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. 9,566,289 to Baker et al.
`Ser. No. 15/046,322, filed February 17, 2016
`Issue Date: February 14, 2017
`
`Title: BORON-CONTAINING SMALL MOLECULES
`
`Inter Partes Review No. 2018-01359
`
`_____________________________
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.9,566,289
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.100 et. seq.
`
`

`

`Page
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ........................................................................................ i
`TABLE OF AUTHORITIES ................................................................................ iv
`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) .......................................... xi
`4.
`Service Information, § 42.8(b)(4) ..................................................... xii
`(i)
`Electronic Mailing Addresss .................................................. xii
`(ii)
`Postal Mailing Address .......................................................... xii
`INTRODUCTION ................................................................................................. 1
`GROUNDS FOR STANDING .............................................................................. 1
`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 .......................................................................... 7
`2.
`Freeman ...................................................................... 12
`3.
`Samour ........................................................................ 16
`II.
`Level of Ordinary Skill in the Art .................................................... 18
`III. The ’289 Patent Prosecution History. ............................................... 19
`IDENTIFICATION OF THE CHALLENGE ....................................................... 23
`
`4.
`
`
`
`-i-
`
`

`

`Explanation Of Ground 1 For Unpatentability: Claims 1
`& 2 of the ’289 Patent are Obvious Over Austin in View
`
`1.
`
`2.
`
`3.
`
`All Elements of Claims 1 & 2 are Obvious Over
`
`A POSITA Would Have Had Reason to Combine
`
`A POSITA Would Have Had a Reasonable
`Expectation of Success in Combining Austin and
`
`Explanation Of Ground 2 For Unpatentability: Claims 4–
`7 & 10– 11 of the ’289 Patent are Obvious Over Austin in
`
`IV. Claim Construction .......................................................................... 24
`V. How the claims are unpatentable. ..................................................... 26
`A.
`of Brehove ............................................................................. 28
`
`Austin in View of Brehove ........................................... 29
`
`Austin and Brehove ...................................................... 30
`
`Brehove ........................................................................ 33
`View of Brehove and Samour ................................................ 38
`
`Over Austin in View of Brehove and Samour ............... 38
`
`Combining the Same .................................................... 42
`Handbook .............................................................................. 43
`
`Brehove, Samour, and the Excipients Handbook .......... 44
`
`Expectation of Success in Combining the Same ........... 48
`of Freeman ............................................................................ 48
`
`B.
`
`C.
`
`D.
`
`1.
`
`2.
`
`All Elements of Claims 4–7 & 10–11 are Obvious
`
`A POSITA Would Have Had Reason to Combine
`Austin, Brehove, and Samour and Would Have had
`a Reasonable Expectation of Success
`in
`
`Explanation Of Ground 3 For Unpatentability: Claims 3,
`8–9 & 12–15 of the ’289 Patent are Obvious Over Austin
`in View of Brehove, Samour, and
`the Excipients
`
`1.
`
`2.
`
`All Elements of Claims 3, 8–9 & 12–15 of the
`’289 Patent are Obvious Over Austin in View of
`
`A POSITA Would Have Had Reason to Combine
`Austin, Brehove, Samour, and
`the Excipients
`Handbook and Would Have had a Reasonable
`
`Explanation Of Ground 4 For Unpatentability: Claims 1
`& 2 of the ’289 Patent are Obvious Over Austin in View
`
`
`
`-ii-
`
`

`

`1.
`
`All Elements of Claims 1 & 2 are Obvious Over
`
`2.
`
`3.
`
`A POSITA Would Have Had Reason to Combine
`
`A POSITA Would Have Had a Reasonable
`Expectation of Success in Combining Austin and
`
`
`Austin in View of Freeman .......................................... 49
`
`Austin and Freeman ..................................................... 50
`
`Freeman ...................................................................... 53
`E.
`View of Freeman and Samour ............................................... 56
`F.
`Handbook .............................................................................. 58
`G. No Secondary Considerations Overcome This Strong
`Showing of Obviousness. ....................................................... 58
`CONCLUSION ................................................................................................... 60
`
`Explanation Of Ground 5 For Unpatentability: Claims 4–
`7 & 10–11 of the ’289 Patent are Obvious Over Austin in
`
`Explanation Of Ground 6 For Unpatentability: Claims 3,
`8–9 & 12–15 of the ’289 Patent are Obvious Over Austin
`in View of Freeman, Samour, and the Excipients
`
`
`
`
`
`-iii-
`
`

`

`TABLE OF AUTHORITIES
`
`CASES
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966).................................................................................. 27, 58
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ................................................................... 27
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ..................................................................... 59
`
`In re Bigio,
`381 F.3d 1320 (Fed. Cir. 2004) ................................................................... 27
`
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) ..................................................................... 27
`
`In re Gershon,
`372 F.2d 535 (CCPA 1967) ........................................................................ 59
`
`In re ICON Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) ................................................................... 28
`
`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986) ................................................................... 29
`
`In re Piasecki,
`745 F.2d 1468 (Fed. Cir. 1984) ................................................................... 58
`
`Innovation Toys, LLC v. MGA Entm’t, Inc.,
`637 F.3d 1314 (Fed. Cir. 2011) ................................................................... 28
`
`Kao Corp. v. Unilever United States, Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ..................................................................... 59
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................. passim
`
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ..................................................................... 59
`
`
`
`-iv-
`
`

`

`Okajima v. Bourdeau,
`261 F.3d 1350 (Fed. Cir. 2001) ................................................................... 19
`
`PAR Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ................................................................... 27
`
`Ryko Mfg. Co. v. Nu–Star, Inc.,
`950 F.2d 714 (Fed. Cir. 1991) ..................................................................... 59
`
`Scientific Plastic Products, Inc. v. Biotage AB,
`766 F.3d 1355 (Fed. Cir. 2014) ................................................................... 28
`
`Unwired Planet, LLC v. Google Inc.,
`841 F.3d 995 (Fed. Cir. 2016) ..................................................................... 27
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ................................................................... 59
`
`STATUTES
`
`35 U.S.C. § 103(a) ................................................................................................ 26
`
`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).............................................................................................. 1
`
`37 C.F.R. § 42.104(b)(5) ....................................................................................... 26
`
`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
`
`SHORT FORM
`
`Ex. 1001 U.S. Patent No. 9,566,289
`
`Ex. 1002 Prosecution History of the ‘289 Patent
`
`‘289 Patent
`
`
`
`Ex. 1003 Declaration of Stephen Kahl, Ph.D
`
`Kahl Decl.
`
`Ex. 1004 Curriculum Vitae of Stephen Kahl, Ph.D
`
`
`
`Ex. 1005 Declaration of S. Narasimha Murthy, Ph.D
`
`Murthy Decl.
`
`Ex. 1006 Curriculum Vitae of S. Narasimha Murthy, Ph.D
`
`
`
`Ex. 1007 Austin et al., PCT Pub. No. WO 1995/033754
`
`Austin
`
`
`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
`
`IPR2018-00169 with exhibit labeling updated to identify this proceeding.
`
`
`
`-vi-
`
`

`

`EXHIBIT1
`
`DESCRIPTION
`
`SHORT FORM
`
`Ex. 1008 Brehove, U.S. Patent Pub. No. 2002/0165121
`
`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 Handbook of Pharmaceutical Excipients (Arthur
`H. Kibbe ed., 3d ed. 2000)
`
`Excipients
`Handbook
`
`Ex. 1012 U.S. Patent No. 7,582,621
`
`‘621 Patent
`
`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
`
`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
`
`IPR ‘785, FWD
`
`Ex. 1019 U.S. Patent No. 4,202,894
`
`‘894 Patent
`
`Ex. 1020
`
`Murdan, Sudaxshina. “Drug delivery to the nail
`following topical application.” International
`journal of pharmaceutics 236, no. 1 (2002): 1–26.
`
`Murdan 2002
`
`Ex. 1021 BioborJF® Specification Sheet (2015)
`
`Ex. 1022 BioborJF® Material Safety Data Sheet (2004)
`
`
`
`
`
`
`
`-vii-
`
`

`

`EXHIBIT1
`
`DESCRIPTION
`
`SHORT FORM
`
`Ex. 1023
`
`Remington: The Science and Practice of Pharmacy
`(Lippincott Williams & Wilkins eds., 21st ed. 2005)
`
`Ex. 1024
`
`Hawley’s Condensed Chemical Dictionary
`(John Wiley & Sons, Inc., 13th ed. 1997)
`
`Ex. 1025
`
`Ex. 1026
`
`Ex. 1027
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=6440876, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/64408
`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/3198
`(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/11499
`245 (retrieved on May 26, 2017)
`
`Ex. 1028
`
`Meds. & Healthcare Prods. Regulatory Agency,
`Curanail 5% Nail Lacquer (Amorolfine
`Hydrochloride) PL 10590/0049, UK Public
`Assessment Report (approved July 4, 2006)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ex. 1029
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=22497760, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/22497
`760 (retrieved on May 26, 2017)
`
`
`
`
`
`-viii-
`
`

`

`EXHIBIT1
`
`DESCRIPTION
`
`SHORT FORM
`
`Ex. 1030
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=61764, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/61764
`(retrieved on May 26, 2017)
`
`
`
`Ex. 1031
`
`Mertin, Dirk, and Lippold, Bernhard C. “In-vitro
`permeability of the human nail and of a keratin
`membrane from bovine hooves: Prediction of the
`penetration rate of antimycotics through the nail
`plate and their efficacy.” Journal of pharmacy
`and pharmacology 49, no. 9 (1997): 866–872
`
`Mertin 1997
`
`Ex. 1032
`
`Groziak, Michael P. “Boron therapeutics on the
`horizon,” American journal of therapeutics 8, no.
`5 (2001): 321–328
`
`Groziak 2001
`
`Ex. 1033
`
`Ex. 1034
`
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=66827, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/66827
`(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/27759
`22 (retrieved on May 26, 2017)
`
`
`
`Ex. 1035
`
`Aldrich Handbook of Fine Chemicals and
`Laboratory Equipment (Sigma-Aldrich, 2004)
`
`Exs.
`1036–1042
`
`Ex. 1043
`
`Intentionally omitted- Exhibit numbers not used
`
`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 1-15 of
`
`the ’289 patent in IPR2018-00169 (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. Patent No. 9,549,938 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. 9,566,289
`
`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. 9,549,938
`
`• U.S. Patent No. 9,572,823
`
`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.
`
`
`
`-xi-
`
`

`

`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 1-15 of U.S. Patent No. 9,566,289 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 1-15 the ’289 patent was instituted in
`
`IPR2018-00169 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 IPR2018-00169, updated
`
`with identifying information regarding the present petitioner and to present the
`
`Identification of the Challenge in table format. A motion for Joinder with
`
`IPR2018-00169 is being filed concurrently with this Petition.
`
`The ’289 Patent claims, which relate to pharmaceutical formulations
`
`comprising tavaborole, are unpatentable over prior art which taught the use of the
`
`claimed compound as a fungicide for which a person of ordinary skill in the art
`
`(“POSITA”) would have had a reasonable expectation of success.
`
`GROUNDS FOR STANDING
`
`Petitioner certifies pursuant to 37 C.F.R. § 42.104(a) that the ’289 patent is
`
`available for inter partes review and that Petitioner is not estopped or barred from
`
`requesting inter partes review challenging the identified ’289 patent claims on the
`
`
`
`-1-
`
`

`

`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 person of ordinary skill
`
`in the art (“POSITA”) before February 16, 2005. (Ex. 1003, Kahl Decl. ¶ 30.) Dr.
`
`Kahl (whose declaration is submitted herewith) has been studying boron-
`
`containing compounds as therapeutic agents for over 45 years (as have others of
`
`skill in the art), including the administration of boron-containing compounds to
`
`humans as a treatment. (Ex. 1003, Kahl Decl. ¶ 30.)
`
`Groziak 2001 (Ex. 1032) reviews the then-current research and development
`
`concerning boron-based therapeutics for use in humans. (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
`
`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.
`
`
`
`-2-
`
`

`

`that are simply internally complexed versions of boronic acids.” (Ex. 1032 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-
`
`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),
`
`
`3 Ex. 1007, Austin et al., PCT Pub. No. WO 1995/033754 (“Austin”).
`
`
`
`-3-
`
`

`

`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
`
`(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-
`
`
`4 Tavaborole is referred to as 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole in
`
`the ‘289 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.
`
`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”).
`
`
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`-4-
`
`

`

`based compounds are effective against the pathogens that cause onychomycosis,
`
`including Candida albicans and dermatophytes. (Ex. 1003, Kahl Decl. ¶ 34.)
`
`1.
`
`
`
`Austin7
`
`Austin (Ex. 1007) discloses just such bioactivity with its three preferred
`
`compounds, in particular tavaborole, making it obvious to try for therapeutic use in
`
`humans. (Ex. 1007, Austin at 39; Ex. 1003, Kahl Decl. ¶ 35.) It is the exact same
`
`compound claimed for use in the ’289 Patent and was not novel in February 2005.
`
`(Ex. 1003, Kahl Decl. ¶ 35; Ex. 1005, Murthy Decl. ¶ 60.)
`
`Austin not only discloses “5- and 6-fluoro or bromo-1,3 dihydro-1hydroxy-
`
`2,1-benzoxaborole” (which includes 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. ¶ 60.) In Table
`
`9, it 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. ¶ 63.) 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.
`
`
`7 Supra, n.3.
`
`
`
`-5-
`
`

`

`1007, Austin at 39; Ex. 1003, Kahl Decl. ¶ 36; Ex. 1005, Murthy Decl. ¶ 63.) 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.
`
`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. ¶¶ 60, 65.)
`
`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. ¶ 61.) 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;
`
`Ex. 1005, Murthy Decl. ¶ 63.) 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. ¶ 63.)
`
`
`
`-6-
`
`

`

`Thus, Austin discloses a biocide composition formulated with tavaborole as
`
`a preferred fungicide to effectively inhibit onychomycosis-causing Candida
`
`albicans, 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. ¶¶ 64, 66.) As of February 16, 2005, a POSITA
`
`would consider the preferred compound of Austin, the same compound recited in
`
`claims 1–15 of the ’289 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.)
`
`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. ¶¶ 67–68.) Brehove disclosed the
`
`effective use of the following boron-containing compounds to treat onychomycosis
`
`in humans:
`
`
`8 Supra, n.5.
`
`
`
`-7-
`
`

`

`(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. ¶ 68.) 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.
`
`¶ 71.) 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.
`
`
`
`-8-
`
`

`

`1005, Murthy Decl. ¶ 70.) 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. ¶ 70.) The BioborJF® specification sheet explains:
`
`
`(Ex. 1021 at 1; Ex. 1005, Murthy Decl. ¶ 70.) BioborJF® is a recognized
`
`
`
`antifungal for industrial applications.
`
`
`
`(Ex. 1021 at 1; Ex. 1005, Murthy Decl. ¶ 70.) 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:
`
`
`
`-9-
`
`

`

`
`
`(Ex. 1022 at 1; Ex. 1005, Murthy Decl. ¶ 70.)
`
`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. ¶ 72.) In all five
`
`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. ¶ 72.)
`
`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 ability to deliver
`
`concentrated active
`
`ingredient as
`
`the solvent evaporates”; and “[a]nother
`
`formulation [that] is conveniently applied once per week in a cellulose acetate
`
`lacquer base.” (Ex. 1008, Brehove ¶ [0018]; Ex. 1005, Murthy Decl. ¶ 73.)
`
`
`
`-10-
`
`

`

`Brehove provides that the active ingredient may be combined with a
`
`“penetration enhancer” that “increases the permeability of the skin to a drug,” (Ex.
`
`1008, Brehove ¶ [0027]; Ex. 1005, Murthy Decl. ¶ 74) and, in at least some
`
`formulations, the “mineral oil, petroleum jelly and paraffin wax help protect the
`
`skin against irritation or drying and serve as a reservoir for the active ingredient
`
`permitting extended continuous diffusion and penetration into the nail.” (Ex. 1008,
`
`Brehove ¶ [0025]; Ex. 1005, Murthy Decl. ¶ 74.)
`
`Brehove also provides that the active fungicidal ingredient may be combined
`
`with an organic film former, and that “[m]any suitable film-forming polymers are
`
`known.” (Ex. 1008, Brehove at ¶ [0026]; Ex. 1005, Murthy Decl. ¶ 75.)
`
`Brehove teaches the effectiveness of its organo-boron compounds against
`
`Candida albicans at concentrations “between 0.1 wt% and 25 wt% of the
`
`composition.” (Ex. 1008, Brehove ¶ [0032], Table 1, Claim 14; Ex. 1005, Murthy
`
`Decl. ¶ 76.)
`
`Thus, Brehove taught a boron-based industrial fungicide to treat humans.
`
`(Ex. 1003, Kahl Decl. ¶ 40.) This is real world proof that a POSITA would not be
`
`discouraged, and would in fact select a boron-based industrial fungicide for use in
`
`humans to treat onychomycosis. (Ex. 1003, Kahl Decl. ¶ 40.) It discloses topical
`
`formulations of boron-based compounds, which were