`
`Paper 1, November 21, 2017
`
`In the United States Patent and Trademark Office
`
`Before the Patent Trial and Appeal Board
`
`FLATWING PHARMACEUTICALS, LLC,
`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. 2018-00169
`______________________
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`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 Address .............................................................. xii
`
`(ii) Postal Mailing Address ..................................................................... xii
`
`(iii) Hand-Delivery Address ..................................................................... xii
`
`(iv) Telephone number ............................................................................. xii
`
`(v) Facsimile Number ............................................................................. xii
`
`INTRODUCTION .................................................................................................... 1
`
`GROUNDS FOR STANDING ................................................................................ 1
`
`BACKGROUND ...................................................................................................... 2
`
`I.
`
`Scope And Content Of The Prior Art ......................................................... 2
`
`A. Boron-Containing Compounds In General. ....................................... 2
`
`B. Prior Art Patents And Printed Publications. ...................................... 4
`
`– i –
`
`
`
`
`
`1. Austin........................................................................................... 5
`
`2. Brehove ........................................................................................ 7
`
`3. Freeman .................................................................................... 12
`
`4. Samour ...................................................................................... 16
`
`II. Level of Ordinary Skill in the Art ............................................................ 18
`
`III. The ’289 Patent Prosecution History. ....................................................... 19
`
`IDENTIFICATION OF THE CHALLENGE ..................................................... 24
`
`I. The Claims Challenged ............................................................................ 24
`
`II. Specific Grounds And Art. ....................................................................... 26
`
`III. Claim Construction ................................................................................... 27
`
`IV. How the claims are unpatentable. ............................................................. 29
`
`A. Explanation Of Ground 1 For Unpatentability: Claims 1 & 2 of
`the ’289 Patent are Obvious Over Austin in View of Brehove ......... 31
`
`1. All Elements of Claims 1 & 2 are Obvious Over Austin in
`View of Brehove ....................................................................... 31
`
`2. A POSITA Would Have Had Reason to Combine Austin and
`Brehove ..................................................................................... 33
`
`3. A POSITA Would Have Had a Reasonable Expectation of
`Success in Combining Austin and Brehove .............................. 36
`
`B. Explanation Of Ground 2 For Unpatentability: Claims 4–7 & 10–
`11 of the ’289 Patent are Obvious Over Austin in View of Brehove
`and Samour ....................................................................................... 41
`
`1. All Elements of Claims 4–7 & 10–11 are Obvious Over
`Austin in View of Brehove and Samour .................................... 41
`
`2. A POSITA Would Have Had Reason to Combine Austin,
`
`– ii –
`
`
`
`
`
`Brehove, and Samour and Would Have had a Reasonable
`Expectation of Success in Combining the Same ...................... 44
`
`C. 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 Handbook .............................. 46
`
`1. All Elements of Claims 3, 8–9 & 12–15 of the ’289 Patent
`are Obvious Over Austin in View of Brehove, Samour, and
`the Excipients Handbook .......................................................... 47
`
`2. A POSITA Would Have Had Reason to Combine Austin,
`Brehove, Samour, and the Excipients Handbook and Would
`Have had a Reasonable Expectation of Success in
`Combining the Same ................................................................. 50
`
`D. Explanation Of Ground 4 For Unpatentability: Claims 1 & 2 of
`the ’289 Patent are Obvious Over Austin in View of Freeman ........ 51
`
`1. All Elements of Claims 1 & 2 are Obvious Over Austin in
`View of Freeman ...................................................................... 51
`
`2. A POSITA Would Have Had Reason to Combine Austin and
`Freeman .................................................................................... 53
`
`3. A POSITA Would Have Had a Reasonable Expectation of
`Success in Combining Austin and Freeman ............................. 56
`
`E. Explanation Of Ground 5 For Unpatentability: Claims 4–7 & 10–
`11 of the ’289 Patent are Obvious Over Austin in View of Freeman
`and Samour ....................................................................................... 59
`
`F. 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 Handbook ............................. 60
`
`G. No Secondary Considerations Overcome This Strong Showing of
`Obviousness. ..................................................................................... 61
`
`CONCLUSION ....................................................................................................... 62
`
`– iii –
`
`
`
`
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .......................................................................................... 29, 61
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ............................................................................ 30
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) .............................................................................. 62
`
`In re Bigio,
`381 F.3d 1320 (Fed. Cir. 2004) ............................................................................ 30
`
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) .............................................................................. 30
`
`In re Gershon,
`372 F.2d 535 (CCPA 1967) .................................................................................. 62
`
`In re ICON Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) ..................................................................... 30, 31
`
`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986) ............................................................................ 32
`
`In re Piasecki,
`745 F.2d 1468 (Fed. Cir. 1984) ............................................................................ 61
`
`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) .............................................................................. 61
`
`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) .............................................................................. 61
`
`– 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) ............................................................................ 30
`
`Ryko Mfg. Co. v. Nu–Star, Inc.,
`950 F.2d 714 (Fed. Cir. 1991) .............................................................................. 61
`
`Scientific Plastic Products, Inc. v. Biotage AB,
`766 F.3d 1355 (Fed. Cir. 2014) ............................................................................ 31
`
`Unwired Planet, LLC v. Google Inc.,
`841 F.3d 995 (Fed. Cir. 2016) .............................................................................. 30
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ............................................................................ 61
`
`STATUTES
`
`35 U.S.C. § 102 ................................................................................................. 24, 26
`
`35 U.S.C. § 103 ........................................................................................... 24, 26, 29
`
`35 U.S.C. § 316 ........................................................................................................ 24
`
`35 U.S.C. §§ 311–319 ................................................................................................ 1
`
`37 C.F.R. § 42 et. seq. ..................................................................................... passim
`
`REGULATIONS
`
`
`
`
`
`
`
`– 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. 9,566,289
`
`Ex. 1002 Prosecution History of the ’289 Patent
`
`Ex. 1003 Declaration of Stephen Kahl, Ph.D
`
`SHORT FORM
`
`’289 Patent
`
`
`
`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
`
`1 As indicated in Petitioner’s mandatory disclosure of related matters, infra at x,
`
`Austin
`
`this petition is one of four that Petitioner has filed concurrently, requesting inter
`
`partes review of U.S. Patents Nos. 9,549,938 B2, 9,566,289 B2, 9,566,290 B2, and
`
`9,572,823 B2. To avoid confusion, Petitioner has numbered the same or
`
`corresponding exhibits consistently across all four Petitions, and in each filing has
`
`omitted Exhibits not discussed in that Petition.
`
`– vi –
`
`
`
`
`
`EXHIBIT1
`DESCRIPTION
`Ex. 1008 Brehove, U.S. Patent Pub. No. 2002/0165121
`
`SHORT FORM
`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
`Ex. 1011 Handbook of Pharmaceutical Excipients (Arthur H.
`Kibbe ed., 3d ed. 2000)
`Ex. 1012 U.S. Patent No. 7,582,621
`
`Samour
`Excipients
`Handbook
`’621 Patent
`
`Ex. 1013 Prosecution History of the ’621 Patent
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01776 (P.T.A.B. Feb. 23, 2017), Paper 70
`Ex. 1015 U.S. Patent No. 7,767,657
`
`Ex. 1014
`
`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
`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
`
`Ex. 1018
`
`Ex. 1020
`
`Murdan, Sudaxshina. “Drug delivery to the nail
`following topical application.” International journal
`of pharmaceutics 236, no. 1 (2002): 1–26.
`Ex. 1021 BioborJF® Specification Sheet (2015)
`
`Ex. 1022 BioborJF® Material Safety Data Sheet (2004)
`Ex. 1023 Remington: The Science and Practice of Pharmacy
`(Lippincott Williams & Wilkins eds., 21st ed. 2005)
`
`– vii –
`
`
`
`IPR ’776, FWD
`
`’657 Patent
`
`
`
`IPR ’780, FWD
`
`IPR ’785, FWD
`
`’894 Patent
`
`Murdan 2002
`
`
`
`
`
`
`
`
`
`EXHIBIT1
`DESCRIPTION
`Ex. 1024 Hawley’s Condensed Chemical Dictionary (John
`Wiley & Sons, Inc., 13th ed. 1997)
`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
`(retreived 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)
`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/22497
`760 (retrieved on May 26, 2017)
`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)
`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
`
`Ex. 1027
`
`Ex. 1028
`
`Ex. 1029
`
`Ex. 1030
`
`Ex. 1031
`
`
`
`Ex. 1025
`
`Ex. 1026
`
`SHORT FORM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Mertin 1997
`
`– viii –
`
`
`
`SHORT FORM
`
`Groziak 2001
`
`
`
`
`
`
`
`
`
`
`
`
`
`EXHIBIT1
`
`Ex. 1032
`
`DESCRIPTION
`Groziak, Michael P. “Boron therapeutics on the
`horizon,” American journal of therapeutics 8, no. 5
`(2001): 321–328
`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)
`
`Ex. 1033
`
`Ex. 1034
`
`Exs.
`1036–1042 Intentionally omitted- Exhibit numbers not used
`
`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 real parties-in-interest are FlatWing Pharmaceuticals, LLC, Rajneesh
`
`Ahuja, and Wicker Pharmaceuticals, LLC
`
`(collectively “FlatWing” or
`
`“Petitioner”).
`
`2.
`
`Related Matters, § 42.8(b)(2).
`
`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.
`
`This petition is one of four petitions that Petitioner has filed concurrently,
`
`requesting inter partes review of U.S. Patents Nos. 9,549,938 B2, 9,566,289 B2,
`
`9,566,290 B2, and 9,572,823 B2. Docket numbers for those P.T.A.B. proceedings
`
`are not yet available, but each of the four would or could affect, or be affected by, a
`
`decision in any of the other three proceedings
`
`– x –
`
`
`
`
`
`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.
`
`Lead counsel is:
`
`Philip D. Segrest, Jr. (Reg. No. 39,021)
`
`Back-up counsel is:
`
`– xi –
`
`
`
`
`
`4.
`
`Eric J. Rakestraw (Reg. No. 68,740).
`
`Service Information, § 42.8(b)(4)
`
`Papers concerning this matter should be served on the following:
`
`(i)
`
`Electronic Mailing Address
`
`Petitioner consents to service by email at:
`
`Philip.Segrest@HuschBlackwell.com
`Eric.Rakestraw@HuschBlackwell.com
`PTAB-ERakestraw@HuschBlackwell.com
`
`(ii) Postal Mailing Address
`
`HUSCH BLACKWELL, LLP
`Attn: Philip D. Segrest, Jr.
`120 South Riverside Plaza
`Suite 2200
`Chicago, Illinois 60606
`
`(iii) Hand-Delivery Address
`
`Same as postal mailing address.
`
`(iv) Telephone number
`
`(312) 655-1500
`
`(v) Facsimile Number
`
`(312) 655-1501
`
`– xii –
`
`
`
`
`
`INTRODUCTION
`
`FlatWing requests inter partes review under 35 U.S.C. §§ 311–319 and
`
`cancellation of claims 1–15 of U.S. Patent No. 9,566,289 (“’289 patent,” Ex.
`
`1001). The Office is authorized to charge petition fees and deficiencies to Deposit
`
`Acct. No. 23-0920, Cust. ID No. 24628. The ’289 Patent which relates to
`
`pharmaceutical formulations comprising tavaborole is invalid 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
`
`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.
`
`– 1 –
`
`
`
`
`
`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 (one of petitioner’s declarants) 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
`
`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
`
`
`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 –
`
`
`
`
`
`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),
`
`based on Austin’s disclosure of tavaborole4 as one of three preferred anti-fungal
`
`
`3 Ex. 1007, Austin et al., PCT Pub. No. WO 1995/033754 (“Austin”).
`
`4 Tavaborole is referred to as 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole in
`
`
`
`– 3 –
`
`
`
`
`
`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-
`
`based compounds are effective against the pathogens that cause onychomycosis,
`
`including Candida albicans and dermatophytes. (Ex. 1003, Kahl Decl. ¶ 34.)
`
`
`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”).
`
`– 4 –
`
`
`
`
`
`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
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`compound claimed for use in the ’289 Patent and was not novel in February 2005.
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`(Ex. 1003, Kahl Decl. ¶ 35; Ex. 1005, Murthy Decl. ¶ 60.)¶
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`Austin not only discloses “5- and 6-fluoro or bromo-1,3 dihydro-1hydroxy-
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`2,1-benzoxaborole” (which includes tavaborole), it includes tavaborole among
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`“[p]referred compounds” on the front page of the publication. (Ex. 1007, Austin at
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`[57] (Abstract); Ex. 1003, Kahl Decl. ¶ 36; Ex. 1005, Murthy Decl. ¶ 60.) In Table
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`9, it reports the antifungal bioactivity of the 5-fluoro (Example 64), 5-bromo
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`(Example 68), and 6-fluoro (Example 70) compounds. (Ex. 1007, Austin at 39; Ex.
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`1003, Kahl Decl. ¶ 36; Ex. 1005, Murthy Decl. ¶ 63.) Of the preferred compounds,
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`tavaborole (5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) demonstrated the
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`lowest Minimum Inhibitory Concentration (“MIC”) values, as low as five (5) parts
`
`per million (“ppm”), against several pathogens, including Candida albicans. (Ex.
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`1007, Austin at 39; Ex. 1003, Kahl Decl. ¶ 36; Ex. 1005, Murthy Decl. ¶ 63.) In
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`other words, of the three preferred compounds tested, tavaborole inhibited the
`
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`7 Supra, n.3.
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`– 5 –
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`
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`visible growth of Candida albicans (a fungus that causes onychomycosis,
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`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. ¶¶ 60, 65.)
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`Austin also discloses preparation of benzoxaborole derivatives, specifically
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`teaches tavaborole, even including its melting point and elemental analysis, and
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`formulations including tavaborole. (Ex. 1007, Austin at 24:1–15, 25 [Table 5], and
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`38:15–26; Ex. 1005, Murthy Decl. ¶ 61.) Austin further teaches that the
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`“concentration of the oxaborole in the biocide composition is . . . preferably from 1
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`to 50%, especially from 5 to 30% and more especially from 10 to 20% by weight
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`relative to the total weight of the biocide composition.” (Ex. 1007, Austin at 9:5–9;
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`Ex. 1005, Murthy Decl. ¶ 63.) Austin provides that “oxaborole . . . is preferably
`
`formulated in a composition together with a carrier,” carriers including “water or a
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`water-miscible organic solvent,” where “suitable water-miscible organic solvents
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`are . . . alcohols such as ethanol or glycols such as . . . propylene glycol.” (Ex. 1007,
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`Austin at 8:11–38; Ex. 1005, Murthy Decl. ¶ 63.)
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`Thus, Austin discloses a biocide composition formulated with tavaborole as
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`a preferred fungicide to effectively inhibit onychomycosis-causing Candida
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`albicans, in carriers including water-miscible solvents, such as ethanol and
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`– 6 –
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`
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`propylene glycol, at preferred concentrations of 5 to 30% and 10 to 20% by weight
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`relative to the total weight of the biocide composition. (Ex. 1007, Austin at 8:34–
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`39, 9:5–9; Ex. 1005, Murthy Decl. ¶¶ 64, 66.) As of February 16, 2005, a POSITA
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`would consider the preferred compound of Austin, the same compound recited in
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`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,
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`e.g., boron-based cyclic compounds. (Ex. 1003, Kahl Decl. ¶ 45.)
`
`2.
`
`Brehove8
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`Brehove is a U.S. patent application publication that disclosed the use of
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`boron-containing compounds as anti-fungal agents to treat onychomycosis in
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`humans more than a year before the priority date of February 16, 2005. (Ex. 1003,
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`Kahl Decl. ¶ 37; Ex. 1005, Murthy Decl. ¶¶ 67–68.) Brehove disclosed the effective
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`use of the following boron-containing compounds to treat onychomycosis in
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`humans:
`
`
`8 Supra, n.5.
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`– 7 –
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`
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`(Ex. 1003, Kahl Decl. ¶ 38.)
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`Brehove discloses the topical application of boron-based compounds to
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`“treat and prevent the spread of nail infections or onychomycosis caused by
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`bacteria, fungi and other pathogens.” (Ex. 1008, Brehove at [57] (Abstract),
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`¶ [0003]; Ex. 1005, Murthy Decl. ¶ 68.) Brehove taught preparing topical
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`compositions containing these boron-based compounds were “highly effective” to
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`successfully treat humans suffering from onychomycosis. (See, e.g., Ex. 1008,
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`Brehove ¶¶ [0030]–[0038]; Ex. 1003, Kahl Decl. ¶ 40; Ex. 1005, Murthy Decl.
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`¶ 71.) This is the same pathogen inhibited in Austin with a boron-based compound.
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`(Ex. 1003, Kahl Decl. ¶ 40.)
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`Not only did Brehove successfully treat humans with this boron-based
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`compound, the compound was commercially sold as an industrial biocide for fuel
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`under the trade name BioborJF®. (Exs. 1021, 1022; Ex. 1003, Kahl Decl. ¶ 40.)
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`These compounds were previously sold commercially in antifungal additives for
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`leaded motor fuels in order to improve combustion efficiency, and U.S. Patent No.
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`2,741,548 had taught their synthesis. (Ex. 1008, Brehove ¶¶ [0015], [0023]; Ex.
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`1005, Murthy Decl. ¶ 70.) These compounds had been used under the trade name
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`BioborJF® as an antifungal fuel additive since 1965. (See Exs. 1021, 1022; Ex.
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`1005, Murthy Decl. ¶ 70.) The BioborJF® specification sheet explains:
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`– 8 –
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`
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`(Ex. 1021 at 1; Ex. 1005, Murthy Decl. ¶ 70.) BioborJF® is a recognized
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`antifungal for industrial applications.
`
`
`(Ex. 1021 at 1; Ex. 1005, Murthy Decl. ¶ 70.) The material safety datasheet for
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`BioborJF® from January 1, 2004, discloses its active ingredients as 2,2’-(1-
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`methyltrimethylene dioxy) bis-(4-methyl-1,3,2-dioxaborinane) and/or 2,2’-oxybis
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`(4,4,6-trimethyl-1,3,2-dioxaborinane), the very same compounds used to treat
`
`onychomycosis in humans by Brehove:
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`– 9 –
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`
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`
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`(Ex. 1022 at 1; Ex. 1005, Murthy Decl. ¶ 70.)
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`Brehove specifically applied topical compositions containing the active
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`ingredient in BioborJF® to five volunteers who presented with onychomycosis.
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`(Ex. 1008, Brehove ¶¶ [0034]–[0038]; Ex. 1005, Murthy Decl. ¶ 72.) In all five
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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
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`“[n]o skin irritation” seen or observed, and the patent stated “no side effects are
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`evident.” (Ex. 1008, Brehove ¶¶ [0022], [0030], [0034]–[0038]; Ex. 1005, Murthy
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`Decl. ¶ 72.)
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`Brehove further describes a number of topical formulations of the boron-
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`based compounds, including “[o]ne formulation [that] is conveniently applied
`
`nightly in a petroleum jelly or mineral oil base”; “[d]ilute compositions of the
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`active compounds in alcohol or acetone base [that have] the ability to deliver
`
`concentrated active ingredient as the solvent evaporates”; and “[a]nother
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`formulation [that] is conveniently applied once per week in a cellulose acetate
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`lacquer base.” (Ex. 1008, Brehove ¶ [0018]; Ex. 1005, Murthy Decl. ¶ 73.)
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`– 10 –
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`
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`
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`Brehove provides that the active ingredient may be combined with a
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`“penetration enhancer” that “increases the permeability of the skin to a drug,” (Ex.
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`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,
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`Brehove ¶ [0025]; Ex. 1005, Murthy Decl. ¶ 74.)
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`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.)
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`Brehove teaches the effectiveness of its organo-boron compounds against
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`Candida albicans at concentrations “between 0.1 wt% and 25 wt% of the
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`composition.” (Ex. 1008, Brehove ¶ [0032], Table 1, Claim 14; Ex. 1005, Murthy
`
`Decl. ¶ 76.)
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`Thus, Brehove taught a boron-based industrial fungicide to treat humans.
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`(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 previously used as leaded
`
`fuel additives, for application directly to the nail and surrounding skin of humans
`
`– 11 –
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`
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`to effectively treat onychomycosis. (Ex. 1008, Brehove ¶¶ [0005], [0018], [0034]-
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`[0038]; Ex. 1005, Murthy Decl. ¶ 78.)
`
`3.
`
`Freeman9
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`Freeman is an international patent application publication that discloses the
`
`use of boron-c