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Patent No.: US 9187749 B2 EXPRESSION 29-33 3 US009 187749B2 (12) United States Patent (10) Patent No.: US 9,187,749 B2 Bhattacharjee et al. (45) Date of Patent: Nov. 17, 2015 (54) METHODS FOR MODULATING FACTOR 12 6,794,499 B2 9/2004 Wengel et al. EXPRESSION 29-33 3: Wengeet al. W - - enge 7,399,845 B2 7/2008 Seth et al. (75) Inventors: Gourab Bhattacharjee, San Diego, CA 7.427.672 B2 9/2008 Imanishi et al. (US); Alexey Revenko, San Diego, CA 7,547,684 B2 6/2009 Seth et al. (US); Robert A. MacLeod, San Diego, 7,696,345 B2 4/2010 Allerson et al. CA (US) 2001/005.3519 A1 12/2001 Fodor et al. 2003/0228597 A1 12/2003 COWSert et al. 2004/0171570 A1 9, 2004 A11 tal. (73) Assignee: s rhymaceutical, Inc., Carlsbad, 2005/O130923 A1 6, 2005 SN al 2007/0031844 A1 2/2007 Khvorova et al. 2007/0192882 A1* 8, 2007 Dewald ........................... 800, 14 (*) Notice: Subject to any disclaimer, the term of this 2008/0039618 A1 2/2008 Allerson et al. patent is extended or adjusted under 35 3.93.9 A. 1939. Ny's al. U.S.C. 154(b) by 38 days. 2009 OO64350 A1 3, 2009 Dewaldwayze et al. 2010.01374.14 A1 6, 2010 Freier et al. (21) Appl. No.: 14/124,621 2010/03241 14 A1 12/2010 Dewald 2011/0067.124 A1 3/2011 Dewald ........................... 800, 13 (22) PCT Filed: Jun. 8, 2012 2012/0309035 A1 12/2012 Lindahl et al. .................. 435/13 2013/0331434 A1* 12/2013 Monia et al. ................ 514.f44 A (86). PCT No.: PCT/US2012/041747 S371 (c)(1) FOREIGN PATENT DOCUMENTS C s (2), (4) Date: Feb. 28, 2014 WO WO99,14226 3, 1999 WO WOO3,OO46O2 1, 2003 (87) PCT Pub. No.: WO2012/170947 W. W. 39.95. 1339. PCT Pub. Date: Dec. 13, 2012 WO WO 2007 134181 11, 2007 WO WO 2008.101157 8, 2008 (65) Prior Publication Data WO WO 2008,150729 12/2008 WO WO 2008,1544O1 12/2008 US 2014/02283OO A1 Aug. 14, 2014 WO WO 2009 OO6478 1, 2009 WO WO 2009/115478 9, 2009 WO WO 2010/094732 8, 2010 Related U.S. Application Data (Continued) (60) Provisional application No. 61/495,943, filed on Jun. 10, 2011, provisional application No. 61/496,456, OTHER PUBLICATIONS filed on Jun. 13, 2011. DonaldOa. Kylee C tPh aaCCCatical DesignS. 1995 1233-254.* (51) Int. Cl. Merriam-Webster online retrieved on Mar. 5, 2015 definition for CI2N IS/II (2006.01) prophylactically. Retrieved from: Google, pp. 1-3.* CI2N IS/II3 (2010.01) Cugno et al. Trends Mol. Med. 15:69-78, 2009.* A6 IK 4.8/00 (2006.01) Adcock et al., “A laboratory approach to the evaluation of hereditary A6 IK3I/7088 (2006.01) hypercoagulability” Am. J. Clin. Pathol. (1997) 108(4):434-449. A6 IK 45/06 (2006.01) (Continued) (52) U.S. Cl. CPC ........ CI2N 15/1137 (2013.01); A61 K3I/7088 (2013.01); A61K 45/06 (2013.01); A61 K Primary Examiner — Brian Whiteman 48/005 (2013.01); C12N 15/113 (2013.01); CI2N 2310/11 (2013.01); C12N 23.10/315 . 4) tigny Agent, or Firm — Knobbe, Martens, Olson & (2013.01); C12N 23.10/3231 (2013.01); C12N Ca 23.10/3341 (2013.01); C12N 23.10/341 O A O (2013.01) (57) ABSTRACT (58) Field of Classification Search CPC ........... C12N 2310/11; C12N 23.10/31; C12N Disclosed herein are methods for decreasing Factor 12 and 2310/32: C12N 231 O/33 treating or preventing inflammatory conditions in an indi See application file for complete search history. vidual in need thereof. Examples of disease conditions that (56) References Cited can be ameliorated with the administration of antisense com pounds targeted to Factor 12 include hereditary angioedema U.S. PATENT DOCUMENTS (HAE). Methods for inhibiting Factor 12 can also be used as a prophylactic treatment to prevent individuals at risk for 5,801,154 A 9, 1998 Baracchini et al. developing an inflammatory condition, such as, hereditary 6,268,490 B1 7/2001 Imanishi et al. 6,525, 191 B1 2/2003 Ramasamy angioedema. 6,582,908 B2 6, 2003 Fodor et al. 6,670,461 B1 12/2003 Wengel et al. 6,770,748 B2 8/2004 Imanishi et al. 22 Claims, 2 Drawing Sheets US 9,187,749 B2 Page 2 (56) References Cited Foster et al., “Inhibition of the activation of Hageman factor (factor XII) by extracts of Schistosoma mansoni.” J. Lab. Clin. Med. (1992) 120(5): 735-9. FOREIGN PATENT DOCUMENTS Freier et al., “The ups and downs of nucleic acid duplex stability: WO WO 2010/11 1702 9, 2010 structure-stability studies on chemically-modified DNA:RNA WO WO 2012/0647.58 5, 2012 duplexes” Nucleic Acids Research (1997) 25(22):4429-4443. WO WO 2012/170947 12/2012 Frieden et al., “Expanding the design horizon of antisense oligonucleotides with alpha-L-LNA'Nucleic Acids Research (2003) OTHER PUBLICATIONS 31(21):6365-6372. Gautschi et al., “Activity of a Novel bcl-2/bcl-XL-Bispecific Albaek et al., “Analogues of a Locked Nucleic Acid with Three Antisense Oligonucleotide Against Tumors of Diverse Histologic Carbon 2',4'-Linkages: Synthesis by Ring-Closing Metathesis and Origins' J. Natl. Cancer Inst. (2001) 93(6):463-471. Influence of Nucleic Acid Duplex Stability” J. Org. Chem. (2006) Gigliet al., “Interaction of plasmakallikrein with the C1 inhibitor.” J. 71:7731-774O. Immunol. (1970) 104:574-581. Altmann et al., “Second-generation antisense oligonucleoties: struc Han et al., “Increased vascular permeability in C1 inhibitor-deficient ture-activity relationships and the design of improved signal mice mediated by the bradykinin type 2 receptor.” J. Clin. Invest. transduction inhibitors' Biochem. Soc. Trans. (1996) 24: 630-637. (2002) 109: 1057-1063. Altmann et al., “Second Generation of Antisense Oligonucleotides: Hazegh-Azam et al., “The Corn Inhibitor of Activated Hageman From Nuclease Resistance to Biological Efficacy in Animals” Factor: Purification and Properties of Two Recombinant Forms of the Chimia (1996) 50: 168-176. Protein’ Protein Expr. Purif. (1998) 13(2): 143-149. Altmann et al., “Second Generation AntiSense Oligonucleotides— Hojima et al., “Pumpkin seed inhibitor of human factor XIIa (acti Inhibition of PKC-a and c-RAF Kinase Expression by Chimeric vated Hageman factor) and bovine trypsin' Biochemistry (1982) Oligonucleotides Incorporating 5'-Substituted Carbocyclic 21(16): 3741-3746. Nucleosides and 2'-O-Ethylene Glycol Substituted Ribonucleosides' Isawa et al., “Identification and characterization of plasmakallikrein Nucleosides Nucleotides (1997) 16(7-9): 917-926. kinin System inhibitors from Salivary glands of the blood-sucking Altschul et al., “Basic Local Alignment Search Tool” J. Mol. Biol. insect Triatoma infestans.” FEBS J. (2007) 274(16): 4271-4286. (1990) 215: 403-410. Kaplanet al., “Pathways for bradykinin formation and inflammatory Aulak et al., "Chymotrypsin inhibitory activity of normal C1-inhibi disease.” J. Allergy Clin. Immunol. (2002) 109(2): 195-209. tor and a P1 Arg to His mutant: evidence for the presence of overlap Kato et al., “Identification and characterization of the plasma kal ping reactive centers.” Protein Sci. (1993)2(5): 727-732. likrein-kinin system inhibitor, haemaphysalin, from hard tick, Bertina et al., “Mutation in blood coagulation factor V associated Haemaphysalis longicornis' Thromb. Haemost. (2005) 93: 359-67. with resistance to activated protein C.” Nature (1994)369(6475):64 Kleinschnitz et al., “Targeting coagulation factor XII provides pro 67. tection from pathological thrombosis in cerebral ischemia without Bjorket al., “Mechanism of the anticoagulantaction of heparin.” Mol interfering with hemostasis' J. Exper. Med. (2006) 203:513-518. Cell Biochem. (1982) 48(3):161-182. Koshkin et al., “LNA (Locked Nucleic Acids): Synthesis of the Bouillet et al. “Disease expression in women with hereditary Adenine, Cytosine, Guanine, 5-Methylcytosine, Thymine and Uracil angioedema' Am. J. Obstet. Gynecol. (2008) 199: 484.e1-484.e4. Biocyclonucleoside Monomers, Oligomerisation, and Unprec Braasch et al., “Locked nucleic acid (LNA): fine-tuning the recogni edented Nucleic Acid Recognition’ Tetrahedron (1998). 54:3607 tion of DNA and RNA” Chem. Biol. (2001) 8:1-7. 3630. Branch et al., “A good antisense molecule is hard to find.” TIBS Kumar et al., “The First Analogues of LNA (Locked Nucleic Acids): (1998) 23:45-50. Phosphorothioate-LNA and 2'-Thio-LNA' Bioorg. Med. Chem. Lett. Chan et al., “The inhibition of activated factor XII (hageman factor) (1998) 8:2219-2222. by antithrombin III: The effect of other plasma proteinase inhibitors' Leumann, “DNA Analogues: From Supramolecular Principles to Biochem. Biophys. Res. Comm. (1977) 74(1): 150-158. Biological Properties' Bioorganic & Medicinal Chemistry (2002) Cichon et al., “Increased activity of coagulation factor XII (Hageman 10:841-854. factor) causes hereditary angioedema type III Am. J. Hum. Genet. Mackenzie et al., “Plasma prekallikrein levels are positively associ (2006) 79: 1098-1104. ated with circulating lipid levels and the metabolic syndrome in Citarella et al., “The Second Exon-Encoded Factor XII Region Is children.” Appl. Physiol. Nutr. Metab. (2010) 35: 518-525. Involved in the Interaction of Factor XII With Factor XI and DoesNot Mahdiet al., “Factor XII interacts with the multiprotein assembly of Contribute to the Binding Site for Negatively Charged Surfaces” urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 Blood (1998) 92: 41.98-4206. on endothelial cell membranes' Blood (2002)99(10): 3585-3596. Citarella et al., “Identification of aputative binding site for negatively Maher et al., “Comparative hybrid arrest by tandem antisense charged surfaces in the fibronectin type II domain of human factor oligodeoxyribonucleotides O oligodeoxyribonucleoside XII—an immunochemical and homology modeling approach.” methylphosphonates in a cell-free system” Nuc. Acid. Res. (1988) Thromb. Haemost. (2000) 84(6): 1057-1065. 16:3341-3358.
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