Claims for Patent: 9,370,581

Summary for Patent: 9,370,581

Title:	Carbohydrate conjugates as delivery agents for oligonucleotides
Abstract:	The present invention provides iRNA agents comprising at least one subunit of the formula (I): wherein: A and B are each independently for each occurrence O, N(RN) or S; X and Y are each independently for each occurrence H, OH, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, —P(Z′)(Z″)O-Linker-OP(Z′″)(Z″″)O-oligonucleotide, a nucleotide, an oligonucleotide, —P(Z′)(Z″)-formula (I), —P(Z′)(Z″)- or -Linker-R; R is LG, -Linker-LG, or has the structure shown below: LG is independently for each occurrence a carbohydrate, e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide; RN is independently for each occurrence H, methyl, ethyl, propyl, isopropyl, butyl, or benzyl; and Z′, Z″, Z′″ and Z″″ are each independently for each occurrence O or S.
Inventor(s):	Muthiah Manoharan, Kallanthottathil G. Rajeev, Jayaprakash Nair, Martin Maier
Assignee:	Alnylam Pharmaceuticals Inc
Application Number:	US14/329,540
Patent Claims:	1. A modified TTR-targeting oligonucleotide comprising a structure shown below: wherein LG is independently for each occurrence a ligand; and wherein the oligonucleotide targets the TTR gene. 2. A modified TTR-targeting oligonucleotide comprising a structure shown in formula (II)-(V): wherein: q2A, q2B, q3A, q3B, q4A, q4B, q5A, q5B and q5C for each represent independently occurrence 0-20 and wherein the repeating unit can be the same or different; p2A, p2B, p3A, p3B, p4A, p4B, p5A, p5B, p5C, T2A, T2B, T3A, T3B, T4A, T4B, T5A, T5B, and T5C are each independently for each occurrence absent, CO, NH, O, S, OC(O), NHC(O), CH2, CH2NH or CH2O; Q2A, Q2B, Q3A, Q3B, Q4A, Q4B, Q5A, Q5B, and Q5C are independently for each occurrence absent, alkylene, substituted alkylene wherein one or more methylenes can be interrupted or terminated by one or more of O, S, S(O), SO2, N(RN), C(R′)═C(R″), C≡C or C(O); R2A, R2B, R3A, R3B, R4A, R4B, R5A, R5B, and R5C are each independently for each occurrence absent, NH, O, S, CH2, C(O)O, C(O)NH, NHCH(Ra)C(O), —C(O)—CH(Ra)—NH—, CO, CH═N—O, or heterocyclyl; L2A, L2B, L3A, L3B, L4A, L5A, L5B and L5C are each independently for each occurrence a carbohydrate; R′ and R″ are each independently H, C1-C6 alkyl, OH, SH or N(RN)2; RN is independently for each occurrence methyl, ethyl, propyl, isopropyl, butyl or benzyl; and Ra is H or amino acid side chain, wherein the oligonucleotide targets the TTR gene. 3. The modified oligonucleotide of claim 1, wherein the modified oligonucleotide is double stranded. 4. The modified oligonucleotide of claim 3, wherein the structure is at the 3′-end of one of the strands. 5. The modified oligonucleotide of claim 4, wherein the structure is at the 3′-end of the sense strand. 6. The modified oligonucleotide RNA agent of claim 1, wherein the structure is 7. The modified oligonucleotide agent of claim 1, wherein the structure is 8. The modified oligonucleotide RNA agent of claim 1, wherein LG is carbohydrate. 9. The modified oligonucleotide of claim 8, wherein the carbohydrate is selected from the group consisting of monosaccharide, disaccharide, trisaccharide, tetrasaccharide and polysaccharide. 10. The modified oligonucleotide of claim 1, wherein LG is galactose or N-acetylgalactosamine. 11. The modified oligonucleotide of claim 1, wherein at least one of the nucleotide sugars of the modified oligonucleotide is modified at the 2′ position to replace 2′ hydroxyl. 12. The modified oligonucleotide of claim 11, wherein the 2′ hydroxyl is replaced with a moiety selected from the group consisting of 2′-H, 2′-methoxyethyl, 2′-OCH3, 2′-O-allyl, 2′-C-allyl, and 2′-fluoro. 13. The modified oligonucleotide of claim 1, wherein the oligonucleotide comprises 2′-deoxy, 2′-methoxyethyl, and a phosphorothioate linkage. 14. The modified oligonucleotide of claim 1, wherein the oligonucleotide comprises 2′-deoxy, LNA, and a phosphorothioate linkage. 15. The modified oligonucleotide of claim 1, wherein the modified oligonucleotide is single stranded. 16. The modified oligonucleotide of claim 15, wherein the modified oligonucleotide is a hairpin or antisense. 17. A method of modulating the expression of a target TTR gene in a cell, comprising providing to said cell the modified oligonucleotide of claim 1. 18. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 alone or in combination with a pharmaceutically acceptable carrier or excipient. 19. A modified TTR-targeting oligonucleotide comprising a structure of wherein the oligonucleotide targets the TTR gene. 20. A modified TTR-targeting oligonucleotide comprising a structure of wherein the oligonucleotide targets the TTR gene.