(12) United States Patent
`US 9,549,938 B2
`(10) Patent N0.:
`
` Baker et a]. (45) Date of Patent: *Jan. 24, 2017
`
`
`US009549938B2
`
`(72)
`
`(54) BORON-CONTAINING SMALL MOLECULES
`.
`(71) Applicant: Anacor Pharmaceuticals, Inc., Palo
`Altos CA (Us)
`Inventors: Stephen J. Baker, Collegeville, PA
`(US); Tsutomu Akama, Sunnyvale, CA
`(US); Vincent S. Hernandez,
`Watsonville, CA (US); Karin M. Hold,
`Belmont, CA (US); Kirk Maples, San
`Jose, CA (US); Jacob J. Plattner,
`Berkeley, CA (US); Virginia Sanders,
`San Francisco, CA (US); Yong-Kang
`Zhang, San Jose, CA (US); Gregory T.
`Fieldson, Morgantown, WV (US);
`James J. Leyden, Malvern, CA (US)
`
`(73) Assignee: Anacor Pharmaceuticals, Inc., Palo
`Alto, CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. N0.: 15/068,352
`
`(22)
`
`Filed:
`
`Mar. 11, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2016/0184334 A1
`
`Jun. 30, 2016
`
`Related U.S. Application Data
`
`(60) Continuation of application No. 15/046,322, filed on
`Feb. 17, 2016, which is a continuation of application
`No. 14/537,771, filed on Nov. 10, 2014, which is a
`continuation of application No. 14/201,459, filed on
`Mar. 7, 2014, now Pat. No. 9,353,133, which is a
`continuation of application No. 13/356,488, filed on
`Jan. 23, 2012, now Pat. No. 8,722,917, which is a
`continuation of application No. 12/629,753, filed on
`Dec. 2, 2009, now Pat. No. 8,115,026, which is a
`division of application No. 11/505,591, filed on Aug.
`16, 2006, now Pat. No. 7,767,657, which is a
`continuation-in-part of application No. 11/357,687,
`filed on Feb. 16, 2006, now Pat. No. 7,582,621,
`application No. 15/068,352, filed on Mar. 11, 2016,
`which is a continuation-in—part of application No.
`13/874,329, filed on Apr. 30, 2013, now Pat. No.
`8,889,656, which is a continuation of application No.
`13/224,252,
`filed on Sep. 1, 2011, now Pat. No.
`8,440,642, which is a continuation of application No.
`12/507,010, filed on Jul. 21, 2009, now Pat. No.
`8,039,451, which is a continuation of application No.
`11/357,687.
`(60) Provisional application No. 60/654,060, filed on Feb.
`16, 2005, provisional application No. 60/755,227,
`(Continued)
`
`(5 1 )
`
`Int. Cl.
`A61K 31/69
`C07F 5/02
`
`(2006.01)
`(2006.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(200601)
`(200601)
`(200601)
`(200901)
`(200901)
`(200901)
`
`C07F 5/04
`C07H 19/06
`C07H 19/16
`C07H 21/00
`C07H 23/00
`A61K 31/70
`A61K 31/7076
`A61K 9/00
`A61K 47/10
`A61K 9/08
`(52) U.S. Cl.
`CPC ............. A61K 31/69 (2013.01); A61K 9/0012
`(2013.01); A61K 9/08 (2013.01); A61K 31/70
`(2013.01); A61K 31/7076 (2013.01); A61K
`47/10 (2013.01); C07F 5/025 (2013.01); C07F
`5/04 (2013.01); C07H 19/06 (2013.01); C07H
`19/16 (2013.01); C07H 21/00 (2013.01);
`C07H 23/00 (2013.01)
`(58) Field of Classification Search
`USPC ............................................................ 514/64
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`2,260,336 A
`2,741,548 A
`2,831,866 A
`
`10/1941 Prescott et al.
`4/1956 Darling et 31.
`4/1958 Freeman et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`
`0969531
`0765331 Bl
`
`1/2000
`8/2000
`
`(Continued)
`
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 13/673,860, filed Nov. 9, 2012, Anacor Pharmaceu-
`ticals, Inc.
`
`(Continued)
`
`Primary Examiner 7 Rei-Tsang Shiao
`(74) Attorney, Agent, or Firm 7 Morgan, Lewis &
`Bockius LLP
`
`(57)
`
`ABSTRACT
`
`This invention relates to compounds useful for treating
`fungal
`infections, more specifically topical
`treatment of
`onychomycosis and/or cutaneous fungal
`infections. This
`invention is directed to compounds that are active against
`fungi and have properties that allow the compound, when
`placed in contact with a patient, to reach the particular part
`of the skin, nail, hair, claw or hoof infected by the fungus.
`In particular the present compounds have physiochemical
`properties that facilitate penetration of the nail plate.
`
`6 Claims, 63 Drawing Sheets
`
`FIatWing Ex. 1001, p. 1
`
`FlatWing Ex. 1001, p. 1
`
`

`

`US 9,549,938 B2
`
`Page 2
`
`Related US. Application Data
`
`filed on Dec. 30, 2005, provisional application No.
`60/746,361, filed on May 3, 2006.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
`
`3,093,659
`3,104,255
`3,297,525
`3,370,957
`3,686,398
`3,816,472
`3,873,279
`4,202,894
`4,602,011
`4,716,035
`4,766,113
`4,822,822
`4,894,220
`4,919,934
`4,977,268
`5,264,206
`5,348,947
`5,348,948
`5,498,407
`5,591,731
`5,668,258
`5,688,928
`5,831,045
`5,880,188
`5,962,498
`6,042,845
`6,080,774
`6,083,903
`6,143,794
`6,221,640
`6,224,887
`6,306,628
`6,369,098
`6,521,619
`6,699,994
`6,800,645
`6,855,848
`7,074,392
`7,169,603
`7,205,425
`7,217,701
`7,390,806
`7,446,236
`7,465,836
`7,582,621
`
`7,767,657
`7,816,344
`8,039,450
`8,039,451
`8,115,026
`8,168,614
`8,440,642
`8,722,917
`8,889,656
`
`2002/0010332
`2002/0028831
`2002/0161230
`2002/0165121
`2002/0193672
`2003/0032673
`2003/0181766
`2004/0077601
`2004/0224923
`2004/0259833
`2004/0259842
`2005/0054644
`2005/0125852
`2006/0009386
`
`6/1963
`9/1963
`1/1967
`2/1968
`8/1972
`6/1974
`3/1975
`5/1980
`7/1986
`12/1987
`8/1988
`4/1989
`1/1990
`4/1990
`12/1990
`11/1993
`9/1994
`9/1994
`3/1996
`1/1997
`9/1997
`11/1997
`11/1998
`3/1999
`10/1999
`3/2000
`6/2000
`7/2000
`11/2000
`4/2001
`5/2001
`10/2001
`4/2002
`2/2003
`3/2004
`10/2004
`2/2005
`7/2006
`1/2007
`4/2007
`5/2007
`6/2008
`11/2008
`12/2008
`9/2009
`
`8/2010
`10/2010
`10/2011
`10/2011
`2/2012
`5/2012
`5/2013
`5/2014
`11/2014
`
`1/2002
`3/2002
`10/2002
`11/2002
`12/2002
`2/2003
`9/2003
`4/2004
`11/2004
`12/2004
`12/2004
`3/2005
`6/2005
`1/2006
`
`Bell et a1.
`Emrick et a1.
`Grier
`Wagner et a1.
`Kohn et a1.
`Shapiro et a1.
`Singer
`Pfiffner
`West et a1.
`Sampathkamar
`West et a1.
`Arita et a1.
`Nabi et a1.
`Deckner et a1.
`McPhail et a1.
`Bohn et a1.
`Patel et a1.
`Patel et a1.
`Atlas
`Kennedy et a1.
`Stolowitz
`Stolowitz
`Stolowitz et a1.
`Austin et a1.
`Driedger et a1.
`Sun et a1.
`Murugesan et a1.
`Adams et a1.
`Chaudhuri et a1.
`Tao et a1.
`Samour et a1.
`Rothschild et a1.
`Pershadsingh et a1.
`Link et a1.
`Babu et a1.
`Cox et a1.
`Scherer et a1.
`Friedman et a1.
`Hedley et a1.
`Shibasaki et a1.
`Mikoshiba et a1.
`Lee et a1.
`Naud et a1.
`Lee et a1.
`Baker
`....................... C07F 5/02
`514/64
`
`Baker et a1.
`Baker et a1.
`Akama et a1.
`Baker et a1.
`Baker et a1.
`Baker et a1.
`Baker et a1.
`Baker et al.
`Baker
`....................... C07F 5/02
`514/64
`
`Vollmuller et a1.
`Manley
`Meudt et a1.
`Brehove
`Walsh et a1.
`Nagy
`Satoh et a1.
`Adams et a1.
`Lee et a1.
`Benkovic et a1.
`Mikoshiba et a1.
`Lee et a1.
`Caenepeel et a1.
`Stossel et al.
`
`2006/0222671 A1
`2006/0234981 A1
`2007/0155699 A1
`2007/0286822 A1
`2007/0293457 A1
`2009/0227541 A1
`2010/0048570 A1
`2010/0256092 A1
`2013/0059802 A1
`2013/0059803 A1
`2013/0064783 A1
`2013/0210770 A1
`2014/0142064 A1
`2014/0221631 A1
`2015/0065459 A1
`2015/0119364 A1
`
`10/2006 Weidner
`10/2006 Baker et a1.
`7/2007 Baker et a1.
`12/2007 Sanders et a1.
`12/2007 Baker et a1.
`9/2009 Baker et a1.
`2/2010 Kim et a1.
`10/2010 Xia et a1.
`3/2013 Baker et a1.
`3/2013 Baker et a1.
`3/2013 Baker et a1.
`8/2013 Baker et a1.
`5/2014 Baker et a1.
`8/2014 Baker et a1.
`3/2015 Baker et a1.
`4/2015 Baker et a1.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`JP
`JP
`JP
`JP
`JP
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`1155698 A1
`1 444 981 A1
`2002-53583 A
`2002-508359 A
`2003-212837 A
`2004-514669 A
`2005-022986 A
`W0 9533754
`W0 9622023 A1
`W0 9812206 A1
`W0 0027822
`W0 0044387 A1
`W0 0075142 A2
`W0 0114578 A1
`W0 0149303 A1
`W0 0187846 A2
`W0 0244184
`W0 03/009689 A1
`WO 03033002 A1
`WO 03059916 A2
`WO 2004/043925 A2
`WO 2004056322 A2
`WO 2004081008 A1
`WO 2005002577 A1
`WO 2005013892 A3
`WO 2005/066172
`WO 2005/110410 A2
`WO 2005/123054
`WO 2005123094 A2
`WO 2006007384
`WO 2006062731 A1
`WO 2006079843 A1
`WO 2006089067 A2
`WO 2006096131 A1
`WO 2007022437 A2
`WO 2007078340 A2
`WO 2007095638 A2
`WO 2007146965 A2
`WO 2008157726 A1
`WO 2009111676 A2
`WO 2009140309 A2
`WO 2010028005 A1
`WO 2010045503 A
`WO 2010045505 A1
`WO 2015/171186
`
`11/2001
`8/2004
`2/2002
`3/2002
`7/2003
`5/2004
`1/2005
`5/1995
`7/1996
`3/1998
`5/2000
`8/2000
`12/2000
`3/2001
`7/2001
`11/2001
`6/2002
`2/2003
`4/2003
`7/2003
`5/2004
`7/2004
`9/2004
`1/2005
`2/2005
`7/2005
`11/2005
`12/2005
`12/2005
`1/2006
`6/2006
`8/2006
`8/2006
`9/2006
`2/2007
`7/2007
`8/2007
`12/2007
`12/2008
`9/2009
`11/2009
`3/2010
`4/2010
`4/2010
`11/2015
`
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 14/977,052, filed Dec. 21, 2015, Anacor Pharma-
`ceuticals, Inc.
`Adamczyk-Wozniac, et a1., “Benzoxaborolesgold Compounds
`with new applications”,
`Journal of Organometalic Chemistry
`694,3533-3541 (2009).
`Akama, et a1., “Discovery and structure-activity study of novel
`benzoxaborole anti-inflammatory agent (AN2728) for the potential
`topical treatment of psoriasis and atopic dernatitis”, Bioorganic &
`Medicinal Chemistry Letters, (2009) 19: 2129-2132.
`
`FIatWing Ex. 1001, p. 2
`
`FlatWing Ex. 1001, p. 2
`
`

`

`US 9,549,938 B2
`
`Page 3
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Alexander, et al., “Imprinted Polymers as Protecting Groups for
`Regioselective Modification of Polyfunctional Substrates”, J. Am.
`Chem. Soc. 1999, 121, 6640-6651.
`on Topical Therapy of
`Alley,
`et
`al.,
`“Recent Progress
`Onychomycosis”, Expert Opinion Investigate Drugs(Feb. 2007)
`16(2): 157-67.
`Austin, et al., “Oxaboroles and Salts and their Use of Biocides for
`Plastics”, CAS, vol. 124, pp. 234-024, (1996).
`Bailey, et al., “Boron-Containing Antibacterial Agents: Effects on
`Growth and Morphology of Bacteria Under Various Culture Con-
`ditions,” Antimicrobial Agents and Chemotherapy, 17(04):549-553,
`(Apr. 1980).
`Baker, et al., “Discovery of New Boron-Containing Antifungal
`Agent,
`5-Fluoro-1,3 -dihydro-1-hydroxy-2,
`1-benzoxaborole
`(AN2690) for Potential Treatment of Onychomoycosis”, Journal of
`Medicinal Chemistry, vol. 49, No. 15; pp. 4447-4450, (Jul. 27,
`2006).
`Baker, et al., “Identification of a Novel Boron-Containing Antibac-
`terial Agent (AN0128) with Anti-inflammatory activity, for the
`Potential Treatment of Cutaneous Diseases”, Bioorganic & Medici-
`nal Chemistry Letters (2006) 16: 5963-5937.
`Baker, et al., “Progress on New Therapeutics for Fungal Nail
`Infections”, Annual Reports in Medicinal Chemistry, vol. 40: pp.
`323-335, (2005).
`Bell, et al., “Design, synthesis and evaluation of a novel series of
`spiroketals based on the structure of the antibacterial gyrase inhibi-
`tor novobiocin”, J. Chem. Soc., Perkin Trans., 1997 vol. 18, No. 1,
`pp. 2789-2801.
`Bessis, N., “Gene Therapy for Rheumatoid Arthritis,” J. Gene Med,
`vol. 4; pp. 581-591 (2002).
`Brown, et al., “Chiral Synthesis via Organoboranes. 35. Simple
`Procedures for the Efficient Recycling of the Terpenyl Chiral
`Auxiliaries and Convenient Isolation of the Homoallylic Alcohols in
`Asymmetric Allyl- and Crotylboration of Aldehydes,” J. Org.
`Chem., vol. 57, No. 24; pp. 6608-6614, (1992).
`Cairns, et al., “Derivatives of 1,4-Xylene-2,5-diboronic acid and
`1,4-xylene-2-boronic acid”, J. Org. Chem. vol. 29; pp. 2810-2812,
`(1964).
`Chander, et al. “Prevalence of Fungal Corneal Ulcers in Northern
`India”, Infections, vol. 22, No. 3; pp. 207-209, (1994).
`Chemical Abstracts Registry No. 159752-29-1, Entered STN Dec.
`23, 1994.
`Chemical Abstracts Registry No. 71889-05-9, Entered STN Nov.
`16, 1984.
`Chemical Abstracts Registry No. 845302-09-2, Entered STN Mar.
`11, 2005.
`Chemical Abstracts Registry No. 849062-11-9, Entered STN Apr.
`22, 2005.
`Chemical Abstracts Registry No. 849062-10-8, Entered STN Apr.
`22, 2005.
`Coalition for Aflordable Drugs XLLC, v. Anacor Pharmaceuticals,
`Inc., Case No. IPR2015-01776, US. Pat. No. 7,582,621 B2, Deci-
`sion entered: Feb. 23, 2016, Paper No. 24, 16 pages.
`Coalition for Aflordable Drugs XLLC, v. Anacor Pharmaceuticals,
`Inc., Case No. IPR2015-01780, US. Pat. No. 7,767,657 B2, Deci-
`sion filed: Feb. 23, 2016, Paper No. 24, 28 pages.
`Coalition for Aflordable Drugs XLLC, v. Anacor Pharmaceuticals,
`Inc., Case No. IPR2015-01785, US. Pat. No. 7,767,657 B2, Deci-
`sion filed: Feb. 23, 2016, Paper No. 24, 26 pages.
`Cody et a1. CAS: 142: 168379, 2004.
`Cui, et al., “Organoboron Compounds with an 8-Hydroxyquinolato
`Chelate and Its Derivatives: Substituent Effects on Structures and
`Luminescence,” Inorganic Chemistry, vol. 44, No. 03; pp. 601-609,
`(Feb. 7, 2005).
`Cusack, S., et al., “The 2 A Crystal Structure of leucyl-tRNA
`Synthetase and its Complex with a Leucyl-Adenylate Analogue.”
`EMBO Journal, vol. 19; pp. 2351-2361, (2000).
`
`J. Org.
`
`Dale, et al., “Substituted Styrenes VII. Syntheses and some Reac-
`tions of the Vinylbenzeneboronic Acids” J. Org. Chem. vol. 27; pp.
`2598-2603, (Jan. 1, 1962).
`Demir et al., “Generation of Aryl Radicals from Arylboronic Acids
`by Manganese(III) Acetate:
`Synthesis
`of Biaryls
`and
`Heterobiaryls”, J. Org. Chem. 2003, 68, 578-580.
`Denis, “Pharmacology 1104 Lecture: Drug Classifications & Char-
`acteristics of Antimicrobials” (2003).
`Dian, “International Nomenclature of Organics”, China Petro-
`chemical Press, lst Edition; 50-51 (Jan. 21, 2004).
`Falck, et al., "Bromo-Boronolactonization of Olefins”,
`Chem. 2001, 66. 7148-7150.
`Farfan, et al., “Through-Bond Modulation on NiB Ring Formation
`Shown by NMR and X-Ray Diffraction Studies of Borate Deriva-
`tives of Pyridyl Alcohols,” J. Chem. Soc. Perkin Trans., vol. 2; pp.
`527-532 (1992).
`Ferrer, “Targeting Aminoacyl-tRNA Synthetases for the Treatment
`of Fungal Infections”, Drug News Perspective, vol. 19, No. 6; pp.
`347-348, (Jul/Aug. 2006).
`Fevig et a1. CAS: 137: 125150, 2002.
`Fungicide: Definition from Answercom, (1998).
`Goodman, et al., “Goodman & Gilman’s Manual of Pharmacology
`and Therapeutics” Chapter 40,681-694 (2008).
`Grassberger, et al., “Degradation of 1,2-dihydro-1-hydroxy-2-
`(organosulfonyl)2,3,1-benzodiasaborines and -thieno[3,2-d][1 ,,3]
`diazaborines in Alkaline Aqueous Solutions”, Liebigs Annalen Der
`Chemie, vol. 4; pp. 683-688, (1985).
`Guo-Zheng, et al., “Single Site Transarylation of 2,2‘-Dimetalized-
`1,1'-Binaphthyl
`to Aminocloroborates
`and
`Synthesis
`of
`2-Binaphthyl Boron Compounds,” Youji Huaxue/Organic Chemis-
`try, Science Press, vol. 16, No. 02; pp. 139-144, (1996) (English
`Abstract).
`of
`“Arylboronic Acids VIII. Reactions
`al.,
`et
`Haynes,
`boronphthalide” J. Org. Chem. vol. 29, No. 11; pp. 3229-3233,
`(1964).
`Hauck, et al., “Preparation and Anticonvulsant Activity of Some
`Aryldialkylsuccinirnides” Research Lab of Parke Davis Co. (1967).
`He, et al., “Small-Molecule Inhibition of TNF-alpha”, Science, vol.
`310, No. 5750; pp. 1022-1025, (Nov. 11, 2005).
`Hui, et al., “In Vitro Penetration of a Novel Oxaborole Antifungal
`(AN2690) into the Human Nail Plate”, Journal of Pharmaceutical
`Sciences (2007) 96(10): 2622-2631.
`Ishihara et a1. CAS: 141: 388701, 2004.
`Kamikawa, et al., “Stereoselective Synthesis of Both Enantiomers
`of Axially
`Chiral
`Biaryls
`Utilizing
`Planar
`Chiral
`Tricarbonyl(arene)chromium Complexes”, pp. 1375-1384, J. Org.
`Chem, vol. 61, 1996.
`Lampe, et al., “Synthesis and Protein Kinase Inhibitory Activity of
`Balanol Analogues with Modified Benzophenone Subunits”,
`J.
`Med. Chem., vol. 45(12); pp. 2624-2643, (2002).
`Lee, K., et al., “Molecular Study of the Editing Active Site of
`Escherichia coli Leucyl-tRNA Synthetase: Two Amino Acid Bind-
`ing Site in the Editing Domain”, vol. 54; pp. 693-704, (2004).
`of
`Lennarz,
`et
`al.,
`“Arylboronic Acids.
`IV. Reactions
`Boronophthalide” J. Am. Chem. Soc. vol. 82; pp. 2172-2175,
`(1960).
`Li, et al., “An Improved Protocol for Preparation of 3-Pyridyl- and
`Some Arylboronic Acids”, J. Org. Chem., vol. 67; pp. 5394-5397,
`(2002).
`Luan, et al., “Inhibition of Experimental Periodontitis by a topical
`boron-base antimicrobial” J Dent. Res, 87(2):148-152 (2008).
`Koster, et al., “Cyclisierugen von Bor-Stickstoff—Verbindugen in der
`Hietz” Liebigs Ann. Chem., vol. 720; pp. 23-31, (1968).
`XXXIX.
`Koster,
`et
`al.,
`“Boron
`Compounds,
`Alkenoxy(diorgany)boranes Substituted at
`the Alkeonxy Group
`from 2-methylacrolein and triorganylboranes,” Justus Liebigs
`Annalen Der Chemie, No. 06; pp. 1116-1134, (1976).
`McMillin, et al., “Systemic Aspects of Psoriasis: An Integrative
`Model Based on Intestinal Etiology”, Int. Med. vol. 2, Issue 2/3,
`(1999).
`Mikami et a1. CAS: 122: 314944, 1995.
`
`FIatWing Ex. 1001, p. 3
`
`FlatWing Ex. 1001, p. 3
`
`

`

`US 9,549,938 B2
`Page 4
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`
`
`VIoeder, et al., “Kinetic Analysis of the Asymmetric Amplification
`exhibited by B-chlorodiisopinocampheylborane,” Journal of Physi-
`cal Organic Chemistry, vol. 17, No. 4; pp. 317-324, (Apr. 2004).
`VIonovich, et al., “Total Synthesis of (——)-Steganone Utilizing a
`Samarium(II) Iodide Promoted 8-Endo Ketyl-Olefin Cyclization”,
`J. Am. Chem. Soc. 2000, 122, 52-57.
`VIorissette, et al., “High-throughput Crystallization: Polymorphs,
`Salts, Co-Crystals and Solvates of Pharmaceutical Solids”,
`Advanced Drug Delivery Reviews, vol. 56; pp. 273-300, (2004).
`VIotokazu, et al., “Stereoselective induction of an axial chirality by
`Suzuki cross coupling of tricaronyl (arene) chromium complexes
`with arylboronic acids”, J. Chem. Soc., Chem. Commun., 1994, vol.
`23, pp. 2697-2698.
`VIurdan, “Drug Delivery to the Nail Following Topical Applica-
`tion”, International Journal of Pharmaceutics, vol. 236: pp. 1-26,
`(2002).
`\I. Miyaura, “Product subclass 7: hydroxyboranes”, Science of
`Synthesis 2004, 6, 257-300.
`Oshima, et al., “Regiospecific Glycosidation of Unprotected Sugars
`via Arylboronic Activation”, J. Am. Chem. Soc. 1999, 121, 2315-
`2316.
`Patani, et al., “Bioisosterism: ARational Approach to Drug Design”,
`Chem. Rev., vol. 96; pp. 3147-3176 (1996).
`Perola, E., et al., “Successful Virtual Screening of a Chemical
`Database for Farnesltransferase Inhibitor Leads.” vol. 43; pp. 401-
`4008, (2000).
`Qin, et al., “Luminescent Organoboron Quinolate Polymers,” Jour-
`nal of the American Chemical Society, vol. 126, No. 22; pp.
`7015-7018, (Jun. 9, 2004).
`Qin, Clinical Mycology, Fudan Press, Shanghai Medical University
`Press, pp. 92, 111, 340-341, 365, 437 and 487 (2001) With English
`Translation.
`Rau, et al., “Pd-catalyzed synthesis, characterization and modifica-
`tion of poly(p-phenylene)s bearing butoxymethyl side chains”, pp.
`2225-2238, Makromol. Chem. 194, 1993.
`Resnick, et al., “Chemoenzymatic Synthesis of Chiral Boronates for
`the 1H NMR Determination of the Absolute Configuration and
`Enantiomeric Excess of Bacterial and Synthetic cis-Diols”, pp.
`3546-3549, J. Org. Chem., 1995, vol. 60.
`Robinson et al. CAS: 132: 43141, 1999.
`Rock, et al., “An Antifungal Agents Inhibits Aminoacyl-tRNA
`Synthetase by Trapping tRNA in the Editing Site”, Science, vol.
`316, No. 5832; pp. 1759-1761, (Jun. 22, 2007).
`Silverman, “The Organic Chemistry of Drug Design and Drug
`Action”, 2nd Edition, Northwestern University, Department of
`Chemistry, Evanston, Illinois, Section 2: 29-32 (2004).
`Snyder, et al. “Common Bacteria Whose Susceptibility to Antimi-
`crobials in no longer Predictable” J. Med. Liban, vol. 48 No. 4; pp.
`208-214, (2000).
`Stones et al. CAS: 141: 271084, 2004.
`Sugar, et al., “Comparison of Three Methods of Antifungal Sus-
`ceptibility Testing with the Proposed NCCLS Standard Broth
`Macrodilution Assay: Lack of Effect of Phenol Red” Diagn.
`Microbiol. Infect. Dis. vol. 21; pp. 129-133, (1995).
`Tabuchi,
`et
`al.,
`“Anticoccidial Activity of
`some Azacyclo
`Organoborinates,” Heterocycles, vol. 60, No. 01; pp. 177-182,
`(2003).
`Tan, Y—L, et al., “Dilithiation of arenetricarbonylchromium(0) com-
`plexes with enantioselective quench: application to chiral biaryl
`synthesis”, Department of Chemestry, London, pp. 3269-3280, vol.
`24, 2001.
`Tatsumi, et al., “Therapeutic Efficacy of Topically applied KP-103
`against Experimental Tinea Uguium in Guinea Pigs in Comparison
`with Amorolfine and Terbinafine”, Antimicrobial Agents and Che-
`motherapy, vol. 46, No. 12; pp. 3797-3801 (2002).
`some
`of
`Toporcer,
`et
`al.,
`“Preparation
`and
`Properties
`Tetracoordinate Boron Compounds. The Pseudo-metal Ion Con-
`cept,” Inorganic Chemistry, vol. 4, No. 11; pp. 649-1655, (Nov.
`1965).
`
`Torssell, “Zur Kenntnis der Arylborasauren III*, Bromierung der
`Tolyborsauren nach Wohl-Ziegler”, Arkiv for Kemi, Band 10 nr 36,
`Sep. 12, 1956.
`Toyota, et al., “Intramolecular C:OIIIB Interactions in o-Boron
`Substituted Benzaldehyde, Acetophenone, and Benzophenone”,
`Bull.Chem. Soc. Jpn., 75, 2667-2671 (2002).
`Trujillo, et al., “X-Ray Crystallographic Study of Boroxazolidones,
`Obtained from L-ornithine, L-methionine, Kainic acid and 2,6-
`pyridinedicarboxylic acid”, Journal of Organometallic Chemistry,
`vol. 571; pp. 21-29, (1998).
`Tschampel, et al., “Arylboronic Acids. VIi. Some Reactions to
`o-Formybenzeneboronic Acids”, J. Org. Chem. vol. 29, No. 8; pp.
`2168-2172, (1964).
`Turner, et al., Current Pharmaceutical Design, vol. 2; pp. 209-224
`(1996).
`Uemura, et al., “Stereoselective induction of an axial chirality by
`Suzuki cross coupling of tricaronyl (arene) chromium complexes
`with arylboronic acids”, J. Chem. Soc., Chem. Commun., 1994, vol.
`23, pp. 2697-2698.
`Vippagunta,
`“Crystalline Solids”, Advanced Drug Delivery
`Reviews, vol. 48; pp. 3-26, (2001).
`Wang, et al. “Synthetic Strategies Based on Aromatic Metalationi
`Cross Coupling Links. A Concise Formal Synthesis of the
`Azaphenanthrene Alkaloid Eupolauramine”, pp. 4883-4884, Tetra-
`hedron Letters, vol. 32, No. 37, 1991, Great Britain.
`Wang, et al., “Expression, Purification and Characterization of
`Human CAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B,
`C, and D”, Biochemical and Biophysical Research Communica-
`tions, vol. 234; pp. 320-324, (1997).
`Williams, et al., “Foye’s Principles of Medicinal Chemistry”, 5th
`Edition, 2002, Lippincoot Williams & Wilkins, p. 59.
`Wulff, et al., “On the chemistry of binding sites VII, Enantioselec-
`tive binding using chiral boronic acids”, pp. 216-221, Recl. Tray.
`Chim. Pays-Bas 109, 1990.
`Ye, et al., “Convenient and Versatile Syntheis of formyl-substituted
`Benzoxaboroles”, Tetrahedron, vol. 65; pp. 8738-8744, (2009).
`Zhdankin, et al., “Synthesis and Structure of Benzoboroxoles:
`Novel Organboron Heterocycles,” Tetrahedron Letters, vol. 40; pp.
`6705-6708, (1999).
`a Self-assembled Cyclodextrin-
`Zhou,
`et al., “Hemodextrin:
`Porphyrin Construct That Binds Dioxygen,” Biophysical Chemis-
`try, 105:639-648 (2003).
`Zhou, et al., “Structure-activity Studies on a Library of Potent
`Calix[4]arene-based PDGF Antagonists that Inhibit PDGF-stimu-
`lated PDGFR Tyrosine Phosphorylation,” Org. Biomol. Chem.,
`422376-2386 (2006).
`Zhou, et al., “Pattern Recognition of Proteins Based on an Array of
`Functionalized Porphyrins,” J. Am. Chem. Soc., 128:2421-2425
`(2006).
`Zixing, et al., “Synthesis of Aromatic Nitrogen-containing Hetero-
`cyclic Derivatives of Asymmetric Diarylborinic Acids,” Wuhan
`Daxue Xuebo-Wuhan University Journal, vol. 3; pp. 67-71, (1990),
`(English Abstract).
`“Structure-Activity Studies led to the Discovery of AN2898 in
`Development for Topical Treatment of Psoriasis and Atopic Der-
`matitis”, Scientific Presentation at the American Academy of Der-
`matology Annual Meeting, San Francisco, CA Mar. 6-10, 2009.
`“AN2898 Inhibits Cytokines Relevant to Topical Treatment of
`Psoriasis and Atopic Dermatitis”, Scientific Presentation at the
`American Academy of Dermatology Annual Meeting, San Fran-
`cisco, CA Mar. 6-10, 2009.
`“AN2718 has Broad Spectrum Antifungal Activity Necessary for
`the Topical Treatment of Skin and Nail Fungal Infections”, Scien-
`tific Presentation at the American Academy of Dermatology Annual
`Meeting, San Francisco, CA Mar. 6-10, 2009.
`“AN2718 Demonstrates Significant Efficacy in Three Phase Ib
`Psoriasis Microplaque Trials” Scientific Presentation at the Ameri-
`can Academy of Dermatology Annual Meeting, San Francisco, CA
`Mar. 6-10, 2009.
`“AN2728 Demonstrates Significant Safety and Efficacy in Phase IIa
`Double Blind Trial in Plaque Type Psoriasis”, Scientific Presenta-
`tion at the American Academy of Dermatology Annual Meeting,
`San Francisco, CA Mar. 6-10, 2009.
`
`FIatWing Ex. 1001, p. 4
`
`FlatWing Ex. 1001, p. 4
`
`

`

`US 9,549,938 B2
`
`Page 5
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`“AN2728 Preclinical Studies Demonstrate an Acceptable Safety
`Profile for the Topical Treatment of Psoriasis and Atopic Dermati-
`tis”, Scientific Presentation at the American Academy of Derma-
`tology Annual Meeting, San Francisco, CA May 6-10, 2009.
`“A New Class of Benzoxaborole-based Potent Antitrypanosomal
`Agents:
`Probing Effect
`of Different Linkage Groups
`in
`Trypanosoma brucei Growth Inhibition”, Scientific Presentation at
`the American Society of Tropical Medicine and Hygiene Confer-
`ence, New Orleans , LA Dec. 7-11, 2008.
`“AN2920, a Novel Oxaborole, Shows In Vitro and In Vivo Activity
`Against Trypanosomal brucei”, Scientific Presentation at the Ameri-
`can Society of Tropical Medicine and Hygiene Conference, New
`Orleans, LA Dec. 7-11, 2008.
`“A Novel Oxaborole, AN3520, Show Efficacy against Human
`African Trypanosomiasis In Vitro and In Vivo, Including Promise in
`a Murine CNS Model of T. brucei Infection”, Scientific Presentation
`at the American Society of Tropical Medicine and Hygiene Con-
`ference, New Orleans, LA Dec. 7-11, 2008.
`“Antifungal Activity and Mechanism of Action of a Benzoxaborole,
`AN27l8, which is in Development for the Treatment of Tinea
`Pedis”, Scientific Presentation at the 48th Interscience Conference
`on Antimicrobial Agents and Chemotherapy, Washington, DC. Oct.
`25-28, 2008.
`“AN2728 Ointment, a Novel Oxaborole with Anti-Inflammatory
`Activity, Demonstrates Safety and Significant Efficacy in a Phase Ib
`Psoriasis Plaque Test”, Scientific Presentation at Montagna Sym-
`posium on Biology of Skin, Gleneden Beach, OR, Oct. 2-6, 2008.
`“Preclinical Toxicology of AN2728, a Novel Oxaborole in Devel-
`opment for the Topical Treatment of Psoriasis”, Scientific Presen-
`tation at the International Investigative Dermatology Conference,
`Kyoto, Japan, May 14-18, 2008.
`“AN2898, a Novel Oxaborole Compound with Anti-Inflammatory
`Activity: Mechanism of Action and in vitro Cytokine Inhibition”,
`Scientific Presentation at the International Investigative Dermatol-
`ogy Conference, Kyoto, Japan, May 14-18, 2008.
`“Structure-Activity Studies of AN2728 and AN2898, Novel
`Oxaborole Compounds with Anti-Inflammatory Activity”, Scien-
`tific Presentation at the International Investigative Dermatology
`Conference, Kyoto, Japan, May 14-18, 2008.
`“In Vitro Activity and Mechanism of Action of AN2728, a Novel
`Oxaborole in Development for Treatment of Psoriasis”, Scientific
`Presentation at the International Investigative Dermatology Confer-
`ence, Kyoto, Japan, May 14-18, 2008.
`“AN2898, a Novel Oxaborole Compound with Anti-Inflammatory
`Activity: Results of In Vivo Eificacy and Preclinical Safety Stud-
`ies”, Scientific Presentation at the International Investigative Der-
`matology Conference, Kyoto, Japan, May 14-18, 2008.
`“AN2728, a Novel Oxaborole in Development for Treatment of
`Psoriasis, Demonstrates Significant Activity in a Micro Plaque
`Study”, Scientific Presentation at the International Investigative
`Dermatology Conference, Kyoto, Japan, May 14-18, 2008.
`“Preclinical Toxicology of AN2728, a Novel Borinic Acid Ester
`with Anti-Inflammatory Activity”, American Academy of Derma-
`tology, 65th Annual Meeting, Washington, DC, Feb. 2-6, 2007.
`“AN2728, a Novel Oxaborole with Broad-Spectrum In Vitro Anti-
`Inflammatory Activity”, American Academy of Dermatology, 65th
`Annual Meeting, Washington, DC, Feb. 2-6, 2007.
`“In Vitro Nail Penetration of AN2690, Effect of Vehicle and
`Co-Efficient of Efficacy”, American Academy of Dermatology, 65th
`Annual Meeting, Washington, DC, Feb. 2-6, 2007.
`“Interim Results of a Multi-Center Study to Evaluate the Safety and
`Eificacy of Topically Applied AN2690 5.0% and 7.5% Solutions for
`the Treatment of Onychomycosis of the Great Toenail”, American
`Academy of Dermatology, 65th Annual Meeting, Washington, DC,
`Feb. 2-6, 2007.
`“In vivo Nail Residence Time of AN2690, a Novel Broad-Spectrum
`Antifungal Agent in Development for the Topical Treatment of
`Onychomycosis”, American Academy of Dermatology, 65th Annual
`Meeting, Washington, DC, Feb. 2-6, 2007.
`
`“An Open-Label, Multi-dose Study of Absorption and Systemic
`Pharmacokinetics of AN2690 Applied as a 7.5% Solution to All
`Toenails
`of Adult
`Patients with Moderate
`to
`Severe
`Onychomycosis”, American Academy of Dermatology, 65th Annual
`Meeting, Washington, DC, Feb. 2-6, 2007.
`a Novel
`“Medicinal Chemistry Development of AN2728,
`Oxaborole in Development for the Topical Treatment of Psoriasis”,
`American Academy of Dermatology, 65th Annual Meeting, Wash-
`ington, DC, Feb. 2-6, 2007.
`“Skin Penetration and Anti-Inflammatory Activity of AN2728, a
`Novel Oxaborole”, American Academy of Dermatology, 65th
`Annual Meeting, Washington, DC, Feb. 2-6, 2007.
`“Nail Penetration and Nail Concentration of AN2690, a Novel
`Broad-Spectrum Antifungal Agent in Development for the Topical
`Treatment of Onychomycosis”, Scientific Presentation at the Ameri-
`can Associate of Pharmaceutical Scientist, Annual Meeting, San
`Antonio, TX, Oct. 29-Nov. 2, 2006.
`Aswell et al. CAS: 141: 296025, 2004.
`Naumov, et al. “Polyfunctionalized Aryllead Triacetates in a Cas-
`cade Synthesis of Tetracyclic Isochromanocoumarin-Type Com-
`pounds”, Synthesis 2005, pp. 1178-1182.
`Mikami, et al., “Synthesis of Sugar-containing Polymers by Self-
`condensation with Diboronic Acid”, J.Chem. Soc., Chem. Com-
`mun., 1995, pp. 153-154.
`Stones, et al. “Modular Solid-Phase Synthetic Approach to Opti-
`mize Structural and Electronic Properties of Oligoboronic Acid
`Receptors and Sensors for the Aqueous Recognition of Oligosac-
`charides”, Chem.Eur. J. 2004, 10, pp. 92-100.
`Linnane, et al. “The Synthesis and Properties of a Calixarene-based
`‘Sugar Bowl’”, J. chem. Soc., Chem. Commun., 1995, pp. 1997-
`1998.
`Coalition for Aflordable Drugs XLLC, v. Ahacor Pharmaceuticals,
`Inc., Case No. Unassigned, US. Pat. No. 7,582,621, Petition for
`Inter Partes Review ofU.S. Pat. No. 7,582,621, 66 pages. [IPR2015-
`01776].
`Coalition for Aflordable Drugs XLLC, v. Ahacor Pharmaceuticals,
`Inc., Case No. Unassigned, US. Pat. No. 7,582,621, Power of
`Attorney in Inter Partes Review, 3 pages. [IPR2015-01776].
`Coalition for Aflordable Drugs XLLC, v. Ahacor Pharmaceuticals,
`Inc., Case No. Unassigned, US. Pat. No. 7,582,621, Appendix of
`Exhibits, 3 pages. [IPR2015-01776].
`Declaration of Stephen Kahl, Ph.D. [Exhibit 1006].
`Curriculum Vitae of Stephen B. Kahl, Ph.D. [Exhibit 1007].
`Declaration of S. Narasimha Murthy, Ph.D. [Exhibit 1008].
`Curriculum Vitae of S. Narasimha Murthy, Ph.D. [Exhibit 1009].
`BioborJF® Specification Sheet (2015) [Exhibit 1024].
`BioborJF® Material Safety Data Sheet (2004) [Exhibit 1025].
`Michael P. Groziak, Boron Therapeutics on the Horizon, 8 Am. J. of
`Therapeutics 321-28 (2001) [Exhibit 1027].
`Declaration of Ryan J. Fletcher [Exhibit 1030].
`Kerydin® Prices, available at http://www.goodrx.com/kerydin (last
`visited Aug. 6, 2015). [Exhibit 1031].
`Q1Group LLC, 2015 Medicare Part D Plan’s Negotiated Retail
`Drug Price, Kerydin 5% Topical Solution (Jul. 2015), available at
`http://www.q1medicare.com/PartD-2015MedicarePlan
`RetailDrugPriceprintphp?stateReg-13MI&ndc-5 572401 1121&for-
`mulary-00015191&contractId-H2322&planId-008&segmentId:0
`&zipCountyCode:26115&cplanType-M&cletter-K&cmode-state
`[Exhibit 1032].
`Declaration of Stephen Kahl, Ph.D. [Exhibit 1009].
`Curriculum Vitae of Stephen Kahl, Ph.D. [Exhibit 1010].
`Declaration of S. Narasimha Murthy, Ph.D. [Exhibit 1011].
`Curriculum Vitae of S. Narasimha Murthy, Ph.D. [Exhibit 1012].
`Dirk Mertin & Bernhard C. Lippold, In-vitro Permeability of the
`Human Nail and of a Keratin Membrane from Bovine Hooves:
`Penetration of Chloramphenicol from Lipophilic Vehicles and a
`Nail Lacquer, 49 J. Pharmacy & Pharmacology 241 (1997) [Exhibit
`1030].
`National Center for Biotechnology Information (NCBI), PubChem
`Compound Database, CID:6440876, available at https://pubchem.
`ncbi.nlm.nih.gov/compound/6440876 (last visited Jul. 31, 2015)
`[Exhibit 1035].
`
`FIatWing Ex. 1001, p. 5
`
`FlatWing Ex. 1001, p. 5
`
`

`

`US 9,549,938 B2
`
`Page 6
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`
`
`
`
`National Center for Biotechnology Information (NCBI), PubChem
`Compound Database, SID:24898472, available at https://pubchem.
`ncbi.nlm.nih.gov/substance/24898472 (last visited Jul. 31, 2015)
`[Exhibit 1036].
`Remington: The Science and Practice of Pharmacy (Lippincott
`Williams & Wilkins, 2lst ed. 2005) [Exhibit 1037].
`Hawley’s Condensed Chemical Dictionary (John Wiley & Sons,
`Inc., 13th ed. 1997) [Exhibit 1038].
`Aldrich Handbook of Fine Chemicals and Laboratory Equipment
`(2003-2004) [Exhibit 1039].
`\Iational Center for Biotechnology Information (\ICBI), PubChem
`Compound Database, CID-2484, available at https://ubchem.ncbi.
`nlm.nih..ov/compound/2484 (last visited Aug. 11, 2015) [Exhibit
`1040].
`\Iational Center for Biotechnology Information (\ICBI), PubChem
`Compound Database, CID:3198, available at htlps://pubchem.ncbi.
`nlm.nih.gov/compound/3198 (last visited Aug. 2, 2015) [Exhibit
`1041].
`\Iational Center for Biotechnology Information (\ICBI), PubChem
`Co