Claims for Patent: 8,828,956

Summary for Patent: 8,828,956

Title:	Carbohydrate conjugates as delivery agents for oligonucleotides
Abstract:	The present invention provides iRNA agents comprising at least one subunit of the formula (I): ##STR00001## wherein: A and B are each independently for each occurrence O, N(R.sup.N) 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 L.sup.G, -Linker-L.sup.G, or has the structure shown below: ##STR00002## L.sup.G is independently for each occurrence a carbohydrate, e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide; R.sup.N 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):	Manoharan; Muthiah (Cambridge, MA), Rajeev; Kallanthottathil G. (Cambridge, MA), Jayaprakash; Narayanannair K. (Cambridge, MA), Maier; Martin (Cambridge, MA)
Assignee:	Alnylam Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	13/693,478
Patent Claims:	1. A modified RNA agent comprising a structure shown below: ##STR00124## wherein: L.sup.G is independently for each occurrence a ligand; and all of the nucleotide sugars of the modified RNA agent are modified. 2. A modified RNA agent comprising a structure shown in formula (II) -(V): ##STR00125## wherein: q.sup.2A, q.sup.2B, q.sup.3A, q.sup.3B, q.sup.4A, q.sup.4B, q.sup.5A, q.sup.5Band q.sup.5C represent independently for each occurrence 0-20 and wherein the repeating unit can be the same or different; P.sup.2A, P.sup.2B, P.sup.3A, P.sup.3B, P.sup.4A, P.sup.4B, P.sup.5A, P.sup.5B, P.sup.5C, T.sup.2A, T.sup.2B, T.sup.3A, T.sup.3B, T.sup.4A, T.sup.4B, T.sup.5A, T.sup.5B, and T.sup.5C are each independently for each occurrence absent, CO, NH, O, S, OC(O), NHC(O), CH.sub.2, CH.sub.2NH or CH.sub.2O; Q.sup.2A, Q.sup.2B, Q.sup.3A, Q.sup.3B, Q.sup.4A, Q.sup.4B, Q.sup.5A, Q.sup.5B, and Q.sup.5C are independently for each occurrence absent, alkylene, substituted alkylene wherin one or more methylenes can be interrupted or terminated by one or more of O, S, S(O), SO.sub.2, N(R.sup.N), C(R').dbd.C(R''), C.ident.C or C(O); R.sup.2A, R.sup.2B, R.sup.3A, R.sup.3B, R.sup.4A, R.sup.4B, R.sup.5A, R.sup.5B, and R.sup.5C are each independently for each occurrence absent, NH, O, S, CH.sub.2, C(O)O, C(O)NH, NHCH(R.sup.a)C(O), --C(O)--CH(R.sup.a)--NH--, CO, CH.dbd.N--O, ##STR00126## or heterocyclyl; L.sup.2A, L.sup.2B, L.sup.3A, L.sup.3B, L.sup.4A, L.sup.4B, L.sup.5A, L.sup.5B and L.sup.5C are each independently for each occurrence a carbohydrate; R' and R'' are each independently H, C.sub.1-C.sub.6 alkyl, OH, SH or N(R.sup.N).sub.2; R.sup.N is independently for each occurrence methyl, ethyl, propyl, isopropyl, butyl or benzyl; and R.sup.a is H or amino acid side chain, wherein all of the nucleotide sugars of the modified RNA agent are modified. 3. The modified RNA agent of claim 1, wherein the modified RNA agent is double stranded. 4. The modified RNA agent of claim 3, wherein the structure is at the 3'-end of one of the strands. 5. The modified RNA agent of claim 4, wherein the structure is at the 3'-end of the sense strand. 6. The modified RNA agent of claim 1, wherein the structure is ##STR00127## 7. The modified agent of claim 1, wherein the structure is ##STR00128## 8. A modified RNA agent comprising a structure of ##STR00129## wherein all of the nucleotide sugars of the modified RNA agent are modified. 9. A modified RNA agent comprising a structure of ##STR00130## wherein all of the nucleotide sugars of the modified RNA agent are modified. 10. The modified RNA agent of claim 1, wherein L.sup.G is carbohydrate. 11. The modified RNA agent of claim 10, wherein the carbohydrate is selected from the group consisting of monosaccharide, disaccharide, trisaccharide, tetrasaccharide and polysaccharide. 12. The modified RNA agent of claim 1, wherein L.sup.G is galactose or N-acetylgalactosamine. 13. The modified RNA agent of claim 1, wherein the nucleotide sugars of the modified RNA agent are modified at the 2' position to replace 2' hydroxyl. 14. The modified RNA agent of claim 13, wherein the 2' hydroxyl is replaced with a moiety selected from the group consisting of 2'-methoxyethyl, 2'-OCH.sub.3, 2'--O-allyl, 2'--C-allyl, and 2'-fluoro. 15. A method of modulating the expression of a target gene in a cell, comprising providing to said cell a modified RNA agent of claim 1. 16. A pharmaceutical composition comprising a modified RNA agent of claim 1 alone or in combination with a pharmaceutically acceptable carrier or excipient.