Case: 17-1947 Document: 19 Page: 1 Filed: 08/04/2017
`2017-1947
`
`In the United States Court of Appeals for the Federal Circuit
`
`
`ANACOR PHARMACEUTICALS, INC.,
`
`
`Appellant-Patent Owner,
`
`
`v.
`
`
`
`JOSEPH MATAL,
`
`Acting Undersecretary of Commerce
`for Intellectual Property and Interim
`Director of the United States Patent &
`Trademark Office,
`
`Intervenor.
`
`
`
`
`
`
`
`
`
`Appeal from the United States Patent and Trademark Office,
`Patent Trial and Appeal Board in No. IPR2015-01776
`
`
`BRIEF OF APPELLANT-PATENT OWNER
`
`
`
`
`Michael N. Kennedy
`Andrea G. Reister
`Evan S. Krygowski
`COVINGTON & BURLING LLP
`One CityCenter
`850 Tenth Street, NW
`Washington, DC 2001
`Tel: (202) 662-6000
`Fax: (202) 662-6291
`
`Attorneys for Appellant-
`Patent Owner
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`FlatWing Ex. 1043, p. 1
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`Case: 17-1947 Document: 19 Page: 2 Filed: 08/04/2017
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`CERTIFICATE OF INTEREST
`Pursuant to Federal Circuit Rule 47.4, Counsel for the Appellant-Patent
`
`Owner Anacor Pharmaceuticals, Inc. certifies the following:
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`1.
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`2.
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`3.
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`4.
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`The full name of every party or amicus represented by me is:
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`Anacor Pharmaceuticals, Inc.
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`The name of the real party in interest (if the party named in the caption
`is not the real party in interest) represented by me is:
`
`Sandoz Inc. was a real party in interest in IPR2015-01776 under 37 C.F.R.
`§ 42.8(b)(1), but Sandoz Inc. is not represented by me.
`
`All parent corporations and any publicly held companies that own 10
`percent or more of the stock of the party or amicus curiae represented by
`me are:
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`Pfizer Inc.
`
`The names of all law firms and the partners or associates that appeared
`for the party or amicus now represented by me in the trial court or agency
`or are expected to appear in this court (and who have not or will not enter
`an appearance in this case) are:
`
`Covington & Burling LLP: Enrique D. Longton, Jeffrey B. Elikan, George F.
`Pappas, Christopher K. Eppich, Paul J. Berman.
`
`Date: August 4, 2017
`
`
`
`
`i
`
`Respectfully Submitted:
`
` /s/ Michael N. Kennedy
`Michael N. Kennedy
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`FlatWing Ex. 1043, p. 2
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`Case: 17-1947 Document: 19 Page: 3 Filed: 08/04/2017
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`TABLE OF CONTENTS
`CERTIFICATE OF INTEREST ................................................................................ i
`TABLE OF AUTHORITIES .................................................................................... v
`STATEMENT OF RELATED CASES .................................................................. vii
`TABLE OF ABBREVIATIONS ........................................................................... viii
`JURISDICTIONAL STATEMENT ......................................................................... 1
`STATEMENT OF THE ISSUES ON APPEAL ...................................................... 1
`INTRODUCTION .................................................................................................... 3
`STATEMENT OF THE CASE ................................................................................. 7
`I.
`Claim 6 of the ’621 patent claims a method of treating onychomycosis,
`which is a fungal infection of the nail. ........................................................... 8
`A. Onychomycosis is primarily caused by dermatophytes, not
`yeasts such as those disclosed in Petitioner’s primary reference. ........ 8
`The record here demonstrates the lack of guidance in the prior
`art concerning the possible use of boron-containing compounds
`to treat onychomycosis. ...................................................................... 11
`Proceedings before the Board. ...................................................................... 13
`A.
`The Petition argued that a POSA would have extrapolated the
`properties described in either Brehove or Freeman to the
`compounds of Austin based on the compounds’ alleged structural
`similarities. ......................................................................................... 13
`The Board found the compounds of Austin, Brehove and
`Freeman to be structurally dissimilar. ............................................... 14
`The Board found a reasonable expectation of successfully
`treating dermatophytes only by departing from the Petitioner’s
`original obviousness theory. ............................................................... 15
`SUMMARY OF THE ARGUMENT ..................................................................... 17
`
`B.
`
`II.
`
`B.
`
`C.
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`ii
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`FlatWing Ex. 1043, p. 3
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`Case: 17-1947 Document: 19 Page: 4 Filed: 08/04/2017
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`II.
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`B.
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`B.
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`STANDARD OF REVIEW .................................................................................... 21
`ARGUMENT .......................................................................................................... 22
`I.
`The FWD should be reversed for failing to provide adequate notice of
`the arguments and evidence on which the FWD is based. ........................... 22
`A.
`The outcome-determinative
`argument
`in
`the Board’s
`obviousness analysis for Claim 6 was not in the Petition. ................. 24
`The Board’s analysis of Claim 6 relied entirely on evidence that
`was not in the Petition. ....................................................................... 27
`The FWD should be reversed for improperly shifting the burden of
`proving nonobviousness onto Anacor. ......................................................... 30
`A.
`The Board improperly required Anacor to prove that tavaborole’s
`activity against C. albicans does not provide a reasonable
`expectation of activity against dermatophytes. .................................. 32
`The Board improperly required Anacor to prove that potency
`against C. parapsilosis is unrelated to potency against C.
`albicans. ............................................................................................. 34
`III. The FWD should be reversed because the Board’s obviousness theory
`lacks a rational underpinning and is not supported by substantial
`evidence. ....................................................................................................... 36
`A.
`Substantial evidence does not support the conclusion that the
`compounds of Austin are “structurally similar” to the compounds
`of Brehove and Freeman. ................................................................... 39
`1.
`Petitioner did not disagree that the compounds of Austin
`possess structural differences from the compounds of
`Brehove and Freeman. ............................................................. 40
`The Board ignored evidence from both parties that a
`POSA would have expected structural differences
`between the compounds of Austin, Brehove and Freeman
`to cause those compounds to exhibit different biological
`activities. .................................................................................. 42
`
`2.
`
`iii
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`FlatWing Ex. 1043, p. 4
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`Case: 17-1947 Document: 19 Page: 5 Filed: 08/04/2017
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`3.
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`B.
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`C.
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`The Board failed to show by substantial evidence that the
`compounds of Austin, Brehove and Freeman are
`“structurally similar.” ............................................................... 43
`Substantial evidence does not support the conclusion that the
`compounds of Austin are “functionally similar”
`to
`the
`compounds of Freeman. ..................................................................... 47
`Substantial evidence does not support the conclusion that the
`combination of Austin and Freeman would provide a POSA with
`a reasonable expectation of successfully treating dermatophytes
`with tavaborole. .................................................................................. 48
`CONCLUSION ....................................................................................................... 51
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`iv
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`FlatWing Ex. 1043, p. 5
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`Case: 17-1947 Document: 19 Page: 6 Filed: 08/04/2017
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`
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`TABLE OF AUTHORITIES
`
` Page(s)
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`Cases
`In re Beasley,
`117 F. App’x 739 (Fed. Cir. 2004) ............................................................... 22, 44
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015 ................................................................ 17, 22, 23
`Cuozzo Speed Techs., LLC v. Lee,
`136 S.Ct. 2131 (2016) ......................................................................................... 23
`Daiichi Sankyo Co, Ltd. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .......................................................................... 37
`Dell Inc. v. Acceleron, LLC,
`818 F.3d 1293, 1301 (Fed. Cir. 2016) ................................................................ 23
`Duke Univ. v. BioMarin Pharm. Inc.,
`--- F. App’x ----, 2017 WL 1458866 (Fed. Cir. Apr. 25, 2017) ......................... 47
`In re Gartside,
`203 F.3d 1305 (Fed. Cir. 2000) .............................................................. 21, 44, 50
`In re Grabiak,
`769 F.2d 729 (Fed. Cir. 1985) ............................................................................ 37
`Intellectual Ventures II LLC v. Ericsson Inc.,
`--- Fed. App’x ----, 2017 WL 1380616 (Fed. Cir. Apr. 18, 2017) ..................... 31
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ........................................................ 24, 28, 29, 30
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 36
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 36, 38
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) ...................................................................passim
`
`v
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`FlatWing Ex. 1043, p. 6
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`Case: 17-1947 Document: 19 Page: 7 Filed: 08/04/2017
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`
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`In re NuVasive, Inc.,
`841 F.3d 966 (Fed. Cir. 2016) .....................................................................passim
`Oil States Energy Serv., LLC v. Greene’s Energy Grp., LLC,
`No. 16-712, 2017 WL 2507340 (U.S. June 12, 2017) ........................................ 51
`Rovalma S.A. v. Bohler-Edelstahl GmbH & Co. KG,
`856 F.3d 1019 (Fed. Cir. 2017) .......................................................................... 22
`SAS Inst., Inc. v. ComplementSoft, LLC,
`825 F.3d 1341 (Fed. Cir. 2016) .............................................................. 17, 23, 24
`W.L. Gore Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................... 35
`Statutes
`5 U.S.C. § 554(b)(3)................................................................................................. 23
`5 U.S.C. § 554(c) ..................................................................................................... 23
`5 U.S.C. § 556(d) ..................................................................................................... 23
`28 U.S.C. § 1295(a)(4)(A) ......................................................................................... 1
`35 U.S.C. § 311 .......................................................................................................... 1
`35 U.S.C. § 312(a)(3) ......................................................................................... 23, 28
`35 U.S.C. § 316(e) ................................................................................................... 30
`Other Authorities
`37 C.F.R. § 42.3 ......................................................................................................... 1
`37 C.F.R. § 42.23(b) .............................................................................. 23, 28, 29, 30
`Office Patent Trial Practice Guide,
`77 Fed. Reg. 48,756, 48,767 (Aug. 14, 2012) .................................................... 29
`
`
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`vi
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`FlatWing Ex. 1043, p. 7
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`Case: 17-1947 Document: 19 Page: 8 Filed: 08/04/2017
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`STATEMENT OF RELATED CASES
`Counsel for Anacor Pharmaceuticals, Inc. are not aware of any other cases
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`pending in this or any other court that will directly affect, or be directly affected by,
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`this Court’s decision in this appeal.
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`vii
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`FlatWing Ex. 1043, p. 8
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`Case: 17-1947 Document: 19 Page: 9 Filed: 08/04/2017
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`’621 patent
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`Anacor
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`APA
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`Austin
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`Board
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`Brehove
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`CFAD
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`FDA
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`Freeman
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`FWD
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`MIC
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`PBA
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`POSA
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`PTO
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`TABLE OF ABBREVIATIONS
`U.S. Patent Number 7,582,621
`
`Anacor Pharmaceuticals, Inc. (Appellant-Patent Owner)
`
`Administrative Procedure Act
`
`Int’l Pat. Appl. No. PCT/GB95/01206, to Peter William
`Austin et al. (filed May 26, 1995) (Ex. 1002)
`
`Patent Trial and Appeal Board
`
`U.S. Pat. Appl. No. 10/077,521, to James Edward Brehove
`(filed Feb. 15, 2002) (Ex. 1003)
`
`Coalition for Affordable Drugs X LLC (Petitioner)
`
`U.S. Food and Drug Administration
`
`Int’l Pat. Appl. No. PCT/US02/23252, to Amihay Freeman
`et al. (filed Jul. 23, 2002) (Ex. 1004)
`
`Final Written Decision
`
`minimum inhibitory concentration
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`phenyl boronic acid
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`person of ordinary skill in the art
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`U.S. Patent and Trademark Office
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`viii
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`FlatWing Ex. 1043, p. 9
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`Case: 17-1947 Document: 19 Page: 10 Filed: 08/04/2017
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`JURISDICTIONAL STATEMENT
`The Board had jurisdiction over IPR2015-01776 pursuant to 35 U.S.C. § 311
`
`and 37 C.F.R. § 42.3. The Board filed its FWD regarding the patentability of the
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`’621 patent on February 23, 2017. Anacor timely appealed on April 24, 2017. This
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`Court has jurisdiction under 28 U.S.C. § 1295(a)(4)(A).
`
`STATEMENT OF THE ISSUES ON APPEAL
`The single claim at issue on this appeal is drawn to a method of using a
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`compound named tavaborole to treat tinea unguium, the most common form of a
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`nail infection known as onychomycosis. Tinea unguium is caused by a family of
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`fungi called dermatophytes. The parties agree that Petitioner’s primary reference,
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`Austin, is silent about the activity of tavaborole’s class of compounds against
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`dermatophytes. The Board nonetheless found that Austin could be combined with
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`references disclosing different classes of compounds (Brehove and Freeman) to
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`arrive at the claimed invention, based on an assertion that the various compounds at
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`issue had “similar functional activity” and a POSA’s alleged knowledge that a
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`compound’s activity against the yeast C. albicans, as disclosed in Austin, provides a
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`reasonable expectation of activity against the dermatophytes that cause tinea
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`unguium. The issues on appeal are:
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`1. Whether the Board provided Anacor with notice of, and adequate
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`opportunity to respond to, the outcome-determinative argument that because activity
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` 1
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`FlatWing Ex. 1043, p. 10
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`Case: 17-1947 Document: 19 Page: 11 Filed: 08/04/2017
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`against C. albicans is predictive of activity against dermatophytes, the disclosure of
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`activity against C. albicans in Austin would have provided a POSA with a reasonable
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`expectation of successfully treating dermatophytes.
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`2. Whether the Board improperly shifted onto Anacor the burden of
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`disproving essential factual premises of its obviousness finding, namely that (i) C.
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`albicans activity provides a reasonable expectation of dermatophyte activity, and (ii)
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`Austin and Freeman disclose similar functional activities because activity against C.
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`albicans is closely related to activity against a different yeast, C. parapsilosis.
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`3A. Whether the Board’s obviousness theory—that a POSA would have
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`had a motivation to combine references disclosing structurally dissimilar
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`compounds, and a reasonable expectation of success in doing so, based on some
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`structural similarity between the compounds and a “similar functional activity”—
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`lacks a rational underpinning.
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`3B. Whether the Board lacked substantial evidence in support of its factual
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`findings that (i) the benzoxaboroles of Austin share a meaningful structural similarity
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`with the compounds of either Brehove or Freeman, (ii) the compounds of Austin and
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`Freeman disclose an overlapping functional activity, and (iii) a POSA would have
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`expected Austin’s benzoxaboroles to have activity against dermatophytes based on
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`Freeman’s disclosure of activity for phenyl boronic acid and pentafluorophenyl
`
` 2
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`
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`boronic acid.
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`FlatWing Ex. 1043, p. 11
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`

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`Case: 17-1947 Document: 19 Page: 12 Filed: 08/04/2017
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`INTRODUCTION
`After the obviousness theory on which trial was actually instituted was
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`decisively refuted, the Board “change[d] theories midstream,” without providing
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`Anacor with notice of the new obviousness theory or an adequate opportunity to
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`respond to that theory. The Board then applied its new theory to invalidate Claim 6
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`based on obviousness combinations that were not in the Petition. Thus, Anacor’s
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`patent rights were extinguished without the due process and fairness to which
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`Anacor was entitled.
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`At institution, the Board described Petitioner’s argument for Ground 1 as
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`follows: “both Austin and Brehove disclose [a class of compounds called] boron
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`heterocycles, and … a person of ordinary skill in the art would have expected that
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`compounds that share structural features would likely share functional features … .”
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`Appx320; see also Appx323 (describing a similar argument for Ground 2).
`
`Invalidating Claim 6 requires looking beyond Austin because the compounds in that
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`reference are tested only against a yeast called C. albicans, not a dermatophyte as
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`required by Claim 6. Thus, the Petition asserted that a POSA would have expected
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`the compounds of Austin to have activity against dermatophytes (as in Claim 6),
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`allegedly like the compounds of either Brehove or Freeman, based on structural
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`similarities among the compounds disclosed in the three references.
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` 3
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`FlatWing Ex. 1043, p. 12
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`Case: 17-1947 Document: 19 Page: 13 Filed: 08/04/2017
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`Anacor prepared its defense based on the Petition’s theory. During a two-day
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`cross examination, Petitioner’s chemistry expert admitted that significant structural
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`differences exist between Austin’s benzoxaboroles and the compounds of either
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`Brehove or Freeman. Petitioner’s formulation expert, Dr. Murthy, discredited his
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`own structural similarity arguments with the acknowledgment that he is not a
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`chemist. Appx5263. Meanwhile, Anacor’s chemistry expert, Dr. Reider, presented
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`evidence showing meaningful differences between the compounds in the asserted
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`references, and also demonstrated why a POSA would have expected even small
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`structural differences to result in unpredictable biological changes. This
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`unpredictability, in turn, would defeat any notion that there would be a reasonable
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`expectation of success in combining Austin with either Brehove or Freeman.
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` Having seen the essential premise of the Petition’s obviousness theory
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`destroyed, Petitioner began shifting to a new theory. Proving Claim 6 obvious
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`requires showing a reasonable expectation of success that tavaborole (one of the
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`multitude of compounds disclosed in Austin) would treat onychomycosis caused by
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`a dermatophyte. The Petition attempted to show this through Brehove and Freeman.
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`Petitioner’s Reply, by contrast, argued that a reasonable expectation of success was
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`established by combining (a) Austin’s disclosure that tavaborole had activity against
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`a yeast, C. albicans, which rarely even causes onychomycosis; and (b) references
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`not even cited in the Petition, Segal and Mertin, which the Reply argued established
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` 4
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`FlatWing Ex. 1043, p. 13
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`

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`Case: 17-1947 Document: 19 Page: 14 Filed: 08/04/2017
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`that activity against dermatophytes could be predicted by observed activity against
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`yeasts. This was essentially a new obviousness combination outside the grounds on
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`which trial was instituted.
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`The FWD turned on the Reply’s new argument. The Board found that
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`Austin’s own disclosure of activity against C. albicans was sufficient for a POSA to
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`predict activity against dermatophytes. But every piece of evidence cited by the
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`Board in accepting the new argument was presented with Anacor’s Response or
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`Petitioner’s Reply, not the Petition. The Board never revealed to Anacor that it
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`would consider the new argument, let alone use it to decide the fate of Claim 6. The
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`Board’s decision, therefore, violates Anacor’s due process and APA procedural
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`rights by failing to provide both notice of the outcome-determinative argument and
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`an adequate opportunity to respond. (See Part I below.)
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`The Board compounded its error by shifting the burden of persuasion onto
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`Anacor with respect to key aspects of the obviousness inquiry. (See Part II below.)
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`For example, Petitioner’s new obviousness argument cited a handful of examples of
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`other antifungals with similar activity against both dermatophytes and C. albicans.
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`Petitioner never addressed how these unrelated antifungals are relevant to the
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`question of whether a POSA would have expected Austin’s compounds to have
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`activity against dermatophytes. Despite a total lack of evidence related to tavaborole,
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`the Board accepted Petitioner’s argument and effectively shifted onto Anacor the
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` 5
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`FlatWing Ex. 1043, p. 14
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`Case: 17-1947 Document: 19 Page: 15 Filed: 08/04/2017
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`burden of proving that tavaborole would be expected to behave differently against
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`dermatophytes than Petitioner’s isolated examples.
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`The Board also shifted onto Anacor the burden of proving that Austin and
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`Freeman do not disclose “similar functional activity.” Despite the acknowledged
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`structural differences between the classes of compounds of Austin and Freeman, the
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`Board found that a POSA would have been motivated to combine the references with
`
`a reasonable expectation of success because Austin’s compounds possess activity
`
`against C. albicans while Freeman’s compounds allegedly possess activity against
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`C. parapsilosis. The Board accepted as fact that these represent similar functional
`
`activities, even though Petitioner presented no evidence on the issue, and the Board
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`faulted Anacor for the sufficiency of its evidence to the contrary. But the burden of
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`proof was Petitioner’s, and Anacor should not be punished for the absence of
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`evidence in record.
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`Not only is there a lack of evidence that Austin and Freeman disclose “similar
`
`functional activity,” but the FWD lacks substantial evidence that Austin’s
`
`benzoxaboroles are structurally similar to Brehove’s dioxaborinanes or Freeman’s
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`boronic acids. (See Part III below.) Although these classes of compounds all contain
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`boron atoms, Petitioner’s chemistry expert conceded that the structures are different,
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`and even explained why a POSA would have expected the compounds of Austin and
`
`Freeman to have different biological activities as a result of their structural
`
` 6
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`FlatWing Ex. 1043, p. 15
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`

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`Case: 17-1947 Document: 19 Page: 16 Filed: 08/04/2017
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`differences. Moreover, the FWD lacks substantial evidence that Freeman would
`
`have provided a reasonable expectation of success that Austin’s compounds would
`
`have activity against dermatophytes because one of the two compounds Petitioner
`
`identified as relevant from Freeman does not have any activity against
`
`dermatophytes. When the evidence is taken as a whole, it is clear that a POSA would
`
`not have had a motivation to combine the asserted references or a reasonable
`
`expectation of success in doing so.
`
`The Board’s decision for Claim 6 should be reversed for any one of these
`
`reasons.
`
`STATEMENT OF THE CASE
`U.S. Patent No. 7,582,621 (“the ’621 Patent”) claims methods of treating
`
`infections in animals comprising administering a therapeutically effective amount of
`
`the compound “tavaborole” (1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole).
`
`The ’621 Patent claims priority to a provisional application filed on February 16,
`
`2005. At issue in this appeal is the patentability of Claim 6 of the ’621 Patent. This
`
`claim narrows the method of treating “an infection” with tavaborole from
`
`independent Claim 1 to a method of treating “tinea unguium,” which is the most
`
`common form of “onychomycosis.”
`
` 7
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`FlatWing Ex. 1043, p. 16
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`

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`Case: 17-1947 Document: 19 Page: 17 Filed: 08/04/2017
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`I.
`
`Claim 6 of the ’621 patent claims a method of treating onychomycosis,
`which is a fungal infection of the nail.
`Onychomycosis refers to a fungal infection of the nail plate or nail bed.
`
`Appx6286. Onychomycosis can occur in either fingernails or toenails, and it is
`
`“characterized by the thickening of the nail, discoloration, separation of the nail plate
`
`from the nail bed, accumulation of subungual debris, nail plate dystrophy, and nail
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`brittleness.” Appx6289–90. Tinea unguium is onychomycosis caused by
`
`dermatophytes. Appx71; Appx1219.
`
`A. Onychomycosis is primarily caused by dermatophytes, not yeasts
`such as those disclosed in Petitioner’s primary reference.
`Dermatophytes are a class of fungi responsible for 90% to 95% of
`
`onychomycosis cases. Appx1558; Appx6288. Dermatophytes are uniquely
`
`successful at colonizing nails because they contain an enzyme called keratinase,
`
`which breaks down the major protein component of nails (i.e., keratin) for nutrients.
`
`Appx6286–88; Appx6301. The dermatophytes most often responsible for tinea
`
`unguium are Trichophyton (“T.”) rubrum, T. mentagrophytes, T. tonsurans, and
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`Epidermophyton floccosum. Appx6288–89.
`
`Candida albicans is a yeast disclosed in Austin and Brehove, not a
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`dermatophyte. C. albicans is responsible for less than 5% of onychomycosis cases.
`
`Appx6291–92 (citing Ex. 2049 (3.2%), Ex. 2027 (1–2%), Ex. 2066 (5.4%), Ex. 2059
`
`(0% in toenail onychomycosis), Ex. 2067 (0% in toenail onychomycosis), Ex. 2039
`
` 8
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`FlatWing Ex. 1043, p. 17
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`

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`Case: 17-1947 Document: 19 Page: 18 Filed: 08/04/2017
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`(7%)). Petitioner’s topical formulation expert, Dr. Murthy, initially argued that C.
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`albicans is “the most common pathogen associated with onychomycosis.”
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`Appx1211 (citing Ex. 1003 (Brehove) at ¶ 18). However, Dr. Murthy later agreed
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`that “T. rubrum is by far the most common pathogen causing onychomycosis.”
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`Appx5229; see also Appx5230; Appx10189 (Dr. Murthy admitting that mycology
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`is not his expertise).
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`Dermatophytes and C. albicans have enzymatic differences that not only
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`cause them to behave differently, but also potentially present different targets for
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`pharmaceuticals. For example, C. albicans does not produce keratinase, and thus, is
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`less capable of penetrating the nail than dermatophytes. Appx6300–01. Also unlike
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`dermatophytes, C. albicans produces a number of different enzymatic virulence
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`factors, such as phospholipases to break down cell membranes and allow C. albicans
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`to invade systemically and disseminate via the blood. Appx6300. The different
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`enzymatic virulence factors in dermatophytes and C. albicans usually cause these
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`classes of fungi to infect different parts of the body. Appx6300–01.
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`C. parapsilosis is the only yeast tested in Freeman. It is part of the normal
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`flora of the body as the major colonizer of the hands and subungual regions of
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`healthy adults. Appx6293–94. Anacor’s mycology expert Dr. Ghannoum presented
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`evidence that C. parapsilosis is merely a contaminant, and not a cause of
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`onychomycosis, because it normally lives in the subungual areas of healthy adults.
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` 9
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`FlatWing Ex. 1043, p. 18
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`Case: 17-1947 Document: 19 Page: 19 Filed: 08/04/2017
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`
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`Id. (citing Ex. 2049 and Ex. 2069). Petitioner’s expert, Dr. Murthy does not disagree
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`that C. parapsilosis is the major colonizer of healthy hands. See Appx1751;
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`Appx5230.
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`The record shows that dermatophytes and yeasts have many differences due
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`to the genetic dissimilarities between them. See, e.g., Appx6298–6300. In fact,
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`dermatophytes and yeasts “diverge at the taxonomic level of class”—the same
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`taxonomic level within the Kingdom Animalia at which mammals and fish diverge.
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`Id. The genetic differences between dermatophytes and yeasts, such as C. albicans,
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`cause these microorganisms to exhibit different “morphologies, macroscopic and
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`microscopic appearances, rates of growth, and biochemical characteristics.” Id.
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`Dermatophytes and yeasts also have different sensitivities to antifungal
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`compounds. The only mycologist in this case, Dr. Ghannoum, concluded that “a
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`2005 POSA could not have predicted the activity of a compound against
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`dermatophytes based on the activity against a different fungal microorganism, such
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`as a yeast.” Appx6318. Dr. Ghannoum provided the example of ketoconazole,
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`which “has potent antifungal activity against C. albicans but has poor activity
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`against the Trichophyton spp. T. rubrum and T. mentagrophytes.” Id. (citing Ex.
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`2105).
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`10
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`FlatWing Ex. 1043, p. 19
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`Case: 17-1947 Document: 19 Page: 20 Filed: 08/04/2017
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`
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`B.
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`The record here demonstrates the lack of guidance in the prior
`art concerning the possible use of boron-containing compounds to
`treat onychomycosis.
`The compound recited in Claim 6, tavaborole, as well as the various
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`compounds disclosed in the asserted references, contain boron atoms. Boron-
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`containing compounds rarely appear in medicinal chemistry literature. Indeed, most
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`examples of boron-containing compounds tested in animals resulted in unacceptable
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`toxicities. See Appx239–42, and citations therein; Appx6223–26, and citations
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`therein. Until the approval of Anacor’s KERYDIN® product, only one other boron-
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`containing drug was on the market. VELCADE®, which is a boronic acid and not a
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`benzoxaborole, had been approved for refractory multiple myeloma, a serious form
`
`of cancer. Appx4392; Appx6230. As is fairly common with cancer drugs,
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`VELCADE® exhibited severe side effects, including peripheral neuropathy and
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`major organ toxicities. Id. Consequently, little was known about the biological
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`properties of any boron-containing compound.
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`Tavaborole is from a class of compounds called “benzoxaboroles,” which had
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`never been tested in any animals as of 2005. Consequently, the relevant biological
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`properties, such as nail penetration, stability, efficacy, and even solubility, had not
`
`been reported for any member of this class of compounds. To identify
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`benzoxaboroles in the prior art, one must venture into prior art concerning biocides
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`for industrial applications. See Appx378–79. One example is the “Austin” reference
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`11
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`FlatWing Ex. 1043, p. 20
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`Case: 17-1947 Document: 19 Page: 21 Filed: 08/04/2017
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`
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`(Int’l Pat. Appl. No. PCT/GB95/01206, Ex. 1002), which disclosed that tavaborole
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`kills a handful of industrially relevant fungi, including C. albicans. Appx1067,
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`Example 64. Austin does not disclose the use of its benzoxaboroles in animals, and
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`instead shows that its compounds are useful as plastic preservatives. Appx1070–71.
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`The “Brehove” reference (U.S. Pat. Appl. No. 10/077,521, Ex. 1003) discloses
`
`an apparently unsuccessful attempt to develop a boron-containing pharmaceutical.
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`In this reference, an individual attempted to treat onychomycosis caused by C.
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`albicans using the active ingredients in a fuel additive called BioBor. Appx1081.
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`These compounds are boron-containing dioxaborinanes. Id. Brehove does not
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`disclose the use of its dioxaborinanes against any microorganism other than C.
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`albicans. Appx1083–84; see also Appx29.
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`The final reference upon which trial was instituted, “Freeman”, (Int’l Pat.
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`Appl. No. PCT/US02/23252, Ex. 1004) also discloses an attempt to develop a boron-
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`containing compound, in this case a boronic acid, as an onychomycosis treatment.
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`This reference, unlike Brehove, does not test its compounds against C. albicans. See
`
`Appx1099. Freeman also discloses no in vivo tests—it reports nothing more than
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`the potency of its compounds in Petri dishes. See id. Two compounds in Freeman
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`are relevant to this case: phenyl boronic acid (“PBA”) and pentafluorophenyl
`
`boronic acid. The former compound displayed activity against dermatophytes when
`
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`12
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`FlatWing Ex. 1043, p. 21
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`Case: 17-1947 Document: 19 Page: 22 Filed: 08/04/2017
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`tested at very high concentrations, and the latter displayed “no effect” against
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`dermatophytes. Id.
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`II.
`
`Pro