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Cha Kuin Taiteit Van De La Man Unita Man United CHA KUIN TAITEIT US009814777B2VAN DE LA MAN UNITA MAN UNITED (12 ) United States Patent ( 10 ) Patent No. : US 9 ,814 , 777 B2 Manoharan et al. (45 ) Date of Patent: Nov . 14 , 2017 (54 ) TARGETING LIPIDS (58 ) Field of Classification Search CPC . A61K 31 /7088 ; A61K 31 /713 ; A61K 47 / 16 ; @( 71 ) Applicant : Arbutus Biopharma Corporation , A61K 47 / 22 ; A61K 47 / 28 ; A61K Burnaby, BC (CA ) 47/ 48092 ; A61K 47 / 48215 ; CO7H 21/ 02 USPC .. .. 514 / 44 , 777 , 784 ; 536 / 17. 9 , 5 ; 544 /258 ; @(72 ) Inventors : Muthiah Manoharan , Cambridge , MA 552 /502 ; 560/ 159 ( US ) ; Kallanthottathil G . Rajeev , See application file for complete search history. Cambridge , MA (US ) ; Jayaprakash K . Nair , Cambridge , MA (US ) ; Muthusamy Jayaraman , Cambridge, (56 ) References Cited MA (US ) U . S . PATENT DOCUMENTS (73 ) Assignee : Arbutus Biopharma Corporation , 5 , 994 ,517 A 11 / 1999 Ts ' o et al. Burnaby, British Columbia ( CA ) 6 , 906 , 182 B2 6 / 2005 Ts ' o et al . 7 , 109 , 165 B2 9 / 2006 Matulic - Adamic et al . 7 , 491 , 805 B2 . 2 /2009 Vargeese et al . ( * ) Notice: Subject to any disclaimer, the term of this 7 , 803 , 397 B2 * 9 / 2010 Heyes et al. .. 424 / 450 patent is extended or adjusted under 35 2002 / 0086356 A1 7 / 2002 Tuschl et al. U . S . C . 154 ( b ) by 0 days . 2003 /0148928 A1 8 / 2003 Beigelman et al . 2004 /0110296 Al 6 /2004 Vargeese et al . 2004 / 0259247 Al 12 / 2004 Tuschl et al . ( 21 ) Appl. No. : 14 / 060, 353 2006 /0148740 A17 / 2006 Platenburg 2009 /0325297 A1 12 / 2009 Tian et al . (22 ) Filed : Oct. 22, 2013 2012 /0101148 AI 4 / 2012 Aking et al. (65 ) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2014 /0179761 A1 Jun . 26 , 2014 EP 0957107 11 / 1999 US 2016 /0375137 A9 Dec . 29 , 2016 WO WO 90 / 12096 10 / 1990 wo 1997043296 Al 11 / 1997 WO WO 99 /52932 10 / 1999 Related U . S . Application Data WO WO 99 /65925 12 / 1999 WO WO 00 / 44914 8 / 2000 (63 ) Continuation of application No . 12 /328 , 669 , filed on WO WO 02 /085908 10 / 2002 WO WO 02 /094185 11 /2002 Dec. 4 , 2008, now abandoned . WO WO 2004 / 024757 3 / 2004 WO WO 2004 /080406 9 / 2004 (60 ) Provisional application No . 60 / 992 , 309 , filed on Dec . WO WO 2004 /090108 10 / 2004 4 , 2007 , provisional application No . 61 /013 , 597 , filed (Continued ) on Dec . 13 , 2007 , provisional application No . 61/ 127 ,751 , filed on May 14 , 2008 , provisional OTHER PUBLICATIONS application No. 61/ 091, 093 , filed on Aug . 22 , 2008 , provisional application No . 61/ 097 , 261, filed on Sep . Nunez et al. Journal of Carbohydrate Chemistry , vol. 22 , No. 6 , pp . 16 , 2008 . 395 - 406 , 2003. * (Continued ) (51 ) Int. Cl. A61K 31/ 7088 ( 2006 . 01 ) A61K 31 / 713 ( 2006 .01 ) Primary Examiner — Janet Epps- Smith A61K 47 / 16 ( 2006 .01 ) ( 74 ) Attorney, Agent, or Firm — Viksnins Harris Padys A61K 47 / 22 ( 2006 .01 ) Malen LLP A61K 47 /28 ( 2006 .01 ) A61K 31 /7004 ( 2006 . 01 ) ( 57 ) ABSTRACT A61K 31 / 7052 ( 2006 .01 ) A61K 31 /70 ( 2006 . 01 ) The present invention provides targeting lipids of structure A61K 4748 ( 2006 .01 ) CO7H 21/ 02 ( 2006 .01 ) L 100 - linker- L 101 (CI ), A61K 48 /00 ( 2006 .01 ) where L 100 is a lipid , lipophile , alkyl , alkenyl or alkynyl , (52 ) U . S . CI. L101 is a ligand or CH , CH , (OCH , CH , ) , O (CH , ) , CH , ??? .. .. A61K 47 /28 (2013 .01 ) ; A61K 31/ 70 ligand , p is 1 - 1000 , and q is 1 - 20 . In addition , the invention ( 2013 .01 ) ; A61K 31 / 7004 ( 2013 .01 ) ; A61K provides compositions and methods for the delivery of 31/ 7052 (2013 .01 ) ; A61K 31 /7088 (2013 .01 ) ; therapeutic agents to cells . In particular , these include novel A61K 31/ 713 ( 2013 . 01 ) ; A61K 47/ 16 lipids and nucleic acid - lipid particles that provide efficient (2013 . 01 ) ; A61K 47 / 22 ( 2013 .01 ) ; A61K encapsulation of nucleic acids and efficient delivery of the 47 / 48046 (2013 .01 ) ; A61K 47/ 48092 encapsulated nucleic acid to cells in vivo . ( 2013 .01 ) ; A61K 47 /48215 ( 2013 .01 ) ; C07H 21/ 02 (2013 .01 ) ; A61K 48/ 00 (2013 .01 ) ; YO2P 20 /55 (2015 . 11) 11 Claims, 20 Drawing Sheets US 9 ,814 Page , 2777 B2 References Cited Krapcho et al. , “ Mono -Protected Diamines . N -tert -Butoxycarbonyl ( 56 ) a ,f3 - Alkanediamines from - O - Alkanediamines ” , Synthetic Commu nications, 2559 -2564 ( 1990 ) . FOREIGN PATENT DOCUMENTS Li et al ., “ Folate -Mediated Targeting of Antisense WO WO 2004 /094595 11 / 2004 Oligodeoxynucleotides to Ovarian Cancer Cells ” , Pharmaceutical WO WO 2006 / 020768 2 / 2006 Research , vol . 15 ( 10 ) , 1540 -1545 ( 1998 ). WO WO 2006 /078278 7 / 2006 Liu et al. , “ Targeted Drug Delivery to Chemoresistant Cells : Folic Acid Derivatization of FDUMP [ 10 ] Enhances Cytotoxicity Toward 5 - FU -Resistant Human Colorector Tumor Cells ” , Journal of OTHER PUBLICATIONS Organic Chemistry , vol. 66 ( 17 ) , 5655 -5663 (2001 ) . Rensen et al. J . Med . Chem . 2004 , 47 , 5798 -5808 . * Mahato , R . I . et al. , “ Physicochemical and Disposition Characteris Sliedregt et al . Journal of Medicinal Chemistry , vol. 42, No. 4 , Feb . tics of Antisense Oligonucleotides Complexed with Glycosylated 25, 1999 , pp . 609 -618 . * Poly ( L - lysine ) ” , Biochemical Pharmacology , vol. 53 , Pergamon , Zimmermann et al. Nature Publishing Group , vol. 441, No . 7089 , Oxford , GB , vol. 53, 887 - 895, XP000197861, ISSN : 0006 - 2952 pp . 111 - 114 . * (Jan . 1997 ). Akinc et al. , “ Targeted Delivery of RNAi Therapeutics with Endog Mahato et al. , “ Modulation of Gene Expression by Antisense and enous and Exogenous Ligand - Based Mechanisms” , Molecular Antigene Oligodeoxynucleotides and Small Interfering RNA ” , Therapy vol. 18 ( 7 ) , 1357 - 1364 ( 2010 ) . Expert Opinion on Drug Delivery , vol. 2 ( 1 ) , 3 -28 (2005 ) . Biessen , et al ., “ The Cholesterol Derivative of a Triantennary Maier et al . , “ Synthesis of Antisense Oligonucleotides Conjugated Galactoside with High Affinity for Hepatic Asialoglycoprotein to a Multivalent Carbohydrate Cluster for Cellular Targeting” , Bioconjugate Chemistry , vol. 14 , 18 -29 , XP002510288 (2003 ) . Receptor: A Potent Cholesterol Lowering Agent” , Journal of Murata et al. , “ Design of Quaternary Chitosan Conjugate Having Medicinal Chemistry , vol . 38 ( 11) , 1846 - 1852 ( 1995 ) . Antennary Galactose Residues as a Gene Delivery Tool” , Carbo Biessen et al ., “ Synthesis of Cluster Galactosides with High Affinity hydrate Polymers , vol . 32 ( 2 ) , 105 - 109 ( 1997 ) . for the Hepatic Asialoglycoprotein Receptor” , Journal of Medicinal Nunez et al. , Journal of Carbohydrate Chemistry, vol. 22 , No. 6 , Chemistry, vol . 38 ( 9 ) , 1538 -1546 . 395 - 406 (2003 ) . Chiu et al. , “ RNAi in Human Cells : Basic Structural and Functional Rensen et al ., “ Design and Synthesis of Novel Features of Small Interfering RNA ” , Molecular Cell , vol . 10 , N - Acetylgalactosamine - Terminated Glycolipids for Targeting of 549 - 561 ( 2002 ) . Lipoproteins to the Hepatic Asialoglycoprotein Receptor” , Journal Choi et al. , “ Targeting Cancer Cells with DNA - Assembled of Medicinal Chemistry, vol . 47 ( 23 ) , 5798 -5808 (2004 ) . Dendrimers : A Mix and Match Strategy for Cancer” , Cell Cycle , Sioud , “ On the Delivery of Small Interfering RNAs into Mamma vol . 4 ( 5 ) , 669 -671 ( 2005 ) . lian Cells ” , Expert Opinion on Drug Delivery , vol. 2 ( 4 ), 639 -651 Connolly et al. , “ Binding and Endocytosis of Cluster Glycosides by ( 2005 ) . Rabbit Hepatocytes ” , The Journal of Biological Chemistry , vol . 257 Six et al . , “ An Efficient and Stereoselective Synthesis of 1 , 2 - 0 ( 2 ) , 939 -645 ( 1982 ) . Dialkyl 3 0 Beta D Glycosyl- SN -Glycerols ” , Tetrahedron Letters , Crossman et al. , “ Synthesis of Some Second -Generation Substrate vol. 24 ( 12 ) , 1229 - 1232 ( 1983 ) . Analogues of Early Intermediates in the Biosynthetic Pathway of Six et al ., “ Influence of Carbohydrate Moities on Monolayer Prop Glycosylphosphatidylinositol Membrane Anchors ” , Carbohydrate erties of Dialkylglyceryletherglycosides , Simple Model Com Research , vol . 321 ( 1 - 2 ) , 2 -51 ( 1999 ) . pounds of the Glycolipids of Halophilic Bacteria ” , Journal of Dubber et al. , “ Solid - Phase Synthesis of Multivalent Colloid and Interface Science , vol. 93 ( 1 ) , 109 - 114 . Glycoconjugates on a DNA Synthesizer ” , Bioconjugate Chemistry , Sliedregt et al. , “ Design and Synthesis of Novel Amphiphilic vol. 14 ( 1 ) , 239 - 246 ( 2003 ) . Dendritic Galactosides for Selective Targeting of Liposomes to the Guo et al. , “ Construction of Folate -Conjugated PRNA of Hepatic Asialoglycoprotein Receptor” , Journal of Medicinal Chem Bateriophase phi29 DNA Packaging Motor for Delivery of Chime istry , vol. 42 , No . 4 , 609 -618 ( 1999 ) . ric siRNA to Nasopharyngeal Carcinoma Cells ” , Gene Therapy , Vaino et al. , " Synthesis of a D - Lactosyl Cluster - Nucleoside Con vol. 13 ( 10 ) , 814 - 820 ( 2006 ) . jugate” , Chemical Communications , 19 , 1871 -1872 ( 1997 ) . Hamzavi et al. , " Modulation of the Pharmacokinetic Properties of Wolfrum et al. , “ Mechanisms and optimization of in vivo delivery PNA : Preparation of Galactosyl, Mannosyl, Fucosyl, of lipophilic siRNAs" , Nature Biotechnology 25 ( 10 ) , 1149 - 1157 N - Acetylgalactosaminyl , and N -Acetylglucosaminyl Derivatives of ( 2007 ) . 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