(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/006740 A2 15 January 2015 (15.01.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 47/48 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 14/046425 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 11 July 2014 ( 11.07.2014) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (30) Priority Data: ZW. 61/845,279 11 July 2013 ( 11.07.2013) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: ALNYLAM PHARMACEUTICALS, INC. kind of regional protection available): ARIPO (BW, GH, [US/US]; 300 Third Street, Cambridge, MA 02142 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (72) Inventors: MANOHARAN, Muthiah; 300 Third Street, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Cambridge, MA 02142 (US). NAIR, Jayaprakash, K.; EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 300 Third Street, Cambridge, MA 02142 (US). KAN- MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, DASAMY, Pachamuthu; 300 Third Street, Cambridge, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, MA 02142 (US). MATSUDA, Shigeo; 300 Third Street, KM, ML, MR, NE, SN, TD, TG). Cambridge, MA 02142 (US). KELIN, Alexander, V.; 300 Third Street, Cambridge, MA 02142 (US). JAYARA- Published: MAN, Muthusamy; 300 Third Street, Cambridge, MA — without international search report and to be republished 02142 (US). RAJEEV, Kallanthottathil, G.; 300 Third upon receipt of that report (Rule 48.2(g)) Street, Cambridge, MA 02142 (US). (74) Agent: LESSLER, Jay, P.; Blank Rome LLP, The Chrysler Building, 405 Lexington Ave., New York, NY 10174-0208 (US). < © ©o © (54) Title: OLIGONUCLEOTIDE-LIGAND CONJUGATES AND PROCESS FOR THEIR PREPARATION (57) Abstract: The present invention relates to ligand conjugates of oligonucleotides (e.g., iRNA agents) and methods for their pre - paration. The ligands are derived primarily from monosaccharides These conjugates are useful for the in vivo delivery of oligonuc- leotides. OLIGONUCLEOTIDE-LIGAND CONJUGATES AND PROCESS FOR THEIR PREPARATION RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 61/845,279, filed July 11, 2013, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to ligand conjugates of oligonucleotides (e.g., iRNA agents) and methods for their preparation. The ligands are derived primarily from monosaccharides. These conjugates are useful for the in vivo delivery of oligonucleotides. BACKGROUND OF THE INVENTION Efficient delivery to cells in vivo requires specific targeting and substantial protection from the extracellular environment, particularly serum proteins. One method of achieving specific targeting is to conjugate a targeting moiety to the iRNA agent. The targeting moiety helps in targeting the iRNA agent to the required target site. One way a targeting moiety can improve delivery is by receptor mediated endocytotic activity. This mechanism of uptake involves the movement of iRNA agent bound to membrane receptors into the interior of an area that is enveloped by the membrane via invagination of the membrane structure or by fusion of the delivery system with the cell membrane. This process is initiated via activation of a cell- surface or membrane receptor following binding of a specific ligand to the receptor. Many receptor-mediated endocytotic systems are known and have been studied, including those that recognize sugars such as galactose, mannose, mannose-6-phosphate, peptides and proteins such as transferrin, asialoglycoprotein, vitamin B12, insulin and epidermal growth factor (EGF). The Asialoglycoprotein receptor (ASGP-R) is a high capacity receptor, which is highly abundant on hepatocytes. The ASGP-R shows a 50-fold higher affinity for N-Acetyl-D-Galactosylamine (GalNAc) than D-Gal. Previous work has shown that multivalency is required to achieve nM affinity, while spacing among sugars is also crucial. Recently, certain carbohydrate conjugates have been shown to be a valuable delivery alternatively to liposomes for siRNA delivery. SUMMARY OF THE INVENTION The present invention relates to ligand conjugates of oligonucleotides or other biologically active agents which have one or more advantageous properties, such as improved delivery of the oligonucleotide or other biologically active agents, lower manufacturing costs or fewer manufacturing issues, or better chemical stability. These conjugates provide effective delivery of oligonucleotides and other biologically active agents. In one embodiment, the present invention relates to a ligand (e.g., carbohydrate) conjugate of an oligonucleotide (e.g., an iRNA agent) or other biologically active agent of the formula I: Formula I wherein the Oligonucleotide is an oligonucleotide, such as an siRNA, microRNA, antimiR, antagomir, microRNA mimic, decoy, immune stimulatory, G-quadruplex, splice altering, ssRNA, antisense, aptamer, stem-loop RNA or DNA or one of the two strands of any double stranded RNA or DNA or double stranded shortemer RNA or DNA (e.g, siRNA); the Biologically Active Agent is any biologically active agent; the Linker is a linking group between the Ligand(s) and the Oligonucleotide or other biologically active agent, where the Linker may be selected from the linking groups in Table 1 or 1A; and the Ligand(s) are sugar-derived, where (i) the Ligand(s) may be attached to the same or different atoms in the Linker, (ii) the conjugate contains from 1 to 12 Ligands (preferably 1 to 5 or 1 to 3 Ligands), and (iii) the Ligand(s) may be selected from (a) the Ligands in Table 2 or 2A, 2 (b) - R -(R )k, where 9 R is absent (in which case k=l) or a spacer (also referred to as a ligand backbone) having two or more sites of attachment for the R groups, R is a targeting monomer selected from Table 3, and k is 1 to 6 (preferably 1 to 5 or 1 to 3), each R3 may be attached to the same or different atoms in R2 ; and (c) the Ligands in Table 4 or 4A. The conjugate includes at least one Linker from Table 1 or 1A or from the examples, one Ligand from Table 2, 2A, 4, or 4A, or one targeting monomer from Table 3 or 3A. For example, the nucleoside linkers described in the examples can be used as the Linker. In one embodiment, the conjugate includes (i) at least one Linker from Table 1 or 1A or from the examples, (ii) one Ligand from Table 2, 2A, 4, or 4A, and (iii) one targeting monomer from Table 3 or 3A. 9 R can be an amino acid-, polypeptide- (e.g., a dipeptide or tripeptide), heteroaryl- (e.g., a triazole), or sugar-containing group. In one preferred embodiment, each R group is attached via 9 an amide, ether, or amino group to R . In one embodiment, R is attached via an amide group. Each entry in Tables 2, 2A, 4, and 4A shows a spacer bound to at least one targeting monomer. The spacers are bound to the targeting monomers either through a heteroatom (which is at a terminus of the spacer), such as a nitrogen atom, or at the anomeric carbon to the sugar group of a targeting monomer (as shown below). The heteroatom attachment point in the structures shown in Tables 2, 2A, 4, and 4A is the first nitrogen atom when walking along the chain from the sugar group (left side of the ligand) to the remainder of the ligand (right side). The spacers for two ligands in Table 2A are shown in the table below (the arrows indicate the points of attachment for the targeting monomers R , and the right side of the spacer is attached to the Linker). Suitable spacers are also shown in Table 5 below. The Oligonucleotide is preferably attached to the Linker through (i) the 3' or 5'-terminal of the oligonucleotide, (ii) one or more sugar moieties of the nucleoside present in the oligonucleotide independent of position, or (iii) one or more base moieties of the nucleoside present independent of position. In one embodiment, the Ligand is conjugated to one of the two strands of a double stranded siRNA via a Linker. In one embodiment, the Ligand(s) target the asialoglycoprotein receptor (ASGPR). In another embodiment, the Ligand(s) target the liver, such as the parenchymal cells of the liver. The Ligand(s) may be an unmodified or modified monosaccharide, disaccharide, trisaccharide, tetrasaccharide, or higher polysaccharide. The oligonucleotide can be attached to the Linker via a cleavable group (e.g., phosphate, phosphorothiate, or amide) or a non-cleavable group (e.g., ether, carbamate, or C-C (e.g., a bond between two carbon atoms or -CH 2-CH2-)). As described herein, the cleavable or non-cleavable group is within the Oligonucleotide of Formula I. In one embodiment, the -Linker- Ligand is not L96 (shown in the examples).