I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US009566290B2
`
`c12) United States Patent
`Baker et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,566,290 B2
`*Feb.14,2017
`
`(54) BORON-CONTAINING SMALL MOLECULES
`
`(71) Applicant: Anacor Pharmaceuticals, Inc., Palo
`Alto, CA (US)
`
`(72)
`
`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 ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 15/134,286
`
`(22) Filed:
`
`Apr. 20, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2016/0228463 Al
`
`Aug. 11, 2016
`
`Related U.S. Application Data
`
`(60) Continuation of application No. 15/091,394, filed on
`Apr. 5, 2016, which is a continuation of application
`No. 15/068,352, filed on Mar. 11, 2016, which is a
`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, now
`abandoned, 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, and a continuation-in-part of application
`No. 11/357,687, filed on Feb. 16, 2006, now Pat. No.
`7,582,621, said application No. 14/537,771 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
`
`(60) Provisional application No. 60/755,227, filed on Dec.
`30, 2005, provisional application No. 60/746,361,
`filed on May 3, 2006, provisional application No.
`(Continued)
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 31169
`C07F 5102
`C07F 5104
`C07H 19106
`C07H 19116
`C07H 21100
`C07H 23100
`A61K 31170
`A61K 3117076
`A61K 9100
`A61K 47110
`A61K 9108
`(52) U.S. Cl.
`CPC ............. A61K 31169 (2013.01); A61K 910012
`(2013.01); A61K 9108 (2013.01); A61K 31170
`(2013.01); A61K 3117076 (2013.01); A61K
`47110 (2013.01); C07F 51025 (2013.01); C07F
`5104 (2013.01); C07H 19106 (2013.01); C07H
`19116 (2013.01); C07H 21100 (2013.01);
`C07H 23100 (2013.01)
`(58) Field of Classification Search
`USPC ............................................................ 514/64
`See application file for complete search history.
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`2,260,336 A
`2,741,548 A
`
`10/1941 Prescott et al.
`4/1956 Darling et al.
`(Continued)
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`
`1/2000
`0969531
`8/2000
`0765331 Bl
`(Continued)
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 13/861,846, filed Apr. 12, 2013, now abandoned.
`U.S. Appl. No. 13/673,860, filed Nov. 9, 2012, now abandoned.
`U.S. Appl. No. 13/607,321, filed Sep. 7, 2012, now abandoned.
`U.S. Appl. No. 13/607,405, filed Sep. 7, 2012, now abandoned.
`U.S. Appl. No. 13/607,250, filed Sep. 7,2012, now abandoned.
`U.S. Appl. No. 15/091,394, filed Apr. 5, 2016.
`U.S. Appl. No. 15/068,352, filed Mar. 11, 2016.
`U.S. Appl. No. 15/046,322, filed Feb. 17, 2016.
`U.S. Appl. No. 14/977,052, filed Dec. 21, 2015.
`U.S. Appl. No. 14/537,771, filed Nov. 10, 2014.
`U.S. Appl. No. 14/537,694, filed Nov. 10, 2014, now abandoned.
`U.S. Appl. No. 14/165,428, filed Mar. 7, 2014, now abandoned.
`U.S. Appl. No. 14/688,581, filed Apr. 16, 2015.
`(Continued)
`Primary Examiner - Rei-Tsang Shiao
`(74) Attorney, Agent, or Firm - Morgan, Lewis &
`Bockius LLP
`ABSTRACT
`(57)
`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.
`12 Claims, 63 Drawing Sheets
`
`FlatWing Ex. 1001, p. 1
`
`

`

`US 9,566,290 B2
`Page 2
`
`Related U.S. Application Data
`
`continuation of application No. 11/357,687, filed on
`Feb. 16, 2006, now Pat. No. 7,582,621.60/654,060,
`filed on Feb. 16, 2005, provisional application No.
`60/654,060, filed on Feb. 16, 2005.
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`2,831,866 A
`3,093,659 A
`3,104,255 A
`3,297,525 A
`3,370,957 A
`3,686,398 A
`3,816,472 A
`3,873,279 A
`4,202,894 A
`4,602,011 A
`4,716,035 A
`4,766,113 A
`4,822,822 A
`4,894,220 A
`4,919,934 A
`4,977,268 A
`5,264,206 A
`5,348,947 A
`5,348,948 A
`5,498,407 A
`5,591,731 A
`5,668,258 A
`5,688,928 A
`5,831,045 A
`5,880,188 A
`5,962,498 A
`6,042,845 A
`6,080,774 A
`6,083,903 A
`6,143,794 A
`6,221,640 Bl
`6,224,887 Bl
`6,306,628 Bl
`6,369,098 Bl
`6,521,619 B2
`6,699,994 Bl
`6,800,645 Bl
`6,855,848 B2
`7,074,392 Bl
`7,169,603 B2
`7,205,425 B2
`7,217,701 B2
`7,390,806 B2
`7,446,236 B2
`7,465,836 B2
`7,582,621 B2 *
`
`4/1958 Freeman et al.
`6/1963 Bell et al.
`9/1963 Emrick et al.
`111967 Grier
`2/1968 Wagner et al.
`8/1972 Kohn et al.
`6/1974 Shapiro et al.
`3/1975 Singer
`5/1980 Pfiffner
`7/1986 West et al.
`12/1987 Sampathkamar
`8/1988 West et al.
`4/1989 Arita et al.
`111990 Nabi et al.
`4/1990 Deckner et al.
`12/1990 McPhail et al.
`11/1993 Bohn et al.
`9/1994 Patel et al.
`9/1994 Patel et al.
`3/1996 Atlas
`111997 Kennedy et al.
`9/1997 Stolowitz
`11/1997 Stolowitz
`11/1998 Stolowitz et al.
`3/1999 Austin et al.
`10/1999 Driedger et al.
`3/2000 Sun et al.
`612000 Murugesan et al.
`712000 Adams et al.
`11/2000 Chaudhuri et al.
`4/2001 Tao et al.
`5/2001 Sam our et al.
`10/2001 Rothschild et al.
`412002 Pershadsingh et al.
`212003 Link et al.
`3/2004 Babu et al.
`10/2004 Cox et al.
`212005 Scherer et al.
`712006 Friedman et al.
`112007 Hedley et al.
`4/2007 Shibasaki et al.
`5/2007 Mikoshiba et al.
`6/2008 Lee et al.
`1112008 Naud et al.
`12/2008 Lee et al.
`912009 Baker ....................... C07F 5102
`514/64
`
`8/2010 Baker et al.
`7,767,657 B2
`10/2010 Baker et al.
`7,816,344 B2
`10/2011 Akama et al.
`8,039,450 B2
`10/2011 Baker et al.
`8,039,451 B2
`212012 Baker et al.
`8,115,026 B2
`512012 Baker et al.
`8,168,614 B2
`112013 Xia et al.
`8,343,944 B2
`512013 Baker et al.
`8,440,642 B2
`612013 Hernandez et al.
`8,461,134 B2
`612013 Akama et al.
`8,461,135 B2
`612013 Zhou et al.
`8,461,336 B2
`612013 Wheeler et al.
`8,461,364 B2
`612013 Akama et al.
`8,470,803 B2
`8/2013 Baker et al.
`8,501,712 B2
`10/2013 Akama et al.
`8,546,357 B2
`4/2014 Hernandez et al.
`8,703,742 B2
`5/2014 Jarnagin et al.
`8,716,478 B2
`5/2014 Baker et al.
`8,722,917 B2
`10/2014 Akama et al.
`8,853,186 B2
`8,889,656 B2 * 11/2014 Baker ....................... C07F 5102
`514/64
`
`8,895,534 B2
`9,012,431 B2
`9,029,353 B2
`9,145,429 B2
`9,156,860 B2
`9,243,003 B2
`9,353,133 B2
`200210010332 Al
`2002/0028831 Al
`2002/0161230 Al
`2002/0165121 Al
`2002/0193672 Al
`2003/0032673 Al
`2003/0181766 Al
`2004/0077601 Al
`2004/0224923 Al
`2004/0259833 Al
`2004/0259842 Al
`2005/0054644 Al
`2005/0125852 Al
`2006/0009386 Al
`2006/0222671 Al
`2006/0234981 Al
`200710155699 Al
`2007 /0286822 Al
`2007/0293457 Al
`200910227 541 Al
`2010/0048570 Al
`2010/0256092 Al
`2013/0059802 Al
`2013/0059803 Al
`2013/0064783 Al
`2013/0210770 Al
`2014/0142064 Al
`2014/0221631 Al
`2015/0065459 Al
`2015/0119364 Al
`
`11/2014 Baker et al.
`412015 Akama
`512015 Baker et al.
`912015 Jarnagin et al.
`10/2015 Akama et al.
`112016 Conde et al.
`512016 Baker et al.
`112002 Vollmuller et al.
`3/2002 Manley
`10/2002 Meudt et al.
`11/2002 Brehove
`12/2002 Walsh et al.
`212003 Nagy
`9/2003 Satoh et al.
`412004 Adams et al.
`11/2004 Lee et al.
`12/2004 Benkovic et al.
`12/2004 Mikoshiba et al.
`3/2005 Lee et al.
`6/2005 Caenepeel et al.
`112006 Stossel et al.
`10/2006 Weidner
`10/2006 Baker et al.
`7/2007 Baker et al.
`12/2007 Sanders et al.
`12/2007 Baker et al.
`912009 Baker et al.
`2/2010 Kim et al.
`10/2010 Xia et al.
`3/2013 Baker et al.
`3/2013 Baker et al.
`3/2013 Baker et al.
`8/2013 Baker et al.
`512014 Baker et al.
`8/2014 Baker et al.
`3/2015 Baker et al.
`412015 Baker et al.
`
`FOREIGN PATENT DOCUMENTS
`
`1155698 Al
`EP
`1 444 981 Al
`EP
`2002-53583 A
`JP
`2002-508359 A
`JP
`2003-212837 A
`JP
`2004-514669 A
`JP
`2005-022986 A
`JP
`WO 9533754
`WO
`WO 9622023 Al
`WO
`WO 9812206 Al
`WO
`WO 0027822
`WO
`WO 0044387 Al
`WO
`WO 0075142 A2
`WO
`WO 0114578 Al
`WO
`WO 0149303 Al
`WO
`WO 0187846 A2
`WO
`WO 0244184
`WO
`WO 03/009689 Al
`WO
`WO 03033002 Al
`WO
`WO 03059916 A2
`WO
`WO WO 2004/043925 A2
`WO
`WO 2004056322 A2
`WO
`WO 2004081008 Al
`WO
`WO 2005002577 Al
`WO
`WO 2005013892 A3
`WO WO 2005/066172
`WO WO 2005/110410 A2
`WO WO 2005/123054
`WO
`WO 2005123094 A2
`WO
`WO 2006007384
`WO
`WO 2006062731 Al
`WO
`WO 2006079843 Al
`WO
`WO 2006089067 A2
`WO
`WO 2006096131 Al
`WO
`WO 2007022437 A2
`WO
`WO 2007078340 A2
`WO
`WO 2007095638 A2
`WO
`WO 2007146965 A2
`WO
`WO 2008157726 Al
`
`1112001
`8/2004
`212002
`3/2002
`7/2003
`512004
`1/2005
`5/1995
`7 /1996
`3/1998
`512000
`8/2000
`12/2000
`3/2001
`712001
`1112001
`612002
`212003
`4/2003
`7/2003
`512004
`7/2004
`912004
`1/2005
`212005
`7 /2005
`1112005
`12/2005
`12/2005
`112006
`612006
`8/2006
`8/2006
`912006
`212007
`7/2007
`8/2007
`12/2007
`12/2008
`
`FlatWing Ex. 1001, p. 2
`
`

`

`US 9,566,290 B2
`Page 3
`
`(56)
`
`WO
`WO
`WO
`WO
`WO
`WO
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`WO 2009111676 A2
`WO 2009140309 A2
`WO 2010028005 Al
`WO 2010045503 A
`WO 2010045505 Al
`WO 2015/171186
`
`912009
`1112009
`3/2010
`4/2010
`4/2010
`1112015
`
`OTHER PUBLICATIONS
`U.S. Appl. No. 111762,038, filed Jun. 12, 2007, now abandoned.
`U.S. Appl. No. 11/865,725, filed Oct. 1, 2007, now abandoned.
`U.S. Appl. No. 12/752,789, filed Apr. 1, 2010, now abandoned.
`U.S. Appl. No. 14/536,483, filed Nov. 7, 2014.
`U.S. Appl. No. 14/666,075, filed Mar. 23, 2015.
`U.S. Appl. No. 13/062,450, filed Mar. 4, 2011.
`U.S. Appl. No. 12/464,829, filed May 12, 2009, now abandoned.
`U.S. Appl. No. 12/873,036, filed Aug. 31, 2010, now abandoned.
`U.S. Appl. No. 13/503,016, filed Jun. 25, 2012, now allowed.
`U.S. Appl. No. 12/857,305, filed Aug. 16, 2010, now abandoned.
`U.S. Appl. No. 12/852,351, filed Aug. 6, 2010.
`U.S. Appl. No. 14/852,122, filed Sep. 11, 2015.
`U.S. Appl. No. 12/944,699, filed Nov. 11, 2010, now abandoned.
`U.S. Appl. No. 14/969,467, filed Dec. 15, 2015.
`U.S. Appl. No. 14/221,637, filed Mar. 21, 2014.
`U.S. Appl. No. 14/852,220, filed Sep. 11, 2015.
`U.S. Appl. No. 14/760,208, filed Jul. 10, 2015.
`U.S. Appl. No. 14/394,427, filed Oct. 14, 2014.
`U.S. Appl. No. 14/765,152, filed Jul. 31, 2015.
`U.S. Appl. No. 14/906,849, filed Jan. 21, 2016.
`U.S. Appl. No. 14/910,996, filed Feb. 8, 2016.
`Patent Owner's Response Pursuant to 37 C.F.R. § 42.120, 74 pages,
`IPR2015-01776, Jun. 6, 2016.
`Patent Owner's Exhibit List, 22 pages, IPR2015-01776, Jun. 6,
`2016.
`Curriculum Vitae of Mahmoud A. Ghannoum, IPR2015-01776, Jun.
`6, 2016 [Exhibit 2029].
`Curriculum Vitae of Paul J. Reider, Ph.D., IPR2015-01776, Jun. 6,
`2016 [Exhibit 2030].
`Curriculum Vitae of Howard Ira Maibach, M.D., (Honorary) Ph.D.,
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2031].
`Deposition of Narasirnha Murthy, Ph.D., vol. 1 of 3, Case No.
`IPR2015-0l 776 U.S. Pat. No. 7,582,621, Case No. IPR2015-01780
`U.S. Pat. No. 7,767,657, Case No. IPR2015-0l 785 U.S. Pat. No.
`7,767,567, May 4, 5, 6, and 12, 2016, 638 pages, Jun. 6, 2016
`[Exhibit 2032].
`Deposition of Stephen B. Kahl, Ph.D., vol. 1, Case No. IPR2015-
`01776 U.S. Pat. No. 7,582,621, Case No. IPR2015-01780 U.S. Pat.
`No. 7,767,657, Case No. IPR2015-01785 U.S. Pat. No. 7,767,567,
`Apr. 7 and 8, 2016, 583 pages, Jun. 6, 2016 [Exhibit 2033].
`Declaration of Paul J. Reider, Ph.D. in Support of Patent Owner
`Response, 96 pages, IPR2015-0l 776, Jun. 6, 2016 [Exhibit 2034].
`Declaration of Mahmoud A. Ghannoum, Ph.D. E.M.B.A., in Sup(cid:173)
`port of Patent Owner Response, Pursuant to 37 C.F.R. § 42.120, 85
`pages, IPR2015-01776, Jun. 6,2016 [Exhibit 2035].
`Declaration of Majella Lane, Ph.D., in Support of Patent Owner
`Response, Pursuant to 37 C.F.R. § 42.120, 28 pages, IPR2015-
`01776, Jun. 6, 2016 [Exhibit 2036].
`Declaration of Howard I. Maibach, Ph.D., in Support of Patent
`Owner Response, Pursuant to 37 C.F.R. § 42.120, 33 pages,
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2037].
`Fletcher et al., Onychomycosis: The Development of a Clinical
`Diagnostic Aid for Toenail Disease, Part I. Establishing Discrimi(cid:173)
`nating Historical and Clinical Features, Brit. J. Dermatol., vol. 150,
`No. 4, pp. 701-705 (2004), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2038].
`
`Kemna & Elewski, A U.S. Epidemiologic Survey of Superficial
`Fungal Diseases, J. Am. Acad. of Dermatol., vol. 35, No. 4, pp.
`539-542, (1996), IPR2015-01776, Jun. 6, 2016 [Exhibit 2039].
`Shivakumar, Repka, & Murthy, Transungual Drug Delivery: an
`Update, J. Drug Del. Sci. Tech., vol. 24, No. 3, pp. 301-310 (2014)
`(Ex. 3 from Murthy Deposition), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2040].
`Topical Nail Products and Ungual Drug Delivery (S. Narasirnha
`Murthy & Howard I. Maibach eds., 2013) (Ex. 4 from Murthy
`Deposition), 300 pages, IPR2015-01776, Jun. 6, 2016 [Exhibit
`2041].
`Koo et al., Synthesis and Comparative Toxicology of a Series of
`Polyhedral Borane Anion-Substituted Tetraphenyl Porphyrins,
`J.Med. Chem., vol. 50, pp. 820-827 (2007), IPR2015-0l 776, Jun. 6,
`2016 [Exhibit 2042].
`Office of Toxic Substances, Envirornnental Protection Agency,
`"Preliminary Investigation of Effects on the Environment of Boron,
`Indium, Nickel, Selenium, Vanadium and Their Compounds," EPA-
`56/2-75-005A (Aug. 1975) available at http://nepis.epa.gov/Exe/
`ZyPDF.cgi/9101277V.PDF?Docker9l01277V.PDF, 118 pages,
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2043].
`Van Proosdij-Hartzerna, Boriumverbindingen: Verleden, Heden en
`Toekomst, Ned. T. Geneesk., vol. 110, No. 51, pp. 2260-2269
`(1966) with certified English translation, IPR2015-01776, Jun. 6,
`2016 [Exhibit 2044].
`Elewski et al., Efficacy, Safety and Tolerability of Topical
`Terbinafine Nail Solution in Patients with Mild-to-Moderate Toenail
`Onychomycosis: Results from Three Randomized Studies using
`Double-Blind Vehicle-Controlled and Open-Label Active-Con(cid:173)
`trolled Designs, J. Eur. Acad. Derm. & Vener., vol. 27, No. 3, pp.
`287-294 (2013), IPR2015-01776, Jun. 6, 2016 [Exhibit 2045].
`Cecil Textbook of Medicine, (J. Claude Bennett & Fred Plum ed.,
`1996), 6 pages, IPR2015-01776, Jun. 6, 2016 [Exhibit 2046].
`Hay et al., Fungal ( onychomycosis) and other Infections Involving
`the Nail Apparatus in Baran and Dawber's Diseases of the Nails and
`their Management, (R. Baran et al., eds., 2001), 51 pages, IPR2015-
`01776, Jun. 6, 2016 [Exhibit 2047].
`EPA Correspondence, 1992 Labeling Rev., Amended Biobor Label
`available at https://www3 .epa. gov /pesticides/chem_search/ppls/
`065217-00001-19920403.pdf, 5 pages, IPR2015-01776, Jun. 6,
`2016 [Exhibit 2048].
`Ghannoum et al., A Large-Scale North American Study of Fungal
`Isolates From Nails: The Frequency of Onychomycosis, Fungal
`Distribution, and Antifungal Susceptibility Patterns, J. Am. Acad.
`Dermatol., vol. 43, No. 4, pp. 641-648 (2000), IPR2015-0l 776, Jun.
`6, 2016 [Exhibit 2049].
`Segal et al., Treatment of Candida Nail Infection with Terbinafine,
`J. Am. Acad. Dermatol., vol. 35, No. 6, pp. 958-961 (1996),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2050].
`Rock et al., Antifungal Agent Inhibits an Aminoacyl-tRNA
`Synthetase by Trapping tRNA in the Editing Site, Science, vol. 316,
`pp.1759-1761 (2007), IPR2015-01776, Jun. 6, 2016 [Exhibit2051].
`Soloway et al., Penetration of Brain and Brain Tumor by Aromatic
`J.
`Compounds as a Function of Molecular Substituents,
`Pharmacol. & Exp. Therapeutics, vol. 129, pp. 310-314 (1960),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2052].
`Baran et al., Onychomycosis: The Current Approach to Diagnosis
`and Therapy, Martin Dunitz Publishers, London, U.K. (1999),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2053].
`Gupchup & Zatz, Structural Characteristics and Permeability Prop(cid:173)
`erties of the Human Nail: A Review, 50 J. Cosmet. Sci. 363, 363-85
`(Nov./Dec. 1999), IPR2015-01776, Jun. 6, 2016 [Exhibit 2054].
`Elkeeb et al., Tranungual Drug Delivery: Current Status, 384
`Internat. J. Pharm. 1-8 (2010), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2055].
`
`FlatWing Ex. 1001, p. 3
`
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`US 9,566,290 B2
`Page 4
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Scher, Onychomycosis: Therapeutic Update, J. Am. Acad. Derm.,
`vol. 40, No. 6 (part 2), pp. S21-S26 (1999), IPR2015-01776, Jun. 6,
`2016 [Exhibit 2056].
`Baeza et al., cDNA Representational Difference Analysis Used in
`the Identification of Genes Expressed by Trichophyton rubrum
`During Contact with Keratin, Microbes & Infection, vol. 9, pp.
`1415-1421 (2007), IPR2015-01776, Jun. 6, 2016 [Exhibit 2057].
`Hamaguchi et al., Characterization of an Extracellular Keratinase
`from Microsporum canis, Jpn. J. Med. Mycol., vol. 41, No. 4, pp.
`257-262, (2000), IPR2015-01776, Jun. 6, 2016 [Exhibit 2058].
`Foster et al., Epidemiologic Surveillance of Cutaneous Fungal
`Infection in the United States from 1999 to 2002, Am. Acad.
`Dermatol., vol. 50, No. 5, pp. 748-752 (2004), IPR2015-01776, Jun.
`6, 2016 [Exhibit 2059].
`Jinna & Finch, Spotlight on Tavaborole for the Treatment of
`Onychomycosis, Drug Des. Devel. Ther., vol. 5, No. 9, pp. 6185-
`6190, (Nov. 20, 2015), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2060].
`Childs-Kean & Jourjy, Antifungal Penetration into the Nail and New
`Topicals for Onychomycosis, Curr. Fungal Infect. Rep., vol. 10, pp.
`24-29 (2016), IPR2015-01776, Jun. 6, 2016 [Exhibit 2061].
`Rosen & Stein Gold, Antifungal Drugs for Onychomycosis: Effi(cid:173)
`cacy, Safety, and Mechanisms of Action, Semin. Cutan. Med. Surg.,
`vol. 35, No. 3S, pp. S51-S55 (Mar. 2016), IPR2015-01776, Jun. 6,
`2016 [Exhibit 2062].
`Poulakos et al., Efinaconazole and Tavaborole: Emerging
`the Topical Treatment of
`Antifungal Alternatives
`for
`Onychomycosis, J. Pharm. Pract., advance online publication, doi:
`10.1177 /0897190016630904, pp. 1-11(2016), IPR2015-01776, Jun.
`6, 2016 [Exhibit 2063].
`Drake et al., Effect of Onychomycosis on Quality of Life, J. Am.
`Acad. Dermatol., vol. 38, No. 5, Part 1, pp. 702-704 (1998),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2064].
`Scher et al., Onychomycosis: Diagnosis and Definition of Cure, J.
`Am. Acad. Dermatol., vol. 56, No. 6, pp. 939-944 (2007), IPR2015-
`01776, Jun. 6, 2016 [Exhibit 2065].
`Sununerbell et al., Onychomycosis, Tinea Pedis and Tinea Manuum
`Caused by Non-Dermatophytic Filamentous Fungi, Mycoses, vol.
`32, No. 12, pp. 609-619 (1989), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2066].
`Ellis et al., Non-Dermatophytes in Onychomycosis of the Toenails,
`Brit. J. Dermatol., vol. 136, pp. 490-493 (1997), IPR2015-0l 776,
`Jun. 6,2016 [Exhibit 2067].
`McGinley et al., Composition and Density of Microflora in the
`Subungual Space of the Hand, J. Clin. Microbiol., vol. 26, No. 5, pp.
`950-953 (1988), IPR2015-01776, Jun. 6, 2016 [Exhibit 2068].
`Strausbaugh et al., High Frequency of Yeast Carriage on Hands of
`Hospital Personnel, J. Clin. Microbiol., vol. 32, No. 9, pp. 2299-
`2300 (1994), IPR2015-01776, Jun. 6, 2016 [Exhibit 2069].
`Elewski, Onychomycosis: Pathogenesis, Diagnosis, and Manage(cid:173)
`ment, Clin. Microbiol. Rev., vol. 11, No. 3, pp. 415-429(1998),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2070].
`Sununerbell, Nondermatophytic Molds Causing Dermatophytosis(cid:173)
`in Laboratory Handbook of
`Like Nail and Skin Infection,
`Dermatophytes, Chap. 8, pp. 213-256 (Kane et at. eds. 1997),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2071].
`Weitzman & Sununerbell, the Derrnatophytes, Clin. Microbio. Rev.,
`vol. 8, No. 2, pp. 240-259 (1995), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2072].
`Gupta et al., Pulse ltraconazole vs. Continuous Terbinafine for the
`Treatment of Dermatophyte Toenail Onychomycosis in Patients
`with Diabetes Mellitus, J. Euro. Acad. Dermatol. & Venerol., vol.
`20, pp. 1188-1193 (2006), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2073].
`FD A Approved Label for Sporanox® (Supplement 034, Action Date
`14, 2004) available at http://www.accessdata.fda.gov/
`Jul.
`drugsatfda_docs/appletter/2004/200 83s034,035ltr.pdf (letter) and
`
`http:/ /www. accessdata.f da. gov I drugsatf da_ docs/label/ 2004/2 0083 s
`034,035lbl.pdf (label), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2074].
`FDA Approved Label for Lamisil® (Supplement 012, Action Date
`Jan. 21, 2004) available at http://www.accessdata.fda.gov/
`drugsatfda_docs/appletter/2004/205 39slr012ltr.pdf (letter) and
`http:/ /www. accessdata.f da. gov I drugsatf da_ docs/label/ 2004/
`20539sl rO 12_lamisil_lbl.pdf (label), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2075].
`FDA Approved Label for Gris-PEG® (Supplement 046, Action
`Date Mar. 26, 2003) available at http://www.accessdata.fda.gov/
`drugsatfda_docs/appletter/2003/504 75slr046ltr.pdf (letter) and
`http:/ /www. accessdata.f da. gov I drugsatf da_ docs/label/ 2003/
`50475sl r046_gris-peg_lbl.pdf (label), IPR2015-01776, Jun. 6,
`2016 [Exhibit 2076].
`FDA Approved Label for Penlac®, (Supplement 004, Action Date
`Dec. 3, 2004) available at http://www.accessdata.fda.gov/
`drugsatfda_docs/appletter/2004/210 22s004ltr.pdf (letter) and
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21022s
`004lbl.pdf(label), IPR2015-01776, Jun. 6, 2016 [Exhibit 2077].
`Naglik et al., Candida albicans Secreted Aspartyl Proteinases in
`Virulence and Pathogenesis, Microbio. & Molecular Bio. Revs., vol.
`67, No. 3, pp. 400-428 (2003), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2078].
`Hattori et al., Keratinolytic Proteinase Produced by Candida
`albicans, Sabouraudia: J. Med. Vet. Mycology, vol. 22, No. 3, pp.
`175-183 (1984), IPR2015-01776, Jun. 6, 2016 [Exhibit 2079].
`Weary & Canby, Absence of Keratinolytic Activity in Three Strains
`of Candida albicans, J. Invest. Derm., vol. 46, No. 5, pp. 464-734
`(1966), IPR2015-01776, Jun. 6, 2016 [Exhibit 2080].
`Nenoff et al., Mycology-An Update. Part 1: Dermatomycoses:
`Causative Agents, Epidemiology and Pathogenesis, J. Dtsch. Derm.
`Ges., vol. 12, No. 3, pp. 188-210 (2014) (including English online
`version on Wiley Online Library), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2081].
`Balkis et al., Mechanisms of Fungal Resistance, Drugs, vol. 62(7),
`pp. 1025-1040 (2002), IPR2015-01776, Jun. 6, 2016 [Exhibit 2082].
`CLSI, Reference Method for Broth Dilution Antifungal Suscepti(cid:173)
`bility Testing of Filamentous Fungi; Approved Standard-Second
`Edition, CLSI document M38-A2 (2008), IPR2015-01776, Jun. 6,
`2016 [Exhibit 2083].
`Ghannoum et al., Intra- and Interlaboratory Study for Testing the
`Antifungal Susceptibilities of Dermatophytes, J. Clin. Microbiol.,
`vol. 42, No. 7, pp. 2977-2979 (2004), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2084].
`Norris et al., Optimal Growth Conditions for the Determination of
`the Antifungal Susceptibility of Three Species of Dermatophytes
`with the Use of a Microdilution Method, J. Am. Acad. Dermatol.,
`vol. 40, No. 6, pp. S9-Sl3, (1999), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2085].
`Jessup et al., Antifungal Susceptibility Testing of Dermatophytes:
`Establishing a Medium for Inducing Conidial Growth and Evalua(cid:173)
`tion of Susceptibility of Clinical Isolates, J. Clin. Microbiol., vol.
`38, No. 1, pp. 341-344 (2000), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2086].
`Kokjohn et al., Evaluation of in vitro Activity of Ciclopirox
`Olamine, Butenafine HCI and Econazole Nitrate Against
`Dermatophytes, Yeasts and Bacteria, Int'! J. Dermatol., vol. 42,
`suppl. 1, pp. 11-17 (2003), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2087].
`NCCLS (now CLSI), Reference Method for Broth Dilution
`Antifungal Susceptibility Testing of Yeasts; Approved Standard(cid:173)
`Second Edition, NCCLS document M27-A2 (2002), IPR2015-
`01776, Jun. 6, 2016 [Exhibit 2088].
`Mukherjee et al., Combination Treatment oflnvasive Fungal Infec(cid:173)
`tions, Clin. Microbiol. Rev., vol. 18, No. 1, pp. 163-194 (2005),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2089].
`Ghannoum & Rice, Antifungal Agents: Mode of Action, Mecha(cid:173)
`nisms of Resistance, and Correlation of These Mechanisms with
`Bacterial Resistance, Clin. Microbiol. Rev., vol. 12, No. 4, pp.
`501-517 (1999), IPR2015-01776, Jun. 6, 2016 [Exhibit 2090].
`
`FlatWing Ex. 1001, p. 4
`
`

`

`US 9,566,290 B2
`Page 5
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Gupta et al., Drug Interactions with Itraconazole, Fluconazole, and
`Terbinafine and their Management, J. Am. Acad. Dermatol., vol. 41,
`No. 2, pp. 237-249 (1999), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2091].
`Gupta & Lyons, The Rise and Fall of Oral Ketoconazole, J.
`Cutaneous Med. & Surgery, vol. 19, No. 4, pp. 352-357 (2015),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2092].
`Gull & Trinci, Griseofulvin Inhibits Fungal Mitosis, Nature, vol.
`244, pp. 292-294 (1973), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2093].
`Ku et al., Mutation of a Major Keratin Phosphorylation Site
`Predisposes to Hepatotoxic Injury in Transgenic Mice, J. Cell Biol.,
`vol. 143, No. 7, pp. 2023-2032 (1998), IPR2015-01776, Jun. 6,2016
`[Exhibit 2094].
`in Oral Treatment of
`Interactions
`Katz, Possible Drug
`Onychomycosis, J. Am. Podiatr. Med. Ass'n, vol. 87, No. 12, pp.
`571-574 (1997), IPR2015-01776, Jun. 6, 2016 [Exhibit 2095].
`Nguyen & Yu, Voriconazole Against Fluconazole-Susceptible and
`Resistant Candida Isolates: in-vitro Efficacy Compared with that of
`Itraconazole and Ketoconazole, J. Antimicrobial Chemotherapy,
`vol. 42, pp. 253-256 (1998), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2096].
`Johnson & Kauffman, Voriconazole: A New Triazole Antifungal
`Agent, Clin. Infect. Dis., vol. 36, No. 5, pp. 630-637 (2003),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2097].
`Elewski & Tavakkol, Safety and Tolerability of Oral Antifungal
`Agents in the Treatment of Fungal Nail Disease: a Proven Reality,
`Ther. Clin. Risk Manag., vol. 1, No. 4, pp. 299-306 (2005),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2098].
`Center for Drug Evaluation and Research, Guidance for Industry:
`Clinical Development and Labeling of Anti-Infective Drug Products
`(1992)
`available
`at
`http://www.fda.gov/downloads/Drugs/
`GuidanceComplianceRegulatoryinforrnation/Guidances/
`UCM070975.pdf, IPR2015-01776, Jun. 6, 2016 [Exhibit 2099].
`Rodgers & Bassler, Treating Onychomycosis, Am. Fam. Physician,
`vol. 63, No. 4, pp. 663-672 (2001), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2100].
`Ghannoum et al., Amorolfine 5% Nail Lacquer Exhibits Potent
`Antifungal Activity Compared to Three Acid-Based Devices Indi(cid:173)
`cated for the Treatment of Onychomycosis An In Vitro Nail Pen(cid:173)
`etration Assay, Derm. & Therapy, vol. 6, No. 1, pp. 69-75 (2016),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2101].
`Declaration of Jennifer Augsburger in Support of Patent Owner's
`Response, IPR2015-01776, Jun. 6, 2016 [Exhibit 2102].
`Fukuoka et al., Genetic Basis for Differential Activities of
`Fluconazole and Voriconazole against Candida krusei, Antimicrob.
`Agents Chemother., vol. 47, No. 4, pp. 1213-1219 (2003), IPR2015-
`01776, Jun. 6, 2016 [Exhibit 2103].
`Orozco et al., Mechanism of Fluconazole Resistance in Candida
`krusei, Antimicrob. Agents Chemother., vol. 42, No. 10, pp. 2645-
`2649 (1998), IPR2015-01776, Jun. 6, 2016 [Exhibit 2104].
`Nimura et al., Comparison of In Vitro Antifungal Activities of
`Topical Antimycotics Launched in 1990s in Japan, Int'! J.
`Antimicrob. Agents, vol. 18, pp. 173-178 (2001), IPR2015-01776,
`Jun. 6, 2016 [Exhibit 2105].
`Ghannoum et al., Terbinafine HCI Nail Solution With and Without
`Nail Penetration Enhancer: Evaluation of Minimum Inhibitory
`Concentration and Minimum Fungicidal Concentrations, (abstract)
`J. Am. Acad. Dermatol., vol. 58, No. 2, suppl. 2, p. AB12 (2008),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2106].
`Ghannoum et al., Determination of the Efficacy of Terbinafine
`Hydrochloride Nail Solution
`in
`the Topical Treatment of
`Dermatophytosis in a Guinea Pig Model, Mycoses, vol. 52, No. 1,
`pp. 35-43 (2009), IPR2015-0l 776, Jun. 6, 2016 [Exhibit 2107].
`Rex et al., Antifungal Susceptibility Testing, Clin. Microbio. Revs.,
`vol. 6, No. 4, pp. 367-381 (1993), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2108].
`
`EPA Correspondence, 1997 Labeling Rev., Amended Biobor Label
`available at www3 .epa. gov /pesticides/chem_search/ppls/065 217-
`000001-19970327 .pdf, IPR2015-01776, Jun. 6, 2016 [Exhibit
`2109].
`Ferrari et al., Occurrence of Heterotrophic Bacteria and Fungi in an
`Aviation Fuel Handling System and its Relationship with Fuel
`Fouling, Revista Argentina de Microbiologia, vol. 30, No. 3, pp.
`105-114 (1998), IPR2015-01776, Jun. 6, 2016 [Exhibit 2110].
`Aly, Ecology and Epidemiology ofDermatophyte Infections, J. Am.
`Acad. Derm., vol. 31, No. 3, pp. S21-S25 (1994), IPR2015-0l 776,
`Jun. 6,2016 [Exhibit 2111].
`Crane & Sanders, Evaluation of a Biocidal Turbine-Fuel Additive,
`Aviation Medical Report-AM 67-21, pp. 1-10 (Federal Aviation
`Administration, Office of Aviation Medicine 1967) available at
`http://www.faa.gov/data_research/research/med_humanfacs/
`oarntechreports/1960s/media/arn67-21.pdf, IPR2015-01776, Jun. 6,
`2016 [Exhibit 2112].
`the Topical Therapy of
`Alley et al., Recent Progress on
`Onychomycosis, Expert Opin. Investig. Drugs, vol. 16, No. 2, pp.
`157-167 (2007), IPR2015-01776, Jun. 6, 2016 [Exhibit 2113].
`Smith & March, March's Advanced Organic Chemistry: Reactions,
`Mechanism, and Structure, John Wiley & Sons, New York, NY (5th
`ed., 2001), IPR2015-01776, Jun. 6, 2016 [Exhibit 2114].
`Batsanov, Van der Weals Radii of Elements, Inorg. Materials, vol.
`37, pp. 871-885 (2001), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2115].
`Henman et al., Effects of Decaborane on Gastric Secretion in the
`Shay Rat, Br. J. Pharmacol., vol. 40, No. 1, p. 164P (1970),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2116].
`Steiner et al., Diphenylborinic Acid Is a Strong Inhibitor of Serine
`Proteases, Bioorg. & Med. Chem. Lett., vol. 4, pp. 2417-2420
`(1994), IPR2015-01776, Jun. 6, 2016 [Exhibit 2117].
`Hall, Boronic Acids, Prep. and App. in Organic Synthesis and Med.,
`pp. 123-13l(Wiley-VCH, 2005), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2118].
`Hall, Boronic Acids, Prep. and App. in Organic Synthesis and Med.,
`pp. 28-49 (Wiley-VCR, 2005), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2119].
`Iliev et al., Skin Roughness is Negatively Correlated to Irritation
`with DMSO, but not with NaOH and SLS, Exp. Dermatol., vol. 6,
`No. 4, pp. 157-160 (1997), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2120].
`DiMasi et al., Innovation in the Pharmaceutical Industry: New
`Estimates ofR&D Costs, J. Health. Econ., vol. 47, pp. 20-33 (2016),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2121].
`Endo, The Discovery and Development of HMG-CoA Reductase
`Inhibitors, J. Lipid Res., vol. 33, pp. 1569-1582 (1992), IPR2015-
`01776, Jun. 6, 2016 [Exhibit 2122].
`O'Driscoll et al., Simvastatin, an Hmg-Coenzyme A Reductase
`Inhibitor, Improves Endothelial Function Within 1 Month, Circu(cid:173)
`lation, vol. 95, pp. 1126-1131 (1997), IPR2015-01776, Jun. 6, 2016
`[Exhibit 2123].
`Tenjarla et al., Preparation, Characterization, and Evaluation of
`Miconazole-Cyclodextrin Complexes for Improved Oral and Topi(cid:173)
`cal Delivery, J. Pharm. Sci., vol. 87, No. 4, pp. 425-429 (1998),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2124].
`Dixon & Villar, Bioactive Diversity and Screening Library Selec(cid:173)
`tion Via Affinity Fingerprinting, J. Chem. Info. & Comp. Sci., vol.
`38, pp. 1192-1203 (1998), IPR2015-01776, Jun. 6, 2016 [Exhibit
`2125].
`Silverman, The Organic Chemistry of Drug Design and Drug
`Action, Elsevier Academic Press, Evanston, II. (2d Ed., 2004),
`IPR2015-01776, Jun. 6, 2016 [Exhibit 2126].
`Cursiefen & Bergua, Acute Bilateral Blindness Caused by Acci(cid