USO0956629OB2

(12) United States Patent (10) Patent No.: US 9,566.290 B2 Baker et al. (45) Date of Patent: *Feb. 14, 2017

(54) BORON-CONTAINING SMALL MOLECULES (51) Int. Cl. A6II 3/69 (2006.01) (71) Applicant: Anacor Pharmaceuticals, Inc., Palo C07F 5/02 (2006.01) Alto, CA (US) C07F 5/04 (2006.01) C7H 9/06 (2006.01) (72) Inventors: Stephen J. Baker, Collegeville, PA C7H 9/16 (2006.01) (US); Tsutomu Akama, Sunnyvale, CA C7H 2L/00 (2006.01) (US); Vincent S. Hernandez, C7H 23/00 (2006.01) Watsonville, CA (US); Karin M. Hold, A63L/70 (2006.01) Belmont, CA (US); Kirk Maples, San A 6LX 3L/7076 (2006.01) Jose, CA (US); Jacob J. Plattner, A6IR 9/00 (2006.01) Berkeley, CA (US); Virginia Sanders, A6II 47/10 (2006.01) San Francisco, CA (US); Yong-Kang A6IR 9/08 (2006.01) Zhang, San Jose, CA (US); Gregory T. (52) U.S. Cl. CPC ...... A6 IK3I/69 (2013.01); A61K 9/0012 Fieldson, Morgantown, WV (US); (2013.01); A61K 9/08 (2013.01); A61 K3I/70 James J. Leyden, Malvern, CA (US) (2013.01); A61 K3I/7076 (2013.01); A61 K Assignee: 47/10 (2013.01); C07F 5/025 (2013.01); C07F (73) Anacor Pharmaceuticals, Inc., Palo 5/04 (2013.01); C07H 19/06 (2013.01); C07H Alto, CA (US) 19/16 (2013.01); C07H 21/00 (2013.01); C07H 23/00 (2013.01) (*) Notice: Subject to any disclaimer, the term of this (58) Field of Classification Search patent is extended or adjusted under 35 USPC ...... 514/64 U.S.C. 154(b) by 0 days. See application file for complete search history. This patent is Subject to a terminal dis (56) References Cited claimer. U.S. PATENT DOCUMENTS (21) Appl. No.: 15/134,286 2,260,336 A 10, 1941 Prescott et al. (22) Filed: Apr. 20, 2016 2,741,548 A 4, 1956 Darling et al. (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2016/0228463 A1 Aug. 11, 2016 EP O969,531 1, 2000 EP O765331 B1 8, 2000 Related U.S. Application Data (Continued) (60) Continuation of application No. 15/091,394, filed on OTHER PUBLICATIONS Apr. 5, 2016, which is a continuation of application U.S. Appl. No. 13/861,846, filed Apr. 12, 2013, now abandoned. No. 15/068,352, filed on Mar. 11, 2016, which is a U.S. Appl. No. 13/673,860, filed Nov. 9, 2012, now abandoned. continuation of application No. 15/046,322, filed on U.S. Appl. No. 13/607.321, filed Sep. 7, 2012, now abandoned. Feb. 17, 2016, which is a continuation of application U.S. Appl. No. 13/607,405, filed Sep. 7, 2012, now abandoned. No. 14/537,771, filed on Nov. 10, 2014, now U.S. Appl. No. 13/607.250, filed Sep. 7,2012, now abandoned. U.S. Appl. No. 15/091,394, filed Apr. 5, 2016. abandoned, which is a continuation of application No. U.S. Appl. No. 15/068,352, filed Mar. 11, 2016. 14/201459, filed on Mar. 7, 2014, now Pat. No. U.S. Appl. No. 15/046,322, filed Feb. 17, 2016. 9,353,133, which is a continuation of application No. U.S. Appl. No. 14/977,052, filed Dec. 21, 2015. 13/356,488, filed on Jan. 23, 2012, now Pat. No. U.S. Appl. No. 14/537,771, filed Nov. 10, 2014. 8.722,917, which is a continuation of application No. U.S. Appl. No. 14/537,694, filed Nov. 10, 2014, now abandoned. 12/629,753, filed on Dec. 2, 2009, now Pat. No. U.S. Appl. No. 14/165.428, filed Mar. 7, 2014, now abandoned. 8,115,026, which is a division of application No. U.S. Appl. No. 14/688,581, filed Apr. 16, 2015. 11/505,591, filed on Aug. 16, 2006, now Pat. No. (Continued) 7,767,657, and a continuation-in-part of application Primary Examiner — Rei-Tsang Shiao No. 1 1/357,687, filed on Feb. 16, 2006, now Pat. No. (74) Attorney, Agent, or Firm — Morgan, Lewis & 7.582,621, said application No. 14/537,771 is a Bockius LLP continuation-in-part of application No. 13/874,329, (57) ABSTRACT filed on Apr. 30, 2013, now Pat. No. 8,889,656, which This invention relates to compounds useful for treating is a continuation of application No. 13/224.252, filed fungal infections, more specifically topical treatment of on Sep. 1, 2011, now Pat. No. 8,440,642, which is a onychomycosis and/or cutaneous fungal infections. This continuation of application No. 12/507.010, filed on invention is directed to compounds that are active against Jul. 21, 2009, now Pat. No. 8,039,451, which is a fungi and have properties that allow the compound, when placed in contact with a patient, to reach the particular part (60) Provisional application No. 60/755,227, filed on Dec. of the skin, nail, hair, claw or hoof infected by the fungus. 30, 2005, provisional application No. 60/746,361, In particular the present compounds have physiochemical filed on May 3, 2006, provisional application No. properties that facilitate penetration of the nail plate. (Continued) 12 Claims, 63 Drawing Sheets US 9,566.290 B2 Page 2

Related U.S. Application Data 8,895,534 B2 11/2014 Baker et al. 9,012.431 B2 4/2015 Akama continuation of application No. 1 1/357.687, filed on 9,029,353 B2 5/2015 Baker et al. Feb. 16, 2006, now Pat. No. 7,582,621.60/654,060, 9,145,429 B2 9/2015 Jarnagin et al. filed on Feb. 16, 2005, provisional application No. 9,156,860 B2 10/2015 Akama et al. 9,243,003 B2 1/2016 Conde et al. 60/654,060, filed on Feb. 16, 2005. 9,353,133 B2 5, 2016 Baker et all (56) References Cited 2002fOO 10332 A1 1/2002 Vollmuller et al. 2002fOO28831 A1 3/2002 Manley 2002/0161230 A1 10, 2002 Meudt et al. U.S. PATENT DOCUMENTS 2002fO165121 A1 11/2002 Brehove 2.831,866 A 4, 1958 Freeman et al. 38885 A. 1339: Walsh et al. 3.093,659 A 6, 1963 Bell et al. agy 3.104,255 A 9, 1963 Emricket al. 2003. O181766 A1 9, 2003 Satoh et al. 3.357.525 A 1, 1967 Grier 2004/OO776O1 A1 4/2004 Adams et al. 3.370,957 A 2f1968 Wagner et all 2004/0224923 Al 11/2004 Lee et al. 3.686,398 A 8, 1972 E. al 2004/0259833 A1 12/2004 Benkovic et al. 3.816.47 A 6, 1974 Shapiro et al 2004/0259842 A1 12/2004 Mikoshiba et al. 3873.276 A 3, 1975 SE 2005.0054644 A1 3/2005 Lee et al. 4202.894 A 5, 1980 SE, 2005/O125852 A1 6/2005 Caenepeel et al. 4.602011 A 7, 1986 West et all 2006,0009386 A1 1/2006 Stossel et al. 476,035 A 12, 1987 Sam athkamar 2006/0222671 A1 10, 2006 Weidner 4.76613 A 8, 1988 Sp al 2006/0234981 A1 10, 2006 Baker et al. 4,822,822 A 4, 1989 Arita et al 2007/O155699 A1 7/2007 Baker et al. 4894.220 A 1, 1990 Nabi et al. 2007/0286822 A1 12/2007 Sanders et al. 4.919,934 A 4, 1990 Deckner et al 2007,02934.57 A1 12/2007 Baker et al. 4977.268 A 12, 1990 McPhail et al. 2009/0227541 A1 9, 2009 Baker et al. 5,264.206 A 11/1993 Bohn et all 2010.0048570 A1 2/2010 Kim et al. 5.348,947 A 9, 1994 Patel et al, 2010, O256092 A1 10, 2010 Xia et al. - I w 2013,00598O2 A1 3/2013 Baker et al. 5,348,948 A 9, 1994 Patel et al. 2013,00598O3 A1 3, 2013 Baker et all 5.498,407 A 3, 1996 Atlas 5.59.1731 A 1/1997 Kennedy et all 2013, OO64783 A1 3/2013 Baker et al. 5,668,258- - - A 9, 1997 Stollowitzly et al. 2013,0210770 A1 8, 2013 Baker et al. 5,688,928 A 11, 1997 Stollowitz 2014/O142064 A1 5, 2014 Baker et al. 5,831,045 A 11/1998 Stollowitz et al. 2014/0221631 A1 8, 2014 Baker et al. 5,880,188 A 3, 1999 Austin et al. 2015,0065459 A1 3/2015 Baker et al. 5,962.498 A 10/1999 Driedger et al. 2015, 0119364 A1 4/2015 Baker et al. 6,042,845. A 3, 2000 Sun et al. 6,080,774 A 6/2000 Murugesan et al. FOREIGN PATENT DOCUMENTS 6,083,903. A 7/2000 Adams et al. 6,143,794. A 11/2000 Chaudhuri et al. EP 1155698 A1 11 2001 6,221,640 B1 4/2001 Tao et al. EP 1 444981 A1 8, 2004 6,224,887 B1 5, 2001 Samour et al. JP 2002-53583 A 2, 2002 6,306.628 B1 10/2001 Rothschild et al. JP 2002-508359 A 3, 2002 6,369,098 B1 4/2002 Pershadsingh et al. JP 2003-212837. A T 2003 6,521,619 B2 2/2003 Link et al. JP 2004-5.14669. A 5, 2004 6,699.994 B1 3, 2004 Babu et al. JP 2005-022986 A 1, 2005 6,800,645 B1 10/2004 Cox et al. WO WO 9533754 5, 1995 6,855,848 B2 2/2005 Scherer et al. WO WO 9622O23 A1 T 1996 7,074,392 B1 7/2006 Friedman et al. WO WO 9812206 A1 3, 1998 7,169,603 B2 1/2007 Hedley et al. WO WOOO27822 5, 2000 7,205.425 B2 4/2007 Shibasaki et al. WO WOOO44387 A1 8, 2000 7,217,701 B2 5, 2007 Mikoshiba et al. WO WOOO75142 A2 12/2000 7,390,806 B2 6, 2008 Lee et al. WO WO O114578 A1 3, 2001 7,446,236 B2 11/2008 Naud et al. WO WO O149303 A1 T 2001 7.465,836 B2 12/2008 Lee et al. WO WO O187846 A2 11/2001 7,582,621 B2 * 9/2009 Baker ...... CO7F 5/O2 WO WO O244.184 6, 2002 514,64 WO WO O3,OO9689 A1 2, 2003 7,767,657 B2 8, 2010 Baker et al. WO WO O30330O2 A1 4/2003 7.816,344 B2 10/2010 Baker et al. WO WO O3059916 A2 T 2003 8,039,450 B2 10/2011 Akama et al. WO WO 2004/043925 A2 5, 2004 8,039,451 B2 10/2011 Baker et al. WO WO 2004.056322 A2 T 2004 8, 115,026 B2 2/2012 Baker et al. WO WO 2004081008 A1 9, 2004 8,168,614 B2 5, 2012 Baker et al. WO WO 2005OO2577 A1 1, 2005 8,343,944 B2 1/2013 Xia et al. WO WO 2005O13892 A3 2, 2005 8.440,642 B2 5, 2013 Baker et al. WO WO 2005/066172 7/2005 8.461,134 B2 6/2013 Hernandez et al. WO WO 2005/110410 A2 11/2005 8.461,135 B2 6/2013 Akama et al. WO WO 2005/123054 12/2005 8.461,336 B2 6, 2013 Zhou et al. WO WO 2005 123094 A2 12/2005 8.461,364 B2 6, 2013 Wheeler et al. WO WO 2006007384 1, 2006 8,470,803 B2 6/2013 Akama et al. WO WO 2006062731 A1 6, 2006 8,501,712 B2 8, 2013 Baker et al. WO WO 2006O79843 A1 8, 2006 8,546,357 B2 10/2013 Akama et al. WO WO 2006089067 A2 8, 2006 8,703,742 B2 4/2014 Hernandez et al. WO WO 2006096.131 A1 9, 2006 8,716.478 B2 5/2014 Jarnagin et al. WO WO 2007022437 A2 2, 2007 8,722,917 B2 5, 2014 Baker et al. WO WO 2007078340 A2 7/2007 8,853,186 B2 10/2014 Akama et al. WO WO 2007095638 A2 8, 2007 8,889,656 B2 * 1 1/2014 Baker ...... CO7F 5/O2 WO WO 2007 146965 A2 12/2007 514,64 WO WO 2008157726 A1 12/2008 US 9,566.290 B2 Page 3

(56) References Cited Kemna & Elewski. A U.S. Epidemiologic Survey of Superficial Fungal Diseases, J. Am. Acad. of Dermatol., vol. 35. No. 4, pp. FOREIGN PATENT DOCUMENTS 539-542, (1996), IPR2015-01776, Jun. 6, 2016 Exhibit 2039. Shivakumar, Repka, & Murthy, Transungual Drug Delivery: an WO WO 2009111676 A2 9, 2009 WO WO 2009 140309 A2 11/2009 Update, J. Drug Del. Sci. Tech., vol. 24. No. 3, pp. 301-310 (2014) WO WO 2010O28005 A1 3, 2010 (Ex. 3 from Murthy Deposition), IPR2015-01776, Jun. 6, 2016 WO WO 2010O45503 A 4/2010 Exhibit 2040. WO WO 2010O455.05 A1 4/2010 Topical Nail Products and Ungual Drug Delivery (S. Narasimha WO WO 2015/171186 11/2015 Murthy & Howard I. Maibach eds., 2013) (Ex. 4 from Murthy Deposition), 300 pages, IPR2015-01776, Jun. 6, 2016 Exhibit OTHER PUBLICATIONS 2041. . Appl. No. 1 1/762,038, filed Jun. 12, 2007, now abandoned. Koo et al., Synthesis and Comparative Toxicology of a Series of . Appl. No. 1 1/865,725, filed Oct. 1, 2007, now abandoned. Polyhedral Borane Anion-Substituted Tetraphenyl Porphyrins, . Appl. No. 12,752,789, filed Apr. 1, 2010, now abandoned. J.Med. Chem., vol. 50, pp. 820-827 (2007), IPR2015-01776, Jun. 6, . Appl. No. 14/536,483, filed Nov. 7, 2014. 2016 Exhibit 2042. . Appl. No. 14/666,075, filed Mar. 23, 2015. Office of Toxic Substances, Environmental Protection Agency, . Appl. No. 13/062,450, filed Mar. 4, 2011. “Preliminary Investigation of Effects on the Environment of Boron, . Appl. No. 12.464,829, filed May 12, 2009, now abandoned. Indium, Nickel, Selenium, Vanadium and Their Compounds,” EPA . Appl. No. 12/873,036, filed Aug. 31, 2010, now abandoned. 56/2-75-005A (Aug. 1975) available at http://nepis.epa.gov/Exe/ . Appl. No. 13/503,016, filed Jun. 25, 2012, now allowed. ZyPDF.cgi/910 1277V.PDF?Dockey=910 1277V.PDF, 118 pages, . Appl. No. 12/857.305, filed Aug. 16, 2010, now abandoned. IPR2015-01776, Jun. 6, 2016 Exhibit 2043). . Appl. No. 12/852.351, filed Aug. 6, 2010. Van Proosdij-Hartzema, Boriumverbindingen: Verleden, Heden en . Appl. No. 14/852,122, filed Sep. 11, 2015. Toekomst, Ned. T. Geneesk., vol. 110, No. 51, pp. 2260-2269 . Appl. No. 12/944,699, filed Nov. 11, 2010, now abandoned. (1966) with certified English translation, IPR2015-01776, Jun. 6, . Appl. No. 14/969.467, filed Dec. 15, 2015. 2016 Exhibit 2044. . Appl. No. 14/221,637, filed Mar. 21, 2014. Elewski et al., Efficacy, Safety and Tolerability of Topical . Appl. No. 14/852.220, filed Sep. 11, 2015. . Appl. No. 14/760,208, filed Jul. 10, 2015. Terbinafine Nail Solution in Patients with Mild-to-Moderate Toenail . Appl. No. 14/394.427, filed Oct. 14, 2014. Onychomycosis: Results from Three Randomized Studies using . Appl. No. 14/765,152, filed Jul. 31, 2015. Double-Blind Vehicle-Controlled and Open-Label Active-Con . Appl. No. 14/906,849, filed Jan. 21, 2016. trolled Designs, J. Eur, Acad. Derm. & Vener, vol. 27. No. 3, pp. .S. Appl. No. 14/910.996, filed Feb. 8, 2016. 287-294 (2013), IPR2015-01776, Jun. 6, 2016 Exhibit 2045. Patent Owner's Response Pursuant to 37 C.F.R. S. 42.120, 74 pages, Cecil Textbook of Medicine, (J. Claude Bennett & Fred Plum ed., IPR2015-01776, Jun. 6, 2016. 1996), 6 pages, IPR2015-01776, Jun. 6, 2016 Exhibit 2046. Patent Owner's Exhibit List, 22 pages, IPR2015-01776, Jun. 6, Hay et al., Fungal (onychomycosis) and other Infections Involving 2016. the Nail Apparatus in Baran and Dawber's Diseases of the Nails and Curriculum Vitae of Mahmoud A. Ghannoum, IPR2015-01776, Jun. their Management, (R. Baran et al., eds., 2001), 51 pages, IPR2015 6, 2016 Exhibit 2029. 0.1776, Jun. 6, 2016 Exhibit 2047. Curriculum Vitae of Paul J. Reider, Ph.D., IPR2015-01776, Jun. 6, EPA Correspondence, 1992 Labeling Rev. Amended Biobor Label 2016 Exhibit 2030. available at https://www3.epa.gov/pesticides/chem search/ppls/ Curriculum Vitae of Howard Ira Maibach, M.D., (Honorary) Ph.D., 065217-00001-19920403.pdf, 5 pages, IPR2015-01776, Jun. 6, IPR2015-01776, Jun. 6, 2016 Exhibit 2031. 2016 Exhibit 2048. Deposition of Narasimha Murthy, Ph.D., vol. 1 of 3, Case No. Ghannoum et al., A Large-Scale North American Study of Fungal IPR2015-01776 U.S. Pat. No. 7,582,621, Case No. IPR2015-01780 Isolates From Nails: The Frequency of Onychomycosis, Fungal U.S. Pat. No. 7,767,657, Case No. IPR2015-01785 U.S. Pat. No. Distribution, and Antifungal Susceptibility Patterns, J. Am. Acad. 7,767.567, May 4, 5, 6, and 12, 2016, 638 pages, Jun. 6, 2016 Exhibit 2032. Dermatol., vol.43, No. 4, pp. 641-648 (2000), IPR2015-01776, Jun. Deposition of Stephen B. Kahl, Ph.D., vol. 1, Case No. IPR2015 6, 2016 Exhibit 2049. 0.1776 U.S. Pat. No. 7,582,621, Case No. IPR2015-01780 U.S. Pat. Segal et al., Treatment of Candida Nail Infection with Terbinafine, No. 7,767,657, Case No. IPR2015-01785 U.S. Pat. No. 7,767.567, J. Am. Acad. Dermatol., vol. 35. No. 6, pp. 958-961 (1996), Apr. 7 and 8, 2016, 583 pages, Jun. 6, 2016 Exhibit 2033). IPR2015-01776, Jun. 6, 2016 Exhibit 2050. Declaration of Paul J. Reider, Ph.D. in Support of Patent Owner Rock et al., Antifungal Agent Inhibits an Aminoacyl-tRNA Response, 96 pages, IPR2015-01776, Jun. 6, 2016 Exhibit 2034). Synthetase by Trapping tRNA in the Editing Site, Science, vol. 316, Declaration of Mahmoud A. Ghannoum, Ph.D. E.M.B.A., in Sup pp. 1759-1761 (2007), IPR2015-01776, Jun. 6, 2016 Exhibit 2051. port of Patent Owner Response, Pursuant to 37 C.F.R. S. 42.120, 85 Soloway et al., Penetration of Brain and Brain Tumor by Aromatic pages, IPR2015-01776, Jun. 6.2016 Exhibit 2035). Compounds as a Function of Molecular Substituents, J. Declaration of Majella Lane, Ph.D., in Support of Patent Owner Pharmacol. & Exp. Therapeutics, vol. 129, pp. 310-314 (1960), Response, Pursuant to 37 C.F.R. S. 42.120, 28 pages, IPR2015 IPR2015-01776, Jun. 6, 2016 Exhibit 2052). 0.1776, Jun. 6, 2016 Exhibit 2036). Baran et al., Onychomycosis: The Current Approach to Diagnosis Declaration of Howard I. Maibach, Ph.D., in Support of Patent and Therapy, Martin Dunitz Publishers, London, U.K. (1999), Owner Response, Pursuant to 37 C.F.R. S. 42.120, 33 pages, IPR2015-01776, Jun. 6, 2016 Exhibit 2053. IPR2015-01776, Jun. 6, 2016 Exhibit 2037. Gupchup & Zatz, Structural Characteristics and Permeability Prop Fletcher et al., Onychomycosis: The Development of a Clinical erties of the Human Nail: A Review, 50 J. Cosmet. Sci. 363, 363-85 Diagnostic Aid for Toenail Disease, Part I. Establishing Discrimi (Nov./Dec. 1999), IPR2015-01776, Jun. 6, 2016 Exhibit 2054. nating Historical and Clinical Features, Brit. J. Dermatol., vol. 150, Elkeeb et al., Tranungual Drug Delivery: Current Status, 384 No. 4, pp. 701-705 (2004), IPR2015-01776, Jun. 6, 2016 Exhibit Internat. J. Pharm. 1-8 (2010), IPR2015-01776, Jun. 6, 2016 2038. Exhibit 2055. US 9,566.290 B2 Page 4

(56) References Cited http://www.accessdata.fda.gov/drugsatfda docs/label/2004/20083s 034,035lbl.pdf (label), IPR2015-01776, Jun. 6, 2016 Exhibit OTHER PUBLICATIONS 2074. FDA Approved Label for Lamisil(R) (Supplement 012, Action Date Scher, Onychomycosis: Therapeutic Update, J. Am. Acad. Derm. Jan. 21, 2004) available at http://www.accessdata.fda.gov/ vol. 40, No. 6 (part 2), pp. S21-S26 (1999), IPR2015-01776, Jun. 6, drugsatfda docs/appletter/2004/205 39slr012ltrpdf (letter) and 2016 Exhibit 2056. http://www.accessdata.fda.gov/drugsatfda docs/label/2004, Baeza et al., cDNA Representational Difference Analysis Used in 20539sl rO 12 lamisil Iblpdf (label), IPR2015-01776, Jun. 6, 2016 the Identification of Genes Expressed by Trichophyton rubrum Exhibit 2075. During Contact with Keratin, Microbes & Infection, vol. 9, pp. FDA Approved Label for Gris-PEG(R) (Supplement 046. Action 1415-1421 (2007), IPR2015-01776, Jun. 6, 2016 Exhibit 2057. Date Mar. 26, 2003) available at http://www.accessdata.fda.gov/ Hamaguchi et al., Characterization of an Extracellular Keratinase drugsatfda docs/appletter/2003/504 75slr046ltrpdf (letter) and from Microsporum canis, Jpn. J. Med. Mycol., vol. 41, No. 4, pp. http://www.accessdata.fda.gov/drugsatfda docs/label/2003/ 257-262, (2000), IPR2015-01776, Jun. 6, 2016 Exhibit 2058. 50475sl rO46 gris-peg lbl.pdf (label), IPR2015-01776, Jun. 6, Foster et al., Epidemiologic Surveillance of Cutaneous Fungal 2016 Exhibit 2076). Infection in the United States from 1999 to 2002, Am. Acad. FDA Approved Label for PenlacR), (Supplement 004. Action Date Dermatol., vol. 50, No. 5, pp. 748-752 (2004), IPR2015-01776, Jun. Dec. 3, 2004) available at http://www.accessdata.fda.gov/ 6, 2016 Exhibit 2059. drugsatfda docs/appletter/2004/210 22.s004ltripdf (letter) and Jinna & Finch, Spotlight on Tavaborole for the Treatment of http://www.accessdata.fda.gov/drugsatfda docs/label/2004/21022s Onychomycosis, Drug Des. Devel. Ther... vol. 5, No. 9, pp. 6185 0041blpdf (label), IPR2015-01776, Jun. 6, 2016 Exhibit 2077. 6190, (Nov. 20, 2015), IPR2015-01776, Jun. 6, 2016 Exhibit Naglik et al., Candida albicans Secreted Aspartyl Proteinases in 2060. Virulence and Pathogenesis, Microbio. & Molecular Bio. Revs. vol. Childs-Kean & Joury, Antifungal Penetration into the Nail and New 67, No. 3, pp. 400-428 (2003), IPR2015-01776, Jun. 6, 2016 Topicals for Onychomycosis, Curr. Fungal Infect. Rep., vol. 10, pp. Exhibit 2078. 24-29 (2016), IPR2015-01776, Jun. 6, 2016 Exhibit 2061. Hattori et al., Keratinolytic Proteinase Produced by Candida Rosen & Stein Gold, Antifungal Drugs for Onychomycosis: Effi albicans, Sabouraudia: J. Med. Vet. Mycology, vol. 22, No. 3, pp. cacy, Safety, and Mechanisms of Action, Semin. Cutan. Med. Surg., 175-183 (1984), IPR2015-01776, Jun. 6, 2016 Exhibit 2079). vol. 35, No. 3S, pp. S51-S55 (Mar. 2016), IPR2015-01776, Jun. 6, Weary & Canby, Absence of Keratinolytic Activity in Three Strains 2016 Exhibit 2062. of Candida albicans, J. Invest. Derm., vol. 46, No. 5, pp. 464-734 Poulakos et al., Efinaconazole and Tavaborole: Emerging (1966), IPR2015-01776, Jun. 6, 2016 Exhibit 2080). Antifungal Alternatives for the Topical Treatment of Nenoff et al., Mycology—An Update. Part 1: Dermatomycoses: Onychomycosis, J. Pharm. Pract... advance online publication, doi: Causative Agents, Epidemiology and Pathogenesis, J. Dtsch. Derm. 10.1177/08971900 16630904, pp. 1-11 (2016), IPR2015-01776, Jun. Ges., vol. 12, No. 3, pp. 188-210 (2014) (including English online 6, 2016 Exhibit 2063). version on Wiley Online Library), IPR2015-01776, Jun. 6, 2016 Drake et al., Effect of Onychomycosis on Quality of Life, J. Am. Exhibit 2081. Acad. Dermatol., vol. 38, No. 5, Part 1, pp. 702-704 (1998), Balkis et al., Mechanisms of Fungal Resistance, Drugs, vol. 62(7), IPR2015-01776, Jun. 6, 2016 Exhibit 2064. pp. 1025-1040 (2002), IPR2015-01776, Jun. 6, 2016 Exhibit 2082). Scher et al., Onychomycosis: Diagnosis and Definition of Cure, J. CLSI, Reference Method for Broth Dilution Antifungal Suscepti Am. Acad. Dermatol., vol. 56, No. 6, pp. 939-944 (2007), IPR2015 bility Testing of Filamentous Fungi; Approved Standard-Second 0.1776, Jun. 6, 2016 Exhibit 2065). Edition, CLSI document M38-A2 (2008), IPR2015-01776, Jun. 6, Summerbell et al., Onychomycosis, Tinea Pedis and Tinea Manuum 2016 Exhibit 2083. Caused by Non-Dermatophytic Filamentous Fungi, Mycoses, vol. Ghannoum et al., Intra- and Interlaboratory Study for Testing the 32, No. 12, pp. 609-619 (1989), IPR2015-01776, Jun. 6, 2016 Antifungal Susceptibilities of Dermatophytes, J. Clin. Microbiol. Exhibit 2066. vol. 42, No. 7, pp. 2977-2979 (2004), IPR2015-01776, Jun. 6, 2016 Ellis et al., Non-Dermatophytes in Onychomycosis of the Toenails, Exhibit 2084. Brit. J. Dermatol., vol. 136, pp. 490-493 (1997), IPR2015-01776, Norris et al., Optimal Growth Conditions for the Determination of Jun. 6.2016 Exhibit 2067). the Antifungal Susceptibility of Three Species of Dermatophytes McGinley et al., Composition and Density of Microflora in the with the Use of a Microdilution Method, J. Am. Acad. Dermatol., Subungual Space of the Hand, J. Clin. Microbiol., vol. 26, No. 5, pp. vol. 40, No. 6, pp. S9-S13, (1999), IPR2015-01776, Jun. 6, 2016 950-953 (1988), IPR2015-01776, Jun. 6, 2016 Exhibit 2068. Exhibit 2085. Strausbaugh et al., High Frequency of Yeast Carriage on Hands of Jessup et al., Antifungal Susceptibility Testing of Dermatophytes: Hospital Personnel, J. Clin. Microbiol., vol. 32, No. 9, pp. 2299 Establishing a Medium for Inducing Conidial Growth and Evalua 2300 (1994), IPR2015-01776, Jun. 6, 2016 Exhibit 2069). tion of Susceptibility of Clinical Isolates, J. Clin. Microbiol., vol. Elewski, Onychomycosis: Pathogenesis, Diagnosis, and Manage 38, No. 1, pp. 341-344 (2000), IPR2015-01776, Jun. 6, 2016 ment, Clin. Microbiol. Rev., vol. 11, No. 3, pp. 415-429(1998), Exhibit 2086). IPR2015-01776, Jun. 6, 2016 Exhibit 2070. Kokjohn et al., Evaluation of in vitro Activity of Ciclopirox Summerbell, Nondermatophytic Molds Causing Dermatophytosis Olamine, Butenafine HCl and Econazole Nitrate Against Like Nail and Skin Infection, in Laboratory Handbook of Dermatophytes, Yeasts and Bacteria, Int'l J. Dermatol., vol. 42. Dermatophytes, Chap. 8, pp. 213-256 (Kane et at, eds. 1997), suppl. 1, pp. 11-17 (2003), IPR2015-01776, Jun. 6, 2016 Exhibit IPR2015-01776, Jun. 6, 2016 Exhibit 2071. 2087. Weitzman & Summerbell, the Dermatophytes, Clin. Microbio. Rev. NCCLS (now CLSI), Reference Method for Broth Dilution vol. 8, No. 2, pp. 240-259 (1995), IPR2015-01776, Jun. 6, 2016 Antifungal Susceptibility Testing of Yeasts; Approved Standard— Exhibit 2072. Second Edition, NCCLS document M27-A2 (2002), IPR2015 Gupta et al., Pulse ltraconazole vs. Continuous Terbinafine for the 0.1776, Jun. 6, 2016 Exhibit 2088). Treatment of Dermatophyte Toenail Onychomycosis in Patients Mukherjee et al., Combination Treatment of Invasive Fungal Infec with Diabetes Mellitus, J. Euro. Acad. Dermatol. & Venerol., vol. tions, Clin. Microbiol. Rev., vol. 18, No. 1, pp. 163-194 (2005), 20, pp. 1188-1193 (2006), IPR2015-01776, Jun. 6, 2016 Exhibit IPR2015-01776, Jun. 6, 2016 Exhibit 2089. 2073. Ghannoum & Rice, Antifungal Agents: Mode of Action, Mecha FDAApproved Label for Sporanox(R) (Supplement 034. Action Date nisms of Resistance, and Correlation of These Mechanisms with Jul. 14, 2004) available at http://www.accessdata.fda.gov/ Bacterial Resistance, Clin. Microbiol. Rev., vol. 12, No. 4, pp. drugsatfda docs/appletter/2004/200 83s034,035ltrpdf (letter) and 501-517 (1999), IPR2015-01776, Jun. 6, 2016 Exhibit 2090). US 9,566.290 B2 Page 5

(56) References Cited EPA Correspondence, 1997 Labeling Rev. Amended Biobor Label available at www3.epa.gov/pesticides/chem search/ppls/065217 OTHER PUBLICATIONS 000001-19970327.pdf, IPR2015-01776, Jun. 6, 2016 Exhibit 2109. Gupta et al., Drug Interactions with Itraconazole, Fluconazole, and Ferrari et al., Occurrence of Heterotrophic Bacteria and Fungi in an Terbinafine and their Management, J. Am. Acad. Dermatol., vol. 41. Aviation Fuel Handling System and its Relationship with Fuel No. 2, pp. 237-249 (1999), IPR2015-01776, Jun. 6, 2016 Exhibit Fouling, Revista Argentina de Microbiologia, vol. 30, No. 3, pp. 2091. 105-114 (1998), IPR2015-01776, Jun. 6, 2016 Exhibit 2110). Gupta & Lyons, The Rise and Fall of Oral Ketoconazole, J. Aly, Ecology and Epidemiology of Dermatophyte Infections, J. Am. Cutaneous Med. & Surgery, vol. 19, No. 4, pp. 352-357 (2015), Acad. Derm., vol. 31, No. 3, pp. S21-S25 (1994), IPR2015-01776, IPR2015-01776, Jun. 6, 2016 Exhibit 2092. Jun. 6.2016 Exhibit 2111. Gull & Trinci, Griseofulvin Inhibits Fungal Mitosis, Nature, vol. Crane & Sanders, Evaluation of a Biocidal Turbine-Fuel Additive, 244, pp. 292-294 (1973), IPR2015-01776, Jun. 6, 2016 Exhibit Aviation Medical Report—AM 67-21, pp. 1-10 (Federal Aviation 2093. Administration, Office of Aviation Medicine 1967) available at Ku et al., Mutation of a Major Keratin Phosphorylation Site http://www.faa.gov/data research/research/med humanfacs/ Predisposes to Hepatotoxic Injury in Transgenic Mice, J. Cell Biol. oamtechreports/1960s/media/amó7-21.pdf, IPR2015-01776, Jun. 6, 2016 Exhibit 2112). vol. 143, No. 7, pp. 2023-2032 (1998), IPR2015-01776, Jun. 6, 2016 Alley et al., Recent Progress on the Topical Therapy of Exhibit 2094. Onychomycosis, Expert Opin. Investig. Drugs, vol. 16, No. 2, pp. Katz, Possible Drug Interactions in Oral Treatment of 157-167 (2007), IPR2015-01776, Jun. 6, 2016 Exhibit 2113). Onychomycosis, J. Am. Podiatr. Med. Ass'n, vol. 87, No. 12, pp. Smith & March, March's Advanced Organic Chemistry: Reactions, 571-574 (1997), IPR2015-01776, Jun. 6, 2016 Exhibit 2095). Mechanism, and Structure, John Wiley & Sons, New York, NY (5th Nguyen & Yu, Voriconazole Against Fluconazole-Susceptible and ed., 2001), IPR2015-01776, Jun. 6, 2016 Exhibit 2114). Resistant Candida Isolates: in-vitro Efficacy Compared with that of Batsanov, Van der Weals Radii of Elements, Inorg. Materials, vol. Itraconazole and Ketoconazole, J. Antimicrobial Chemotherapy, 37, pp. 871-885 (2001), IPR2015-01776, Jun. 6, 2016 Exhibit vol. 42, pp. 253-256 (1998), IPR2015-01776, Jun. 6, 2016 Exhibit 2115. 2096. Henman et al., Effects of Decaborane on Gastric Secretion in the Johnson & Kauffman, Voriconazole: A New Triazole Antifungal Shay Rat, Br. J. Pharmacol., vol. 40, No. 1, p. 164P (1970), Agent, Clin. Infect. Dis... vol. 36, No. 5, pp. 630-637 (2003), IPR2015-01776, Jun. 6, 2016 Exhibit 2116. IPR2015-01776, Jun. 6, 2016 Exhibit 2097. Steiner et al., Diphenylborinic Acid Is a Strong Inhibitor of Serine Elewski & Tavakkol, Safety and Tolerability of Oral Antifungal Proteases, Bioorg. & Med. Chem. Lett., vol. 4, pp. 2417-2420 Agents in the Treatment of Fungal Nail Disease: a Proven Reality, (1994), IPR2015-01776, Jun. 6, 2016 Exhibit 2117. Hall, Boronic Acids, Prep. and App. in Organic Synthesis and Med., Ther. Clin. Risk Manag., vol. 1, No. 4, pp. 299-306 (2005), pp. 123-131(Wiley-VCH, 2005), IPR2015-01776, Jun. 6, 2016 IPR2015-01776, Jun. 6, 2016 Exhibit 2098. Exhibit 2118. Center for Drug Evaluation and Research, Guidance for Industry: Hall, Boronic Acids, Prep. and App. in Organic Synthesis and Med., Clinical Development and Labeling of Anti-Infective Drug Products pp. 28-49 (Wiley-VCH, 2005), IPR2015-01776, Jun. 6, 2016 (1992) available at http://www.fda.gov/downloads/Drugs, Exhibit 2119. GuidanceComplianceRegulatoryInformation/Guidances/ Iliev et al., Skin Roughness is Negatively Correlated to Irritation UCM070975.pdf, IPR2015-01776, Jun. 6, 2016 Exhibit 2099. with DMSO, but not with NaOH and SLS, Exp. Dermatol., vol. 6, Rodgers & Bassler, Treating Onychomycosis, Am. Fam. Physician, No. 4, pp. 157-160 (1997), IPR2015-01776, Jun. 6, 2016 Exhibit vol. 63, No. 4, pp. 663-672 (2001), IPR2015-01776, Jun. 6, 2016 2120. Exhibit 2100. DiMasi et al., Innovation in the Pharmaceutical Industry: New Ghannoum et al. Amorolfine 5% Nail Lacquer Exhibits Potent Estimates of R&D Costs, J. Health. Econ... vol. 47, pp. 20-33 (2016), Antifungal Activity Compared to Three Acid-Based Devices Indi IPR2015-01776, Jun. 6, 2016 Exhibit 2121. cated for the Treatment of Onychomycosis An In Vitro Nail Pen Endo, The Discovery and Development of HMG-CoA Reductase etration Assay, Derm. & Therapy, vol. 6, No. 1, pp. 69-75 (2016), Inhibitors, J. Lipid Res., vol. 33, pp. 1569-1582 (1992), IPR2015 IPR2015-01776, Jun. 6, 2016 Exhibit 2101). 0.1776, Jun. 6, 2016 Exhibit 2122. Declaration of Jennifer Augsburger in Support of Patent Owner's O'Driscoll et al., Simvastatin, an Hmg-Coenzyme A Reductase Response, IPR2015-01776, Jun. 6, 2016 Exhibit 2102. Inhibitor, Improves Endothelial Function Within 1 Month, Circu Fukuoka et al., Genetic Basis for Differential Activities of lation, vol. 95, pp. 1126-1131 (1997), IPR2015-01776, Jun. 6, 2016 Fluconazole and Voriconazole against Candida krusei, Antimicrob. Exhibit 2123. Agents Chemother, vol. 47, No. 4, pp. 1213-1219 (2003), IPR2015 Tenjarla et al., Preparation, Characterization, and Evaluation of 0.1776, Jun. 6, 2016 Exhibit 2103). Miconazole-Cyclodextrin Complexes for Improved Oral and Topi Orozco et al., Mechanism of Fluconazole Resistance in Candida cal Delivery, J. Pharm. Sci., vol. 87, No. 4, pp. 425-429 (1998), krusei, Antimicrob. Agents Chemother, vol. 42, No. 10, pp. 2645 IPR2015-01776, Jun. 6, 2016 Exhibit 2124). 2649 (1998), IPR2015-01776, Jun. 6, 2016 Exhibit 2104). Dixon & Villar, Bioactive Diversity and Screening Library Selec Nimura et al., Comparison of In Vitro Antifungal Activities of tion Via Affinity Fingerprinting, J. Chem. Info. & Comp. Sci., vol. Topical Antimycotics Launched in 1990s in Japan, Int'l J. 38, pp. 1192-1203 (1998), IPR2015-01776, Jun. 6, 2016 Exhibit Antimicrob. Agents, vol. 18, pp. 173-178 (2001), IPR2015-01776, 2125. Jun. 6, 2016 Exhibit 2105. Silverman, The Organic Chemistry of Drug Design and Drug Ghannoum et al., Terbinafine HCl Nail Solution With and Without Action, Elsevier Academic Press, Evanston, Il. (2d Ed., 2004), Nail Penetration Enhancer: Evaluation of Minimum Inhibitory IPR2015-01776, Jun. 6, 2016 Exhibit 2126. Concentration and Minimum Fungicidal Concentrations, (abstract) Cursiefen & Bergua, Acute Bilateral Blindness Caused by Acci J. Am. Acad. Dermatol., vol. 58, No. 2, suppl. 2, p. AB12 (2008), dental Methanol Intoxication During Fire "Eating.” Br. J. IPR2015-01776, Jun. 6, 2016 Exhibit 2106. Ophthamol., vol. 86, pp. 1064-1065 (2002), IPR2015-01776, Jun. 6, Ghannoum et al., Determination of the Efficacy of Terbinafine 2016 Exhibit 2127. Hydrochloride Nail Solution in the Topical Treatment of DeCamp & Kahl et al., Specific Inhibition of HIV-1 Protease by Dermatophytosis in a Guinea Pig Model, Mycoses, vol. 52, No. 1, Boronated Porphyrins, J. Med. Chem... vol. 35, pp. 3426-3428 pp. 35-43 (2009), IPR2015-01776, Jun. 6, 2016 Exhibit 2107. (1992), IPR2015-01776, Jun. 6, 2016 Exhibit 2128). Rex et al., Antifungal Susceptibility Testing, Clin. Microbio. Revs. Soloway, Correlation of Drug penetration of Brain and Chemical vol. 6, No. 4, pp. 367-381 (1993), IPR2015-01776, Jun. 6, 2016 Structure, Science, vol. 128, pp. 1572-1574 (1958), IPR2015 Exhibit 2108. 0.1776, Jun. 6, 2016 Exhibit 2129. US 9,566.290 B2 Page 6

(56) References Cited Boislambert & Wangen, Respecting a New Tranquilizer (Critical Study), Nanterre Departmental Center (1960) with certified English OTHER PUBLICATIONS translation, IPR2015-01776, Jun. 6, 2016 Exhibit 2153. Biobor JF Service Bulletin No. 982, Biobor JF Aviation Fuel Soloway et al., Evaluation of Boron Compounds for Use in Neutron Additive (1992), IPR2015-01776, Jun. 6, 2016 Exhibit 2154). Capture Therapy of Brain Tumors. I. Animal Investigations, J. Wu et al., Cell Immobilization Using PVA Crosslinked with Boric Pharmacol. & Exp. Therapeutics, vol. 134, pp. 117-122 (1961), Acid, Biotech. & Bioeng, vol. 39, pp. 447-449 (1992), IPR2015 IPR2015-01776, Jun. 6, 2016 Exhibit 2130. 0.1776, Jun. 6, 2016 Exhibit 2155. Soloway et al., Penetration of Brain and Brain Tumor by Aromatic Freeman Prosecution History, Amendment & Remarks (Aug. 5, Compounds as a Function of Molecular Substituents. III, J. Med. 2009), IPR2015-01776, Jun. 6, 2016 Exhibit 2156). Chem., vol. 5, pp. 191-196 (1962), IPR2015-01776, Jun. 6, 2016 Roberts, Onychomycosis: Current Treatment and Future Chal Exhibit 2131. lenges, 141 (Suppl. 56) Brit. J. of Derm. 1, 1-4 (1999), IPR2015 Dominguez et al. S1 Heterocyclic Thrombin Inhibitors, Bioorg. & 0.1776, Jun. 6, 2016 Exhibit 2158. Med. Chem. Lett., vol. 7, pp. 79-94 (1997), IPR2015-01776, Jun. 6, Vlahovic at al., Evaluation of the Appearance of Nail Polish 2016 Exhibit 2133). Following Daily Treatment of Ex Vivo Human Fingernails with Fevig et al., Rational Design of Boropeptide Thrombin Inhibitors: Topical Soliutionss of Tavaborole or Efinaconazole, J. of Drugs in B.B-Dialkylphenethylglycine P2 Analogs of Dup 714 With Greater Derm. (2016), IPR2015-01776, Jun. 6, 2016 Exhibit 2159). Selectivity over Complement Factor I and an Improved Safety Freedberg et al., Fitzpatrick's Dermatology in General Medicine, Profile, Bioorg. & Med. Chem. Lett., vol. 8, pp. 301-306 (1998), McGraw-Hill Co. (6th ed. 2003), IPR2015-01776, Jun. 6, 2016 IPR2015-01776, Jun. 6, 2016 Exhibit 2134). Exhibit 2160. Lewis, Sax's Dangerous Properties of Industrial Materials, John Rosen et al., Onychomycosis: Epidemiology, Diagnosis, and Treat Wiley & Sons, New York, NY. (10th ed., 2000), IPR2015-01776, ment in a Changing Lanscape, J. of Drugs in Derm... vol. 14, No. 3, Jun. 6, 2016 Exhibit 2135. pp. 223-228 (2015), IPR2015-01776, Jun. 6, 2016 Exhibit 2161). Vyakaranam et al., New Boron Analogues of Pyrophosphates and Tom & Kane, Management of Toenail Onychomycosis, Am. J. Deoxynucleoside Boranophosphates, Metal Based Drugs, vol. 8, pp. Health-Syst. Pharm, vol. 56, No. 9, pp. 865-871 (1999), IPR2015 145-148 (2001), IPR2015-01776, Jun. 6, 2016 Exhibit 2136). 0.1776, Jun. 6, 2016 Exhibit 2162. Philipp & Bender, Inhibition of Serine Proteases by Arylboronic Stier et al., Patient Satisfaction with Oral versus Nonoral Thera Acids, PNAS USA, vol. 68, pp. 478-480 (1971), IPR2015-01776, peutic Approaches in Onychomycosis, J. of the Am. Pod. Med. Jun. 6, 2016 Exhibit 2137. Assoc., vol. 91, No. 10, pp. 521-527 (Nov./Dec. 2001), IPR2015 Kettner & Shenvi. Inhibition of the Serine Proteases Leukocyte 0.1776, Jun. 6, 2016 Exhibit 2163). Elastase, Pancreatic Elastase, Cathepsin G, and Chymotrypsin by Del Rosso, The Role of Topical Antifungal Therapy for Peptide Boronic Acids, J. Biol. Chem... vol. 259, pp. 15106-15114 Onychomycosis and the Emergence of Newer Agents, J. of Clin. and (1984), IPR2015-01776, Jun. 6, 2016 Exhibit 2138. Aesth. Derm., vol. 7, No. 7, pp. 10-18 (2014), IPR2015-01776, Jun. Whyte et al., Molecular Recognition With Boronic Acids—Appli 6, 2016 Exhibit 2164). cations in Chemical Biology, J. Chem. Biol., vol. 6, pp. 161-174 Wang & Sun, Human Nail and Its Topical Treatment: Brief Review (2013), IPR2015-01776, Jun. 6, 2016 Exhibit 2139. of Current Research and Development of Topical Antifungal Drug Biobor Label (Kahl Dep. Ex. 77), IPR2015-01776, Jun. 6, 2016 Delivery for Onychomycosis Treatment, J. of Cosm. Sci., vol. 50. Exhibit 2140). No. 1, pp. 71-74 (1999), IPR2015-01776, Jun. 6, 2016 Exhibit Truhautet al. Effects of Repeated Injections of Low Doses of Boron 2165). Derivatives on Reproductive Function in Rats, C. R. Acad. Sc. Paris, Ameen et al., British Association of Dermatologists’ Guidelines for pp. 5099-5102 (May 20, 1964) with certified English translation, the Management of Onychomycosis 2014, British J. Dermatol., vol. IPR2015-01776, Jun. 6, 2016 Exhibit 2141. 171, No. 5, pp. 937-958 (2014), IPR2015-01776, Jun. 6, 2016 Truhaut & Nguyen, Study of the Distribution of Three Boron Exhibit 2166. Derivatives in Organisms and the Rate of Unbinding Over the Vlahovic et al., Diagnosis and Management of Onychomycosis: Course of Various Forms of Experimental Intoxication in Animals, Perspectives from a Joint Podiatric Medicine-Dermatology Round Ann. Biol. Clin., vol. 23, pp. 84-105 (1965) with certified English table, J. of the Am. Pod. Med. Assoc., vol. 106, No. 2, pp. 155-162 translation, IPR2015-01776, Jun. 6, 2016 Exhibit 2142). (Mar/Apr. 2016), IPR2015-01776, Jun. 6, 2016 Exhibit 2167). FDA Approved Label for VelcadeR (Action Date May 13, 2003) Gupta & Paquet, Improved Efficacy in Onychomycosis Therapy, available at http://www.accessdata.fda.gov/drugsatfla docs/ap Clinics in Derm., vol. 31, No. 5, pp. 555-563 (2013), IPR2015 pletter/2003/216 02ltrpdf (letter) and http://www.accessdata.fda. 0.1776, Jun. 6, 2016 Exhibit 2168). gov/drugsatfia docs/label/2003/021602 lbl.pdf (label), IPR2015 Daly et al., Antifungals, in Handbook of Systemic Drug Treatment 0.1776, Jun. 6, 2016 Exhibit 2143). in Dermatology (Wakelin et al. eds. 2015), IPR2015-01776, Jun. 6, Austin Prosecution History, Amendment & Remarks (Jul. 7, 1998), 2016 Exhibit 2169. IPR2015-01776, Jun. 6, 2016 Exhibit 2145. U.S. Dept. of Health & Human Services, Health, United States, Caujolle, Recherches Pharmacologiques Sur Les Derives 2015 (May 2016), IPR2015-01776, Jun. 6, 2016 Exhibit 2170). Organiques Du Bore. Therapie, No. XV, pp. 791-802 (1960) with Effendy, Therapeutic Strategies in Onychomycosis, J. of the Euro. certified English translation, IPR2015-01776, Jun. 6, 2016 Exhibit Acad. of Derm. and Venereol., vol. 4. Suppl. 1, pp. S3-S10 (1995), 2147. IPR2015-01776, Jun. 6, 2016 Exhibit 217 1). Article 4(a) of Council Directive, Official Journal of the European Bodman et al., Topical Treatments for Onychomycosis: A Historical Communities, No. L. 262/169-200 (Jul 27, 1976), IPR2015-01776, Perspective, J. Am. Podiatr. Med. Assoc., vol. 93, No. 2, pp. Jun. 6, 2016 Exhibit 2148. 136-141 (2003), IPR2015-01776, Jun. 6, 2016 Exhibit 2172. The Ministry for Public Health and the National Health Insurance FDA Center for Drug Evaluation and Research, Dermatologic and Program, J. Off. Rep. Fr., pp. 483-485 (1972) with certified English Ophthalmic Drugs Advisory Committee Meeting, Nov. 4, 1999 translation, IPR2015-01776, Jun. 6, 2016 Exhibit 2149). (Transcript) available at http://www.fda.gov/ohrms/dockets/ac/99/ Dictionnaire Vidal (Office de Vulgarisation Pharmaceutique, Paris, transcpt/3564t 1.pdf, IPR2015-01776, Jun. 6, 2016 Exhibit 2173. 1964) with certified English translation, IPR2015-01776, Jun. 6, NexMed Mar. 31, 2009 Form 10-Q, http://www.sec.gov/Archives/ 2016 Exhibit 2150). edgar/data 1017491/0001144204090 25204/v148508 10q.htm, Dictionnaire Vidal (Office de Vulgarisation Pharmaceutique, Paris, IPR2015-01776, Jun. 6, 2016 Exhibit 2174. 1964) with certified English translation, IPR2015-01776, Jun. 6, PRWeb, MediQuest Announces Sale of Late Stage Onychomycosis 2016 Exhibit 2151. Program to EFFELL LLC, First in a Series of Asset Sales, Sep. 19. Vidal, Le Dictionnaire (80th ed., France, 2004) with certified 2012, http://www.prweb.com/releases/2012/9/prweb991 1525.htm, English translation, IPR2015-01776, Jun. 6, 2016 Exhibit 2152. IPR2015-01776, Jun. 6, 2016 Exhibit 2175). US 9,566.290 B2 Page 7

(56) References Cited quer, J. Pharm. Pharmacol., vol. 49, No. 3, pp. 241-245 (1997), IPR2015-01776, Jun. 6, 2016 Exhibit 2194). OTHER PUBLICATIONS Murthy et al., Iontophoretic Drug Delivery across Human Nail, J. Pharm. Sciences, vol. 96, No. 2, pp. 305-311 (2007), IPR2015 SEC, Watson Pharmaceuticals Reports Earnings Per Share of S0.48 0.1776, Jun. 6, 2016 Exhibit 21951. for Fourth Quarter 2003, Feb. 5, 2004, https://www.sec.gov/Ar Marty, Amorolfine Nail Lacquer: a Novel Formulation, J. Eur, Acad. chives/edgar/data/884629/00011046590400 2780, a04-1963 Dermatol. & Venerol., vol. 4. Suppl. 1, pp. S17-S21 (1995), lex99d 1.htm, IPR2015-01776, Jun. 6, 2016 Exhibit 2176). IPR2015-01776, Jun. 6, 2016 Exhibit 2196. SEC, Macrochem Discontinues Research and Product Development Baran, Nail Damage Caused by Weed Killers and Insecticides, Arch. Activities, Terminates Substantially All Non-Management Person Dermatol., vol. 110, No. 1, p. 467 (1974), IPR2015-01776, Jun. 6, nel, Will Seek Buyer for Company or Its Assets, Sep. 1, 2005, 2016 Exhibit 21971. http://www.sec.gov/Archives/edgar/data/743884/0000743884.0500 Little & Gordon, Survival of Fungus Cultures Maintained under 0054/exhibitO91.txt, IPR2015-01776, Jun. 6, 2016 Exhibit 2177. Mineral Oil for Twelve Years, Mycologia, vol. 59, pp. 733-736 PRNewswire, Celtic Pharma Announces Presentation of Preclinical (1967), IPR2015-01776, Jun. 6, 2016 Exhibit 2198). Data at the 69th Annual Meeting of the AAD in New Orleans, Feb. Comaish & Greener, The Inhibiting Effect of Soft Paraffin on the 7, 2011, http://www.prnewswire.com/news-releases/celtic-pharma Köbner Response in Psoriasis, British J. of Dermatol., vol. 94, pp. announces-presentation-of-preclinical-data-at-the-69th-annual 195-200 (1976), IPR2015-01776, Jun. 6, 2016 Exhibit 2199). meeting-of-the-aad-in-new-orleans- 115474199.html, IPR2015 Williams & Barry, Penetration Enhancers, Advanced Drug Delivery 0.1776, Jun. 6, 2016 Exhibit 2178. Revs., vol. 56, p. 603-18 (2004), IPR2015-01776, Jun. 6, 2016 Song & Deresinski, Hepatoxicity of Antifungal Agents, Investiga Exhibit 2200. tional Drugs, vol. 6, No. 2, pp. 170-177 (2005), IPR2015-01776, Jungbauer et al., Toxic Hygroscopic Contact Reaction to N-methyl Jun. 6, 2016 Exhibit 2179. 2-pyrrollidone, Contact Dermatitis, vol. 45, No. 5, pp. 303-304 Vlahovic, Onychomycosis Evaluation, Treatment Options, Manag (2001), IPR2015-01776, Jun. 6, 2016 Exhibit 2201). ing Recurrence, and Patient Outcomes, Clin. Podiatr. Med. Surg. Structural Diagrams in Kahl Deposition, IPR2015-01776, Jun. 6. (2016) (article in press), IPR2015-01776, Jun. 6, 2016 Exhibit 2016 Exhibit 2202. 2180. Patent Owner's Response Pursuant to 37 C.F.R. S. 42.120, U.S. Pat. Comments of Vivian Liu, NexMed President and CEO, NexMed No. 7,767,657, 74 pages, IPR2015-01780, Jun. 6, 2016. Investor Update Conference Call (Jul. 8, 2009), IPR2015-01776, Patent Owner's Exhibit List, U.S. Pat. No. 7,767,657, 21 pages, Jun. 6, 2016 Exhibit 2181. IPR2015-01780, Jun. 6, 2016. ProQuest LLC, Terbinafine Gel—MediQuest Therapeutics, Adis Declaration of Paul J. Reider, Ph.D., IPR2015-01780, Jun. 6, 2016 R&D Insight (Mar. 2016), IPR2015-01776, Jun. 6, 2016 Exhibit Exhibit 2034. 2182. Declaration of Mahmoud A. Ghannoum, Ph.D., E.M.B.A., ProQuest LLC, Fluconazole Transdermal Watson Pharmaceuti IPR2015-01780, Jun. 6, 2016 Exhibit 2035. cals, Adis R&D Insight (Dec. 2015), IPR2015-01776, Jun. 6, 2016 Declaration of Majella Lane, Ph.D., IPR2015-01780, Jun. 6, 2016 Exhibit 2183. Exhibit 2036). ProQuest LLC, Terbinafine Topical Celtic Pharma, Adis R&D Declaration of Howard I. Maibach, M.D., Ph.D., IPR2015-01780, Insight (May 2015), IPR2015-01776, Jun. 6, 2016 Exhibit 2184). Jun. 6, 2016 Exhibit 2037. Gupta & Studholme, Novel Investigational Therapies for Declaration of Jennifer Augsburger in Support of Patent Owner's Onychomycosis: an Update, Expert Opin. Investig. Drugs, vol. 25. Response, IPR2015-01780, Jun. 6, 2016 Exhibit 2102. No. 3, pp. 297-305 (2016), IPR2015-01776, Jun. 6, 2016 Exhibit The Merck Index: An Encyclopedia of Chemicals, Drugs, and 2185. Biologicals (Merck Research Laboratories, 13th ed., 2001), Summerbell, Epidemiology and Ecology of Onychomycosis, Der IPR2015-01780, Jun. 6, 2016 Exhibit 2157. matology, vol. 194, suppl. 1, pp. 32-36 (1997), IPR2015-01776, Jun. Barnett & Scher, Nail Cosmetics, Int'l J. of Dermatol., vol. 31, No. 6, 2016 Exhibit 2186. 10, pp. 675-681 (1992), IPR2015-01780, Jun. 6, 2016 Exhibit Curriculum vitae of Majella Lane, Ph.D., IPR2015-01776, Jun. 6, 2202. 2016 Exhibit 2187. Patent Owner's Response Pursuant to 37 C.F.R. S. 42.120, U.S. Pat. Walters et al., Physiochemical Characterization of the Human Nail: No. 7,767,657, 68 pages, IPR2015-01785, Jun. 6, 2016. Permeation Pattern for Water and the Homologous Alcohols and Patent Owner's Exhibit List, U.S. Pat. No. 7,767,657, 19 pages, Differences with Respect to the Stratum Corneum, J. Pharm. IPR2015-01785, Jun. 6, 2016. Pharmacol. 1983, vol. 35, No. 1, pp. 28-33 (1983), IPR2015-01776, Declaration of Paul J. Reider, Ph.D., IPR2015-01785, Jun. 6, 2016 Jun. 6, 2016 Exhibit 2188). Exhibit 2034. Forslind, Biophysical Studies of the Normal Nail, Acta Declaration of Mahmoud A. Ghannoum, Ph.D., E.M.B.A., Dermatovener, vol. 50, pp. 161-168 (1970), IPR2015-01776, Jun. 6, IPR2015-01785, Jun. 6, 2016 Exhibit 2035. 2016 Exhibit 2189). Declaration of Majella Lane, Ph.D., IPR2015-01785, Jun. 6, 2016 Kobayashi et al., Drug Permeation Through the Three Layers of the Exhibit 2036). Human Nail Plate, J. Pharm. Pharmacol., vol. 51, No. 3, pp. 271-278 Declaration of Howard I. Maibach, M.D., Ph.D., IPR2015-01785, (1999), IPR2015-01776, Jun. 6, 2016 Exhibit 2190). Jun. 6, 2016 Exhibit 2037. Runne & Orfanos, The Human Nail: Structure, Growth and Patho Declaration of Jennifer Augsburger in Support of Patent Owner's logical Changes, Curr. Probl. Derm., vol. 9, pp. 102-149 (1981), Response, IPR2015-01785, Jun. 6, 2016 Exhibit 2102. IPR2015-01776, Jun. 6, 2016 Exhibit 2191 Petitioner's Updated Exhibit List, U.S. Pat. No. 7,582,621, 3 pages, Mertin & Lippold, In-vitro Permeability of the Human Nail and of IPR2O15-01776. a Keratin Membrane from Bovine Hooves: Influence of the Partition Patent Owner Anacor Pharmaceuticals, Inc.'s Mandatory Notices Coefficient Octanol/Water and the Water Solubility of Drugs on Under 37 C.F.R. S. 42.8, 4 pages, IPR2015-01776, Sep. 2, 2015. their Permeability and Maximum Flux, J. Pharm. Pharmacol., vol. Patent Owner Anacor Pharmaceuticals, Inc.'s Updated Mandatory 49, No. 1, pp. 30-34 (1997), IPR2015-01776, Jun. 6, 2016 Exhibit Notices Under 37 C.F.R. S. 42.8, 3 pages, IPR2015-01776, Oct. 26, 2192. 2015. European Commission Scientific Committee on Consumer Prod Petitioner's Updated Mandatory Notice Pursuant to 37 C.F.R. S ucts, Opinion on Toluene (Apr. 15, 2008), IPR2015-01776, Jun. 6, 42.8, 5 pages, IPR2015-01776, Jan. 20, 2016. 2016 Exhibit 2193 ). Patent Owner's Objections to Petitioner's Evidence Under 37 Mertin & Lippold, In Vitro Permeability of the Human Nail and of C.F.R. S. 42.64(b)(1), 8 pages, IPR2015-01776, Mar. 8, 2016. a Keratin Membrane from Bovine Hooves: Penetration of Patent Owner Anacor Pharmaceuticals, Inc.'s Updated Mandatory Chloramphenicol from Lipophilic Vehicles and from a Nail Lac Notice, 4 pages, IPR2015-01776, Mar 17, 2016. US 9,566.290 B2 Page 8

(56) References Cited Bessis, N., “Gene Therapy for Rheumatoid Arthritis,” J. Gene Med, vol. 4; pp. 581-591 (2002). OTHER PUBLICATIONS Brown, et al., “Chiral Synthesis Via Organoboranes. 35. Simple Procedures for the Efficient Recycling of the Terpenyl Chiral Petitioner's Updated Exhibit List, U.S. Pat. No. 7,767,657, 5 pages, Auxiliaries and Convenient Isolation of the Homoallylic Alcohols in IPR2O15-01780. Asymmetric Allyl- and Crotylboration of Aldehydes,” J. Org. Patent Owner Anacor Pharmaceuticals, Inc.'s Mandatory Notices Chem., vol. 57, No. 24; pp. 6608-6614, (1992). Under 37 C.F.R. S. 42.8, 4 pages, IPR2015-01780, Sep. 2, 2015. Cairns, et al., “Derivatives of 1,4-Xylene-2,5-diboronic acid and Patent Owner Anacor Pharmaceuticals, Inc.'s Updated Mandatory 1,4-xylene-2-boronic acid”. J. Org. Chem. vol. 29: pp. 2810-2812, Notices Under 37 C.F.R. S. 42.8, 3 pages, IPR2015-01780, Oct. 26, 2015. (1964). Petitioner's Updated Mandatory Notice Pursuant to 37 C.F.R. S Chander, et al. “Prevalence of Fungal Corneal Ulcers in Northern 42.8, 5 pages, IPR2015-01780, Jan. 20, 2016. India'. Infections, vol. 22, No. 3; pp. 207-209, (1994). Patent Owner Anacor Pharmaceuticals, Inc.'s Updated Mandatory Chemical Abstracts Registry No. 159752-29-1, Entered STN Dec. Notice, 4 pages, IPR2015-01780, Mar 17, 2016. 23, 1994. Patent Owner's Objections to Petitioner's Evidence Under 37 Chemical Abstracts Registry No. 71889-05-9. Entered STN Nov. C.F.R. S42.64(b)(1), 19 pages, IPR2015-01780, Mar. 8, 2016. 16, 1984. Patent Owner Anacor Pharmaceuticals, Inc.'s Mandatory Notices Chemical Abstracts Registry No. 845302-09-2, Entered STN Mar. Under 37 C.F.R. S. 42.8, 4 pages, IPR2015-01785, Sep. 2, 2015. 11, 2005. Patent Owner Anacor Pharmaceuticals, Inc.'s Updated Mandatory Chemical Abstracts Registry No. 849062-11-9. Entered STN Apr. Notices Under 37 C.F.R. S. 42.8, 3 pages, IPR2015-01785, Oct. 26, 22, 2005. 2015. Chemical Abstracts Registry No. 849062-10-8. Entered STN Apr. Petitioner's Updated Mandatory Notice Pursuant to 37 C.F.R. S 22, 2005. 42.8, 5 pages, IPR2015-01785, Jan. 20, 2016. Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Patent Owner Anacor Pharmaceuticals, Inc.'s Updated Mandatory Inc., Case No. IPR2015-01776, U.S. Pat. No. 7,582,621 B2, Deci Notice, 4 pages, IPR2015-01785, Mar 17, 2016. sion entered: Feb. 23, 2016, Paper No. 24, 16 pages. Baudoin, Olivier, et al. “A Novel 1.3-Central-to-Axial Chirality Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Induction Approach to Cyclooctadiene Lignans'. Synlett, Oct. 16. Inc., Case No. IPR2015-01780, U.S. Pat. No. 7,767,657 B2, Deci 2003, No. 13, pp. 2009-2012. Cummings, William M. et al. "Arylboronic Acids. A Medium-Size sion filed: Feb. 23, 2016, Paper No. 24, 28 pages. Ring Containing Boronic Ester Groups”. The Journal of Organic Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Chemistry, vol. 34, No. 6, Jun. 1969. Inc., Case No. IPR2015-01785, U.S. Pat. No. 7,767,657 B2, Deci U.S. Appl. No. 14/977,052, filed Dec. 22, 2015. sion filed: Feb. 23, 2016, Paper No. 24, 26 pages. U.S. Appl. No. 14/201459, filed Mar. 7, 2014, now allowed. Cody et al. CAS: 142: 168379, 2004. U.S. Appl. No. 13/673,860, filed Nov. 9, 2012, Anacor Pharmaceu Cui, et al., “Organoboron Compounds with an 8-Hydroxyquinolato ticals, Inc. Chelate and Its Derivatives: Substituent Effects on Structures and U.S. Appl. No. 14/977,052, filed Dec. 21, 2015, Anacor Pharma Luminescence.” Inorganic Chemistry, vol. 44, No. 03: pp. 601-609. ceuticals, Inc. (Feb. 7, 2005). Adamczyk-Wozniac, et al., “Benzoxaboroles—Old Compounds Cusack, S., et al., “The 2 A Crystal Structure of leucyl-tRNA with new applications'. Journal of Organometalic Chemistry Synthetase and its Complex with a Leucyl-Adenylate Analogue.” 694:3533-3541 (2009). EMBO Journal, vol. 19: pp. 2351-2361, (2000). Akama, et al., “Discovery and structure-activity study of novel Dale, et al., “Substituted Styrenes VII. Syntheses and some Reac benzoxaborole anti-inflammatory agent (AN2728) for the potential tions of the Vinylbenzeneboronic Acids' J. Org. Chem. vol. 27, pp. topical treatment of psoriasis and atopic dernatitis'. Bioorganic & 2598-2603, (Jan. 1, 1962). Medicinal Chemistry Letters, (2009) 19: 2129-2132. Demir et al., “Generation of Aryl Radicals from Arylboronic Acids Alexander, et al., “Imprinted Polymers as Protecting Groups for by Manganese(III) Acetate: Synthesis of Biaryls and Regioselective Modification of Polyfunctional Substrates'. J. Am. Heterobiaryls”. J. Org. Chem. 2003, 68,578-580. Chem. Soc. 1999, 121, 6640-6651. Denis, “Pharmacology 1104 Lecture: Drug Classifications & Char Alley, et al., “Recent Progress on Topical Therapy of acteristics of Antimicrobials” (2003). Onychomycosis'. Expert Opinion Investigate Drugs(Feb. 2007) Dian, “International Nomenclature of Organics', China Petro 16(2): 157-67. chemical Press, 1st Edition; 50-51 (Jan. 21, 2004). Austin, et al., “Oxaboroles and Salts and their Use of Biocides for Falck, et al., “Bromo-Boronolactonization of Olefins'. J. Org. Plastics”, CAS, vol. 124, pp. 234-024, (1996). Chem. 2001, 66.7148-7150. Bailey, et al., “Boron-Containing Antibacterial Agents: Effects on Farfan, et al., “Through-Bond Modulation on N. B. Ring Formation Growth and Morphology of Bacteria Under Various Culture Con Shown by NMR and X-Ray Diffraction Studies of Borate Deriva ditions.” Antimicrobial Agents and Chemotherapy, 17(04):549-553, tives of Pyridyl Alcohols,” J. Chem. Soc. Perkin Trans., vol. 2: pp. (Apr. 1980). 527-532 (1992). Baker, et al., “Discovery of New Boron-Containing Antifungal Ferrer, “Targeting Aminoacyl-tRNA Synthetases for the Treatment Agent, 5-Fluoro-1,3-dihydro-1-hydroxy-2, 1-benzoxaborole of Fungal Infections'. Drug News Perspective, vol. 19, No. 6; pp. (AN2690) for Potential Treatment of Onychomoycosis”, Journal of 347-348, (Jul/Aug. 2006). Medicinal Chemistry, vol. 49, No. 15; pp. 4447-4450, (Jul. 27. Fevig et al. CAS: 137: 125150, 2002. 2006). Fungicide: Definition from Answer.com, (1998). Baker, et al., “Identification of a Novel Boron-Containing Antibac Goodman, et al., “Goodman & Gilman's Manual of Pharmacology terial Agent (ANO128) with Anti-inflammatory activity, for the and Therapeutics' Chapter 40:681-694 (2008). Potential Treatment of Cutaneous Diseases”. Bioorganic & Medici Grassberger, et al., “Degradation of 1,2-dihydro-1-hydroxy-2- nal Chemistry Letters (2006) 16:5963-5937. (organosulfonyl)2.3.1-benzodiasaborines and -thieno3.2- Baker, et al., “Progress on New Therapeutics for Fungal Nail d1.3diazaborines in Alkaline Aqueous Solutions'. Liebigs Infections'. Annual Reports in Medicinal Chemistry, vol. 40: pp. Annalen Der Chemie, vol. 4; pp. 683-688, (1985). 323-335, (2005). Guo-Zheng, et al., “Single Site Transarylation of 2,2'-Dimetalized Bell, et al., “Design, synthesis and evaluation of a novel series of 1, 1'-Binaphthyl to Aminocloroborates and Synthesis of spiroketals based on the structure of the antibacterial gyrase inhibi 2-Binaphthyl Boron Compounds.” Youji Huaxue/Organic Chemis tor novobiocin', J. Chem. Soc., Perkin Trans., 1997 vol. 18, No. 1, try, Science Press, vol. 16, No. 02: pp. 139-144. (1996) (English pp. 2789-2801. Abstract). US 9,566.290 B2 Page 9

(56) References Cited Qin, Clinical Mycology, Fudan Press, Shanghai Medical University Press, pp. 92, 111, 340-341, 365, 437 and 487 (2001) With English OTHER PUBLICATIONS Translation. Rau, et al., “Pol-catalyzed synthesis, characterization and modifica Haynes, et al., “Arylboronic Acids VIII. Reactions of tion of poly(p-phenylene)S bearing butoxymethyl side chains', pp. boronphthalide” J. Org. Chem. vol. 29, No. 11; pp. 3229-3233, 2225-2238, Makromol. Chem. 194, 1993. (1964). Resnick, et al., “Chemoenzymatic Synthesis of Chiral Boronates for Hauck, et al., “Preparation and Anticonvulsant Activity of Some the "H NMR Determination of the Absolute Configuration and Aryldialkylsuccinimides' Research Lab of Parke Davis Co. (1967). Enantiomeric Excess of Bacterial and Synthetic cis-Diols', pp. He, et al., “Small-Molecule Inhibition of TNF-alpha'. Science, vol. 3546-3549, J. Org. Chem., 1995, vol. 60. 310, No. 5750; pp. 1022-1025, (Nov. 11, 2005). Robinson et al. CAS: 132: 43141, 1999. Hui, et al., “In Vitro Penetration of a Novel Oxaborole Antifungal Rock, et al., “An Antifungal Agents Inhibits Aminoacyl-tRNA (AN2690) into the Human Nail Plate”, Journal of Pharmaceutical Synthetase by Trapping tiNA in the Editing Site”, Science, vol. Sciences (2007) 96(10): 2622-2631. 316, No. 5832: pp. 1759-1761, (Jun. 22, 2007). Ishihara et at. CAS: 141: 388701, 2004. Silverman, “The Organic Chemistry of Drug Design and Drug Kamikawa, et al., “Stereoselective Synthesis of Both Enantiomers Action', 2nd Edition, Northwestern University, Department of of Axially Chiral Biaryls Utilizing Planar Chiral Chemistry, Evanston, Illinois, Section 2: 29-32 (2004). Tricarbonyl(arene)chromium Complexes', pp. 1375-1384, J. Org. Snyder, et al. “Common Bacteria Whose Susceptibility to Antimi Chem, vol. 61, 1996. crobials in no longer Predictable” J. Med. Liban, vol. 48 No. 4; pp. Lampe, et al., “Synthesis and Protein Kinase Inhibitory Activity of 208-214, (2000). Balanol Analogues with Modified Benzophenone Subunits”. J. Stones et al. CAS: 141: 271084, 2004. Med. Chem., vol. 45(12); pp. 2624-2643, (2002). Sugar, et al., "Comparison of Three Methods of Antifungal Sus Lee, K., et al., “Molecular Study of the Editing Active Site of ceptibility Testing with the Proposed NCCLS Standard Broth Escherichia coli Leucyl-tRNA Synthetase: Two Amino Acid Bind Macrodilution Assay: Lack of Effect of Phenol Red' Diagn. ing Site in the Editing Domain', vol. 54; pp. 693-704. (2004). Microbiol. Infect. Dis. vol. 21; pp. 129-133, (1995). Lennarz, et al., “Arylboronic Acids. IV. Reactions of Tabuchi, et al., “Anticoccidial Activity of some AZacyclo Boronophthalide” J. Am. Chem. Soc. vol. 82: pp. 2172-2175, Organoborinates.” Heterocycles, vol. 60, No. 01: pp. 177-182, (1960). Li, et al., “An Improved Protocol for Preparation of 3-Pyridyl- and (2003). Some Arylboronic Acids”. J. Org. Chem... vol. 67: pp. 5394-5397, Tan, Y-L, et al., “Dilithiation of arenetricarbonylchromium(0) com (2002). plexes with enantioselective quench: application to chiral biaryl Luan, et al., “Inhibition of Experimental Periodontitis by a topical synthesis'. Department of Chemestry, London, pp. 3269-3280, vol. boron-base antimicrobial” J Dent. Res, 87(2): 148-152 (2008). 24, 2001. Koster, et al., “Cyclisierugen von Bor-Stickstoff Verbindugen in der Tatsumi, et al., “Therapeutic Efficacy of Topically applied KP-103 Hietz” Liebigs Ann. Chem... vol. 720; pp. 23-31. (1968). against Experimental Tinea Uguium in Guinea Pigs in Comparison Koster, et al., Boron Compounds, XXXIX. with Amorolfine and Terbinafine”. Antimicrobial Agents and Che Alkenoxy(diorgany)boranes Substituted at the Alkeonxy Group motherapy, vol. 46, No. 12: pp. 3797-3801 (2002). from 2-methylacrolein and triorganylboranes.' Justus Liebigs Toporcer, et al., “Preparation and Properties of some Annalen Der Chemie, No. 06; pp. 1116-1134. (1976). Tetracoordinate Boron Compounds. The Pseudo-metal Ion Con McMillin, et al., “Systemic Aspects of Psoriasis: An Integrative cept.” Inorganic Chemistry, vol. 4, No. 11; pp. 649-1655. (Nov. Model Based on Intestinal Etiology”. Int. Med. vol. 2, Issue 2/3, 1965). (1999). Torssell, “Zur Kenntnis der Arylborasauren III*, Bromierung der Mikami et at. CAS: 122:314944, 1995. Tolyborsauren nach Wohl-Ziegler”, Arkiv for Kemi, Band 10 nr 36, Moeder, et al., “Kinetic Analysis of the Asymmetric Amplification Sep. 12, 1956. exhibited by B-chlorodiisopinocampheylborane,” Journal of Physi Toyota, et al., “Intramolecular C=OB Interactions in o-Boron cal Organic Chemistry, vol. 17. No. 4; pp. 317-324, (Apr. 2004). Substituted Benzaldehyde, Acetophenone, and Benzophenone'. Monovich, et al., “Total Synthesis of (--)-Steganone Utilizing a Bull.Chem. Soc. Jpn. 75, 2667-2671 (2002). Samarium(II) Iodide Promoted 8-Endo Ketyl-Olefin Cyclization'. Trujillo, et al., "X-Ray Crystallographic Study of Boroxazolidones, J. Am. Chem. Soc. 2000, 122, 52-57. Obtained from Lornithine, L-methionine, Kainic acid and 2,6- Morissette, et al., “High-throughput Crystallization: Polymorphs, pyridinedicarboxylic acid'. Journal of Organometallic Chemistry, Salts, Co-Crystals and Solvates of Pharmaceutical Solids', vol. 571; pp. 21-29, (1998). Advanced Drug Delivery Reviews, vol. 56; pp. 273-300, (2004). Tschampel, et al., "Arylboronic Acids. VII. Some Reactions to Motokazu, et al., “Stereoselective induction of an axial chirality by o-Formybenzeneboronic Acids”. J. Org. Chem. vol. 29, No. 8; pp. Suzuki cross coupling of tricaronyl (arene) chromium complexes 2168-2172, (1964). with arylboronic acids”. J. Chem. Soc., Chem. Commun., 1994, vol. Turner, et al., Current Pharmaceutical Design, vol. 2: pp. 209-224 23, pp. 2697-2698. (1996). Murdan, “Drug Delivery to the Nail Following Topical Applica Uemura, et al., “Stereoselective induction of an axial chirality by tion'. International Journal of Pharmaceutics, vol. 236: pp. 1-26, Suzuki cross coupling of tricaronyl (arene) chromium complexes (2002). with arylboronic acids”. J. Chem. Soc., Chem. Commun., 1994, vol. N. Miyaura, “Product subclass 7: hydroxyboranes', Science of 23, pp. 2697-2698. Synthesis 2004, 6, 257-300. Vippagunta, “Crystalline Solids'. Advanced Drug Delivery Oshima, et al., “Regiospecific Glycosidation of Unprotected Sugars Reviews, vol. 48; pp. 3-26, (2001). via Arylboronic Activation”. J. Am. Chem. Soc. 1999, 121, 2315 Wang, et al. “Synthetic Strategies Based on Aromatic Metalation— 2316. Cross Coupling Links. A Concise Formal Synthesis of the Patani, et al., “Bioisosterism: A Rational Approach to Drug Design'. AZaphenanthrene Alkaloid Eupolauramine”, pp. 4883-4884. Tetra Chem. Rev., vol. 96; pp. 3147-3176 (1996). hedron Letters, vol. 32, No. 37, 1991, Great Britain. Perola, E., et al., “Successful Virtual Screening of a Chemical Wang, et al., “Expression, Purification and Characterization of Database for Farnesltransferase Inhibitor Leads.” vol. 43; pp. 401 Human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, 4008, (2000). C, and D'. Biochemical and Biophysical Research Communica Qin, et al., “Luminescent Organoboron Quinolate Polymers,” Jour tions, vol. 234; pp. 320-324, (1997). nal of the American Chemical Society, vol. 126, No. 22; pp. Williams, et al., “Foye's Principles of Medicinal Chemistry”, 5th 7015-7018, (Jun. 9, 2004). Edition, 2002, Lippincoot Williams & Wilkins, p. 59. US 9,566.290 B2 Page 10

(56) References Cited “Preclinical Toxicology of AN2728, a Novel Oxaborole in Devel opment for the Topical Treatment of Psoriasis'. Scientific Presen OTHER PUBLICATIONS tation at the International Investigative Dermatology Conference, Kyoto, Japan, May 14-18, 2008. Wulff, et al., “On the chemistry of binding sites VII, Enantioselec “AN2898, a Novel Oxaborole Compound with Anti-Inflammatory tive binding using chiral boronic acids', pp. 216-221. Recl. Trav. Activity: Mechanism of Action and in vitro Cytokine Inhibition'. Chim. Pays-Bas 109, 1990. Scientific Presentation at the International Investigative Dermatol Ye, et al., "Convenient and Versatile Syntheis of formyl-substituted ogy Conference, Kyoto, Japan, May 14-18, 2008. Benzoxaboroles”, Tetrahedron, vol. 65; pp. 8738-8744, (2009). “Structure-Activity Studies of AN2728 and AN2898, Novel Zhdankin, et al., “Synthesis and Structure of Benzoboroxoles: Oxaborole Compounds with Anti-Inflammatory Activity”. Scien Novel Organboron Heterocycles.” Tetrahedron Letters, vol. 40; pp. tific Presentation at the International Investigative Dermatology 6705-6708, (1999). Conference, Kyoto, Japan, May 14-18, 2008. Zhou, et al., “Hemodextrin: a Self-assembled Cyclodextrin “In Vitro Activity and Mechanism of Action of AN2728, a Novel Porphyrin Construct That Binds Dioxygen.” Biophysical Chemis Oxaborole in Development for Treatment of Psoriasis'. Scientific try, 105:639-648 (2003). Presentation at the International Investigative Dermatology Confer Zhou, et al., “Structure-activity Studies on a Library of Potent ence, Kyoto, Japan, May 14-18, 2008. Calix4larene-based PDGF Antagonists that Inhibit PDGF-stimu “AN2898, a Novel Oxaborole Compound with Anti-Inflammatory lated PDGFR Tyrosine Phosphorylation.” Org. Biomol. Chem. Activity: Results of In Vivo Efficacy and Preclinical Safety Stud 4:2376-2386 (2006). ies'. Scientific Presentation at the International Investigative Der Zhou, et al., “Pattern Recognition of Proteins Based on an Array of matology Conference, Kyoto, Japan, May 14-18, 2008. Functionalized Porphyrins,” J. Am. Chem. Soc., 128:2421-2425 “AN2728, a Novel Oxaborole in Development for Treatment of (2006). Psoriasis, Demonstrates Significant Activity in a Micro Plaque Zixing, et al., “Synthesis of Aromatic Nitrogen-containing Hetero Study”. Scientific Presentation at the International Investigative cyclic Derivatives of Asymmetric Diarylborinic Acids.” Wuhan Dermatology Conference, Kyoto, Japan, May 14-18, 2008. Daxue Xuebo-Wuhan University Journal, vol. 3; pp. 67-71. (1990), “Preclinical Toxicology of AN2728, a Novel Borinic Acid Ester (English Abstract). with Anti-Inflammatory Activity”, American Academy of Derma "Structure-Activity Studies led to the Discovery of AN2898 in tology, 65th Annual Meeting, Washington, DC, Feb. 2-6, 2007. Development for Topical Treatment of Psoriasis and Atopic Der “AN2728, a Novel Oxaborole with Broad-Spectrum In Vitro Anti matitis', Scientific Presentation at the American Academy of Der Inflammatory Activity”, American Academy of Dermatology, 65th matology Annual Meeting, San Francisco, CA Mar. 6-10, 2009. Annual Meeting, Washington, DC, Feb. 2-6, 2007. “AN2898 Inhibits Cytokines Relevant to Topical Treatment of “In Vitro Nail Penetration of AN2690, Effect of Vehicle and Psoriasis and Atopic Dermatitis', Scientific Presentation at the Co-Efficient of Efficacy'. American Academy of Dermatology, 65th American Academy of Dermatology Annual Meeting, San Fran Annual Meeting, Washington, DC, Feb. 2-6, 2007. cisco, CA Mar. 6-10, 2009. “Interim Results of a Multi-Center Study to Evaluate the Safety and “AN2718 has Broad Spectrum Antifungal Activity Necessary for Efficacy of Topically Applied AN2690 5.0% and 7.5% Solutions for the Topical Treatment of Skin and Nail Fungal Infections'. Scien the Treatment of Onychomycosis of the Great Toenail', American tific Presentation at the American Academy of Dermatology Annual Academy of Dermatology, 65th Annual Meeting, Washington, DC, Meeting, San Francisco, CA Mar. 6-10, 2009. Feb. 2-6, 2007. “AN2718 Demonstrates Significant Efficacy in Three Phase Ib “In vivo Nail Residence Time of AN2690, a Novel Broad-Spectrum Psoriasis Microplaque Trials' Scientific Presentation at the Ameri Antifungal Agent in Development for the Topical Treatment of can Academy of Dermatology Annual Meeting, San Francisco, CA Onychomycosis'. American Academy of Dermatology, 65th Annual Mar. 6-10, 2009. Meeting, Washington, DC, Feb. 2-6, 2007. “AN2728 Demonstrates Significant Safety and Efficacy in Phase IIa “An Open-Label, Multi-dose Study of Absorption and Systemic Double Blind Trial in Plaque Type Psoriasis'. Scientific Presenta Pharmacokinetics of AN2690 Applied as a 7.5% Solution to All tion at the American Academy of Dermatology Annual Meeting, Toenails of Adult Patients with Moderate to Severe San Francisco, CA Mar. 6-10, 2009. Onychomycosis'. American Academy of Dermatology, 65th Annual “AN2728 Preclinical Studies Demonstrate an Acceptable Safety Meeting, Washington, DC, Feb. 2-6, 2007. Profile for the Topical Treatment of Psoriasis and Atopic Dermati “Medicinal Chemistry Development of AN2728, a Novel tis', Scientific Presentation at the American Academy of Derma Oxaborole in Development for the Topical Treatment of Psoriasis'. tology Annual Meeting, San Francisco, CA May 6-10, 2009. American Academy of Dermatology, 65th Annual Meeting, Wash “A New Class of Benzoxaborole-based Potent Antitrypanosomal ington, DC, Feb. 2-6, 2007. Agents: Probing Effect of Different Linkage Groups in "Skin Penetration and Anti-Inflammatory Activity of AN2728, a Trypanosoma brucei Growth Inhibition'. Scientific Presentation at Novel Oxaborole”. American Academy of Dermatology, 65th the American Society of Tropical Medicine and Hygiene Confer Annual Meeting, Washington, DC, Feb. 2-6, 2007. ence, New Orleans, LA Dec. 7-11, 2008. "Nail Penetration and Nail Concentration of AN2690, a Novel “AN2920, a Novel Oxaborole, Shows In Vitro and In Vivo Activity Broad-Spectrum Antifungal Agent in Development for the Topical Against Trypanosomal brucei, Scientific Presentation at the Ameri Treatment of Onychomycosis”. Scientific Presentation at the Ameri can Society of Tropical Medicine and Hygiene Conference, New can Associate of Pharmaceutical Scientist, Annual Meeting, San Orleans, LA Dec. 7-11, 2008. Antonio, TX, Oct. 29-Nov. 2, 2006. “A Novel Oxaborole, AN3520, Show Efficacy against Human Aswell et al. CAS: 141: 296025, 2004. African Trypanosomiasis. In Vitro and InVivo, Including Promise in Naumov, et al. “Polyfunctionalized Aryllead Triacetates in a Cas a Murine CNS Model of T. bruceii Infection', Scientific Presentation cade Synthesis of Tetracyclic Isochromanocoumarin-Type Com at the American Society of Tropical Medicine and Hygiene Con pounds”. Synthesis 2005, pp. 1178-1182. ference, New Orleans, LA Dec. 7-11, 2008. Mikami, et al., “Synthesis of Sugar-containing Polymers by Self “Antifungal Activity and Mechanism of Action of a BenZOxaborole, condensation with Diboronic Acid'. J.Chem. Soc., Chem. Com AN2718, which is in Development for the Treatment of Tinea mun., 1995, pp. 153-154. Pedis', Scientific Presentation at the 48th Interscience Conference Stones, et al. “Modular Solid-Phase Synthetic Approach to Opti on Antimicrobial Agents and Chemotherapy, Washington, D.C. Oct. mize Structural and Electronic Properties of Oligoboronic Acid 25-28, 2008. Receptors and Sensors for the Aqueous Recognition of Oligosac “AN2728 Ointment, a Novel Oxaborole with Anti-Inflammatory charides', Chem.Eur. J. 2004, 10, pp. 92-100. Activity, Demonstrates Safety and Significant Efficacy in a Phase Ib Linnane, et al. “The Synthesis and Properties of a Calixarene-based Psoriasis Plaque Test'. Scientific Presentation at Montagna Sym "Sugar Bowl'. J. chem. Soc., Chem. Commun., 1995, pp. 1997 posium on Biology of Skin, Gleneden Beach, OR, Oct. 2-6, 2008. 1998. US 9,566.290 B2 Page 11

(56) References Cited National Center for Biotechnology Information (NCBI), PubChem Compound Database, CID-11499245, available at https://pubchem. OTHER PUBLICATIONS incbi.nlm.nih.gov/compound 11499245 (last visited Aug. 2, 2015) Exhibit 1044). Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Meds. & Healthcare Prods. Regulatory Agency, Curanail 5% Nail Inc., Case No. Unassigned, U.S. Pat. No. 7,582,621, Petition for Lacquer (Amorolfine Hydrochloride) PL 10590/0049, UK Public Inter Partes Review of U.S. Pat. No. 7,582,621, 66 pages. IPR2015 Assessment Report (approved Jul. 4, 2006) Exhibit 1045. 0.1776. National Center for Biotechnology Information (NCBI), PubChem Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Compound Database, CID=22497760, available at https://pubchem. Inc., Case No. Unassigned, U.S. Pat. No. 7,582,621, Power of incbi.nlm.nih.gov/compound 22497760 (last visited Aug. 4, 2015) Attorney in Inter Partes Review, 3 pages. IPR2015-01776). Exhibit 1046. Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, National Center for Biotechnology Information (NCBI), PubChem Inc., Case No. Unassigned, U.S. Pat. No. 7,582,621. Appendix of Compound Database, CID-61764, available at https://pubchem. Exhibits, 3 pages. IPR2015-01776). incbi.nlm.nih.gov/compound 61764 (last visited Aug. 4, 2015) Declaration of Stephen Kahl, Ph.D. Exhibit 1006). Exhibit 1047. Curriculum Vitae of Stephen B. Kahl, Ph.D. Exhibit 1007). Declaration of Kathleen E. Ott Exhibit 1050. Declaration of S. Narasimha Murthy, Ph.D. Exhibit 1008). Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Curriculum Vitae of S. Narasimha Murthy, Ph.D. Exhibit 1009). Inc., Case No. Unassigned, U.S. Pat. No. 7,767,657. Second Petition Biobor.JF(R) Specification Sheet (2015) Exhibit 1024). for Inter Partes Review of U.S. Pat. No. 7,767,657, 70 pages. Biobor.JF(R) Material Safety Data Sheet (2004) Exhibit 1025). IPR2015-01785. Michael P. Groziak, Boron Therapeutics on the Horizon, 8 Am. J. of Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Therapeutics 321-28 (2001) Exhibit 1027). Inc., Case No. Unassigned, U.S. Pat. No. 7,767,657, Power of Declaration of Ryan J. Fletcher Exhibit 1030). Attorney in Second Petition for Inter Partes Review of U.S. Pat. No. Kerydin R. Prices, available at http://www.goodrx.com/kerydin (last 7,767,657, 3 pages. IPR2015-01785. visited Aug. 6, 2015) Exhibit 1031). Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Q1Group LLC, 2015 Medicare Part D Plan's Negotiated Retail Inc., Case No. Unassigned, U.S. Pat. No. 7,767,657. Appendix of Drug Price, Kerydin 5% Topical Solution (Jul. 2015), available at Exhibits for Second Petition for Inter Partes Review of U.S. Pat. No. http://www.ql medicare.com/PartD-2015MedicarePlan 7,767,657, 5 pages. IPR2015-01785. RetailDrugPriceprint.php?stateReg-13MI&ndc-5572401 1121&for National Center for Biotechnology Information (NCBI), PubChem mulary-00015191&contractId H2322&planId—008& Compound Database, CID-66827, available at https://pubchem. segmentId=0&zipCountyCode=26115&cplanType-M&cletter— incbi.nlm.nih.gov/compound 66827 (last visited Aug. 4, 2015) K&cmode—state Exhibit 1032. Exhibit 1046. Declaration of Stephen Kahl, Ph.D. Exhibit 1009). National Center for Biotechnology Information (NCBI), PubChem Curriculum Vitae of Stephen Kahl, Ph.D. Exhibit 1010). Compound Database, CID-2775922, available at https://pubchem. Declaration of S. Narasimha Murthy, Ph.D. Exhibit 1011). incbi.nlm.nih.gov/compound 2775922 (last visited Aug. 4, 2015) Curriculum Vitae of S. Narasimha Murthy, Ph.D. Exhibit 1012). Exhibit 1047. Dirk Mertin & Bernhard C. Lippold, In-vitro Permeability of the Declaration of Kathleen E. Ott. Exhibit 1050. Human Nail and of a Keratin Membrane from Bovine Hooves: Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Penetration of Chloramphenicol from Lipophilic Vehicles and a Inc., Case No. IPR2015-01776, U.S. Pat. No. 7,582,621, Patent Nail Lacquer, 49.J. Pharmacy & Pharmacology 241 (1997) Exhibit Owner Preliminary Response, 70 pages. 1030. FDA Approved Label for Kerydin R. (Rev. Mar. 2015) Exhibit National Center for Biotechnology Information (NCBI), PubChem 2001. Compound Database, CID=6440876, available at https://pubchem. Fairchild et al. In Vitro Determination of Uptake, Retention, incbi.nlm.nih.gov/compound/6440876 (last visited Jul. 31, 2015) Distribution, Biological Efficacy, and Toxicity of Boronated Com Exhibit 1035. pounds for Neutron Capture Therapy: A Comparison of Porphyrins National Center for Biotechnology Information (NCBI), PubChem with Sulfhydryl Boron Hydrides, Cancer Res., vol. 50, pp. 4860 Compound Database, SID=24898472, available at https://pubchem. 4865 (1990) Exhibit 2002). incbi.nlm.nih.gov/substance/24898472 (last visited Jul. 31, 2015) Charifetal. A Historical Perspective on Onychomycosis, Dermatol. Exhibit 1036). Ther. vol. 3, pp. 43-45 (1997) Exhibit 2003). Remington: The Science and Practice of Pharmacy (Lippincott Heath et al., Fatty Acid Biosynthesis as a Target for Novel Anti Williams & Wilkins, 21st ed. 2005) Exhibit 1037). bacterials, Curr. Opin. Invest. Drugs, vol. 5, pp. 146-153 (2004) Hawley's Condensed Chemical Dictionary (John Wiley & Sons, Exhibit 2004). Inc., 13th ed. 1997) Exhibit 1038). Baldocket al., AMechanism of Drug Action Revealed by Structural Aldrich Handbook of Fine Chemicals and Laboratory Equipment Studies of Enoyl Reductase, Science, vol. 274, pp. 2107-2110 (2003-2004) Exhibit 1039. (1996) Exhibit 2005). National Center for Biotechnology Information (NCBI), PubChem Biobor, R.E.D. Facts, EPA-738-R-93-004 (Jun. 1993), http://nepis. Compound Database, CID-2484, available at https://ubchem.ncbi. epa.gov/Exe/ZyPDF.cgi?Dockey=200009P5.PDF Exhibit 2006). nlm.nih...ov/compound 2484 (last visited Aug. 11, 2015) Exhibit Lefkovits et al., Direct Thrombin Inhibitors in Cardiovascular 1040. Medicine, Circulation, vol. 90, pp. 1522-1536 (1994) Exhibit National Center for Biotechnology Information (NCBI), PubChem 2007. Compound Database, CID=3198, available at htlps://pubchem.ncbi. Grassberger et al., Preparation and Antibacterial Activities of New nlm.nih.gov/compound 3198 (last visited Aug. 2, 2015) Exhibit 1,2,3-Diazaborine Derivatives and Analogs, J. Med. Chem... vol. 27. 1041. No. 8, pp. 947-953 (1984). National Center for Biotechnology Information (NCBI), PubChem Baldock et al., Mechanism of Action of Diazaborines, Biochem. Compound Database, CID-68553, available at https://pubchem. Pharm., vol. 55, pp. 1541-1549 (1998). incbi.nlm.nih.gov/compound/68553 (last visited Aug. 2, 2015) Heindel et al. The Developmental Toxicity of Boric Acid in Mice, Exhibit 1042). Rats, and Rabbits, Environ. Health Perspect., vol. 102, suppl. 7, pp. National Center for Biotechnology Information (NCBI), PubChem 107-112 (1994) Exhibit 2010. Compound Database, CID=2812, available at https://pubchem.ncbi. Richardson, Clinical Update: Proteasome Inhibitors in Hematologic nlm.nih.gov/compound 28.12 (last visited Aug. 2, 2015) Exhibit Malignancies, Cancer Treatment Rev., vol. 29, suppl. 1, pp. 33-39 1043). (2003) Exhibit 2011). US 9,566.290 B2 Page 12

(56) References Cited Signature Page to Howard Maibach, M.D., Ph.D., Deposition Tran script, 1 page, IPR2015-01776 Exhibit 2210). OTHER PUBLICATIONS Signature Pages and Errata to Paul J. Reider, Ph.D., Deposition Transcript, 3 pages, IPR2015-01776 Exhibit 2211). Bross et al., Approval Summary for Bortezomib for injection in the Patent Owner's Exhibit List, Sep. 27, 2016, 22 pages, IPR2015 Treatment of Multiple Myeloma, Clin. Cancer Res., vol. 10, pp. O1780. 3954-3964 (2004) Exhibit 2012. Declaration of Michael N. Kennedy in Support of Patent Owner's Adams, Proteasome Inhibitors as Therapeutic Agents, Expert Opin. Motion for Admission Pro Hac Vice of Michael N. Kennedy Under Ther. Patents, vol. 13, No. 1, pp. 45-57 (2003) Exhibit 2013). 37 C.F.R. S. 42.10, Jun. 10, 2016, 4 pages, IPR2015-01780 Exhibit Dorland's Illustrated Medical Dictionary, p. 211 (29th ed. 2000) 2205). Exhibit 2014. Declaration of Jeffrey B. Elikan in Support of Patent Owner's Stedman's Medical Dictionary, p. 204 (27th ed. 2000) Exhibit Motion for Admission Pro Hac Vice of Jeffrey B. Elikan Under 37 2015. C.F.R. S. 42.10, 4 pages, IPR2015-01780 Exhibit 2206). Random House Webster's Unabridged Dictionary, p. 209 (2nd ed. Declaration of George F. Pappas in Support of Patent Owner's Motion for Admission Pro Hac Vice of George F. Pappas Under 37 2001) Exhibit 2016). C.F.R. S. 42.10, Jun. 27, 2016, 4 pages, IPR2015-01780 Exhibit Jordon et al., Boric Acid Poisoning: A Report of a Fatal Adult Case 2207. from Cutaneous Use. A Critical Evaluation of the Use of This Drug Transcript, Deposition of Stephen B. Kahl, Ph.D., Sep. 14, 2016, 75 in Dermatologic Practice, JAMADerm, vol. 75, pp. 720-728 (1957) pages, IPR2015-01780 Exhibit 2208). Exhibit 2017. Transcript, Deposition of Narashimha Murthy, Ph.D., Sep. 17, 2016, Triggle, Pharmacological Receptors: A Century of Discovery—and 125 pages, IPR2015-01780 Exhibit 2209). More, Pharm. Acta Helvetiae, vol. 74, pp. 79-84 (2000) Exhibit Signature Pages and Errata to Majella Lane, Ph.D., Deposition 2019. Transcript, 4 pages, IPR2015-01780 Exhibit 2210). Larsen et al., The Prevalence of Onychomycosis in Patients with Signature Pages and Errata to Mahmoud A. Ghannoum, Ph.D., Psoriasis and Other Skin Diseases, Acta Derm. Venereol., vol. 83, E.M.B.A. Deposition Transcript, 5 pages, IPR2015-01780 Exhibit pp. 206-209 (2003) Exhibit 2020. 2211. Osborne et al., Antifungal Drug Response in an In Vitro Model of Signature Page to Howard Maibach, M.D., Ph.D., Deposition Tran Dermatophyte Nail Infection, Med. Mycol., vol. 42, pp. 159-163 script, 1 page, IPR2015-01780 Exhibit 2212). (2004) Exhibit 2022. Signature Pages and Errata to Paul J. Reider, Ph.D. Deposition Favre et al., Comparison of In Vitro Activities of 17 Antifungal Transcript, 3 pages, IPR2015-01780 Exhibit 2213. Drugs Against a Panel of 20 Dermatophytes by Using a Microdilu Patent Owner's Exhibit List, Sep. 27, 2016, 20 pages, IPR2015 tion Assay, J. Clin. Microbiol., vol. 41, No. 10, pp. 4817-48.19 O1785. (2003) Exhibit 2023. Declaration of Michael N. Kennedy in Support of Patent Owner's Sangster, Octanol-Water Partition Coefficients of Simple Organic Motion for Admission Pro Hac Vice of Michael N. Kennedy Under Compounds, J. Phys. Chem. Ref. Data, vol. 18, pp. 1111-1227 37 C.F.R. S. 42.10, Jun. 10, 2016, 4 pages, IPR2015-01785 Exhibit (1989) Exhibit 2024. 2187. Powers et al., Structure-Based Approach for Binding Site Identifi Declaration of Jeffrey B. Elikan in Support of Patent Owner's cation on AmpC 3-Lactamase, J. Med. Chem... vol. 45, pp. 3222 Motion for Admission Pro Hac Vice of Jeffrey B. Elikan Under 37 3234 (2002) Exhibit 2025. C.F.R. S. 42.10, Jun. 15, 2016, 4 pages, IPR2015-01785 Exhibit Boric Acid, R.E.D. Facts, EPA-738-F-93-006 (Sep. 1993), http:// 2188). archive.epa.gov/pesticides/reregistration/web/pdf.0024 fact.pdf Declaration of George F. Pappas in Support of Patent Owner's Exhibit 2026. Motion for Admission Pro Hac Vice of George F. Pappas Under 37 Vander Straten et al., Cutaneous Infections: Dermatophytosis, C.F.R. S. 42.10, Jun. 27, 2016, 4 pages, IPR2015-01785 Exhibit Onychomycosis, and Tinea Versicolor, Infect. Dis. Clinics N. Am. 2189. vol. 17, pp. 87-112 (2003) Exhibit 2027). Transcript, Deposition of Stephen B. Kahl, Ph.D., Sep. 14, 2016, 75 Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, pages, IPR2015-01785 Exhibit 2190). Inc., Case No. IPR2015-01780, U.S. Pat. No. 7,767,657, Patent Transcript, Deposition of Narashimha Murthy, Ph.D., Sep. 17, 2016, Owner Preliminary Response, 69 pages. 125 pages, IPR2015-01785 Exhibit 2191). Coalition for Affordable Drugs X LLC. v. Anacor Pharmaceuticals, Signature Pages and Errata to Majella Lane, Ph.D. Deposition Inc., Case No. IPR2015-01785, U.S. Pat. No. 7,767,657, Patent Transcript, 4 pages, IPR2015-01785 Exhibit 21921. Owner Preliminary Response, 70 pages. Signature Pages and Errata to Mahmoud A. Ghannoum, Ph.D., Handbook of Aqueous Solubility Data (Samuel H. Yalkowsky & Deposition Transcript, 5 pages, IPR2015-01785 Exhibit 2193 ). Yan. He eds. CRC Press, 2003) Exhibit 2027). Signature Page to Howard Maibach, M.D., Ph.D., Deposition Tran Patent Owner's Updated Exhibit List, Sep. 27, 2016, 22 pages, script, 1 page, IPR2015-01785 Exhibit 2194). IPR2O15-01776. Signature Pages and Errata to Paul J. Reider, Ph.D., Deposition Declaration of Michael N. Kennedy in Support of Patent Owner's Transcript, 3 pages, IPR2015-01785 Exhibit 21951. Motion for Admission Pro Hac Vice of Michael N. Kennedy Under Petitioner's Updated Exhibit List, 8 pages, IPR2015-01776. C.F.R. 37 C.F.R. S. 42.10, 4 pages, IPR2015-01776 Exhibit 2203). Petitioner's Updated Exhibit List, 7 pages, IPR2015-01776. Declaration of Jeffrey B. Elikan in Support of Patent Owner's Supplemental Declaration of Ryan J. Fletcher in Support of Peti Motion for Admission Pro Hac Vice, Jun. 15, 2016, IPR2015-01776 tioner's Supplemental Evidence and Response to Patent Owner's Exhibit 2204. Objections to the Petition Evidence Pursuant to 37 C.F.R. S. 42.54. Declaration of George F. Pappas in Support of Patent Owner's 4 pages, IPR2015-01776 Exhibit 1036). Motion for Admission Pro Hac Vice of George F. Pappas Under Biobor, R.E.D. Facts, EPA-738-R-93-004 (Jun. 1993), http://nepis. C.F.R. 37 C.F.R. S. 42.10, 4 pages, IPR2015-01776 Exhibit 2205). epa.gov/Exe/ZyPDF.cgi?Dockey=200009P5.PDF, 4 pageS, Transcript, Deposition of Stephen B. Kahl, Ph.D., Sep. 14, 2016, 75 IPR2015-01776 Exhibit 1037). pages, IPR2015-01776 Exhibit 2206). Excerpts from the Certified Prosecution History for U.S. Pat. No. Transcript, Deposition of Narashimha Murthy, Ph.D., Sep. 17, 2016, 6,878,365, Including the MSDS Sheet for Biobor.JF(R), 12 pages, 125 pages, IPR2015-01776 Exhibit 2207. IPR2015-01776 Exhibit 1038. Signature Pages and Errata to Majella Lane, Ph.D., Deposition Supplemental Declaration of Stephen Kahl, Ph.D., 4 pages, Transcript, 4 pages, IPR2015-01776 Exhibit 2208. IPR2015-01776 Exhibit 1039. Signature Pages and Errata to Mahmoud Ghannoum, Ph.D., E.M. Supplemental Kerydin Prices, 28 pages, available at http://www. B.A. Deposition Transcript, 5 pages, IPR2015-01776 Exhibit goodrx.com/kerydin, http://www.goodrX.com/how-goodrX-works; 2209. http://www.goodrx.com/press; IPR2015-01776 Exhibit 1040). US 9,566.290 B2 Page 13

(56) References Cited Baker, et al., “Progress on New Therapeuties for Fungal Nail Infections'. Annual Reports in Medicinal Chemistry (2005), vol. 40, OTHER PUBLICATIONS 13 pages, IPR2015-01776 Exhibit 1066). ASTMR. D5134 Qualitative Reference Naphtha Standard, Safety Q1 Medicare 2015 Kerydin Price, 14 pages, available at https:// Data Sheet, Version 3.10, available at http://www.sigmaaldrich. q1 mediacare.com/PartD-2016MedicarePlan-RetailDrugPrice. com/MSDS/MSDS/DisplayMSDSPage.do?country=US& php?ndc=10337090544&letter=K&formulary=00016286& language=en&productNumber=48265-U&brand=SUPELCO& stateReg=13MI&contractId=H2322&planId=008& PageToGoToURL=http%3A%2F%2Fwww.sigmaaldrich. segmentId=0#History; IPR2015-01776 Exhibit 1041). com%2Fcatalog%2Fproduct%2Fsupelco%2F48265u%3Flang%3Den Supplemental Declaration of S. Narashimha Murthy, Ph.D. in (Reider Deposition Ex. No. 12), IPR2015-01776 Exhibit 1067). Support of Petitioner's Supplemental Evidence and Response to Tavaborole, Material Safety Data Sheet, available at http://www. Patent Owner's Objections to the Petition Evidence Pursuant to 37 Syninnova.com/generatemsdspdf.php?pid=SL-264. IPR2O15 C.F.R. S. 42.64, 5 pages, IPR2015-01776 Exhibit 1042). 0.1776 Exhibit 1068). Declaration of Stephen Kahl, Ph.D. in Support of Petition for Inter Center for Drug Evaluation and Research Approval Package for Partes Review of U.S. Pat. No. 7,582,621, 18 pages, IPR2015 JubliaR) topical solution, 10%, available at http://www.accessdata. 0.1776 Exhibit 1043). fda.gov/drugsatfda docs/nda/2014/203567Origlis000ApLtrpdf, Deposition of Narashimha Murthy, Ph.D. in Support of Petitioner's IPR2015-01776 Exhibit 1069). Reply to Patent Owner's Response, 65 pages, IPR2015-01776 Prosecution History for U.S. Pat. No. 7,582,621, 558 pages, Exhibit 1044). IPR2015-01776 Exhibit 1070). Deposition Transcripts of Dr. Majella Lane, Jul. 7-8, 2016, 319 Center for Drug Evaluation and Research Approval Package for pages, IPR2015-01776 Exhibit 1045. Kerydin R topical solution, 5%, available at http://www.accessdata. Deposition of Transcripts Dr. Mahmoud A. Ghannoum, Jul. 18-19, fda.gov/drugsatfda docs/nda/2014/204427Origlis000Approv.pdf. 2016, 352 pages, IPR2015-01776 Exhibit 1046). 9 pages, IPR2015-01776 Exhibit 1071. Deposition Transcript of Dr. Howard Maibach, Jul. 13, 2016, 193 Hideghéty, et al. "Tissue uptake of BSH in patients with pages, IPR2015-01776 Exhibit 1047. glioblastoma in the EORTC 11961 phase I BNCT trial”, Journal of Deposition of Transcripts of Dr. Paul J. Reider, Jul. 21-22, 2016,368 Neuro-Oncology, 62, 2003, pp. 145-156, IPR2015-01776 Exhibit pages, IPR2015-01776 Exhibit 1048. 1072. Progress in Heterocyclic Chemistry, ch. 1, 1-21 (G.W. Gribble & Joensuu, et al. "Boron neutron capture therapy of brain tumors: T.L. Gilchrist eds., 1st ed., 2000) (Reider Dep. Ex. 5) IPR2015 clinical trials at the Finnish facility using boronophenylalanine'. 0.1776 Exhibit 1049. Journal of Neuro-Oncology, 62, 2003, pp. 123-134, IPR2015-01776 Wester, et. al., “In Vivo Percutaneous Absorption of Boric Acid, Exhibit 1073). Henriksson, et al. “Boron neutron capture therapy (BNCT) for Borax, and Disodium Octraborate Tetrahydrate in Humans Com glioblastoma multiforme: A phase II study evaluating a prolonged pared to in Vitro Absorption in Human Skin from Infinite and Finite high-dose of boronophenylalanine (BPA)'. Radiotherapy and Doses', 45 Toxicological Sciences, pp. 42-51 (1998), (Maibach Oncology 88 (2008), pp. 183-191, IPR2015-01776 Exhibit 1074). Dep. Ex. 9) IPR2015-01776 Exhibit 1050. Kushwaha, et al. “Trans-ungual Delivery of AR-12, a Novel Press Release, Anacor, Anacor Co-Founders Recognized for Scien Antifungal Drug Poster Presentation, (Oct. 29, 2015) (Murthy Dep. tific Achievements, Jun. 10, 2009, 2 pages, available at http:// Ex. 1) 1 page, IPR2015-01776 Exhibit 1075). investoranacor.com/releasedetail.cfm?releaseid--527603, IPR2015 Kobayashi, et al. "In vitro permeation of several drugs through the 0.1776 Exhibit 1051). human nail plate: relationship between physicochemical properties Hubbard, S.A., “Comparative Toxicology of Borates', 66 Biologi and nail permeability of drugs'. European Journal of Pharmaceu cal Trace Element Research, Proceedings of the Second Int’l tical Sciences, 21 (2004), pp. 471-477, IPR2015-01776 Exhibit Symposium on the Health Effect of Boron and Its Compounds, 1076). 343-57 (Humana Press, 1998) (“Hubbard”), IPR2015-01776 Greer, D., “Evolving Role of Nondermatophytes in Exhibit 1054). Onychomycosis'. International Journal of Dermatology, vol. 34. Baker, et al., “Therapeutic potential of boron-containing com No. 8, Aug. 1995, (Ghannoum Dep. Ex. 5), 5 pages, IPR2015-01776 pounds”. Future Med. Chem (2009) 1(7), pp. 1275-1288, IPR2015 Exhibit 1077). 0.1776 Exhibit 1056. Galimberti, et al. “The Activity of Ketoconazole in the Treatment of Li, et al. “An Improved Protocol for the Preparation of 3-Pyridyl Onychomycosis'. Oxford Journals, Aug. 1980, pp. 596-598, and Some Arylboronic Acids'. 67 J. Org. Chem (2002), pp. 5394 IPR2015-01776 Exhibit 1078. 5397, IPR2015-01776 Exhibit 1057. Gupta, et al. "Ciclopirox nail lacquer topical Solution 8% in the Donald E. Garrett, Borates Handbook of Deposits, Processing, treatment of toenail onychomycosis'. American Academy of Der Properties, and Use, 333-429 (Academic Press, 1998), IPR2015 matology, Inc., vol. 43, No. 4, 12 pages, (Ghannoum Dep. Ex. 4) 0.1776 Exhibit 1058. IPR2015-01776 Exhibit 1079. Baker, et al., “Boron-containing inhibitors of synthetases”. Chem. Declaration of Ryan J. Fletcher in Support of Petition for Inter Soc. Rev., 2011, 40, pp. 4279-4285, IPR2015-01776 Exhibit 1059. Partes Review of U.S. Pat. No. 7,582,621, 4 pages, IPR2015-01776 Yang, et al. “Boronic Acid Compounds as Potential Pharmaceutical Exhibit 1080. Agents', 23 Medicinal Research Reviews, No. 3, 2003, pp. 346 Signature Pages & Errata Sheets to Stephen B. Kahl, Ph.D. dated 368, IPR2015-01776 Exhibit 1060). Apr. 7-8, 2016 Deposition Transcript, 9 pages, IPR2015-01776 Wester, et al. “In Vivo Percutaneous Absorption of Boron as Boric Exhibit 1081). Acid, Borax, and Disodium Octaborate Tetrahydrate in Humans', Signature Pages & Errata Sheet to Stephen B. Kahl, Ph.D. dated Biological Trace Element Research, 66 Biological Trace Element Sep. 14, 2016 Deposition Transcript, 2 pages, IPR2015-01776 Research, Proceedings of the Second Int'l Symposium on the Health Exhibit 1082). Effect of Boron and Its Compounds 101-09 (Humana Press, 1998) Signature Pages & Errata Sheet to Narasimha Murthy, Ph.D. dated IPR2015-01776 Exhibit 1061. May 4-6, 2016. Deposition Transcript, 8 pages, IPR2015-01776 Certified U.S. Appl. No. 60/654,060, 43 pages, IPR2015-01776 Exhibit 1083. Exhibit 1064). Signature Page & Errata Sheet to Narasimha Murthy, Ph.D. dated Mertin, et al. “In-vitro Permeability of the Human Nail and of a Sep. 17, 2016. Deposition Transcript, 1 page, IPR2015-01776 Keratin Membrane from Bovine Hooves: Prediction of the Penetra Exhibit 1084. tion Rate of Antimycotics through the Nail Plate and their Efficacy”. Email from Ryan James Fletcher to Counsel for Patent Owner dated J. Pharm. Pharmacol., 1997, 49, pp. 866-872, IPR2015-01776 Apr. 5, 2016 regarding Petitioner Response to PO Evidence Objec Exhibit 1065. tions, 1 page, IPR2015-01776 Exhibit 1085. US 9,566.290 B2 Page 14

(56) References Cited Supplemental Declaration of S. Narashimha Murthy, Ph.D. in Support of Petitioner's Supplemental Evidence and Response to OTHER PUBLICATIONS Patent Owner's Objections to the Petition Evidence Pursuant to 37 C.F.R. S. 42.64, 8 pages, IPR2015-01785 Exhibit 1059. Petitioner's Updated Exhibit List, Oct. 11.2016, 10 pages, IPR2015 Supplemental Declaration of Stephen Kahl, Ph.D., 4 pages, O1780. IPR2015-01785 Exhibit 1066. Petitioner's Updated Exhibit List, Aug. 24, 2016, 10 pages, Declaration of Stephen Kahl, Ph.D. in Support of Second Petition IPR2O15-01780. for Inter Partes Review of U.S. Pat. No. 7,767,657, 18 pages, Supplemental Declaration of Kathleen E. Ott in Support in Support of Petitioner's Supplemental Evidence and Response to Patent IPR2015-01785 Exhibit 1069). Owner's Objections to the Petition Evidence Pursuant to 37 C.F.R. Declaration of S. Narasimha Murthy, Ph.D. in Support of Petition S 42.54, 5 pages, IPR2015-01780 Exhibit 1054). er's Reply to Patent Owner's Response, 70 pages, IPR2015-01785 Supplemental Declaration of S. Narashimha Murthy, Ph.D. in Exhibit 1070). Support of Petitioner's Supplemental Evidence and Response to Deposition of Majella Lane, Ph.D., 319 pages, IPR2015-01785 Patent Owner's Objections to the Petition Evidence Pursuant to 37 Exhibit 1071. C.F.R. S. 42.64, 9 pages, IPR2015-01780 Exhibit 1059. Deposition of Mahmoud A. Ghannoum, Ph.D., 352 pages, IPR2015 Gantrez.R. Copolymers, Technical Profile (International Specialty 0.1785 Exhibit 1072). Products (Copyright 1999) with affidavit from Archive.org, 19 Deposition of Howard Maibach, M.D., Ph.D., 193 pages, IPR2015 pages, IPR2015-01780 Exhibit 1060). 0.1785 Exhibit 1073. Aldrich Handbook of Fine Chemicals and Laboratory Equipment Deposition of Paul J. Reider, Ph.D., 368 pages, IPR2015-01785 (2003-2004), 7 pages, IPR2015-01780 Exhibit 1061. Exhibit 1074. Remington: The Science and Practice of Pharmacy (Lippincott Declaration of Ryan J. Fletcher in Support of Petition for Inter Williams & Wilkins, 19th ed. 1995), 9 pages, IPR2015-01780 Partes Review of U.S. Pat. No. 7,767,657, 4 pages, IPR2015-01785 Exhibit 1062). Exhibit 1107). Hawley's Condensed Chemical Dictionary (John Wiley & Sons, Signature Pages & Errata Sheets to Stephen B. Kahl, Ph.D. dated Inc., 12th ed. 1993), 7 pages, IPR2015-01780 Exhibit 1063). Apr. 7-8, 2016, 9 pages, IPR2015-01785 Exhibit 1108). Department of Health and Human Services Letter (1999) Regarding Signature Pages & Errata Sheet to Stephen B. Kahl, Ph.D. dated Clotrimazole (Mycelex(R), 16 pages, IPR2015-01780 Exhibit Sep. 14, 2016, 2 pages, IPR2015-01785 Exhibit 1109). 1065. Signature Pages & Errata Sheet to Narasimha Murthy, Ph.D. dated Supplemental Declaration of Stephen Kahl, Ph.D., 4 pages, May 4-6, 2016, 8 pages, IPR2015-01785 Exhibit 1110). IPR2015-01780 Exhibit 1066. Signature Page & Errata Sheet to Narasimha Murthy, Ph.D. dated Pittrofetal. Loceryl(R) Nail Lacquer—Realization of a New Galeni Sep. 17, 2016, 1 page, IPR2015-01785 Exhibit 1111). cal Approach to Onychomycosis Therapy, Clinical and Experimen Email from Ryan James Fletcher to Counsel for Patent Owner dated tal Dermatology, 17 (Suppl. 1):26-28 (1992), 3pages, IPR2015 Apr. 5, 2016 regarding Petitioner Response to PO Evidence Objec 0.1780 Exhibit 1067). tions, 1 page, IPR2015-01785 Exhibit 1112). Declaration of Stephen Kahl, Ph.D. in Support of First Petition for Patent Owner, Case No. IPR2015-01776, U.S. Pat. No. 7,582,621, Inter Partes Review of U.S. Pat. No. 7,767,657, 18 pages, IPR2015 Petitioner's Objections to Patent Owner's Evidence Under 37 0.1780 Exhibit 1069). C.F.R. S. 42.64(B)(1), Jun. 13, 2016, 188 pages. Deposition of S. Narashimha Murthy, Ph.D. in Support of Petition Petitioner Coalition for Affordable Drugs X LLC's Notice of er's Reply to Patent Owner's Response, 72 pages, IPR2015-01780 Deposition of Mahmoud A. Ghannoum, Ph.D., Jun. 24, 2016, 4 Exhibit 1070). pages, IPR2015-01776. Deposition of Majella Lane, Ph.D., 319 pages, IPR2015-01780 Petitioner Coalition for Affordable Drugs X LLC's Notice of Exhibit 1071. Deposition of Majella Lane, Ph.D., Jun. 24, 2016, 4 pages, Deposition of Mahmoud A. Ghannoum, Ph.D., 352 pages, IPR2015 IPR2O15-01776. 0.1780 Exhibit 1072). Petitioner Coalition for Affordable Drugs X LLC's Notice of Deposition of Howard Maibach, M.D., Ph.D., 193 pages, IPR2015 Deposition of Paul J. Reider, Ph.D., Jun. 24, 2016, 4 pages, 0.1780 Exhibit 1073. IPR2O15-01776. Deposition of Paul J. Reider, Ph.D., 368 pages, IPR2015-01780 Petitioner Coalition for Affordable Drugs X LLC's Notice of Exhibit 1074. Deposition of Howard Maibach, Ph.D., Jul. 1, 2016, 4 pages, Prosecution History(Response to Restriction Requirement) for U.S. IPR2O15-01776. Pat. No. 7,767,657, 8 pages, IPR2015-01780 Exhibit 1105. Petitioner's Reply to Patent Owner's Response, Aug. 24, 2016, 36 Declaration of Ryan J. Fletcher in Support of Petition for Inter pages, IPR2015-01776. Partes Review of U.S. Pat. No. 7,767,657, 4 pages, IPR2015-01780 Petitioner's Request for Oral Argument, Sep. 27, 2016, 4 pages, Exhibit 1107). IPR2O15-01776. Signature Pages & Errata Sheets to Stephen B. Kahl, Ph.D. dated Petitioner's Response to Patent Owner's Identification of new Apr. 7-8, 2016, 9 pages, IPR2015-01780 Exhibit 1108). Arguments and Evidence in Petitioner's Reply, Oct. 4, 2016, 6 Signature Pages & Errata Sheet to Stephen B. Kahl, Ph.D. dated pages, IPR2015-01776. Sep. 14, 2016, 2 pages, IPR2015-01780 Exhibit 1109). Patent Owner's Identification of New Arguments and Evidence in Signature Pages & Errata Sheet to Narasimha Murthy, Ph.D. dated Petitioner's Reply, Sep. 27, 2016, 6 pages, IPR2015-01776. May 4-6, 2016, 8 pages, IPR2015-01780 Exhibit 1110). Patent Owner's Motion for Observations Regarding the Cross Signature Page & Errata Sheet to Narasimha Murthy, Ph.D. dated Examination Testimony of Stephen B. Kahl, Ph.D., Sep. 27, 2016, Sep. 17, 2016, 1 page, IPR2015-01780 Exhibit 1111). 5 pages, IPR2015-01776. Email from Ryan James Fletcher to Counsel for Patent Owner dated Patent Owner's Motion to Exclude Evidence Pursuant to 37 C.F.R. Apr. 5, 2016 regarding Petitioner Response to PO Evidence Objec S 42.64, Sep. 27, 2016, 18 pages, IPR2015-01776. tions, 1 page, IPR2015-01780 Exhibit 1112). Patent Owner's Motion for Observations Regarding the Cross Petitioner's Updated Exhibit List, Oct. 11.2016, 10 pages, IPR2015 Examination Testimony of S. Narasimha Murthy, Ph.D., Sep. 27. O1785. 2016, 10 pages, IPR2015-01776. Petitioner's Updated Exhibit List, Aug. 24, 2016, 10 pages, Patent Owner's Request for Oral Argument Under C.F.R. S. 42.70. IPR2O15-01785. Sep. 27, 2016, 4 pages, IPR2015-01776. Supplemental Declaration of Kathleen E. Ott in Support in Support Trial Hearing Order Regarding IPR2015-01776, 0.1780, and 01785, of Petitioner's Supplemental Evidence and Response to Patent Entered Oct. 4, 2016, 5 pages. Owner's Objections to the Petition Evidence Pursuant to 37 C.F.R. Patent Owner Anacor Pharmaceuticals, Inc.'s Notice of Deposition S 42.54, 5 pages, IPR2015-01785 Exhibit 1054). of Stephen B. Kahl, Ph.D., Sep. 7, 2016, 4 pages, IPR2015-01776. US 9,566.290 B2 Page 15

(56) References Cited Patent Owner's Motion for Admission Pro Hac Vice of Michael N. Kennedy Under C.F.R. S. 42.10, Jun. 13, 2016, 6 pages, IPR2015 OTHER PUBLICATIONS O1780. Patent Owner's Motion to Exclude Evidence Pursuant to 37 C.F.R. Patent Owner's Motion for Admission Pro Hac Vice of Michael N. S 42.64, Sep. 27, 2016, 18 pages, IPR2015-01780. Kennedy Under C.F.R. S. 42.10, Jun. 13, 2016, 6 pages, IPR2015 Patent Owner Anacor Pharmaceuticals, Inc.'s Notice of Deposition O1776. of S. Narasimha Murthy, Ph.D., Sep. 7, 2016, 4 pages, IPR2015 Patent Owner Anacor Pharmaceuticals, Inc.'s Notice of Deposition O1780. of S. Narasimha Murthy, Ph.D., Sep. 7, 2016, 4 pages, IPR2015 Patent Owner's Motion for Observations Regarding the Cross O1776. Examination Testimony of S. Narasimha Murthy, Ph.D., Sep. 27. Patent Owner's Objections to Evidence Under 37 C.F.R. S 2016, 10 pages, IPR2015-01780. 42.64(b)(1), Aug. 31, 2016, 8 pages, IPR2015-01776. Patent Owner's Motion for Admission Pro Hac Vice of George F. Patent Owner's Motions for Pro Hac Vice Admission of Michael N. Pappas Under 37 C.F.R. S. 42.10, Jun. 30, 2016, 6 pages, IPR2015 Kennedy and Jeffrey B. Elikan Under 37 C.F.R. S. 42.10, Entered O1780. Jun. 29, 2016, 3 pages, IPR2015-01776. Patent Owner's Objections to Evidence Under 37 C.F.R. S42. Patent Owner's Motion for Pro Hac Vice Admission of George F. 64(b)(1), Aug. 31, 2016, 8 pages, IPR2015-01780. Pappas Under 37 C.F.R. S. 42.10, Entered Jul. 8, 2016, 3 pages, Patent Owner's Request for Oral Argument Under 37 C.F.R. S IPR2O15-01776. 42.70, Sep. 27, 2016, 5 pages, IPR2015-01780. Patent Owner's Motion for Admission Pro Hac Vice of Jeffrey B. Petitioner's Response to Patent Owner's Motion to Exclude Evi Elikan Under 37 C.F.R. S. 42.10, Jun. 20, 2016, 6 pages, IPR2015 dence Pursuant to 37 C.F.R. S. 42.64. Oct. 11, 2016, 18 pages, O1776. IPR2O15-01780. Patent Owner's Motion for Admission Pro Hac Vice of George F. Petitioner's Response to Patent Owner's Motion for Observations Pappas Under 37 C.F.R. S. 42.10, Jun. 30, 2016, 6 pages, IPR2015 Regarding the Cross-Examination Testimony of Stephen B. Kahl, O1776. Ph.D., Oct. 11, 2016, 5 pages, IPR2015-01780. Petitioner's Response to Patent Owner's Motion to Exclude Evi Petitioner's Response to Patent Owner's Motion for Observations dence Pursuant to 37 C.F.R. S. 42.64, Oct. 11, 2016, 18 pages, Regarding the Cross-Examination Testimony of S. Narasimha IPR2O15-01776. Murthy, Ph.D., Oct. 11, 2016, 14 pages, IPR2015-01780. Petitioner's Response to Patent Owner's Motion for Observations Petitioner's Objections to Patent Owner's Evidence Under 37 Regarding the Cross Examination Testimony of Stephen B. Kahl, C.F.R. S. 42.64(B)(1), Jun. 13, 2016, 168 pages, IPR2015-01785. Ph.D., Oct. 11, 2016, 5 pages, IPR2015-01776. Petitioner Coalition for Affordable Drugs X LLC's Notice of Petitioner's Response to Patent Owner's Motion for Observations Deposition of Mahmoud A. Ghannoum, Ph.D., Jun. 24, 2016, 4 Regarding the Cross-Examination Testimony of S. Narasimha pages, IPR2015-01785. Murthy, Ph.D., Oct. 11, 2016, 14 pages, IPR2015-01776. Petitioner Coalition for Affordable Drugs X LLC's Notice of Petitioner's Objections to Patent Owner's Evidence Under 37 Deposition of Majella Lane, Ph.D., Jun. 24, 2016, 4 pages, C.F.R. S. 42.64(B)(1), Jun. 13, 2016, 186 pages, IPR2015-01780. IPR2O15-01785. Petitioner Coalition for Affordable Drugs X LLC's Notice of Petitioner Coalition for Affordable Drugs X LLC's Notice of Deposition of Mahmoud A. Ghannoum, Ph.D., Jun. 24, 2016, 4 Deposition of Paul J. Reider, Ph.D., Jun. 24, 2016, 4 pages, pages, IPR2015-01780. IPR2O15-01785. Petitioner Coalition for Affordable Drugs X LLC's Notice of Petitioner Coalition for Affordable Drugs X LLC's Notice of Deposition of Majella Lane, Ph.D., Jun. 24, 2016, 4 pages, Deposition of Howard Maibach, Ph.D., Jul. 1, 2016, 4 pages, IPR2O15-01780. IPR2O15-01785. Petitioner Coalition for Affordable Drugs X LLC's Notice of Petitioner's Reply to Patent Owner's Response, Aug. 24, 2016, 36 Deposition of Paul J. Reider, Ph.D., Jun. 24, 2016, 4 pages, pages, IPR2015-01785. IPR2O15-01780. Petitioner's Request for Oral Argument, Sep. 27, 2016, 5 pages, Petitioner Coalition for Affordable Drugs X LLC's Notice of IPR2O15-01785. Deposition of Howard Maibach, Ph.D., Jul. 1, 2016, 4 pages, Petitioner's Response to Patent Owner's Identification of new IPR2O15-01780. Arguments and Evidence in Petitioner's Reply, Oct. 4, 2016, 6 Petitioner's Reply to Patent Owner's Response IPR2015-01780, pages, IPR2015-01785. Aug. 24, 2016, 36 pages. Petitioner's Response to Patent Owner's Motion to Exclude Evi Petitioner's Request for Oral Argument, Sep. 27, 2016, 5 pages, dence Pursuant to 37 C.F.R. S. 42.64. Oct. 11, 2016, 12 pages, IPR2O15-01780. IPR2O15-01785. Petitioner's Response to Patent Owner's Identification of new Petitioner's Response to Patent Owner's Motion for Observations Arguments and Evidence in Petitioner's Reply, Oct. 4, 2016, 6 Regarding the Cross-Examination Testimony of Stephen B. Kahl, pages, IPR2015-01780. Ph.D., Oct. 11, 2016, 5 pages, IPR2015-01785. Trial Hearing Order Regarding, Entered Oct. 4, 2016, 5 pages, Petitioner's Response to Patent Owner's Motion for Observations IPR2O15-01780. Regarding the Cross-Examination Testimony of S. Narasimha Patent Owner's Motions for Pro Hac Vice Admission of Michael N. Murthy, Ph.D., Oct. 11, 2016, 14 pages, IPR2015-01785. Kennedy and Jeffrey B. Elikan Under 37 C.F.R. S. 42.10, Entered Trial Hearing Order, Entered Oct. 4, 2016, 5 pages, IPR2015-01785. Jun. 29, 2016, 3 pages, IPR2015-01780. Patent Owner's Motions for Pro Hac Vice Admission of Michael N. Patent Owner's Motion for Pro Hac Vice Admission of George F. Kennedy and Jeffrey B. Elikan Under 37 C.F.R. S. 42.10, Entered Pappas Under 37 C.F.R. S. 42.10, Entered Jul. 8, 2016, 3 pages, Jun. 29, 2016, 3 pages, IPR2015-01785. IPR2O15-01780. Patent Owner's Motion for Pro Hac Vice Admission of George F. Patent Owner's Motion for Admission Pro Hac Vice of Jeffrey B. Pappas Under 37 C.F.R. S. 42.10, Entered Jul. 8, 2016, 3 pages, Elikan Under 37 C.F.R. S. 42.10, Jun. 20, 2016, 6 pages, IPR2015 IPR2O15-01785. O1780. Patent Owner's Identification of New Arguments and Evidence in Patent Owner's Identification of New Arguments and Evidence in Petitioner's Reply, Sep. 27, 2016, 6 pages, IPR2015-01785. Petitioner's Reply, Sep. 27, 2016, 6 pages, IPR2015-01780. Patent Owner's Motion for Observations Regarding the Cross Patent Owner Anacor Pharmaceuticals, Inc.'s Notice of Deposition Examination Testimony of Stephen B. Kahl, Ph.D., Sep. 27, 2016, of Stephen B. Kahl, Ph.D., Sep. 7, 2016, 4 pages, IPR2015-01780. 5 pages, IPR2015-01785. Patent Owner's Motion for Observations Regarding the Cross Patent Owner's Motion for Observations Regarding the Cross Examination Testimony of Stephen B. Kahl, Ph.D., Sep. 27, 2016, Examination Testimony of S. Narasinnha Murthy, Ph.D., Sep. 27. 5 pages, IPR2015-01780. 2016, 10 pages, IPR2015-01785. US 9,566.290 B2 Page 16

(56) References Cited OTHER PUBLICATIONS

Patent Owner's Motion to Exclude Evidence Pursuant to 37 C.F.R. S 42.64, Sep. 27, 2016, 12 pages, IPR2015-01785. Patent Owner's Request for Oral Argument Under 37 C.F.R. S 42.70, Sep. 27, 2016, 5 pages, IPR2015-01785. Patent Owner Anacor Pharmaceuticals, Inc.'s Notice of Deposition of Stephen B. Kahl, Ph.D., Sep. 7, 2016, 4 pages, IPR2015-01785. Patent Owner Anacor Pharmaceuticals, Inc.'s Notice of Deposition of S. Narasimha Murthy, Ph.D., Sep. 7, 2016, 4 pages, IPR2015 O1785. Patent Owner's Objections to Evidence Under 37 C.F.R. S42. 64(b)(1), Aug. 31, 2016, 8 pages, IPR2015-01785. * cited by examiner U.S. Patent US 9,566.290 B2

C1

C2

C3 C4 ..64

> 64 U.S. Patent Feb. 14, 2017 Sheet 2 of 63 US 9,566.290 B2

FIGURE 1B

re

3 3 3

5 62 CCC 1 321 123 1 6

16

63 4 4 1 6 1 CCC 1 876

2 1 4.

C22 4. | | | >64 U.S. Patent Feb. 14, 2017 Sheet 3 of 63 US 9,566.290 B2

FIGURE 1C

U.S. Patent Feb. 14, 2017 Sheet 4 of 63 US 9,566,290 B2

FIGURE 2A

EXAMPLE 2A

e d . A. pwtO g M Broth used O A. fumigatus ATCC 3073 0. 5 t 0.25 C. albicans ATCC 90.028 a 0. 12 C. albicans F56 g 6 0.25 C. glabrata ATCC 90030 RPM + MOPS 30.5 64 t - C. krusei ATCC 44507 RPM + MOPS 64 t Yaw C. neoformans F285 RPMI 0.25 t 2 < 0.12 C. parapsilosistropicalis ATCC ATCC 13803 22019 EEEEEERPM + MOPS <0.5 Tg 0.5 256 nt Kgs--- E, floccosun ATCC 52066 RPM + MOPS 30.5 - 55 RPM + MOPs < 0.5 4 64 nt >256 M. furfur ATCC 44344 Urea < 0.5 2 nt < 0.5 M. pachydermatis ATCC 96746 Urea < 0.5 30.5 nt < 0.5 M sympodialis ATCC 44031 Urea < 0.5 so.5 nt < 0.5 M. audouini ATCC 42558 RPM + MOPS 2 1 < 0.5 nt < 0.5 M. canis ATCC 1024 RPM + MOPS 2 30.5 < 0.5 nt M. gypseum ATCC 2403 RPMI - MOPS 2 < 0.5 t < 0.5 nt

T. mentagrophytes F31 l RPM + MOPs 0.5 < 0.5 T. rubrun F296 RPM + MoPs 1 < 0.5 1 < 0.12 T. rubrum F296 5%E. keratin powder 2. . . In t nt F not tested U.S. Patent Feb. 14, 2017 Sheet 5 of 63 US 9,566.290 B2

FIGURE 2B

EXAMPLE 2B

() C . n a al E. C O vu 9 .S. d Broth used S. O T. mentagrophytes F31 RPMI - MOPS e T. rubrum F296 RPM + MOPs 8 3. U.S. Patent Feb. 14, 2017 Sheet 6 of 63 US 9,566.290 B2

FIGURE 3

Radioactivity as mg Equivalent/g Nail Samples Nail Samples P value (t-test) Group A Group C (C10) (Ciclopirox) Dorsal/intermediate center 25.65 - 8.80 7.40 - 3.47 Ventral/intermediate center 20.46 - 4.72 3.09 - 2.07 0.0001

Remainder nail 26.06 it 12.41 4.38 it 2.73

* The data represents the mean de S.D. of each group (n = 6). U.S. Patent Feb. 14, 2017 Sheet 7 of 63 US 9,566,290 B2

FIGURE 4

Radioactivity as mg Equivalent/Samples' Sampling day P-value (t-test) Group A (C10) Group C (Ciclopirox) Day 3 0.0609 - 0.0605 0.0011 - 0.0020 0.0043 Day 6 0.155 - 0.1314 0.0013 - 0.0027 0.0022 Day 9 0.3892 - 0.3714 0.0018; 0.0030 0.0022 Day 12 0.6775 - 0.6663 0.0014 - 0.0019 0.0022 Day 15 0.9578 - 0.6106 0.0033 - 0.0041 0.0022 Total 2.24.05 - 1.7325 0.0089 it 0.031 0.0022

* The data represents the meant S.D. of each group (n = 6). U.S. Patent Feb. 14, 2017 Sheet 8 of 63 US 9,566.290 B2

FIGURES

Full thickness Human Nai 5 x 2 u over 5 (lays Application of 50:50 Ethyl acetate Propylene glycol U.S. Patent Feb. 14, 2017 Sheet 9 of 63 US 9,566.290 B2

FIGURE 6

Full thickness Human Nail 5x 2 ul over 5 days application of C10 U.S. Patent Feb. 14, 2017 Sheet 10 of 63 US 9,566.290 B2

FIGURE 7

Full thickness Human Nail 5 x 2l over 5 days Application of C10 U.S. Patent Feb. 14, 2017 Sheet 11 of 63 US 9,566.290 B2

FIGURE 8

F thickness Human Nail 5 x 2 over 5 days Application of Perlac U.S. Patent Feb. 14, 2017 Sheet 12 of 63 US 9,566.290 B2

FIGURE 9

Full thickness human Nail 5 x 2 ul over 5 days Application of locery U.S. Patent Feb. 14, 2017 Sheet 13 of 63 US 9,566.290 B2

Figure 10(1) SUMMARY: SEQ ID NO: 1-15 amino acid sequences of leucyl-tRNA synthetase editing domain SEQ ID NO: 1 amino acid sequences of leucyl-tRNA synthetase editing domain from S. cerivisiae. SEQID NO: 2 amino acid sequences of leucyl-tRNA synthetase editing domain from S. cerivisiae - overexpressed version SEQID NO: 16-17 genomic sequences for tRNA-leu and tRNA-ile from S. cerivisiae. SEQ ID NO: 18-62 tRNA sequences for tRNA-leu A. SEQ ID NO: 1 TPQEYIGVKIEALEFADDAAKIIDSSSDLDKSKKFYFVAATLRPETMYGQTCCFVSPTI EYGIFDAGDSYFITTERAFKNMSYQKLTPKRGFYKPIVTVPGKAFIGTKIHAPQSVYPE LRILPMETVIATKGTGVVTCVPSNSPDDYITTKDLLHKPEYYGIKPEWIDHEIVPIMHTE KYGDLTAKAIVEEKKIQSPKDKNLLAEAKKIAYKEDYYTGTMIYGPYKGEKVEQAKNK VKADMIAAGEAFVYNEPESQDP SEQ ID NO: 2 MTPQEYIGVKIEALEFADDAAKIIDSSSDLDKSKKFYFVAATLRPETMYGQTCCFVSPTI EYGIFDAGDSYFITTERAFKNMSYQKLTPKRGFYKPIVTVPGKAFIGTKIHAPQSVYPE LRILPMETVIATKGTGVVTCVPSNSPDDYITTKDLLHKPEYYGIKPEWIDHEIVPIMHTE KYGDLTAKAIVEEKKIQSPKDKNLLAEAKKIAYKEDYYTGTMIYGPYKGEKVEQAKNK VKADMIAAGEAFVYNEPESQDPQDPNSSSVDKLAAALEHHHHH B. SEQ ID NO:3 G- E.coli crystal structure (185 amino acids) - trNA synthetase editing domain EGVEITFNVNDYDNTLTVYTTRPDTFMGCTYLAVAAGHPLAQKAAENNPELAAFIDECR NTKVAEAEMATMEKKGVDTGFKAVHPLTGEEIPVWAANFVLMEYGTGAVMAVPGHD QRDYEFASKYGLNIKPVILAADGSEPDLSQQALTEKGVLFNSGEFNGLDHEAAFNAIAD KLTAMGVGERK SEQ ID NO: 4 G+ Propionibacter acnes (185 aa) - tRNA synthetase editing domain EGAYVDFTIDGHKEPVRVFTTRPDTLYGATFMVVAPDSALAQEIVSDEARPAFETYLDE VKKKSEIERQATDHEKTGVPLGVEATNPVNGAKVPVWAGDYVLADYGTGAVMAVPA HDQRDLDFARTYGIDVIPVIDTGEADPRESGVATTGDGVYQNSGFLNGIATKAEAIAKM CEFLDEKGIGE U.S. Patent Feb. 14, 2017 Sheet 14 of 63 US 9,566.290 B2

Figure 10(2) SEQ ID NO: 5 from G- Pseudomonas aeruginosa (194 aa)-tRNA synthetase editing domain GMEIGFPYDQASIGHAGQLKVFTTRPDTLMGATYVAVAAEHPLATOAAQNDPQLQAFI DECKRGGVAEADIATOEKKGMATSLFVEHPLTGDKLPVWVANYVLMNYGEGAVMAV PGHDERDFEFANKYGLPIRQVIAKVEGDDDFESSVWKEWYGAKDESVLTVNSGKYDNL GYOAAFDAIGADLEAKGLGQAR SEQ ID NO: 6 G+ Bacillus anthracis (183 aa) - thNA synthetase editing domain EGAEVHFNIDGTDEKFTVFTTRPDTLFGASYCVLAPEHALVADITTADQKEAVEAYINSV KMKSDLERTELAKEKTGVFTGAYAVNPVNGEKLPWIADYVLATYGTGAVMAVPAHD ERDYEFASTFNLPMKEVVKGGDITKEAYTGDGAHVNSAFLDGLNKEEAIAKMIEWLEV TSAGNQKV SEQ ID NO: 7 from G+ Staphylococcus aureus (183 aa) - tRNA synthetase editing domain EGAKVTFKIEQSDQNIEVFTTRPDTIYGTSFLVLSPEHPLVNEITTSDKEQEVKLYQNEA SKKSDLERTDLAKEKTGVFTGTFANPLSGDKLPIWIADYVLSTYGTGAVMAVPGHDER DHEFATKFNLPIIEVIEGGEVQKYAYTGEGKHINSGELDGLENEAAISKAIELLESKGAGE KKV SEQ ID NO: 8 G+ Streptococcus pyogens (182 aa)-tRNA synthetase editing domain GANVTFKVKDTDKNFTVFTTRPDTLFGATYAVLAPEHALVDAITTADQAEAVADYKRQ ASLKSDLARTDLAKEKTGVWTGSYANPVNGKEIPVWIADYVLASYGTGAIMAVPAHD ERDWEFAKQFNLDIIPVLEGGNVEEAAFTEDGLHINSGFLDGLDKASALAKMVEWLEAE GVGNEKV SEQ ID NO:9 G+ Thermus thermophilus (187 aa) - trNA synthetase editing domain EGAEILFPVEGKEVRIPVFTTRPDTLFGATFLVLAPEHPLTLELAAPEKREEVLAYVEAA KRKTEIERQAEGREKTGVFLGAYALNPATGERIPIWTADYVLFGYGTGAIMAVPAHDQR DYEFARKFGLPKKVIERPGEPLPEPLERAYEEPGIMVNSGPFDGTESEEGKRKVIAWLEE KGLGKGR SEQ ID NO: 10 Mycobacterium tuberculosis (186 aa) - trNA synthetase editing domain FEVDIEVFTTRPDTLFGATYLVLAPEHDLVDELVAASWPAGVNPLWTYGGGTPGEAIAA YRRAMAAKSDLERQESREKTGVFVGSYAINPANGEPVPIFIADYVLAGYGTGAIMAVPG HDQRDWDFARAFGLPIVEVIAGGNISESAYTGDGILVNSDYLNGMSVPAAKRAIVDRLE SAGRGRARI SEQ ID NO: 11 Candida albicans (251 aa) - tRNA synthetase editing domain YVGIKIRLTDVAPQAQELFKKESLDVKENKVYLVAATLRPETMYGQTCCFVSPKIDYGV FDAGNGDYFITTERAFKNMSFQNLTPKRGYYKPLFTINGKTLIGSRIDAPYAVNKNLRVL PMETVLATKGTGVVTCVPSDSPDDFVTTRDLANKPEYYGIEKDWVQTDIVPIVHTEKYG DKCAEFLVNDLKIQSPKDSVQLANAKELAYKEGFYNGTMLIGKYKGDKVEDAKPKVK QDLIDEGLAFVYNEPE

U.S. Patent Feb. 14, 2017 Sheet 23 of 63 US 9,566.290 B2

FIGURE 11B

B s B B pH f p O O O O B B f r Hsco O O f

t f pH pH \ O B B O. N. \ O B-N O -Ns O C. FESa By OH

C U.S. Patent Feb. 14, 2017 Sheet 24 of 63 US 9,566.290 B2

FIGURE 11C ph / \ B p H HN fOH HN lo o O2N B 2 B 2B1 N O N O O CH3

OH CH3 ph O2N d OH OH B N | I N O B. B O NH S s NO2 s OH OH / d B N

MeO F U.S. Patent Feb. 14, 2017 Sheet 25 of 63 US 9,566.290 B2

FIGURE 11D

OH OH F d d N N O O (Me)Si F F ph OH B d O N OH O O pH ph ON B B Yo Yo OMe OH

O . 9 O OH / f B ON B Yo Yo ONO2 pH ph O2N B ON B Yo Yo OH OMe U.S. Patent Feb. 14, 2017 Sheet 26 of 63 US 9,566.290 B2

FIGURE 11E

OH C2H d HN 25 OH OH

Yo B v ph O O B OH O NO B N O () HO CN s O ; ; NC s OH H pH pH pH B o B B

CN: o?OH, NO2; COOH Br; OH s s OH pH O Yo Yo B pH N HON O By B C 8. Hd H2 Br O OH pH pH N

-O O 9 pH pH B B pH Bu OH

CF CH3 O O U.S. Patent Feb. 14, 2017 Sheet 27 of 63 US 9,566.290 B2

FIGURE 11 F

OH w N N OSO B I B,* - O (SNC N1 BpH O -N I O Bu w V d U.S. Patent Feb. 14, 2017 Sheet 28 of 63 US 9,566.290 B2

FIGURE 12A U.S. Patent Feb. 14, 2017 Sheet 29 of 63 US 9,566.290 B2 COO. CC). CrC CO, CO: U.S. Patent Feb. 14, 2017 Sheet 30 of 63 US 9,566.290 B2

FIGURE 12C

Mo 2- O :

o CH3 Pses CCC. s Cross. CCI).\/ CCC-ICC--> y C duc OOC OUCC-CO).5. K 3. U.S. Patent Feb. 14, 2017 Sheet 31 of 63 US 9,566.290 B2

FIGURE 12D

EtO re CC O r ICC O w O U.S. Patent Feb. 14, 2017 Sheet 32 of 63 US 9,566.290 B2

FIGURE 12E cCror Col.

Crics - or role is croscoeO / U.S. Patent Feb. 14, 2017 Sheet 33 of 63 US 9,566.290 B2

FIGURE 12F U.S. Patent Feb. 14, 2017 Sheet 34 of 63 US 9,566.290 B2

FIGURE 12G U.S. Patent Feb. 14, 2017 Sheet 35 of 63 US 9,566.290 B2

FIGURE 12H

CCC-C-C- i i

CCC COC s C.C. U.S. Patent Feb. 14, 2017 Sheet 36 of 63 US 9,566.290 B2

FIGURE 12 CCC-COCf S cror or U.S. Patent Feb. 14, 2017 Sheet 37 of 63 US 9,566.290 B2

?IGHRIQ?INH uun?uq???nbE?eO?Ou??Mpunog090poqueOued U.S. Patent US 9,566.290 B2

001,060801090702OZOLO Wn‘O?O?91-)

U.S. Patent Feb. 14, 2017 Sheet 40 of 63 US 9,566.290 B2

9IGIRI[10][H U.S. Patent Feb. 14, 2017 Sheet 41 of 63 US 9,566.290 B2

L w

92 LIGIRI[15)IH

U.S. Patent Feb. 14, 2017 Sheet 46 of 63 US 9,566.290 B2

FIGURE 19B

No. R 0a 32 Br 33 H 34 H 35 Br 36 Br Br 37 H Br 38 H Br 39 Br 40 H 41 Br Br 42 H 43 Br 44 Br 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72

U.S. Patent Feb. 14, 2017 Sheet 48 of 63 US 9,566.290 B2

FIGURE 19D

No. R10a Ria 114 -OMe H H 115 H -OMe -OMe 16 -OMe H -OMe 17 -OMe -OMe H 118 -OMe -OMe -OMe 119 -OMe -OMe -OMe 120 -4-cyanophenoxy H H 121 H -4-cyanophenoxy H 122 H H -4-cyanophenoxy 23 H H H -4-cyanophenoxy 24 -4-cyanophenoxy -4-cyanophenoxy H H 125 H -4-cyanophenoxy -4-cyanophenoxy H 126 H H -4-cyanophenoxy -4-cyanophenoxy 127 -4-cyanophenoxy H -4-cyanophenoxy H 128 H -4-cyanophenoxy H -4-cyanophenoxy 129 -4-cyanophenoxy H H -4-cyanophenoxy 130 H -4-cyanophenoxy -4-cyanophenoxy -4-cyanophenoxy 131 -4-cyanophenoxy H -4-cyanophenoxy -4-cyanophenoxy 132 -4-cyanophenoxy -4-cyanophenoxy H 4-cyanophenoxy 133 -4-cyanophenoxy -4-cyanophenoxy -4-cyanophenoxy H 134 -4-cyanophenoxy -4-cyanophenoxy -4-cyanophenoxy -4-cyanophenoxy 135 -3-cyanophenoxy H H H 136 H -3-cyanophenoxy H H 137 H H -3-cyanophenoxy H 138 H H H -3-cyanophenoxy 39 -3-cyanophenoxy -3-cyanophenoxy H H 140 H -3-cyanophenoxy -3-cyanophenoxy H 41 H H -3-cyanophenoxy -3-cyanophenoxy 42 -3-cyanophenoxy H -3-cyanophenoxy H 143 H -3-cyanophenoxy H -3-cyanophenoxy 144 -3-cyanophenoxy H H -3-cyanophenoxy 145 H -3-cyanophenoxy -3-cyanophenoxy -3-cyanophenoxy 46 -3-cyanophenoxy H -3-cyanophenoxy -3-cyanophenoxy 47 -3-cyanophenoxy -3-cyanophenoxy H -3-cyanophenoxy 148 -3-cyanophenoxy -3-cyanophenoxy -3-cyanophenoxy H 149 -3-cyanophenoxy -3-cyanophenoxy -3-cyanophenoxy -3-cyanophenoxy 150 -2-cyanophenoxy H H H 151 H -2-cyanophenoxy H H 52 H H -2-cyanophenoxy H 53 H H H -2-cyanophenoxy U.S. Patent Feb. 14, 2017 Sheet 49 of 63 US 9,566.290 B2

FIGURE 19E

No. R9a Roa Rita R2 154 -2-cyanophenoxy -2-cyanophenoxy H H 155 H -2-cyanophenoxy -2-cyanophenoxy H 56 H H -2-cyanophenoxy -2-cyanophenoxy 157 -2-cyanophenoxy H -2-cyanophenoxy H 158 H -2-cyanophenoxy H -2-cyanophenoxy 159 -2-cyanophenoxy H H -2-cyanophenoxy 160 H 2-cyanophenoxy -2-cyanophenoxy -2-cyanophenoxy 16 -2-cyanophenoxy H -2-cyanophenoxy -2-cyanophenoxy 162 -2-cyanophenoxy -2-cyanophenoxy H -2-cyanophenoxy 63 -2-cyanophenoxy -2-cyanophenoxy -2-cyanophenoxy H 64 -2-cyanophenoxy -2-cyanophenoxy -2-cyanophenoxy 2-cyanophenoxy 65 -4-chlorophenoxy H H H 166 H -4-chlorophenoxy H H 167 H H -4-chlorophenoxy H 168 H H H 4-chlorophenoxy 169 -4-chlorophenoxy 4-chlorophenoxy H H 170 H -4-chlorophenoxy -4-chlorophenoxy H 171 H H -4-chlorophenoxy -4-chlorophenoxy 72 -4-chlorophenoxy H -4-chlorophenoxy H 173 H -4-chlorophenoxy H -4-chlorophenoxy 74 -4-chlorophenoxy H H -4-chlorophenoxy 75 H -4-chlorophenoxy -4-chlorophenoxy -4-chlorophenoxy 176 -4-chlorophenoxy H 4-chlorophenoxy -4-chlorophenoxy 177 -4-chlorophenoxy -4-chlorophenoxy H 4-chlorophenoxy 178 -4-chlorophenoxy -4-chlorophenoxy 4-chlorophenoxy H 179 -4-chlorophenoxy 4-chlorophenoxy -4-chlorophenoxy -4-chlorophenoxy 180 -3-chlorophenoxy H H H 8 H -3-chlorophenoxy H H 182 H H -3-chlorophenoxy H 183 H H H -3-chlorophenoxy 84 -3-chlorophenoxy -3-chlorophenoxy H H 185 H -3-chlorophenoxy -3-chlorophenoxy H 186 H H -3-chlorophenoxy -3-chlorophenoxy 187 -3-chlorophenoxy H -3-chlorophenoxy H 188 H -3-chlorophenoxy H -3-chlorophenoxy 89 -3-chlorophenoxy H H -3-chlorophenoxy 190 H -3-chlorophenoxy -3-chlorophenoxy -3-chlorophenoxy 9. -3-chlorophenoxy H -3-chlorophenoxy -3-chlorophenoxy 92 -3-chlorophenoxy -3-chlorophenoxy H -3-chlorophenoxy 193 -3-chlorophenoxy -3-chlorophenoxy -3-chlorophenoxy H 194 -3-chlorophenoxy -3-chlorophenoxy -3-chlorophenoxy -3-chlorophenoxy U.S. Patent Feb. 14, 2017 Sheet 50 of 63 US 9,566.290 B2

FIGURE 19F

No. R9. R a R 1a 195 -2-chlorophenoxy H H 96 H -2-chlorophenoxy H 197 H H -2-chlorophenoxy H 198 H H H -2-chlorophenoxy 199 -2-chlorophenoxy -2-chlorophenoxy H H 200 H -2-chlorophenoxy -2-chlorophenoxy H 2O1 H H -2-chlorophenoxy -2-chlorophenoxy 2O2 -2-chlorophenoxy H -2-chlorophenoxy H 203 H -2-chlorophenoxy H -2-chlorophenoxy 204 -2-chlorophenoxy H H -2-chlorophenoxy 205 H -2-chlorophenoxy -2-chlorophenoxy -2-chlorophenoxy 2O6 -2-chlorophenoxy H -2-chlorophenoxy -2-chlorophenoxy 207 -2-chlorophenoxy -2-chlorophenoxy H -2-chlorophenoxy 208 -2-chlorophenoxy -2-chlorophenoxy -2-chlorophenoxy H 209 -2-chlorophenoxy -2-chlorophenoxy -2-chlorophenoxy -2-chlorophenoxy 210 -phenoxy H H H 2 H -phenoxy H H 212 H H -phenoxy H 213 H H H -phenoxy 214 -phenoxy -phenoxy H H 25 H -phenoxy -phenoxy H 216 H H -phenoxy -phenoxy 217 -phenoxy H -phenoxy H 218 H -phenoxy H -phenoxy 29 -phenoxy H H -phenoxy 220 H -phenoxy -phenoxy phenoxy 221 -phenoxy H phenoxy -phenoxy 222 -phenoxy -phenoxy H -phenoxy 223 -phenoxy -phenoxy phenoxy H 224 phenoxy -phenoxy phenoxy -phenoxy 225 -4-cyanophenylthio H H H 226 H -4-cyanophenylthio H H 227 H H -4-cyanophenylthio H 228 H H H -4-cyanophenylthio 229 4-cyanophenylthio -4-cyanophenylthio H H 230 H 4-cyanophenylthio -4-cyanophenylthio H 231 H H -4-cyanophenylthio -4-cyanophenylthio 232 -4-cyanophenylthio H -4-cyanophenylthio H 233 H -4-cyanophenylthio H -4-cyanophenylthio 234 -4-cyanophenylthio H H 4-cyanophenylthio 235 H -4-cyanophenylthio -4-cyanophenylthio -4-cyanophenylthio U.S. Patent Feb. 14, 2017 Sheet 51 of 63 US 9,566.290 B2

FIGURE 19C

No. Ra R10a R la Ra 236 -4-cyanophenylthio H -4-cyanophenylthio -4-cyanophenylthio 237 -4-cyanophenylthio -4-cyanophenylthio H -4-cyanophenylthio 238 -4-cyanophenylthio -4-cyanophenylthio -4-cyanophenylthio H 239 -4-cyanophenylthio -4-cyanophenylthio -4-cyanophenylthio -4-cyanophenylthio 240 -3- H H H cyanophenylthio 241 H 3-cyanophenylthio H H 242 H H -3-cyanophenylthio H 243 H H H -3-cyanophenylthio 244 -3-cyanophenylthio -3-cyanophenylthio H H 245 H -3-cyanophenylthio -3-cyanophenylthio H 246 H H -3-cyanophenylthio -3-cyanophenylthio 247 -3-cyanophenylthio H -3-cyanophenylthio H 248 H -3-cyanophenylthio H -3-cyanophenylthio 249 -3-cyanophenylthio H H -3-cyanophenylthio 250 H -3-cyanophenylthio -3-cyanophenylthio -3-cyanophenylthio 251 -3-cyanophenylthio H -3-cyanophenylthio -3-cyanophenylthio 252 -3-cyanophenylthio -3-cyanophenylthio H -3-cyanophenylthio 253 -3-cyanophenylthio -3-cyanophenylthio -3-cyanophenylthio H 254 -3-cyanophenylthio -3-cyanophenylthio -3-cyanophenylthio -3-cyanophenylthio 255 -2- H H H cyanophenylthio 256 H -2-cyanophenylthio H H 257 H H -2-cyanophenylthio H 258 H H H -2-cyanophenylthio 259 -2-cyanophenylthio -2-cyanophenylthio H H 260 H -2-cyanophenylthio -2-cyanophenylthio H 261 H H -2-cyanophenylthio -2-cyanophenylthio 262 -2-cyanophenylthio H -2-cyanophenylthio H 263 H -2-cyanophenylthio H -2-cyanophenylthio 264 -2-cyanophenylthio H H -2-cyanophenylthio 265 H -2-cyanophenylthio -2-cyanophenylthio -2-cyanophenylthio 266 2-cyanophenylthio H -2-cyanophenylthio -2-cyanophenylthio 267 2-cyanophenylthio -2-cyanophenylthio H -2-cyanophenylthio 268 2-cyanophenylthio -2-cyanophenylthio -2-cyanophenylthio H 269 2-cyanophenylthio -2-cyanophenylthio -2-cyanophenylthio -2-cyanophenylthio 270 H H H 271 -OCHC(O)OH H H 272 H H -OCHC(O)OH H 273 H H H -OCHC(O)OH 274 F -OCHC(O)OH H H 275 H -OCHC(O)OH F H

U.S. Patent Feb. 14, 2017 Sheet 53 of 63 US 9,566.290 B2

FIGURE 19

No. R (a 317 H 318 -CHOH 39 -CHOH 320 -CH2OH 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 34 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357

U.S. Patent Feb. 14, 2017 Sheet 57 Of 63 US 9,566.290 B2

FIGURE 20B

No. R10s 34 -CHPh -NMeS(O)Ph 35 -CHPh -NMeS(O)2Ph 36 -CHPh -CHOH 37 -CHPh H 38 -CH2Ph H -CHOH 39 -CHPh F H 40 -CHPh H 4. -CH2Ph H 42 -CHPh 43 -CHPh 44 -CH2Ph 45 -CHPh 46 -CHPh 47 -CHPh 48 -CHPh 49 -CHPh 50 -CHPh 51 -CHPh 52 -CHPh 53 -CHPh 54 -CHPh 55 -CHPh 56 -CHPh 57 -CHPh. -CH2OH 58 -CHPh -CHOH 59 -CHPh -CHOH 60 -CHPh -CHOH 61 -CHPh -CHOH 62 -CHPh -CHOH 63 -CHPh 64 -CHPh 65 -CHPh 66 -CHPh 67 -CHPh 68 -CHPh 69 -CHPh 70 -CHPh 71 -CHPh 72 -CHPh 73 -CHPh 74 -CHPh 75 -CHPh

U.S. Patent Feb. 14, 2017 Sheet 61 of 63 US 9,566,290 B2

FIGURE 20F

No. 196 Me -CHOH 197 Me -CHOH 198 Me -CHOH 199 Me -CHOH 200 Me 201 Me 2O2 Me 203 Me 204 Me 205 Me 206 Me 207 Me 208 Me 209 210 Me 2. Me 22 Me 213 Me 24 Me 215 Me 26 Me 217 Me 218 Me -CHOH 219 Me -CHOH 220 Me -CHOH 221 Me 222 Me 223 Me 224 Me 225 Me 226 Me 227 Me -N H 228 Me -NH 229 Me 230 Me 231 Me 232 Me 233 Me 234 Me 235 Me 236 Me 237 Me U.S. Patent Feb. 14, 2017 Sheet 62 of 63 US 9,566.290 B2

FIGURE 20G

No. R3a R a 238 Me 239 Me 240 Me 24 Me 242 Me 243 Me 244 Me 245 Me 246 Me 247 Me 248 Me 249 Me 250 Me 251 Me 252 Me 253 Me 254 Me 255 Me 256 Me 257 Me 258 Me 259 Me 260 Me F 3-(phenylthio)-1H 261 Me indol-1-yl 3-(phenylthio)-1H 262 Me H indol-1-yl 3-(phenylthio)-1H 263 Me H H indol-1-yl H 3-(phenylthio)-1H 264 Me H H H indol-1-yl 3-(phenylthio)-1H 265 Me F indol-1-yl H 3-(phenylthio)-1H 266 Me H indol-1-yl H 3-(phenylthio)-1H 267 H indol-1-yl F 3-(phenylthio)-1H 268 Me F indol-1-yl 3-(phenylthio)-1H 269 Me H indol-1-yl 3-(phenylthio)-1H 270 Me F indol-1-yl F 271 Me dibenzylamino H H 272 Me H dibenzylamino H 273 Me H H dibenzylamino H 274 Me H H H dibenzylamino

US 9,566,290 B2 1. 2 BORON-CONTAINING SMALL MOLECULES 12 weeks before any significant therapeutic benefit is real ized. Such long term, high dose systemic therapy can have CROSS-REFERENCE TO RELATED significant adverse effects. For example, terbinafine has been APPLICATIONS reported to have liver toxicity effects and reduces testoster one levels in blood due to adverse effects on the testes. The present application is a continuation of U.S. patent Patient compliance is a problem with Such long term thera application Ser. No. 15/091,394, filed Apr. 5, 2016, which is pies especially those which involve serious adverse effects. a continuation of U.S. patent application Ser. No. 15/068, Moreover, this type of long term oral therapy is inconvenient 352, filed Mar. 11, 2016, which is a continuation of U.S. in the treatment of a horse or other ruminants afflicted with patent application Ser. No. 15/046,322, filed on Feb. 17. 10 fungal infections of the hoof. Accordingly, the risks associ 2016, which is a continuation of U.S. patent application Ser. ated with parenteral treatments generate significant disin No. 14/537,771, filed Nov. 10, 2014, which is a continuation centive against their use and considerable patient non of U.S. patent application Ser. No. 14/201459, filed Mar. 7, compliance. 2014, now U.S. Pat. No. 9,353,133, which is a continuation Surgical removal of all or part of the nail followed by of U.S. patent application Ser. No. 13/356,488, filed Jan. 23, 15 topical treatment also has severe drawbacks. The pain and 2012, now U.S. Pat. No. 8,722,917, which is a continuation discomfort associated with the Surgery and the undesirable of U.S. patent application Ser. No. 12/629,753, filed Dec. 2, cosmetic appearance of the nail or nail bed represent sig 2009, now U.S. Pat. No. 8,115,026, which is a divisional of nificant problems, particularly for patients more sensitive to U.S. patent application Ser. No. 1 1/505,591, filed Aug. 16, physical appearance. Generally, this type of treatment is not 2006, now U.S. Pat. No. 7,767,657, which claims the benefit realistic for ruminants such as horses. of U.S. Provisional Patent Application No. 60/755,227, filed Topical therapy has significant problems too. Topical Dec. 30, 2005, and the benefit of U.S. Provisional Patent dosage forms such as creams, lotions, gels etc., can not keep Application No. 60/746,361, filed May 3, 2006, all of which the drug in intimate contact with the infected area for are incorporated by reference in their entirety for all pur therapeutically effective periods of time. Bandages have poses. U.S. patent application Ser. No. 1 1/505,591 is also a 25 been used to hold drug reservoirs in place in an attempt to continuation-in-part of U.S. patent application Ser. No. enhance absorption of the pharmaceutical agent. However 11/357,687, filed Feb. 16, 2006, now U.S. Pat. No. 7,582, the bandages are thick, awkward, troublesome and generally 621, which claims the benefit of U.S. Provisional Patent lead to poor patient compliance. Application No. 60/654,060, filed Feb. 16, 2005, all of Hydrophilic and hydrophobic film forming topical anti which are incorporated by reference in their entirety for all 30 fungal solutions have also been developed. These dosage purposes. U.S. patent application Ser. No. 14/537,771 is also forms provide improved contact between the drug and the a continuation-in-part of U.S. patent application Ser. No. nail. Topical formulations for fungal infection treatment 13/874,329, filed Apr. 30, 2013, now U.S. Pat. No. 8,889, have largely tried to deliver the drug to the target site (an 656, which is a continuation of U.S. patent application Ser. infected nail bed) by diffusion across or through the nail. No. 13/224.252, filed Sep. 1, 2011, now U.S. Pat. No. 35 Nail is more like hair than stratum corneum with respect 8.440,642, which is a continuation of U.S. patent application to chemical composition and permeability. Nitrogen is the Ser. No. 12/507,010, filed Jul. 21, 2009, now U.S. Pat. No. major component of the nail attesting to the nail’s proteina 8,039,451, which is a continuation of U.S. patent application ceous nature. The total lipid content of mature nail is Ser. No. 1 1/357,687, filed Feb. 16, 2006, now U.S. Pat. No. 0.1-1.0%, while the stratum corneum lipid is about 10% 7,582,621, which claims the benefit of 60/654,060, filed Feb. 40 wfw. The nail is 100-200 times thicker than the stratum 16, 2005, all of which are incorporated by reference in their corneum and has a very high affinity and capacity for entirety for all purposes. binding and retaining antifungal drugs. Consequently little if any drug penetrates through the nail to reach the target site. BACKGROUND FOR THE INVENTION Because of these reasons topical therapy for fungal infec 45 tions have generally been ineffective. Infections of the nail and hoof, known as ungual and/or Compounds known as penetration or permeation enhanc periungual infections, pose serious problems in dermatol ers are well known in the art to produce an increase in the ogy. These ungual and/or periungual can be caused by permeability of skin or other body membranes to a pharma Sources such as fungi, viruses, yeast, bacteria and parasites. cologically active agent. The increased permeability allows Onychomycosis is an example of these serious ungual 50 an increase in the rate at which the drug permeates through and/or periungual infections and is caused by at least one the skin and enters the blood stream. Penetration enhancers fungus. Current treatment for ungual and/or periungual have been Successful in overcoming the impermeability of infections generally falls into three categories: Systemic pharmaceutical agents through the skin. However, the thin administration of medicine; Surgical removal of all or part of stratum corneum layer of the skin, which is about 10 to 15 the nail or hoof followed by topical treatment of the exposed 55 cells thick and is formed naturally by cells migrating toward tissue; or topical application of conventional creams, lotions, the skin surface from the basal layer, has been easier to gels or Solutions, frequently including the use of bandages to penetrate than nails. Moreover, known penetration enhanc keep these dosage forms in place on the nail or hoof. All of ers have not proven to be useful in facilitating drug migra these approaches have major drawbacks. The following tion through the nail tissue. discussion is particularly directed to drawbacks associated 60 Antimicrobial compositions for controlling bacterial and with current treatment of ungual and/or periungual antifun fungal infections comprising a metal chelate of 8-hydroxy gal infections. quinoline and an alkyl benzene Sulfonic acid have been Long term systemic (oral) administration of an antifungal shown to be efficacious due to the increased ability of the agent for the treatment of onychomycosis is often required oleophilic group to penetrate the lipoid layers of micro-cells. to produce a therapeutic effect in the nail bed. For example, 65 The compounds however, do not effectively increase the oral treatment with the antifungal compound terbinafine ability to carry the pharmaceutically active antifungal typically requires administration of 200 to 400 mg/day for through the cornified layer or stratum corneum of the skin. US 9,566,290 B2 3 4 U.S. Pat. No. 4,602,011, West et al., Jul. 22, 1986; U.S. Pat. CP1-like domain in class II ARS, separate editing domains No. 4,766,113, West et al., Aug. 23, 1988. have been found in the enzymes for proline and threonine. Therefore, there is a need in the art for compounds which Although editing is important to ensure the correct charging can effectively penetrate the nail. There is also need in the of tRNAs, it is not essential for viability and is not required art for compounds which can effectively treat ungual and/or 5 for the synthesis of charged tRNAs. For example, in periungual infections. These and other needs are addressed Escherichia coli, in which 10 amino acids in the editing by the current invention. domain of isoleucyl-tRNA synthetase were changed to ala Aminoacyl-tRNA synthetases (ARS) are a family of nine, the resulting mutant was still viable, although it did have many pleiotropic effects, including a noticeable cell essential enzymes that attach amino acids to the 3' terminal growth defect. adenosine end of tRNAs, the charged tRNAs are then used 10 In spite of significant homologies between human, bac by the translation machinery to synthesis proteins from terial and fungal ARS there are a number of compounds that mRNA. Although there are few exceptions, for example in have been developed as anti-infectives. The most notable Gram-positive bacteria and archaea, most organisms have at example of an ARS inhibitor is the commercial antibiotic least one ARS for each amino acid. In the case of eukaryotes, mupirocin (pseudomonic acid), which is sold under the label they have two ARS, one is localized to the cytoplasm while 15 Bactroban. Mupirocin specifically inhibits bacterial iso the other ARS is located in the organelle(s). The ARS leucyl-tRNA synthetases, while its activity against the catalyzes two reactions, as outlined below, the first reaction human homolog is more than 1,000 times less active. adenylates the amino acid with ATP followed by its transfer Mupirocin binds specifically to the synthetic active site and to the 2- or 3'-hydroxyl of the terminal adenosine of tRNA. mutants that are resistant to this drug have mutations in the synthetic domain of leucyl-tRNA synthetase. Likewise, Amino acid (AA)+ATP->AA-AMP+PPi: reveromycin A inhibits the eukaryotic isoleucyl-tRNA syn thetases: Saccharomyces cerevisiae resistance mutants have AA-AMP-tRNA-stRNA-AA-AMP mutations in the synthetic domain. So far all attempts to The family of 20 ARS fall into two distinct structural develop better ARS inhibitors than mupirocin, an isoleucine classes as determined by their crystal structure. Class I. 25 adenylate analogue, have relied on inhibiting the synthetic which have a Rossman like fold, include the ARS for the reactions. following amino acids-arginine, cysteine, glutamate, gluta Since it has been previously thought not to be essential for the synthesis of charged tRNAs, the editing domain of tRNA mine, isolelucine, leucine, lysine (in archaea and some synthetases has not been thought a promising target for drug bacteria), Valine, methionine, tryptophan and tyrosine. Class development. Data from mutational analysis of the ARS II ARS include the enzymes for the amino acids, alanine, 30 editing domains tend to suggest that inhibition of the editing asparagine, aspartate, glycine, histidine, lysine, phenylala mechanism leads only to an increase in mischarged tRNAS nine, proline, serine and threonine. The ARS mediated and does not lead to cell death. Compounds that are active reaction is the major checkpoint of specificity that ensures against, and specific for, the editing domain of the tRNA the correct amino acid is charged to its cognate tRNA. Since synthetase would provide access to a new class of antimi Some amino acids only differ by a single methylene group, 35 crobial therapeutics to augment the arsenal of agents cur for example valine and isoleucine, it has been postulated that rently in use. Quite Surprisingly, the present invention pro the specificity of the synthetic reaction alone can't explain vides Such compounds and methods of using these the observed in vivo accuracy of tRNA charging. The compounds. synthetic active site should be able to exclude amino acids SUMMARY OF THE INVENTION that are not close analogs of the cognate amino acid, but 40 analogous amino acids pose a bigger problem. Therefore to In one aspect, the invention provides a structure according increase specificity, proof-reading and editing must occur. to the following formula: So far nine ARS have been shown to have an editing mechanism that significantly reduces the frequency of mis charged tRNAs. The enzymes for the following amino acids 45 have been shown to have editing activity-alanine, isoleucine, '' leucine, methionine, lysine, phenylalanine, proline, threo G B nine and valine. These ARS can hydrolyse the incorrectly i? DC YOR2 adenylated amino acid AA-AMP (pre-transfer editing) or the D incorrectly charged tRNA (post-transfer editing). To date the 50 nafn isoleucyl, leucyl and valyl-tRNA synthetases have the best characterized editing mechanisms; an additional structural in which R' and R are members independently selected domain called the connective polypeptide I (CP1) inserted in from H, substituted or unsubstituted alkyl, substituted or the synthetic domain has been shown to contain the editing unsubstituted heteroalkyl, substituted or unsubstituted active site. This is located more than 25 A away from the 55 cycloalkyl, substituted or unsubstituted heterocycloalkyl, synthetic active site, which suggests that both the adenylated substituted or unsubstituted aryl, and substituted or unsub amino acid intermediate and amino acid tethered to the 3'end stituted heteroaryl. R' and R, together with the atoms to of the tRNA must be moved from the active site in the which they are attached, can be optionally joined to form a synthetic domain to the editing site for the reaction to be 4- to 7-membered ring. Z1 is a member selected from proof-read. It has been postulated that the 3'end of the 60 charged tRNA is translocated in a similar manner to that of the proof-reading mechanism of DNA polymerases. Much less is known about the translocation of the adenylated R5 amino acid. A similar CP1 domain is also present in the and CHO. methionine and cysteine ARS enzymes, but it is much 65 Smaller than that found in the valine, isoleucine and leucine enzymes. Despite the absence of a direct homolog to the US 9,566,290 B2 5 6 R" and R" are members independently selected from H. FIG. 8 displays the results of a 40 uL/cm aliquot of 8% cyano, substituted or unsubstituted alkyl, substituted or ciclopiroX in W/w commercial lacquer applied per day over unsubstituted heteroalkyl, substituted or unsubstituted five days. No Zone of inhibition observed; full carpet growth cycloalkyl, substituted or unsubstituted heterocycloalkyl, of T. rubrum. substituted or unsubstituted aryl, and substituted or unsub FIG.9 displays the results of a 40 uL/cm aliquot of 5% stituted heteroaryl. R is a member selected from halogen amorolfine w/v in commercial lacquer applied per day over and OR. R. is a member selected from H, substituted or five days. No Zone of inhibition observed; full carpet growth unsubstituted alkyl, substituted or unsubstituted heteroalkyl, of T. rubrum. substituted or unsubstituted cycloalkyl, substituted or unsub FIG. 10(1), FIG. 10(2), FIG. 10(3), FIG. 10(4), FIG. stituted heterocycloalkyl, substituted or unsubstituted aryl, 10 10(5), FIG. 10(6), FIG. 10(7), FIG. 10(8), FIG. 10(9) are and substituted or unsubstituted heteroaryl. A is a member Amino acid sequences for leucyl-tRNA synthetase editing selected from CR" and N. D is a member selected from domains and nucleotide sequences for tRNA-Leu and CR'' and N. E is a member selected from CR'' and N. G tRNA-Ile. (A) Amino acid sequences for leucyl-tRNA syn is a member selected from CR'' and N. R. R', R'' and thetase editing domain from S. cerivisiae in wild type (SEQ R'' are members independently selected from H, OR*, 15 ID NO: 1) and over-expressing form (SEQ ID NO: 2); (B) NR*R**, SR*, S(O)R*, S(O).R*, S(O)NR*R**, Amino acid sequences for leucyl-tRNA synthetase editing nitro, halogen, cyano, Substituted or unsubstituted alkyl, domains from indicated species; (C) Genomic nucleotide substituted or unsubstituted heteroalkyl, substituted or sequence for tRNA-leu and tRNA-ile from S. cerivisiae; in unsubstituted cycloalkyl, substituted or unsubstituted het one embodiment of the invention, an aminoacyl tRNA erocycloalkyl, substituted or unsubstituted aryl, and substi synthetase will bind to the transcribed and methylated tuted or unsubstituted heteroaryl. Each R* and R** are products for which these sequences serve as a template; (D) members independently selected from H, substituted or tRNA-Leu nucleotide sequences from indicated species. unsubstituted alkyl, substituted or unsubstituted heteroalkyl, FIG. 11A, FIG. 11B, FIG. 11C, FIG. 11D, FIG. 11E, FIG. substituted or unsubstituted cycloalkyl, substituted or unsub 11F display structures of cyclic boronic esters. stituted heterocycloalkyl, substituted or unsubstituted aryl, 25 FIG. 12A, FIG. 12B, FIG. 12C, FIG. 12D, FIG. 12E, FIG. and substituted or unsubstituted heteroaryl. R* and R', 12F, FIG. 12G, FIG. 12H, FIG. 12I display different struc along with the atoms to which they are attached, are option tures for portions of the compounds of the invention. ally joined to form a ring. R'' and R', along with the FIG. 13 Effect of ATP on binding of C10 to cdc60. The atoms to which they are attached, are optionally joined to binding assay was conducted with an initial C10 concen form a ring. R'' and R', along with the atoms to which 30 tration of approximately 72-79 uM (pre-equilibrium). they are attached, are optionally joined to form a ring. The FIG. 14 Binding curve of cdc60 against concentration of combination of nitrogens (A+D+E+G) is an integer selected free C10. from 0 to 3. FIG. 15 Data from PPi exchange reaction experiment to determine rate of editing in the presence and absence of C10. BRIEF DESCRIPTION OF THE DRAWINGS 35 FIG. 16 Data from an aminoacylation experiment show ing the effect of C10 at different concentrations on the FIG. 1A, FIG. 1B, FIG. 1C are a table of minimum aminoacylation of tRNA'. inhibitory concentration (MIC) data of cyclic boronic esters FIG. 17 Results from post transfer editing assay con against Various fungi. ducted in S. cerevisiae at differing concentrations of C10 FIG. 2A displays minimum inhibitory concentration 40 across a range of time points. (MIC) for C10, ciclopirox, terbinafine, fluconazole and FIG. 18A, FIG. 18B, FIG. 18C display the names of itraconazole (comparator drugs) against 19 test strains of exemplary compounds of the invention. fungi. FIG. 19A, FIG. 19B, FIG. 19C, FIG. 19D, FIG. 19E, FIG. FIG. 2B displays minimum fungicidal concentration 19F, FIG. 19G, FIG. 19H, FIG. 19I, FIG. 19J, FIG. 19K (MFC) for C10, ciclopirox, terbinafine and itraconazole 45 display exemplary compounds of the invention. (comparator drugs) against 2 test strains of fungi. FIG. 20A, FIG.20B, FIG.20C, FIG. 20D, FIG. 20E, FIG. FIG. 3 displays a comparison of Normalized C10 and 20F, FIG. 20O, FIG. 20H display exemplary compounds of Ciclopirox Equivalent in Each Part of Nail Plate Samples the invention. after 14-day Treatment. FIG. 4 displays a comparison of C10 and Ciclopirox 50 DETAILED DESCRIPTION OF THE Equivalent in Cotton Ball Supporting Bed Samples after INVENTION 14-day Treatment. FIG. 5 displays the results of a placebo for C10 (50:50 I. Definitions and Abbreviations propylene glycol and ethyl acetate) applied per day over five days. Full carpet growth of the organism T rubrum was 55 The abbreviations used herein generally have their con observed. ventional meaning within the chemical and biological arts. FIG. 6 displays the results of a 40 uL/cm aliquot of C10 “Compound of the invention,” as used herein refers to the 10% w/v solution applied per day over five days. Zones of compounds discussed herein, pharmaceutically acceptable inhibition (in the order of the cells shown in the figure) of salts and prodrugs of these compounds. 100%, 67%, 46%, 57%, 38% and 71% were observed for the 60 "Boron containing compounds, as used herein, refers to growth of T. rubrum. Green arrow indicates the measure the compounds of the invention that contain boron as part of ment of Zone of inhibition. their chemical formula. FIG. 7 displays the results of a 40 uL/cm aliquot of C10 MIC, or minimum inhibitory concentration, is the point 10% w/v solution applied per day over five days. Zones of where the compound stops more than 50% of cell growth, inhibition (in the order of the cells shown in the figure) of 65 preferably 60% of cell growth, preferably 70% of cell 74%, 86%, 100%, 82%, 100% and 84% were observed for growth, preferably 80% of cell growth, preferably 90% of the growth of T. rubrum. cell growth, relative to an untreated control. US 9,566,290 B2 7 8 Where substituent groups are specified by their conven —CH=CH N(CH)—CH. Up to two heteroatoms may tional chemical formulae, written from left to right, they be consecutive, such as, for example, —CH NH OCH. equally encompass the chemically identical Substituents, Similarly, the term "heteroalkylene' by itself or as part of which would result from writing the structure from right to another substituent means a divalent radical derived from left, e.g., —CH2O— is intended to also recite —OCH2—. heteroalkyl, as exemplified, but not limited by, —CH2— The term “poly’ as used herein means at least 2. For CH, S CH-CH and CH, S CH-CH example, a polyvalent metal ion is a metal ion having a NH-CH-. For heteroalkylene groups, heteroatoms can Valency of at least 2. also occupy either or both of the chain termini (e.g., alky “Moiety” refers to the radical of a molecule that is leneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, attached to another moiety. 10 and the like). Still further, for alkylene and heteroalkylene The symbol , whether utilized as a bond or displayed linking groups, no orientation of the linking group is implied perpendicular to a bond, indicates the point at which the by the direction in which the formula of the linking group is displayed moiety is attached to the remainder of the mol written. For example, the formula —C(O) R' represents ecule. both —C(O)R and RC(O), . The term “alkyl.” by itself or as part of another substitu 15 The terms “cycloalkyl and "heterocycloalkyl, by them ent, means, unless otherwise stated, a straight or branched selves or in combination with other terms, represent, unless chain, or cyclic hydrocarbon radical, or combination thereof, otherwise stated, cyclic versions of “alkyl and “het which may be fully saturated, mono- or polyunsaturated and eroalkyl, respectively. Additionally, for heterocycloalkyl, a can include di- and multivalent radicals, having the number heteroatom can occupy the position at which the heterocycle of carbon atoms designated (i.e. C-Co means one to ten is attached to the remainder of the molecule. Examples of carbons). Examples of Saturated hydrocarbon radicals cycloalkyl include, but are not limited to, cyclopentyl, include, but are not limited to, groups such as methyl, ethyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, n-propyl, isopropyl. n-butyl, t-butyl, isobutyl, sec-butyl, and the like. Examples of heterocycloalkyl include, but are cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, homologs and isomers of for example, n-pentyl, n-hexyl, 25 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien one having one or more double bonds or triple bonds. 2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and Examples of unsaturated alkyl groups include, but are not the like. limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(buta The terms “halo' or “halogen,” by themselves or as part dienyl), 2.4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1 30 of another Substituent, mean, unless otherwise stated, a and 3-propynyl, 3-butynyl, and the higher homologs and fluorine, chlorine, bromine, or iodine atom. Additionally, isomers. The term “alkyl, unless otherwise noted, is also terms such as "haloalkyl,” are meant to include monoha meant to include those derivatives of alkyl defined in more loalkyl and polyhaloalkyl. For example, the term "halo(C- detail below, such as "heteroalkyl.” Alkyl groups that are C.)alkyl is mean to include, but not be limited to, trifluo limited to hydrocarbon groups are termed “homoalkyl. 35 romethyl, 2.2.2-trifluoroethyl, 4-chlorobutyl, The term “alkylene' by itself or as part of another 3-bromopropyl, and the like. Substituent means a divalent radical derived from an alkane, The term “aryl' means, unless otherwise stated, a poly as exemplified, but not limited, by —CH2CH2CHCH . unsaturated, aromatic, Substituent that can be a single ring or and further includes those groups described below as “het multiple rings (preferably from 1 to 3 rings), which are fused eroalkylene. Typically, an alkyl (or alkylene) group will 40 together or linked covalently. The term "heteroaryl refers to have from 1 to 24 carbon atoms, with those groups having aryl groups (or rings) that contain from one to four heteroa 10 or fewer carbon atoms being preferred in the present toms. In an exemplary embodiment, the heteroatom is invention. A “lower alkyl or “lower alkylene' is a shorter selected from B, N, O, and S, wherein the nitrogen and chain alkyl or alkylene group, generally having eight or Sulfur atoms are optionally oxidized, and the nitrogen fewer carbon atoms. 45 atom(s) are optionally quaternized. A heteroaryl group can The terms “alkoxy.” “alkylamino” and “alkylthio' (or be attached to the remainder of the molecule through a thioalkoxy) are used in their conventional sense, and refer to heteroatom. Non-limiting examples of aryl and heteroaryl those alkyl groups attached to the remainder of the molecule groups include phenyl, 1-naphthyl 2-naphthyl, 4-biphenyl, via an oxygen atom, an amino group, or a Sulfur atom, 1-pyrrolyl 2-pyrrolyl, 3-pyrrolyl 3-pyrazolyl, 2-imidazolyl, respectively. 50 4-imidazolyl pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl The term "heteroalkyl, by itself or in combination with 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isox another term, means, unless otherwise stated, a stable azolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, straight or branched chain, or cyclic hydrocarbon radical, or 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-py combinations thereof, consisting of the stated number of rimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimi carbon atoms and at least one heteroatom. In an exemplary 55 dazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl 2-quinox embodiment, the heteroatoms can be selected from the alinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl, group consisting of B, O, N and S, and wherein the nitrogen dioxaborolane, dioxaborinane and dioxaborepane. Substitu and Sulfur atoms may optionally be oxidized and the nitro ents for each of the above noted aryl and heteroaryl ring gen heteroatom may optionally be quaternized. The heteroa systems are selected from the group of acceptable Substitu tom(s) B, O, N and S may be placed at any interior position 60 ents described below. of the heteroalkyl group or at the position at which the alkyl For brevity, the term “aryl' when used in combination group is attached to the remainder of the molecule. with other terms (e.g., aryloxy, arylthioxy, arylalkyl) Examples include, but are not limited to. —CH2—CH2— includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl is meant to include those radicals 65 in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including -CH=CH-O-CH CH-CH=N OCH, and those alkyl groups in which a carbon atom (e.g., a methylene US 9,566,290 B2 10 group) has been replaced by, for example, an oxygen atom formula -A-(CH2), B–, wherein A and B are indepen (e.g., phenoxymethyl 2-pyridyloxymethyl, 3-(1-naphth dently —CRR' —O— —NR— —S —S(O)—, yloxy)propyl, and the like). —S(O) , —S(O)NR' - or a single bond, and r is an Each of the above terms (e.g., “alkyl, "heteroalkyl.” integer of from 1 to 4. One of the single bonds of the new “aryl' and "heteroaryl') are meant to include both substi ring so formed may optionally be replaced with a double tuted and unsubstituted forms of the indicated radical. Pre bond. Alternatively, two of the substituents on adjacent ferred substituents for each type of radical are provided atoms of the aryl or heteroaryl ring may optionally be below. replaced with a substituent of the formula—(CRR), X Substituents for the alkyl and heteroalkyl radicals (includ (CR"R") , where s and d are independently integers of ing those groups often referred to as alkylene, alkenyl, 10 heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, hetero from 0 to 3, and X is —O— —NR' —S —S(O)—, cycloalkyl, cycloalkenyl, and heterocycloalkenyl) are —S(O) , or—S(O)NR' . The substituents R. R', R" and generically referred to as “alkyl group Substituents.” and R" are preferably independently selected from hydrogen or they can be one or more of a variety of groups selected from, substituted or unsubstituted (C-C)alkyl. but not limited to: OR", =O, —NR", =N OR', 15 "Ring” as used herein, means a Substituted or unsubsti —NR'R", SR', -halogen, OC(O)R', C(O)R', tuted cycloalkyl, substituted or unsubstituted heterocy COR, CONR'R", OC(O)NR'R", NR"C(O)R', cloalkyl, substituted or unsubstituted aryl, or substituted or NR C(O)NR"R", NR"C(O).R', NR C unsubstituted heteroaryl. A ring includes fused ring moieties. (NR'R"R") NR", NR C(NR'R")—NR", S(O)R', The number of atoms in a ring is typically defined by the —S(O).R', -S(O)NR'R", NRSOR', CN and - NO. number of members in the ring. For example, a “5- to in a number ranging from Zero to (2m'+1), where m' is the 7-membered ring' means there are 5 to 7 atoms in the total number of carbonatoms in such radical. R', R", R" and encircling arrangement. The ring optionally included a het R" each preferably independently refer to hydrogen, sub eroatom. Thus, the term “5- to 7-membered ring includes, stituted or unsubstituted heteroalkyl, substituted or unsub for example pyridinyl and piperidinyl. The term “ring stituted aryl, e.g., aryl Substituted with 1-3 halogens, Sub 25 further includes a ring system comprising more than one stituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, “ring, wherein each “ring is independently defined as or arylalkyl groups. When a compound of the invention above. includes more than one R group, for example, each of the R As used herein, the term "heteroatom' includes atoms groups is independently selected as are each R', R", R" and other than carbon (C) and hydrogen (H). Examples include R" groups when more than one of these groups is present. 30 oxygen (O), nitrogen (N) sulfur (S), silicon (Si), germanium When R' and R" are attached to the same nitrogen atom, they (Ge), aluminum (Al) and boron (B). can be combined with the nitrogen atom to form a 5-, 6-, or The symbol “R” is a general abbreviation that represents 7-membered ring. For example, —NR'R" is meant to a substituent group that is selected from substituted or include, but not be limited to, 1-pyrrolidinyl and 4-mor unsubstituted alkyl, substituted or unsubstituted heteroalkyl, pholinyl. From the above discussion of substituents, one of 35 substituted or unsubstituted aryl, substituted or unsubstituted skill in the art will understand that the term “alkyl is meant heteroaryl, substituted or unsubstituted cycloalkyl and sub to include groups including carbon atoms bound to groups stituted or unsubstituted heterocycloalkyl groups. other than hydrogen groups, such as haloalkyl (e.g., —CF The term "derived from includes its plain language and —CH2CF) and acyl (e.g., —C(O)CH, —C(O)CF, meaning and also refers to a molecule that is 99%, 98%, —C(O)CHOCH, and the like). 40 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, Similar to the substituents described for the alkyl radical, 87%. 86%, 85%, 84%, 83%, 82%, 81%, 80%, 75%, 70%, Substituents for the aryl and heteroaryl groups are generi 65%, or 60% homologous to a referenced molecule. The cally referred to as “aryl group substituents.” The substitu molecules referred to in this definition include chains of ents are selected from, for example: halogen, —OR", =O. RNA or DNA, oligonucleotides, polypeptides, or proteins of 45 any length and composition. The term “immunological marker” includes oligonucle otides, proteins, antibodies, peptides, polypeptides, NR C(NR'R"R") NR", NR C(NR'R")—NR", enzymes, or any other molecule able to induce an immune –S(O)R', S(O).R', S(O)NR'R", NRSOR, CN response in appropriate animals or cells or to bind with and —NO. —R', —N, -CH(Ph), fluoro(C-C)alkoxy, 50 specific antibodies. and fluoro(C-C)alkyl, in a number ranging from Zero to the The term "noncognate' is meant to encompass both the total number of open Valences on the aromatic ring system; singular and plural forms of the word, i.e. the phrase and where R', R", R" and R" are preferably independently “noncognate amino acid comprises one or more amino selected from hydrogen, substituted or unsubstituted alkyl, acids. substituted or unsubstituted heteroalkyl, substituted or 55 By “effective” amount of a drug, formulation, or permeant unsubstituted aryl and substituted or unsubstituted het is meant a Sufficient amount of a active agent to provide the eroaryl. When a compound of the invention includes more desired local or systemic effect. A “Topically effective.” than one R group, for example, each of the R groups is “Cosmetically effective.” “pharmaceutically effective,” or independently selected as are each R', R", R" and R" “therapeutically effective” amount refers to the amount of groups when more than one of these groups is present. 60 drug needed to effect the desired therapeutic result. Two of the substituents on adjacent atoms of the aryl or “Topically effective' refers to a material that, when heteroaryl ring may optionally be replaced with a substituent applied to the skin, nail, hair, claw or hoof produces a of the formula -T-C(O) (CRR), U , wherein T and U desired pharmacological result either locally at the place of are independently —NR— —O—, —CRR'— or a single application or systemically as a result of transdermal pas bond, and q is an integer of from 0 to 3. Alternatively, two 65 sage of an active ingredient in the material. of the substituents on adjacent atoms of the aryl or heteroaryl “Cosmetically effective' refers to a material that, when ring may optionally be replaced with a Substituent of the applied to the skin, nail, hair, claw or hoof, produces a US 9,566,290 B2 11 12 desired cosmetic result locally at the place of application of compounds may be radiolabeled with radioactive isotopes, an active ingredient in the material. such as for example tritium (H), iodine-125 ('I) or The term “pharmaceutically acceptable salts' is meant to carbon-14 (''C). All isotopic variations of the compounds of include salts of the compounds of the invention which are the present invention, whether radioactive or not, are prepared with relatively nontoxic acids or bases, depending intended to be encompassed within the scope of the present on the particular Substituents found on the compounds invention. described herein. When compounds of the present invention The term “pharmaceutically acceptable carrier' or “phar contain relatively acidic functionalities, base addition salts maceutically acceptable vehicle' refers to any formulation can be obtained by contacting the neutral form of Such or carrier medium that provides the appropriate delivery of compounds with a Sufficient amount of the desired base, 10 either neat or in a suitable inert solvent. Examples of an effective amount of a active agent as defined herein, does pharmaceutically acceptable base addition salts include not interfere with the effectiveness of the biological activity Sodium, potassium, calcium, ammonium, organic amino, or of the active agent, and that is sufficiently non-toxic to the magnesium salt, or a similar salt. When compounds of the host or patient. Representative carriers include water, oils, present invention contain relatively basic functionalities, 15 both vegetable and mineral, cream bases, lotion bases, acid addition salts can be obtained by contacting the neutral ointment bases and the like. These bases include Suspending form of such compounds with a sufficient amount of the agents, thickeners, penetration enhancers, and the like. Their desired acid, either neat or in a suitable inert solvent. formulation is well known to those in the art of cosmetics Examples of pharmaceutically acceptable acid addition salts and topical pharmaceuticals. Additional information con include those derived from inorganic acids like hydrochlo cerning carriers can be found in Remington. The Science and ric, hydrobromic, nitric, carbonic, monohydrogencarbonic, Practice of Pharmacy, 21st Ed., Lippincott, Williams & phosphoric, monohydrogenphosphoric, dihydrogenphos Wilkins (2005) which is incorporated herein by reference. phoric, Sulfuric, monohydrogensulfuric, hydriodic, or phos "Pharmaceutically acceptable topical carrier and equiva phorous acids and the like, as well as the salts derived from lent terms refer to pharmaceutically acceptable carriers, as relatively nontoxic organic acids like acetic, propionic, 25 described herein above, suitable for topical application. An isobutyric, maleic, malonic, benzoic, Succinic, Suberic, inactive liquid or cream vehicle capable of Suspending or fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolyl dissolving the active agent(s), and having the properties of Sulfonic, citric, tartaric, methanesulfonic, and the like. Also being nontoxic and non-inflammatory when applied to the included are salts of amino acids such as arginate and the skin, nail, hair, claw or hoof is an example of a pharmaceu like, and salts of organic acids like glucuronic or galac 30 tically-acceptable topical carrier. This term is specifically tunoric acids and the like (see, for example, Berge et al., intended to encompass carrier materials approved for use in "Pharmaceutical Salts”, Journal of Pharmaceutical Science topical cosmetics as well. 66:1-19 (1977)). Certain specific compounds of the present The term “pharmaceutically acceptable additive' refers to invention contain both basic and acidic functionalities that preservatives, antioxidants, fragrances, emulsifiers, dyes and allow the compounds to be converted into either base or acid 35 excipients known or used in the field of drug formulation addition salts. and that do not unduly interfere with the effectiveness of the The neutral forms of the compounds are preferably regen biological activity of the active agent, and that is sufficiently erated by contacting the salt with a base or acid and isolating non-toxic to the host or patient. Additives for topical for the parent compounds in the conventional manner. The mulations are well-known in the art, and may be added to the parent form of the compound differs from the various salt 40 topical composition, as long as they are pharmaceutically forms in certain physical properties. Such as solubility in acceptable and not deleterious to the epithelial cells or their polar solvents. function. Further, they should not cause deterioration in the In addition to Salt forms, the present invention provides stability of the composition. For example, inert fillers, compounds which are in a prodrug form. Prodrugs of the anti-irritants, tackifiers, excipients, fragrances, opacifiers, compounds or complexes described herein readily undergo 45 antioxidants, gelling agents, stabilizers, Surfactant, emol chemical changes under physiological conditions to provide lients, coloring agents, preservatives, buffering agents, other the compounds of the present invention. Additionally, pro permeation enhancers, and other conventional components drugs can be converted to the compounds of the present of topical or transdermal delivery formulations as are known invention by chemical or biochemical methods in an ex vivo in the art. environment. 50 The terms "enhancement,” “penetration enhancement” or Certain compounds of the present invention can exist in "permeation enhancement relate to an increase in the unsolvated forms as well as Solvated forms, including permeability of the skin, nail, hair, claw or hoof to a drug, hydrated forms. In general, the Solvated forms are equivalent So as to increase the rate at which the drug permeates to unsolvated forms and are encompassed within the scope through the skin, nail, hair, claw or hoof. The enhanced of the present invention. Certain compounds of the present 55 permeation effected through the use of Such enhancers can invention may exist in multiple crystalline or amorphous be observed, for example, by measuring the rate of diffusion forms. In general, all physical forms are equivalent for the of the drug through animal or human skin, nail, hair, claw or uses contemplated by the present invention and are intended hoof using a diffusion cell apparatus. A diffusion cell is to be within the scope of the present invention. described by Merritt et al. Diffusion Apparatus for Skin Certain compounds of the present invention possess 60 Penetration, J of Controlled Release, 1 (1984) pp. 161-162. asymmetric carbon atoms (optical centers) or double bonds; The term “permeation enhancer or “penetration enhancer' the racemates, diastereomers, geometric isomers and indi intends an agent or a mixture of agents, which, alone or in vidual isomers are encompassed within the scope of the combination, act to increase the permeability of the skin, present invention. nail, hair or hoof to a drug. The compounds of the present invention may also contain 65 The term “excipients' is conventionally known to mean unnatural proportions of atomic isotopes at one or more of carriers, diluents and/or vehicles used in formulating drug the atoms that constitute such compounds. For example, the compositions effective for the desired use. US 9,566,290 B2 13 14 The term “topical administration” refers to the application “Cell washing as used herein, refers to ethanol (or other of a pharmaceutical agent to the external Surface of the skin, organic solvents) and soap/water wash of the inside of the nail, hair, claw or hoof. Such that the agent crosses the diffusion cell. external Surface of the skin, nail, hair, claw or hoof and A "human nail unit', as defined herein, can be the nail enters the underlying tissues. Topical administration 5 plate, the nail bed, proximal nail fold, lateral nail fold and includes application of the composition to intact skin, nail, combinations thereof. hair, claw or hoof, or to an broken, raw or open wound of The term “leaving group” means a functional group or skin, nail, hair, claw or hoof. Topical administration of a atom which can be displaced by another functional group or pharmaceutical agent can result in a limited distribution of atom in a Substitution reaction, such as a nucleophilic the agent to the skin and Surrounding tissues or, when the 10 Substitution reaction. By way of example, representative agent is removed from the treatment area by the blood stream, can result in Systemic distribution of the agent. leaving groups include triflate, chloro, bromo and iodo The term “transdermal delivery” refers to the diffusion of groups; Sulfonic ester groups, such as mesylate, tosylate, an agent across the barrier of the skin, nail, hair, claw orhoof brosylate, nosylate and the like; and acyloxy groups, such as resulting from topical administration or other application of 15 acetoxy, trifluoroacetoxy and the like. a composition. The stratum corneum acts as a barrier and The term "amino-protecting group” means a protecting few pharmaceutical agents are able to penetrate intact skin. group suitable for preventing undesired reactions at an In contrast, the epidermis and dermis are permeable to many amino nitrogen. Representative amino-protecting groups Solutes and absorption of drugs therefore occurs more read include, but are not limited to, formyl; acyl groups, for ily through skin, nail, hair, claw or hoof that is abraded or example alkanoyl groups. Such as acetyl, trichloroacetyl or otherwise stripped of the stratum corneum to expose the trifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxy epidermis. Transdermal delivery includes injection or other carbonyl (Boc); arylmethoxycarbonyl groups, such as ben delivery through any portion of the skin, nail, hair, claw or Zyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl hoof or mucous membrane and absorption or permeation (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), through the remaining portion. Absorption through intact 25 and 1,1-di-(4-methoxyphenyl)methyl; silyl groups, such as skin, nail, hair, claw or hoof can be enhanced by placing the trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and active agent in an appropriate pharmaceutically acceptable the like. vehicle before application to the skin, nail, hair, claw or The term "hydroxy-protecting group” means a protecting hoof. Passive topical administration may consist of applying group Suitable for preventing undesired reactions at a the active agent directly to the treatment site in combination 30 hydroxy group. Representative hydroxy-protecting groups with emollients or penetration enhancers. As used herein, include, but are not limited to, alkyl groups, such as methyl, transdermal delivery is intended to include delivery by ethyl, and tert-butyl, acyl groups, for example alkanoyl permeation through or past the integument, i.e. skin, nail, groups, such as acetyl: arylmethyl groups, such as benzyl hair, claw or hoof. (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), The term “microbial infection” refers to any infection of 35 and diphenylmethyl (benzhydryl, DPM); silyl groups, such a host tissue by an infectious agent including, but not limited as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); to, viruses, bacteria, mycobacteria, fungus and parasites and the like. (see, e.g., Harrison’s Principles of Internal Medicine, pp. Boron is able to form dative bonds with oxygen, sulfur or 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J. nitrogen under some circumstances in this invention. Dative of Medicinal Chem. 42:1481-1485 (1999), herein each 40 bonds are usually weaker than covalent bonds. In situations incorporated by reference in their entirety). where a boron is covalently bonded to at least one oxygen, “Biological medium, as used herein refers to both in Sulfur or nitrogen, and is at the same time datively bonded vitro and in vivo biological milieus. Exemplary in vitro to an oxygen, Sulfur or nitrogen, respectively, the dative “biological media include, but are not limited to, cell bond and covalent bond between the boron and the two culture, tissue culture, homogenates, plasma and blood. In 45 identical heteroatoms can interconvert or be in the form of Vivo applications are generally performed in mammals, a resonance hybrid. There is potential uncertainty Surround preferably humans. ing the exact nature and extent of electron sharing in these “Inhibiting and “blocking,” are used interchangeably situations. The structures Supplied are not intended to herein to refer to the partial or full blockade of an editing include any and all possible bonding scenarios between domain of a tRNA synthetase. 50 boron and the atom to which it is bound. Non limiting “Ventral/intermediate center” as used herein refers to examples of these bonds are as follows: powdered nail samples drilled from the center of the inner surface (facing the nail bed) approximately 0.3-0.5 mm in depth to the surface. The area is beneath the dosed site of the 8 nail place but does not include dosed Surface (dorsal nail 55 OH OH Surface). / HON B & B “Ventral/intermediate center as used herein refers to the N immediate area of dosed site. O O “Remainder nail” as used herein refers to the remaining F F part of the nail that has not been dosed. 60 OH OH “Supporting bed as used herein refers to the cotton ball HON HO N / placed within the Teflon chamber of the diffusion cell to &B G B provide moisture to the nail plate and also to receive +W N chemicals penetrating through the nail plate. OH O "Surfacing washing as used herein refers to ethanol (or 65 F F G) other organic solvents) and Soap/water washing on the counterion surface of the dosed site. US 9,566,290 B2 15 16 -continued A L A L F

O O HO O OH N/ By OH HO M R HO 1 Bin G 10 O - e- HON -O OH F F F OH

15

F L A L OB In another example, dimers of C17 can form under the HO O O - O following conditions:

8 N/ O HO

25 NC y F O OUCC)O

30

A. L

OB 35 O O / B O9)

40 GE counterion F.

“Salt counterion', as used herein, refers to positively charged ions that associate with a compound of the invention 45 when the boron is fully negatively or partially negatively charged. Examples of salt counterions include H. H.O. ammonium, potassium, calcium, magnesium and Sodium. The compounds comprising a boron bonded to a carbon 50 and three heteroatoms (such as three oxygens described in this section) can optionally contain a fully negatively charged boron or partially negatively charged boron, due to the nature of the dative bond between the boron and one of the oxygens. Due to the negative charge, a positively 55 charged counterion may associate with this compound, thus The present invention also encompasses compounds that forming a salt. Examples of positively charged counterions are anhydrides of the cyclic boronic esters are synthesized include H. H.O", calcium, sodium, ammonium, potassium. by Subjecting these compounds to dehydrating conditions. The salts of these compounds are implicitly contained in Examples of these anhydrides are provided below: descriptions of these compounds. 60 The present invention also encompasses compounds that OH are poly- or multi-valent species, including, for example, / species such as dimers, trimers, tetramers and higher Y homologs of the compounds of use in the invention or 65 reactive analogues thereof. For example, dimers of C10 can form under the following conditions: US 9,566,290 B2 17 18 -continued -continued O pH O- Y NC B / N -> B 5 O O O F OC F and OH NC Y 10 CN NO Hip O O O Ao 15 O NC B HO M O CN. O O O O 20 NC B-1B CN O Trimers of the compounds of the invention are also O O produced. For example, trimers of acyclic boronic esters can OH be formed as follows: 25

1/ NC K H2O

F O) OCC)O - F CN 35 o1 O HO

o1 B No OH 40 B B No1 -Bat OH HO NB1 O or O NB1 OH or F F; 45 OH OH H2O -- O 50 OO CN CN.

55 Polymers of the compounds of the invention are also produced through the removal of certain protecting groups B OH in strong acid. For example, trimers of acyclic boronic esters HON-O 1 in On-OH can be formed as follows: B OH B OH 60

OH / B N HO O He US 9,566,290 B2 20 -continued herein, which are functionalized to afford compounds hav F ing water-solubility that is enhanced relative to analogous compounds that are not similarly functionalized. Thus, any of the substituents set forth herein can be replaced with analogous radicals that have enhanced water Solubility. For example, it is within the scope of the invention to replace a hydroxyl group with a diol, or an amine with a quaternary B OH amine, hydroxy amine or similar more water-soluble moiety. In a preferred embodiment, additional water solubility is No 10 HO O OH imparted by substitution at a site not essential for the activity n B1 OH B1 OH towards the editing domain of the compounds set forth herein with a moiety that enhances the water solubility of the parent compounds. Methods of enhancing the water-solu bility of organic compounds are known in the art. Such 15 methods include, but are not limited to, functionalizing an organic nucleus with a permanently charged moiety, e.g., quaternary ammonium, or a group that is charged at a F pH F physiologically relevant pH, e.g. carboxylic acid, amine. NC B Other methods include, appending to the organic nucleus M H2O hydroxyl- or amine-containing groups, e.g. alcohols, poly O Her ols, polyethers, and the like. Representative examples include, but are not limited to, polylysine, polyethyl O eneimine, poly(ethyleneglycol) and poly(propyleneglycol). CN Suitable functionalization chemistries and strategies for 25 these compounds are known in the art. See, for example, Dunn, R. L., et al., Eds. POLYMERIC DRUGS AND DRUG O DELIVERY SYSTEMS, ACS Symposium Series Vol. 469, American Chemical Society, Washington, D.C. 1991. 30 II. Introduction The present invention provides novel boron compounds and methods for the preparation of these molecules. The B No OH pi invention further provides boron compounds as analogs 35 HO O OH comprising a functional moiety, such as a drug moiety and n B1 B1 methods of use for said analogs. OH OH III. The Compounds 40 III.a) Cyclic Boronic Esters In a first aspect, the invention provides a compound having a structure according to Formula I: O O 45 R1a (I) CN CN r Also of use in the present invention are compounds that G B are poly- or multi-valent species, including, for example, 50 species such as dimers, trimers, tetramers and higher homologs of the compounds of use in the invention or DCC nan-1W reactive analogues thereof. The poly- and multi-valent spe cies can be assembled from a single species or more than one species of the invention. For example, a dimeric construct 55 wherein B is boron. R' is a member selected from a can be “homo-dimeric' or "heterodimeric.” Moreover, poly negative charge, a salt counterion, H., cyano, Substituted or and multi-valent constructs in which a compound of the unsubstituted alkyl, substituted or unsubstituted heteroalkyl, invention or a reactive analogue thereof, is attached to an substituted or unsubstituted cycloalkyl, substituted or unsub oligomeric or polymeric framework (e.g., polylysine, dex stituted heterocycloalkyl, substituted or unsubstituted aryl, tran, hydroxyethyl starch and the like) are within the scope 60 and substituted or unsubstituted heteroaryl. M is a member of the present invention. The framework is preferably poly selected from oxygen, sulfur and NR. R* is a member functional (i.e. having an array of reactive sites for attaching selected from H. Substituted or unsubstituted alkyl, substi compounds of use in the invention). Moreover, the frame tuted or unsubstituted heteroalkyl, substituted or unsubsti work can be derivatized with a single species of the inven tuted cycloalkyl, substituted or unsubstituted heterocy tion or more than one species of the invention. 65 cloalkyl, substituted or unsubstituted aryl, and substituted or Moreover, the present invention includes the use of com unsubstituted heteroaryl. J is a member selected from pounds within the motifset forth in the formulae contained (CRR), and CR. R. R', and R are members US 9,566,290 B2 21 22 independently selected from H., cyano, substituted or unsub ethyl, substituted or unsubstituted dialkylaminomethyl, sub stituted alkyl, substituted or unsubstituted heteroalkyl, sub stituted or unsubstituted arylaminomethyl, substituted or stituted or unsubstituted cycloalkyl, substituted or unsubsti unsubstituted indolyl and substituted or unsubstituted tuted heterocycloalkyl, substituted or unsubstituted aryl, and amido. In another exemplary embodiment, each R" and R' substituted or unsubstituted heteroaryl. The index n1 is an 5 is a member independently selected from cyano, Substituted integer selected from 0 to 2. W is a member selected from or unsubstituted methyl, substituted or unsubstituted ethyl, C=O (carbonyl), (CR'R''), and CR. R. R', and R' trifluoromethyl, substituted or unsubstituted hydroxymethyl, are members independently selected from H., cyano, Substi substituted or unsubstituted hydroxyalkyl, substituted or tuted or unsubstituted alkyl, substituted or unsubstituted unsubstituted benzyl, substituted or unsubstituted phenyl, heteroalkyl, substituted or unsubstituted cycloalkyl, substi 10 substituted or unsubstituted mercaptomethyl, substituted or tuted or unsubstituted heterocycloalkyl, substituted or unsubstituted mercaptoalkyl, substituted or unsubstituted unsubstituted aryl, and substituted or unsubstituted het aminomethyl, Substituted or unsubstituted alkylaminom eroaryl. The index m1 is an integer selected from 0 and 1. ethyl, substituted or unsubstituted dialkylaminomethyl, sub A is a member selected from CR" and N. D is a member stituted or unsubstituted arylaminomethyl, substituted or selected from CR'' and N. E is a member selected from 15 unsubstituted indolyl, substituted or unsubstituted amido. CR'' and N. G is a member selected from CR'' and N. In another exemplary embodiment, each R and R“ is a R", R', R'' and R'' are members independently member selected from H, substituted or unsubstituted selected from H, OR*, NR*R**, SR*, S(O)R*, S(O) methyl, substituted or unsubstituted ethyl, substituted or R*, S(O)NR*R**, C(O)R*, C(O)OR*, C(O) unsubstituted propyl. Substituted or unsubstituted isopropyl. NR*R*, nitro, halogen, cyano, substituted or unsubstituted substituted or unsubstituted butyl, substituted or unsubsti alkyl, substituted or unsubstituted heteroalkyl, substituted or tuted t-butyl, substituted or unsubstituted phenyl and sub unsubstituted cycloalkyl, substituted or unsubstituted het stituted or unsubstituted benzyl. In another exemplary erocycloalkyl, substituted or unsubstituted aryl, and substi embodiment, RandR' is a member selected from methyl, tuted or unsubstituted heteroaryl. Each R* and R** are ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl. In members independently selected from H. nitro, halogen, 25 another exemplary embodiment, R is H and R“ is a cyano, substituted or unsubstituted alkyl, substituted or member selected from methyl, ethyl, propyl, isopropyl. unsubstituted heteroalkyl, substituted or unsubstituted butyl, t-butyl, phenyl and benzyl. In another exemplary cycloalkyl, substituted or unsubstituted heterocycloalkyl, embodiment, R is H and R. H. substituted or unsubstituted aryl, and substituted or unsub In another exemplary embodiment, each R', R', R''“ stituted heteroaryl. The combination of nitrogens (A+D+E+ 30 and R' is a member independently selected from H, OR*, G) is an integer selected from 0 to 3. A member selected NR*R**, SR*, S(O)R*, S(O).R*, S(O)NR*R**, from R. R* and Rand a member selected from R. R' C(O)R*, C(O)OR*, C(O)NR*R**, halogen, cyano, and R", together with the atoms to which they are attached, nitro, substituted or unsubstituted methoxy, substituted or are optionally joined to form a 4 to 7 membered ring. R' unsubstituted methyl, substituted or unsubstituted ethoxy, and R", together with the atoms to which they are attached, 35 substituted or unsubstituted ethyl, trifluoromethyl, substi are optionally joined to form a 4 to 7 membered ring. R' tuted or unsubstituted hydroxymethyl, substituted or unsub and R', together with the atoms to which they are attached, stituted hydroxyalkyl, substituted or unsubstituted benzyl, are optionally joined to form a 4 to 7 membered ring. R' substituted or unsubstituted phenyl, substituted or unsubsti and R', together with the atoms to which they are attached, tuted phenyloxy, substituted or unsubstituted phenyl are optionally joined to form a 4 to 7 membered ring. R' 40 methoxy, substituted or unsubstituted thiophenyloxy, sub and R''' together with the atoms to which they are attached, stituted or unsubstituted pyridinyloxy, substituted or unsub are optionally joined to form a 4 to 7 membered ring. R' stituted pyrimidinyloxy, substituted or unsubstituted benzyl and R', together with the atoms to which they are attached, furan, substituted or unsubstituted methylthio, substituted or are optionally joined to form a 4 to 7 membered ring. unsubstituted mercaptomethyl, substituted or unsubstituted In an exemplary embodiment, the compound has a struc 45 mercaptoalkyl, substituted or unsubstituted phenylthio. Sub stituted or unsubstituted thiophenylthio, substituted or ture according to Formula (Ia): unsubstituted phenyl methylthio, substituted or unsubsti tuted pyridinylthio, substituted or unsubstituted pyrimidi (Ia) nylthio, substituted or unsubstituted benzylthiofuranyl, sub 50 stituted or unsubstituted phenylsulfonyl, substituted or unsubstituted benzylsulfonyl, substituted or unsubstituted phenylmethylsulfonyl, substituted or unsubstituted thiophe nylsulfonyl, substituted or unsubstituted pyridinylsulfonyl, substituted or unsubstituted pyrimidinylsulfonyl, substituted 55 or unsubstituted sulfonamidyl, substituted or unsubstituted phenylsulfinyl, substituted or unsubstituted benzylsulfinyl, substituted or unsubstituted phenylmethylsulfinyl, substi tuted or unsubstituted thiophenylsulfinyl, substituted or In another exemplary embodiment, each R and R“ is a unsubstituted pyridinylsulfinyl, substituted or unsubstituted member independently selected from H., cyano, substituted 60 pyrimidinylsulfinyl, Substituted or unsubstituted amino, Sub or unsubstituted methyl, substituted or unsubstituted ethyl, stituted or unsubstituted alkylamino, substituted or unsub trifluoromethyl, substituted or unsubstituted hydroxymethyl, stituted dialkylamino, substituted or unsubstituted trifluo substituted or unsubstituted hydroxyalkyl, substituted or romethylamino, Substituted or unsubstituted aminomethyl, unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted alkylaminomethyl, substituted substituted or unsubstituted mercaptomethyl, substituted or 65 or unsubstituted dialkylaminomethyl, substituted or unsub unsubstituted mercaptoalkyl, substituted or unsubstituted stituted arylaminomethyl, substituted or unsubstituted ben aminomethyl, Substituted or unsubstituted alkylaminom Zylamino, Substituted or unsubstituted phenylamino, Substi US 9,566,290 B2 23 24 tuted or unsubstituted thiophenylamino, substituted or -continued unsubstituted pyridinylamino, substituted or unsubstituted (Ic) pyrimidinylamino, Substituted or unsubstituted indolyl. Sub H O- R1a; stituted or unsubstituted morpholino, substituted or unsub H B stituted alkylamido, substituted or unsubstituted arylamido, M substituted or unsubstituted ureido, Substituted or unsubsti O tuted carbamoyl, and substituted or unsubstituted piperiz R10a inyl. In an exemplary embodiment, R, R', R'' and R' H are selected from the previous list of substituents with the H H exception of C(O)R*, C(O)OR*, C(O)NR*R**. 10 In another exemplary embodiment, R, R', R'' and R'' are members independently selected from fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxylm (Id) ethyl, trifluoromethyl, methoxy, trifluoromethyoxy, ethyl, H O- R1a; diethylcarbamoyl pyridin-2-yl, pyridin-3-yl pyridin-4-yl, 15 Re BI pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, N piperizinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbo O nylmethoxy, carboxymethoxy, thiophenyl, 3-(butylcarbo H nyl) phenylmethoxy, 1H-tetrazol-5-yl, 1-ethoxycarbonylm H ethyloxy-, 1-ethoxycarbonylmethyl-, 1-ethoxycarbonyl-, H H carboxymethoxy-, thiophen-2-yl, thiophen-2-ylthio-, thio phen-3-yl, thiophen-3-ylthio, 4-fluorophenylthio, butylcar bonylphenylmethoxy, butylcarbonylphenylmethyl, butylcar 25 bonylmethyl, 1-(piperidin-1-yl)carbonyl)methyl, (Ie) 1-(piperidin-1-yl)carbonyl)methoxy, 1-(piperidin-2-yl)car bonyl)methoxy, 1-(piperidin-3-yl)carbonyl)methoxy, 1-(4- (pyrimidin-2-yl)piperazin-1-yl)carbonyl)methoxy, 1-(4-(py rimidin-2-yl)piperazin-1-yl)carbonyl)methyl, 1-(4- (pyrimidin-2-yl)piperazin-1-yl)carbonyl, 1-4-(pyrimidin-2- 30 yl)piperazin-1-yl, 1-(4-(pyridin-2-yl)piperazin-1-yl) carbonyl), 1-(4-(pyridin-2-yl)piperazin-1-yl) carbonylmethyl, (1-(4-(pyridin-2-yl)piperazin-1-yl) (If) carbonyl)-methoxy), 1-(4-(pyridin-2-yl)piperazin-1-yl. 1H-indol-1-yl, morpholino-, morpholinyl, morpholinocar 35 bonyl, morpholinylcarbonyl, phenylureido, phenylcarbam oyl, acetamido, 3-(phenylthio)-1H-indol-1-yl, 3-(2-cyano ethylthio)-1H-indol-1-yl, benzylamino, 5-methoxy-3- (phenylthio)-1H-indol-1-yl, 5-methoxy-3-(2- cyanoethylthio)-1H-indol-1-yl)), 5-chloro-1H-indol-1-yl, 40 5-chloro-3-(2-cyanoethylthio)-1H-indol-1-yl)), dibenzy (Ig) lamino, benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1- yl)), 4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phe nyl, 4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio. 45 3-cyanophenylthio. 4-cyanophenylthio. 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 50 (Ih) 3-fluorobenzyloxy, 4-fluorobenzyloxy, unsubstituted phe nyl, unsubstituted benzyl. In an exemplary embodiment, R' is H and R' is H. In an exemplary embodiment, the compound according to 55 Formula (I) or Formula (Ia) is a member selected from:

(Ib) (II) H o-R". 60

65

US 9,566,290 B2 27 28 ethylthio)-1H-indol-1-yl, benzylamino, 5-methoxy-3- In another exemplary embodiment, there is a proviso that (phenylthio)-1H-indol-1-yl, 5-methoxy-3-(2- the compound cannot have a structure according to Formula cyanoethylthio)-1H-indol-1-yl)), 5-chloro-1H-indol-1-yl, (IX): 5-chloro-3-(2-cyanoethylthio)-1H-indol-1-yl)), dibenzy lamino, benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1- yl)), 4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phe (Ix) nyl, 4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, O- R1b l I 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio. R B 3-cyanophenylthio. 4-cyanophenylthio. 2-chlorophenoxy, N 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 10 O 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, R10b H 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-chlorobenzyloxy, R7b 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, and 4-fluorobenzyloxy. 15 wherein R' is a member selected from H. methyl, ethyl and In an exemplary embodiment, the compound has a for phenyl. R' is a member selected from H, OH, NH, SH, mula according to Formulae (II)-(Io) wherein R" is a halogen, Substituted or unsubstituted phenoxy, Substituted or member selected from H, a negative charge and a salt unsubstituted phenylalkyloxy, substituted or unsubstituted counterion and each of the remaining three R groups (R', phenylthio and substituted or unsubstituted phenylalkylthio. R10a, R in (Il), R9, R10a, R2 in (Im), R9, Rila, R2 in R'' is a member selected from H, OH, NH, SH, methyl, (In), R', R'', R' in (Io)) is a member independently substituted or unsubstituted phenoxy, substituted or unsub selected from fluoro, chloro, bromo, nitro, cyano, amino, stituted phenylalkyloxy, substituted or unsubstituted phenyl methyl, hydroxylmethyl, trifluoromethyl, methoxy, trifluo thio and substituted or unsubstituted phenylalkylthio. In romethyoxy, ethyl, diethylcarbamoyl pyridin-2-yl, pyridin another exemplary embodiment, there is a proviso that the 3-yl pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, pip 25 compound cannot have a structure according to Formula (IX) erizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl, wherein R' is a member selected from a negative charge, H 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, and a salt counterion. In another exemplary embodiment, there is a proviso that the compound cannot have a structure 3-(butylcarbonyl) phenylmethoxy, 1H-tetrazol-5-yl, according to Formula (Ix) wherein R'' and R'' are H. In 1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethyl-, 30 another exemplary embodiment, there is a proviso that the 1-ethoxycarbonyl-, carboxymethoxy-, thiophen-2-yl, thio compound cannot have a structure according to Formula (IX) phen-2-ylthio-, thiophen-3-yl, thiophen-3-ylthio, 4-fluoro wherein one member selected from R'' and R' is Hand phenylthio, butylcarbonylphenylmethoxy, butylcarbonyl the other member selected from R'' and R' is a member phenylmethyl, butylcarbonylmethyl, 1-(piperidin-1-yl) selected from halo, methyl, cyano, methoxy, hydroxymethyl carbonyl)methyl, 1-(piperidin-1-yl)carbonyl)methoxy, 35 and p-cyanophenyloxy. In another exemplary embodiment, 1-(piperidin-2-yl)carbonyl)methoxy, 1-(piperidin-3-yl)car there is a proviso that the compound cannot have a structure bonyl)methoxy, 1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbo according to Formula (Ix) wherein R'' and R'' are mem nyl)methoxy, 1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl) bers independently selected from fluoro, chloro, methyl, methyl, 1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl, 1-4- cyano, methoxy, hydroxymethyl, and p-cyanophenyl. In 40 another exemplary embodiment, there is a proviso that the (pyrimidin-2-yl)piperazin-1-yl, 1-(4-(pyridin-2-yl) compound cannot have a structure according to Formula (IX) piperazin-1-yl)carbonyl), 1-(4-(pyridin-2-yl)piperazin-1-yl) wherein R' is a member selected from a negative charge, H carbonylmethyl, (1-(4-(pyridin-2-yl)piperazin-1-yl) and a salt counterion; R7 is H; R' is F and R'' is H. In carbonyl)-methoxy), 1-(4-(pyridin-2-yl)piperazin-1-yl. another exemplary embodiment, there is a proviso that the 1H-indol-1-yl, morpholino-, morpholinyl, morpholinocar 45 compound cannot have a structure according to Formula (IX) bonyl, morpholinylcarbonyl, phenylureido, phenylcarbam wherein R'' and R'', along with the atoms to which they oyl, acetamido, 3-(phenylthio)-1H-indol-1-yl, 3-(2-cyano are attached, are joined to form a phenyl group. In another ethylthio)-1H-indol-1-yl, benzylamino, 5-methoxy-3- exemplary embodiment, there is a proviso that the com (phenylthio)-1H-indol-1-yl, 5-methoxy-3-(2- pound cannot have a structure according to Formula (IX) 50 wherein R' is a member selected from a negative charge, H cyanoethylthio)-1H-indol-1-yl)), 5-chloro-1H-indol-1-yl, and a salt counterion; R' is H; R' is 4-cyanophenoxy; and 5-chloro-3-(2-cyanoethylthio)-1H-indol-1-yl)), dibenzy R is H. lamino, benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1- In another exemplary embodiment, there is a proviso that yl)), 4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phe the compound cannot have a structure according to Formula nyl, 4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, 55 (Iy) 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio. 3-cyanophenylthio. 4-cyanophenylthio. 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-chlorobenzyloxy, 60 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, and 4-fluorobenzyloxy. In an exemplary embodiment, there is a proviso that the compound cannot be a member selected from FIG. 11. In 65 another exemplary embodiment, there is a proviso that the compound cannot be a member selected from C1-C40. US 9,566,290 B2 29 30 wherein R' is a member selected from H, halogen, CN and -continued Substituted or unsubstituted C alkyl. (Iaf) In another exemplary embodiment, there is a proviso that H OH a structure does not have the which is a member selected from Formulae (I) to (Io) at least one member selected from HO n R R3a, R4a, R5, R6a, R7e, R8a, R9a, R10a, Rlla and R12a is nitro, cyano or halogen. In another exemplary embodiment, l- O, there is a proviso that when M is oxygen, W is a member selected from (CR'R''), wherein n1 is 0, J is a member selected from (CRR7), wherein m1 is 1, A is CR, D is CR', E is CR'', G is CR'', the R is not halogen, 10 in which q is a number between 0 and 1. R is halogen. R. methyl, ethyl, or optionally joined with R' to form a R. R. R. and Rare members independently selected from phenyl ring; R" is not unsubstituted phenoxy, C(CH), a member selected from H, substituted or unsubstituted halogen, CF, methoxy, ethoxy, or optionally joined with alkyl, substituted or unsubstituted heteroalkyl, substituted or R" to form a phenyl ring R' is not halogen or optionally unsubstituted cycloalkyl, substituted or unsubstituted het joined with R' to form a phenyl ring; and R' is not 15 erocycloalkyl, substituted or unsubstituted aryl, and substi halogen. In another exemplary embodiment, there is a tuted or unsubstituted heteroaryl. In an exemplary embodi proviso that when M is oxygen, W is a member selected from (CRR"), wherein n1 is 0, J is a member selected ment, there is a proviso that the compound is not a member from (CRR7), wherein m1 is 1, A is CR, D is CR', selected from E is CR'', G1 is CR'', then neither R nor R'' are halophenyl. In another exemplary embodiment, there is a F Me proviso that when M is oxygen, W is a member selected OH, OH, from (CRR), wherein n1 is 0, J is a member selected / / B B from (CRR7), wherein m1 is 1, A is CR, D is CR', M M E is CR, G is CR'?", and R, R and R'' are H, then O O R. R'' and R'' are not H. In another exemplary embodi 25 ment, there is a proviso that when M is oxygen wherein n1 is 1, J is a member selected from (CR'R''), wherein m1 OH pi is 0, A is CR, D is CR9, E is CR, G is CR, R is / H, R is H, R'' is H, R is H, R7 is H, R''' is H, then 30 O is O : in RO, and W is not C=O (carbonyl). In another exemplary embodi M ment, there is a proviso that when M is oxygen, W is CR". B J is CR, A is CR, D is CR10, E is CR, G is CR2, M R, R7, R, R0, R'' and R2 are H, then R and R, HO together with the atoms to which they are attached, do not OH form a phenyl ring. 35 In an exemplary embodiment, the compound of the inven ON l tion has a structure which is a member selected from: OC)O. (Iab) 40 O H (R), In an exemplary embodiment, the compound has a struc Ra x^n R ture is a member selected from:

45 CO (Iag) (Iac) Rb (R)g, " pi Xs-B 1 50 UCC)1N4 O)> 21 (Iah) (R8), (Iad) Ni pi 55 1 S pi R N R 1 O, ><21 O).y 2 (R8), (R8), 60 (Iai) (Ia) N

65 21 (R8), US 9,566,290 B2 31 32 -continued -continued

OH (Ia) C e e Ré-ON N R 5 H- N N f N d l- O and (R) Sa In an exemplary embodiment, R” and R are members (Iak) independently selected from H. methyl, OH HO-CH2 10 N-VB (Rg)f 2 O. EtO HO

15 O O In an exemplary embodiment, R, R and R are each members independently selected from: O

EO HO

Cry Cl C O S.-->try 40 cu, Cly 7\ O, O,O O MeY/N, 50 Me O NC ANN N O NN NC A^ N 55 N N H ; and 60 S N F s

cy F OA s 65 C N a h ; and e N S H-1'N, N d US 9,566,290 B2 33 34 In another exemplary embodiment, R is H and R is a -continued member selected from H. methyl, NC1Nus S 5 O N MeO

N H O 10 s

N Me C S ; and / \, O 15

N C In another exemplary embodiment, Rand Rare, together with the nitrogen to which they are attached, optionally S joined to form a member selected from 25

s r 4fn. 35 N-y s

N In an exemplary embodiment, R is a member selected y 40 from S r EtO HO N- N s 45 s s y y O O

O NC1Nuscy 50 - CA 55 Sry and O 60 O

O US 9,566,290 B2 35 36 In an exemplary embodiment, R is a member selected -continued from OH

O 5 O; HC N- X F A -- or 10

e e C O. and O 15 In an exemplary embodiment, R is a member selected from 21 OH

2O alsN N l N N ^A N N- O; V N O OY 25 21 N NC N OH 30 N l O)O; Me 35 M1 R In an exemplary embodiment, the compound is a member O; selected from

EO 45 r O O OH Ol OH 50 N ~ RO; N- lN HO O;

60 US 9,566,290 B2 37 38 -continued -continued

NC pi

N N O

t OH OH: 10 ON B y O; O

F DOOC)Br 15 H H OH: N N y

O Orio)O

25

30

55

60

65 US 9,566,290 B2 39 40 -continued -continued O H;

B 10 | l, 1 YoM/ C OH: M 15 R 4' O % OESEO

OH: 25 S /

30

35

O OH: / 40 B N O

pi 45 C G a S R O; H1 N 50

55 In an exemplary embodiment, the compound has a struc ture which is described in FIG. 19. In an exemplary embodi ment, the compound has a structure which is described in FIG. 20. In an exemplary embodiment, the compound has a struc 60 ture according to a member selected from Formulae I(b), I(c), I(d), and I(e) wherein said remaining R group (R for I(b), R' for I(c), R' for I(d) and R' for I(e)) is car boxymethoxy. In an exemplary embodiment, the compound has a struc 65 ture which is a member selected from Formulae (If)-(Ik), wherein either R' or R' for Formula (If), either R' or R' for Formula (Ig), either R' or R' for Formula (Ih), US 9,566,290 B2 41 42 either R' or R' for Formula (Ii), either R' or R' for -continued Formula (I), either R''' or R' for Formula (Ik) is halogen, H R1a and the other substituent in the pairing (ex. if: R9a is: F in IO Formula (If), then R" is selected from the following HN B substituent listing), is a member selected from NH, N(CH) 5 Y H, and N(CH). In another exemplary embodiment, the compound has a C H structure which is a member selected from: H H 10 H o-R", s: H o-R" (H3C)HN d I Yo .1 R O 15 C H F H H H H H H O- R1a, i H O- R1a (H3C)N d I 2O N .1 B O Y C H C H H

i H o-R", HN l I N .1 R O O 30 Br H Br H H H O (H3C)HN l in which R* and R** are members selected from: H, 35 Y substituted or unsubstituted alkyl, substituted or unsubsti tuted heteroalkyl, substituted or unsubstituted cycloalkyl, Br H substituted or unsubstituted heterocycloalkyl, substituted or H unsubstituted aryl, and Substituted or unsubstituted het- 40 H eroaryl. In an exemplary embodiment, the compound is a O member selected from (H3C)N d N O H o-R", 45 Br HN l H H N O wherein R' is a member selected from a negative charge, H F 50 H and a salt counterion. H H In another exemplary embodiment, the compound has a H o-R", structure which is a member selected from: (H3C)HN d M 55 O (Iak) HO-CH2 F H H H rN H O- R1a, 60 (R3) - (H3C)N l g 2 N O wherein q is 1 and R is a member selected from fluoro, F 65 chloro and bromo. H H In another exemplary embodiment, the compounds and embodiments described above in Formulae (I)-(Io) can form