nucleoside, each D is a deoxynucleoside; each s is a phosphorothioate internucleoside linkage, and each y is independently either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage, provided that at least one y is a phosphodiester internucleotide linkage. 11. The compound of claim 9, wherein the 5′-region consists of 2-5 linked 5′-region nucleosides; the 3′-region consists of 2-5 linked 3′-region nucleosides; and the central region consists of 8-10 central region nucleosides. 12. The compound of claim 11, wherein each internucleoside linkage of the modified oligonucleotide is either a phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage. 13. The compound of claim 11, wherein the modified oligonucleotide is attached to the remainder of the compound at the 5′-end of the modified oligonucleotide. 14. The compound of claim 13, wherein the modified oligonucleotide is single-stranded. 15. The compound of claim 14, wherein the modified oligonucleotide is complementary to a target nucleic acid. 16. The compound of claim 15, wherein the target nucleic acid is selected from among: mRNA, pre-mRNA, micro-RNA, and long non-coding RNA. 17. A compound having the formula: wherein X is O or S; wherein Bx is a heterocyclic base moiety; and wherein T4 is a nucleoside, a monomeric subunit, or an oligomeric compound. 18. The compound of claim 17, wherein X is S. 19. The compound of claim 17, wherein T4 is an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide. 20. The compound of claim 19, wherein the modified oligonucleotide is a gapmer. 21. The compound of claim 20, wherein the modified oligonucleotide activates RNase H when bound to a complementary target nucleic acid. 22. The compound of claim 21, wherein the at least one modified nucleoside is a modified nucleoside selected from a 2′-F nucleoside, a 2′-OCH3 nucleoside, a 2′-O(CH2)2OCH3 nucleoside, a 2′-OC(CH3)H-4′ nucleoside, and a 2′-OCH2-4′ nucleoside. 23. The compound of claim 22, wherein the modified nucleoside is a 2′-O(CH2)2OCH3 nucleoside. 24. A compound having the formula: wherein X is O or S; wherein Bx is a heterocyclic base moiety; wherein T4 is a nucleoside, a monomeric subunit, or an oligomeric compound. 25. The compound of claim 24, wherein X is S. 26. The compound of claim 24, wherein T4 is an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide. 27. The compound of claim 26, wherein the modified oligonucleotide is a gapmer. 28. The compound of claim 27, wherein the modified oligonucleotide activates RNase H when bound to a complementary target nucleic acid. 29. The compound of claim 28, wherein the at least one modified nucleoside is a modified nucleoside selected from a 2′-F nucleoside, a 2′-OCH3 nucleoside, a 2′-O(CH2)2OCH3 nucleoside, a 2′-OC(CH3)H-4′ nucleoside, and a 2′-OCH2-4′ nucleoside. 30. The compound of claim 29, wherein the modified nucleoside is a 2′-O(CH2)2OCH3 nucleoside.