Paper No.___
`Filed: July 6, 2018
`
`Filed on behalf of: Mylan Pharmaceuticals Inc.
`By: Steven W. Parmelee
`
`Michael T. Rosato
`
`Jad A. Mills
`
`WILSON SONSINI GOODRICH & ROSATI
`
`701 Fifth Avenue, Suite 5100
`
`Seattle, WA 98104-7036
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`
`_____________________________
`
`U.S. Patent No. 9,549,938 to Baker et al.
`Ser. No. 15/068,352, filed March 11, 2016
`Issue Date: January 24, 2017
`
`Title: BORON-CONTAINING SMALL MOLECULES
`
`Inter Partes Review No. 2018-01358
`_____________________________
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.9,549,938
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.100 et. seq.
`
`

`

`Page
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ........................................................................................ I
`EXHIBIT LIST .................................................................................................... VI
`MANDATORY NOTICES ....................................................................................X
`1.
`Real Parties-In-Interest, § 42.8(b)(1) .................................................. x
`2.
`Related Matters, § 42.8(b)(2). ............................................................ x
`3.
`Lead and Back-Up Counsel, § 42.8(b)(3) ......................................... xii
`4.
`Service Information, § 42.8(b)(4) ..................................................... xii
`(i)
`Electronic Mailing Addresss .................................................. xii
`(ii)
`Postal Mailing Address .......................................................... xii
`INTRODUCTION ................................................................................................. 1
`GROUNDS FOR STANDING .............................................................................. 2
`BACKGROUND ................................................................................................... 2
`SCOPE AND CONTENT OF THE PRIOR ART ........................................ 2
`I.
`A.
`Boron-Containing Compounds In General. ........................................ 2
`B.
`Prior Art Patents And Printed Publications. ....................................... 4
`
`Austin ....................................................................................... 5
`1.
`Brehove .................................................................................... 8
`2.
`Freeman ................................................................................ 14
`3.
`Samour .................................................................................. 18
`II.
`LEVEL OF ORDINARY SKILL IN THE ART ........................................ 21
`III. THE ’938 PATENT PROSECUTION HISTORY. .................................... 22
`IDENTIFICATION OF THE CHALLENGE ....................................................... 26
`IV. CLAIM CONSTRUCTION ....................................................................... 27
`
`4.
`
`
`
`-i-
`
`

`

`Explanation Of Ground 1 For Unpatentability: Claims 1 & 2 of
`
`1.
`
`All Elements of Claims 1 & 2 are Obvious Over Austin in
`
`2.
`
`3.
`
`A POSITA Would Have Had Reason to Combine Austin
`
`A POSITA Would Have Had a Reasonable Expectation of
`
`V. HOW THE CLAIMS ARE UNPATENTABLE. ........................................ 28
`A.
`the ’938 Patent are Obvious Over Austin in View of Brehove .......... 30
`
`View of Brehove ..................................................................... 31
`a.
`Independent Claim 1 .................................................... 31
`b.
`Dependent Claim 2 ...................................................... 32
`
`and Brehove........................................................................... 34
`
`Success in Combining Austin and Brehove ............................ 37
`and Samour ...................................................................................... 42
`
`View of Brehove and Samour ................................................. 43
`
`Expectation of Success in Combining the Same ..................... 46
`the ’938 Patent are Obvious Over Austin in View of Freeman ......... 48
`
`View of Freeman ................................................................... 48
`a.
`Independent Claim 1 .................................................... 48
`b.
`Dependent Claim 2 ...................................................... 50
`
`and Freeman .......................................................................... 52
`
`of Success in Combining Austin and Freeman ....................... 55
`and Samour ...................................................................................... 59
`
`B.
`
`C.
`
`D.
`
`Explanation Of Ground 2 For Unpatentability: Claims 3–6 of
`the ’938 Patent are Obvious Over Austin in View of Brehove
`
`1.
`
`2.
`
`All Elements of Claims 3–6 are Obvious Over Austin in
`
`A POSITA Would Have Had Reason to Combine Austin,
`Brehove, and Samour and Would Have had a Reasonable
`
`Explanation Of Ground 3 For Unpatentability: Claims 1 & 2 of
`
`1.
`
`All Elements of Claims 1 & 2 are Obvious Over Austin in
`
`2.
`
`3.
`
`POSITA Would Have Had Reason to Combine Austin
`
`A POSITA Would Have Had a Reasonable Expectation
`
`Explanation Of Ground 4 For Unpatentability: Claims 3–6 of
`the ’938 Patent are Obvious Over Austin in View of Freeman
`
`
`
`-ii-
`
`

`

`1.
`
`2.
`
`All Elements of Claims 3–6 are Obvious Over Austin in
`
`A POSITA Would Have Had Reason to Combine Austin,
`Freeman, and Samour and Would Have had a
`Reasonable Expectation of Success in Combining the
`
`
`View of Freeman and Samour ............................................... 59
`
`Same ...................................................................................... 62
`E.
`of Obviousness. ............................................................................... 64
`CONCLUSION ................................................................................................... 65
`
`No Secondary Considerations Overcome This Strong Showing
`
`
`
`-iii-
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`
`
`CASES
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966).................................................................................. 29, 64
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ................................................................... 29
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ..................................................................... 65
`
`In re Bigio,
`381 F.3d 1320 (Fed. Cir. 2004) ................................................................... 29
`
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) ..................................................................... 29
`
`In re Gershon,
`372 F.2d 535 (CCPA 1967) ........................................................................ 65
`
`In re ICON Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) ................................................................... 30
`
`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986) ................................................................... 31
`
`In re Piasecki,
`745 F.2d 1468 (Fed. Cir. 1984) ................................................................... 64
`
`Innovation Toys, LLC v. MGA Entm’t, Inc.,
`637 F.3d 1314 (Fed. Cir. 2011) ................................................................... 30
`
`Kao Corp. v. Unilever United States, Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ..................................................................... 65
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................. passim
`
`
`
`-iv-
`
`

`

`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ..................................................................... 64
`
`Okajima v. Bourdeau,
`261 F.3d 1350 (Fed. Cir. 2001) ................................................................... 21
`
`PAR Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ................................................................... 29
`
`Ryko Mfg. Co. v. Nu–Star, Inc.,
`950 F.2d 714 (Fed. Cir. 1991) ..................................................................... 64
`
`Scientific Plastic Products, Inc. v. Biotage AB,
`766 F.3d 1355 (Fed. Cir. 2014) ................................................................... 30
`
`Unwired Planet, LLC v. Google Inc.,
`841 F.3d 995 (Fed. Cir. 2016) ..................................................................... 29
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ................................................................... 64
`
`STATUTES
`
`35 U.S.C. § 103(a) ................................................................................................ 28
`
`35 U.S.C. § 315(c) .................................................................................................. 2
`
`RULES
`
`37 C.F.R. § 42.101 .................................................................................................. 2
`
`37 C.F.R. § 42.102 .................................................................................................. 2
`
`37 C.F.R. § 42.104(a).............................................................................................. 2
`
`37 C.F.R. § 42.104(b)(3) ....................................................................................... 27
`
`37 C.F.R. § 42.104(b)(4) ....................................................................................... 28
`
`37 C.F.R. § 42.104(b)(5) ....................................................................................... 28
`
`37 C.F.R. § 42.122(b) ............................................................................................. 2
`
`
`
`-v-
`
`

`

`EXHIBIT LIST
`
`Pursuant to 37 C.F.R. § 42.63(e), petitioner provides the following exhibit
`
`list with the exhibit number, a brief description of each exhibit, and where
`
`applicable the short form used herein.
`
`EXHIBIT1
`
`DESCRIPTION
`
`Ex. 1001 U.S. Patent No. 9,549,938
`
`Ex. 1002 Prosecution History of the ’938 Patent
`
`Ex. 1003 Declaration of Stephen Kahl, Ph.D
`
`Ex. 1004 Curriculum Vitae of Stephen Kahl, Ph.D
`
`Ex. 1005 Declaration of S. Narasimha Murthy, Ph.D
`
`Ex. 1006 Curriculum Vitae of S. Narasimha Murthy, Ph.D
`
`SHORT FORM
`
`’938 Patent
`
`
`
`
`
`
`
`Kahl Decl.
`
`Murthy Decl.
`
`
`1 As indicated in Petitioner’s mandatory disclosure of related matters, infra at –x-,
`
`this petition is one of two that Petitioner has filed concurrently, requesting inter
`
`partes review of U.S. Patents Nos. 9,549,938 B2 and 9,566,289 B2. To avoid
`
`confusion, Petitioner has numbered the same or corresponding exhibits
`
`consistently across the Petitions, and in each filing has omitted Exhibits not
`
`discussed in that Petition. All exhibits are exact copies of the exhibits submitted in
`
`IPR2018-00168 with exhibit labeling updated to identify this proceeding.
`
`
`
`-vi-
`
`

`

`EXHIBIT1
`
`DESCRIPTION
`
`SHORT FORM
`
`Ex. 1007 Austin et al., PCT Pub. No. WO 1995/033754
`
`Ex. 1008 Brehove, U.S. Patent Pub. No. 2002/0165121
`
`Austin
`
`Brehove
`
`Ex. 1009 Freeman et al., PCT Pub. No. WO 2003/009689
`
`Freeman
`
`Ex. 1010 Samour et al., U.S. Patent No. 6,224,887
`
`Samour
`
`Ex. 1011
`
`Intentionally omitted- Exhibit number not used
`
`Ex. 1012 U.S. Patent No. 7,582,621
`
`Ex. 1013 Prosecution History of the ’621 Patent
`
`Ex. 1014
`
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01776 (P.T.A.B. Feb. 23, 2017), Paper
`70
`
`
`
`
`
`’621 Patent
`
`IPR ’776, FWD
`
`Ex. 1015 U.S. Patent No. 7,767,657
`
`’657 Patent
`
`Ex. 1016 Prosecution History of the ’657 Patent
`
`
`
`Ex. 1017
`
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01780 (P.T.A.B. Feb. 23, 2017), Paper
`70
`
`IPR ’780, FWD
`
`Ex. 1018
`
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01785 (P.T.A.B. Feb. 23, 2017), Paper
`70
`
`Ex. 1019 U.S. Patent No. 4,202,894
`
`Murdan, Sudaxshina. “Drug delivery to the nail
`following topical application.” International
`Ex. 1021 BioborJF® Specification Sheet (2015)
`
`Ex. 1020
`
`journal of pharmaceutics 236, no. 1 (2002): 1-26.
`
`
`
`-vii-
`
`IPR ’785, FWD
`
`’894 Patent
`
`Murdan 2002
`
`
`
`

`

`SHORT FORM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EXHIBIT1
`Ex. 1022 BioborJF® Material Safety Data Sheet (2004)
`
`DESCRIPTION
`
`Ex. 1023
`
`Intentionally omitted- Exhibit number not used
`
`Ex. 1024
`
`Intentionally omitted- Exhibit number not used
`
`Ex. 1025
`
`Ex. 1026
`
`Ex. 1027
`
`Ex. 1028
`
`Ex. 1029
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=6440876, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/6440
`8 76 (retrieved on May 26, 2017)
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=3198, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/319
`8 (retrieved on May 26, 2017)
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=11499245, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/1149
`9 245 (retrieved on May 26, 2017)
`
`Meds. & Healthcare Prods. Regulatory
`Agency, Curanail 5% Nail Lacquer
`(Amorolfine Hydrochloride) PL 10590/0049,
`UK Public Assessment Report (approved July
`4, 2006)
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=22497760, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/2249
`7 760 (retrieved on May 26, 2017)
`
`
`
`-viii-
`
`

`

`DESCRIPTION
`
`SHORT FORM
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=61764, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/617
`64 (retrieved on May 26, 2017)
`
`Mertin, Dirk, and Lippold, Bernhard C. “In-vitro
`plate and their efficacy.” Journal of pharmacy
`and pharmacology 49, no. 9 (1997): 866–872
`Groziak, Michael P. “Boron therapeutics on the
`horizon,” American journal of therapeutics 8, no.
`5 (2001): 321–328
`
`permeability of the human nail and of a keratin
`membrane from bovine hooves: Prediction of the
`penetration rate of antimycotics through the nail
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=66827, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/6682
`7 (retrieved on May 26, 2017)
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=2775922, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/2775
`9 22 (retrieved on May 26, 2017)
`
`Intentionally omitted- Exhibit numbers not used
`
`
`
`Mertin 1997
`
`Groziak 2001
`
`
`
`
`
`
`
`
`
`EXHIBIT1
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`Ex. 1034
`
`1035–1042
`
`Exs.
`
`Ex. 1043
`
`Brief of Appellant-Patent Owner, Anacor
`Pharmaceuticals, Inc. v. Joseph Matal, No. 17-
`1947 (Fed. Cir. Aug. 4, 2017)
`
`
`
`
`-ix-
`
`

`

`MANDATORY NOTICES
`
`Petitioner provides the following mandatory disclosures pursuant to 37
`
`C.F.R. § 42.8, which are excluded from the petition type-volume limitations
`
`pursuant to § 42.24.
`
`1.
`
`Real Parties-In-Interest, § 42.8(b)(1)
`
`The following real parties-in-interest are identified: Mylan Pharmaceuticals
`
`Inc., which is the Petitioner in this matter and a wholly owned subsidiary of Mylan
`
`Inc.; Mylan Inc., which is an indirectly wholly owned subsidiary of Mylan N.V.;
`
`and, in an abundance of caution, Mylan N.V.
`
`2.
`
`Related Matters, § 42.8(b)(2).
`
`On June 8, 2018, the Board instituted inter partes review of claims 1-6 of the
`
`’938 patent in IPR2018-00168 (Paper 9) based on a petition filed by FlatWing
`
`Pharmaceuticals, LLC.
`
`There are no judicial matters pending that would affect, or be affected by, a
`
`decision in the proceeding.
`
`Administrative matters that would or could affect or be affected by a
`
`decision in a proceeding instituted on this petition are United States Patent
`
`Applications Ser. No. 15/355,393 and Ser. No. 15/355,813.
`
`Petitioner is filing this Petition concurrently with a petition requesting inter
`
`partes review of U.S. Patents No. 9,566,289 B2. The Board has previously
`
`instituted inter partes review of U.S. Patent Nos. 9.549,938 B2, 9,566,289 B2,
`
`
`
`-x-
`
`

`

`9,566,290 B2, and 9,572,823 B2 in IPR Nos. 2018-00168, 2018-00169, 2018-
`
`00170, and 2018-00171.
`
`In addition, although not currently subject to administrative proceedings that
`
`would affect or be affected by a decision in a proceeding instituted on this petition,
`
`issued patents which assert the same claim of priority as U.S. Patent No. 9,549,938
`
`and have substantially the same specification are:
`
`U.S. Patent No. 7,582,621
`
`U.S. Patent No. 7,767,657
`
`U.S. Patent No. 8,039,451
`
`U.S. Patent No. 8,115,026
`
`U.S. Patent No. 8,440,642
`
`U.S. Patent No. 8,722,917
`
`U.S. Patent No. 8,889,656
`
`U.S. Patent No. 9,353,133
`
`U.S. Patent No. 9,566,290
`
`U.S. Patent No. 9,572,823
`
`U.S. Patent No. 9,566,289
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`
`
`
`-xi-
`
`

`

`3.
`
`Lead and Back-Up Counsel, § 42.8(b)(3)
`
`The following are designated as lead counsel and back-up counsel, pursuant
`
`to 37 C.F.R. § 42.10. A Power of Attorney is being filed concurrently herewith.
`
`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
`
`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
`
`Back-Up Counsel: Jad A. Mills (Reg. No. 63,344)
`
`4.
`
`Service Information, § 42.8(b)(4)
`
`Papers concerning this matter should be served on the following:
`
`(i)
`
`Electronic Mailing Addresss
`
`Petitioner consents to service by email at:
`
`sparmelee@wsgr.com
`
`mrosato@wsgr.com
`
`jmills@wsgr.com
`
`
`
`(ii) Postal Mailing Address
`
`WILSON SONSINI GOODRICH & ROSATI
`
`701 Fifth Avenue, Suite 5100, Seattle, WA 98104-7036
`
`Tel.: 206-883-2542 Fax: 206-883-2699
`
`
`
`-xii-
`
`

`

`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) asks the Board to institute inter
`
`partes review (“IPR”) of claims 1-6 of U.S. Patent No. 9,549,938 to Baker et al.
`
`(Ex. 1001), and that these claims be canceled as unpatentable over the prior art.
`
`The Office is authorized to charge petition fees and deficiencies to Deposit Acct.
`
`No. 23-2415. Inter partes review of claims 1-6 the ’938 patent was instituted in
`
`IPR2018-00168 on June 8, 2018, based on a petition filed by FlatWing
`
`Pharmaceuticals, LLC (“FlatWing”). For the sake of completeness and efficiency,
`
`the present Petition is a practical copy of the petition in IPR2018-00168, updated
`
`with identifying information regarding the present petitioner and to present the
`
`Identification of the Challenge in table format. A motion for Joinder with
`
`IPR2018-00168 is being filed concurrently with this Petition.
`
`The ’938 patent claims a method of treating human onychomycosis caused
`
`by Trichophyton rubrum or Trichophyton mentagrophytes. The method includes
`
`topically administering to a toenail a pharmaceutical composition that contains
`
`tavaborole or a pharmaceutically acceptable salt thereof in an amount sufficient to
`
`treat the infection. The ’938 patent is unpatentable over prior art which taught the
`
`use of tavaborole as a fungicide for which a person of ordinary skill in the art
`
`(“POSITA”) would have had a reasonable expectation of success.
`
`
`
`-1-
`
`

`

`GROUNDS FOR STANDING
`
`Petitioner certifies pursuant to 37 C.F.R. § 42.104(a) that the ’938 patent is
`
`available for inter partes review and that Petitioner is not estopped or barred from
`
`requesting inter partes review challenging the identified ’938 patent claims on the
`
`grounds identified herein. Petitioner is a person who may petition for inter partes
`
`review under 37 C.F.R. § 42.101, and this petition is timely under 37 C.F.R. §§
`
`42.102, 42.122(b) and 35 U.S.C. § 315(c).
`
`BACKGROUND
`
`I.
`
`Scope and Content of the Prior Art
`
`A. Boron-Containing Compounds In General.
`
`Boron-containing compounds were well known to a POSITA before
`
`February 16, 2005. (Ex. 1003, Kahl Decl. ¶ 30.) Like other skilled artisans, Dr.
`
`Kahl (whose declaration is submitted herewith) has been studying boron-
`
`containing compounds as therapeutic agents for over 45 years, including the
`
`administration of boron-containing compounds to humans as a treatment. (Ex.
`
`1003, Kahl Decl. ¶ 30.)
`
`Groziak 2001 (Ex. 1032) published a review of the then-current state of
`
`research and development concerning boron-based therapeutics for use in humans.
`
`
`
`-2-
`
`

`

`(Ex. 1032, Groziak 2001 at 1–22; Ex. 1003, Kahl Decl. ¶ 31.) In particular, Groziak
`
`2001 recognized that it was “not at all surprising to find that most of the boron-
`
`based therapeutics currently on the horizon are either boronic acids themselves or
`
`boron heterocycles that are simply internally complexed versions of boronic
`
`acids.” (Ex. 1032, Groziak 2001 at 2; Ex. 1003, Kahl Decl. ¶ 31.) Dr. Kahl
`
`explains that the statement in Groziak 2001 is correct, because boronic acids and
`
`boron heterocycles often share similar functional properties based on the unique
`
`chemical properties of boron itself. (Ex. 1003, Kahl Decl. ¶ 31.)
`
`Boron-containing compounds are generally considered safe. (Ex. 1003, Kahl
`
`Decl. ¶ 32.) One notable exception is trialkylboranes, which are compounds with
`
`the general formula BR3 where R is an alkyl group. (Ex. 1003, Kahl Decl. ¶ 32.)
`
`Trialkylboranes can spontaneously combust under certain conditions. (Ex. 1003,
`
`Kahl Decl. ¶ 32.) The oxaboroles disclosed by the art discussed infra such as
`
`Austin3 are not trialkylboranes, and a POSITA would recognize that the boron-
`
`
`2 Throughout this Petition, page citations refer to the consecutive page numbers
`
`added in the exhibit label. Paragraph, column, and line number citations refer to
`
`the numbering system used in the original document.
`
`3 Ex. 1007, Austin et al., PCT Pub. No. WO 1995/033754 (“Austin”).
`
`
`
`-3-
`
`

`

`containing compounds of Austin are generally considered safe. (Ex. 1003, Kahl
`
`Decl. ¶ 32.)
`
`Dr. Kahl explained there is no reason a POSITA would have been
`
`discouraged from selecting an oxaborole as disclosed by Austin for consideration
`
`as a topical therapeutic in humans. (Ex. 1003, Kahl Decl. ¶ 33; see also Ex. 1014,
`
`IPR ’776, FWD at 27; Ex. 1017, IPR ’780, FWD at 33–34; Ex. 1018, IPR ’785,
`
`FWD at 30.) As further explained infra and in Dr. Kahl’s declaration (Ex. 1003),
`
`based on Austin’s disclosure of tavaborole4 as one of three preferred anti-fungal
`
`compounds for the treatment of Candida albicans, a POSITA would (i) consider
`
`the compound as obvious to try as a starting point for developing a topical
`
`composition to treat fungal infections and (ii) have a reasonable expectation of
`
`success in doing so. (Ex. 1003, Kahl Decl. ¶ 33.)
`
`B.
`
`Prior Art Patents And Printed Publications.
`
`Not all boron-based compounds are bioactive. (Ex. 1003, Kahl Decl. ¶ 34.)
`
`If a molecule is known to be bioactive against a fungus, such as Candida albicans
`
`
`4 Tavaborole is referred to as 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole in
`
`the ’938 patent and as 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole in
`
`Austin, both of which are the same compound. See, e.g., Ex. 1014, IPR ’776, FWD
`
`at 7.
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`
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`-4-
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`

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`(which is a cause of onychomycosis), a POSITA would consider that molecule as
`
`obvious to try for therapeutic use in humans. (Ex. 1003, Kahl Decl. ¶ 34.) A
`
`POSITA would have been particularly motivated to try such a compound when
`
`other prior art (such as Brehove5 and Freeman6, infra) demonstrates that boron-
`
`based compounds are effective against the pathogens that cause onychomycosis,
`
`including Candida albicans and dermatophytes. (Ex. 1003, Kahl Decl. ¶ 34.)
`
`Austin7
`
`
`1.
`
`Austin (Ex. 1007) discloses just such bioactivity (making it obvious to try
`
`for therapeutic use in humans) with its three preferred compounds, in particular
`
`tavaborole. (Ex. 1007, Austin at 39; Ex. 1003, Kahl Decl. ¶ 35.) It is the exact same
`
`compound claimed for use in the ’938 Patent and was not novel in February 2005.
`
`(Ex. 1003, Kahl Decl. ¶ 35; Ex. 1005, Murthy Decl. ¶ 51.)
`
`Austin not only discloses “5- and 6-fluoro or bromo-1,3 dihydro-1hydroxy-
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`2,1-benzoxaborole” (i.e., tavaborole), it includes tavaborole among “[p]referred
`
`compounds” on the front page of the publication. (Ex. 1007, Austin at [57]
`
`(Abstract); Ex. 1003, Kahl Decl. ¶ 36; Ex. 1005, Murthy Decl. ¶ 51.) In Table 9, it
`
`
`5 Ex. 1008, Brehove, U.S. Patent Pub. No. 2002/0165121 (“Brehove”).
`
`6 Ex. 1009, Freeman et al., PCT Pub. No. WO 2003/009689 (“Freeman”).
`
`7 Supra, n.3.
`
`
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`-5-
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`

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`reports the antifungal bioactivity of the 5-fluoro (Example 64), 5-bromo (Example
`
`68), and 6-fluoro (Example 70) compounds. (Ex. 1007, Austin at 39; Ex. 1003,
`
`Kahl Decl. ¶ 36; Ex. 1005, Murthy Decl. ¶ 52.) Of the preferred compounds,
`
`tavaborole (5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) demonstrated the
`
`lowest Minimum Inhibitory Concentration (“MIC”) values, as low as five (5) parts
`
`per million (“ppm”), against several pathogens, including Candida albicans. (Ex.
`
`1007, Austin at 39; Ex. 1003, Kahl Decl. ¶ 36; Ex. 1005, Murthy Decl. ¶ 53.) In
`
`other words, of the three preferred compounds tested, tavaborole inhibited the
`
`visible growth of Candida albicans (a fungus that causes onychomycosis,
`
`sometimes in conjunction with dermatophytes) at the lowest level of concentration.
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`Austin further discloses that compounds containing an “oxaborole ring” are
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`“particularly effective” as fungicides. (Ex. 1007, Austin at 3:35–40, 12:16–19, 39;
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`Ex. 1005, Murthy Decl. ¶¶ 51, 56.)
`
`Austin also discloses preparation of benzoxaborole derivatives, specifically
`
`teaches tavaborole, even including its melting point and elemental analysis, and
`
`formulations including tavaborole. (Ex. 1007, Austin at 24:1–15, 25 [Table 5], and
`
`38:15–26; Ex. 1005, Murthy Decl. ¶ 52.) Austin further teaches that the
`
`“concentration of the oxaborole in the biocide composition is . . . preferably from 1
`
`to 50%, especially from 5 to 30% and more especially from 10 to 20% by weight
`
`relative to the total weight of the biocide composition.” (Ex. 1007, Austin at 9:5–9;
`
`
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`-6-
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`

`

`Ex. 1005, Murthy Decl. ¶ 54.) Austin provides that “oxaborole . . . is preferably
`
`formulated in a composition together with a carrier,” carriers including “water or a
`
`water-miscible organic solvent,” where “suitable water-miscible organic solvents
`
`are . . . alcohols such as ethanol or glycols such as . . . propylene glycol.” (Ex.
`
`1007, Austin at 8:11–38; Ex. 1005, Murthy Decl. ¶ 53.)
`
`Thus, Austin discloses a biocide composition formulated with tavaborole as
`
`a preferred fungicide to effectively inhibit Candida albicans (which is one of the
`
`fungi that cause onychomycosis) and in carriers including water-miscible solvents,
`
`such as ethanol and propylene glycol, at preferred concentrations of 5 to 30% and
`
`10 to 20% by weight relative to the total weight of the biocide composition. (Ex.
`
`1007, Austin at 8:34–39, 9:5–9; Ex. 1005, Murthy Decl. ¶¶ 53–54.) As of February
`
`16, 2005, a POSITA would consider the preferred compound of Austin, which is
`
`the exact same compound recited in claims 1–6 of the ’938 Patent, obvious to try
`
`to successfully treat onychomycosis in humans based on its disclosed anti-fungal
`
`activity and structural similarities, e.g., boron-based cyclic compounds. (Ex. 1003,
`
`Kahl Decl. ¶ 45.)
`
`
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`-7-
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`

`

`2.
`
`
`
`Brehove8
`
`Brehove is a U.S. patent application publication that disclosed the use of
`
`boron-containing compounds as anti-fungal agents to treat onychomycosis in
`
`humans more than a year before the priority date of February 16, 2005. (Ex. 1003,
`
`Kahl Decl. ¶ 37; Ex. 1005, Murthy Decl. ¶¶ 57–58.) Brehove disclosed the
`
`effective use of the following boron-containing compounds to treat onychomycosis
`
`in humans:
`
`
`
`
`(Ex. 1003, Kahl Decl. ¶ 38.)
`
`
`
`Brehove discloses the topical application of boron-based compounds to
`
`“treat and prevent the spread of nail infections or onychomycosis caused by
`
`bacteria, fungi and other pathogens.” (Ex. 1008, Brehove at [57] (Abstract), ¶
`
`[0003]; Ex. 1005, Murthy Decl. ¶ 58.) Brehove states that “[o]nychomycosis is a
`
`nail disease of the toes and fingers typically caused by the organisms Candida
`
`
`8 Supra, n.5.
`
`
`
`-8-
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`

`

`albicans, Tricophyton mentagrophytes, Tricophyton rubrum, or Epidermpophyton
`
`floccusum.” (Ex. 1008, Brehove ¶ [0005]; Ex. 1003, Kahl Decl. ¶ 39.). Brehove
`
`acknowledges that boron-based compounds “have long been known to exhibit
`
`biocidal activity.” (Ex. 1008, Brehove ¶ [0007]; Ex. 1005, Murthy Decl. ¶ 58.)
`
`Brehove specifically discloses that these boron-based compounds are effective in
`
`vitro against Candida albicans, which is a cause of onychomycosis: “This
`
`invention also comprises a method of treating onychomycosis by topical
`
`application of a composition containing, as an active ingredient, at least one
`
`member selected from the group consisting of 2,2’-(1-methyltrimethylenedioxy)
`
`bis-(4-methyl-1,3,2-dioxaborinane) and 2,2’-oxybis (4,4,6-trimethyl-1,3,2-
`
`dioxaborinane).” (Ex. 1008, Brehove ¶¶ [0017], [0032]–[0033], Table 1; Ex. 1003,
`
`Kahl Decl. ¶ 39.) Brehove, consistent with Austin, recognizes that formulations
`
`containing boron-based compounds have “powerful potency against Candida
`
`albicans. . . . effectively kill[ing] the most common pathogen causing
`
`onychomycosis.” (Ex. 1008, Brehove ¶ [0018]; Ex. 1005, Murthy Decl. ¶ 58.)
`
`Brehove recognizes that Trichophyton rubrum and Trichophyton mentagrophytes
`
`are the common causes of onychomycosis, along with Candida albicans, and that
`
`there was a motivation to try a topical application effective against the pathogens
`
`causing onychomycosis. (Ex. 1008, Brehove ¶¶ [0005], [0016]; Ex. 1005, Murthy
`
`Decl. ¶ 58.)
`
`
`
`-9-
`
`

`

`Brehove taught preparing topical compositions containing these boron-based
`
`compounds were “highly effective” to successfully treat humans suffering from
`
`onychomycosis. (See, e.g., Ex. 1008, Brehove ¶¶ [0030]–[0038]; Ex. 1003, Kahl
`
`Decl. ¶ 40; Ex. 1005, Murthy Decl. ¶ 61.) This is the same pathogen inhibited in
`
`Austin with a boron-based compound. (Ex. 1003, Kahl Decl. ¶ 40.)
`
`Not only did Brehove successfully treat humans with this boron-based
`
`compound, the compound was commercially sold as an industrial biocide for fuel
`
`under the trade name BioborJF®. (Exs. 1021, 1022; Ex. 1003, Kahl Decl. ¶ 40.)
`
`These compounds were previously sold commercially in antifungal additives for
`
`leaded motor fuels in order to improve combustion efficiency, and U.S. Patent No.
`
`2,741,548 had taught their synthesis. (Ex. 1008, Brehove ¶¶ [0015], [0023]; Ex.
`
`1005, Murthy Decl. ¶ 60.) These compounds had been used under the trade name
`
`BioborJF® as an antifungal fuel additive since 1965. (See Exs. 1021, 1022; Ex.
`
`1005, Murthy Decl. ¶ 60.) The BioborJF® specification sheet explains:
`
`(Ex. 1021 at 1; Ex. 1005, Murthy Decl. ¶ 60.) BioborJF® is a recognized
`
`antifungal for industrial applications.
`
`
`
`
`
`-10-
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`

`

`
`
`(Ex. 1021 at 1; Ex. 1005, Murthy Decl. ¶ 60.) The material safety datasheet for
`
`BioborJF® from January 1, 2004, discloses its active ingredients as 2,2’-(1-
`
`methyltrimethylene dioxy) bis-(4-methyl-1,3,2-dioxaborinane) and/or 2,2’-oxybis
`
`(4,4,6-trimethyl-1,3,2-dioxaborinane), the very same compounds used to treat
`
`onychomycosis in humans by Brehove:
`
`(Ex. 1022 at 1; Ex. 1005, Murthy Decl. ¶ 60.)
`
`Brehove specifically applied topical compositions containing the active
`
`ingredient in BioborJF® to five volunteers who presented with onychomycosis.
`
`(Ex. 1008, Brehove ¶¶ [0034]–[0038]; Ex. 1005, Murthy Decl. ¶ 62.) In all five
`
`
`
`
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`-11-
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`

`

`examples, the topical application of the compositions directly to the infected nail,
`
`or cuticle surrounding the infected nail, effectively treated the onychomycosis with
`
`“[n]o skin irritation” seen or observed, and the patent stated “no side effects are
`
`evident.” (Ex. 1008, Brehove ¶¶ [0022], [0030], [0034]–[0038]; Ex. 1005, Murthy
`
`Decl. ¶ 62.)
`
`Brehove further describes a number of topical formulations of the boron-
`
`based compounds, including “[o]ne formulation [that] is conveniently applied
`
`nightly in a petroleum jelly or mineral oil base”; “[d]ilute compositions of the
`
`active compounds in alcohol or acetone base [that have] the abili