IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS X LLC,
`Petitioner,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Case No. IPR2015-01776
`Patent No. 7,582,621
`
`PATENT OWNER PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
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`DC: 5863873-19
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`

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`IPR2015-01776
`
`LIST OF EXHIBITS
`
`EXHIBIT
`Ex. 2001
`
`DESCRIPTION
`FDA Approved Label for KERYDIN® (Rev. 3/2015)
`
`Ex. 2002
`
`Ex. 2003
`
`Ex. 2004
`
`Ex. 2005
`
`Ex. 2006
`
`Ex. 2007
`
`Ex. 2008
`
`Ex. 2009
`
`Ex. 2010
`
`Ex. 2011
`
`Ex. 2012
`
`Ex. 2013
`
`Ex. 2014
`
`Fairchild et al., In Vitro Determination of Uptake, Retention,
`Distribution, Biological Efficacy, and Toxicity of Boronated
`Compounds for Neutron Capture Therapy: A Comparison of
`Porphyrins with Sulfhydryl Boron Hydrides, Cancer Res., vol. 50,
`pp. 4860-65 (1990)
`Charif et al., A Historical Perspective on Onychomycosis, Dermatol.
`Ther. vol. 3, pp. 43-45 (1997)
`Heath et al., Fatty Acid Biosynthesis as a Target for Novel
`Antibacterials, Curr. Opin. Invest. Drugs, vol. 5, pp. 146-53 (2004)
`Baldock et al., A Mechanism of Drug Action Revealed by Structural
`Studies of Enoyl Reductase, Science, vol. 274, pp. 2107-10 (1996)
`Biobor, R.E.D. Facts, EPA-738-R-93-004 (June 1993),
`http://nepis.epa.gov/Exe/ZyPDF.cgi?Dockey=200009P5.PDF
`Lefkovits et al., Direct Thrombin Inhibitors in Cardiovascular
`Medicine, Circulation, vol. 90, pp. 1522-36 (1994)
`Grassberger et al., Preparation and Antibacterial Activities of New
`1,2,3-Diazaborine Derivatives and Analogs, J. Med. Chem., vol. 27,
`no. 8, pp. 947-53 (1984)
`Baldock et al., Mechanism of Action of Diazaborines, Biochem.
`Pharm., vol. 55, pp. 1541-49 (1998)
`Heindel et al., The Developmental Toxicity of Boric Acid in Mice,
`Rats, and Rabbits, Environ. Health Perspect., vol. 102, suppl. 7, pp.
`107-12 (1994)
`Richardson, Clinical Update: Proteasome Inhibitors in
`Hematologic Malignancies, Cancer Treatment Rev., vol. 29, suppl.
`1, pp. 33-39 (2003)
`Bross et al., Approval Summary for Bortezomib for injection in the
`Treatment of Multiple Myeloma, Clin. Cancer Res., vol. 10, pp.
`3954-64 (2004)
`Adams, Proteasome Inhibitors as Therapeutic Agents, Expert Opin.
`Ther. Patents, vol. 13, no. 1, pp. 45-57 (2003)
`Dorland’s Illustrated Medical Dictionary, p. 211 (29th ed. 2000)
`
`- i -
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`

`
`IPR2015-01776
`
`EXHIBIT
`Ex. 2015
`
`DESCRIPTION
`Stedman’s Medical Dictionary, p. 204 (27th ed. 2000)
`
`Ex. 2016
`
`Ex. 2017
`
`Ex. 2018
`
`Ex. 2019
`
`Ex. 2020
`
`Ex. 2021
`
`Ex. 2022
`
`Ex. 2023
`
`Ex. 2024
`
`Ex. 2025
`
`Ex. 2026
`
`Ex. 2027
`
`Random House Webster’s Unabridged Dictionary, p. 209 (2nd ed.
`2001)
`Jordon et al., Boric Acid Poisoning: A Report of a Fatal Adult Case
`from Cutaneous Use. A Critical Evaluation of the Use of This Drug
`in Dermatologic Practice, JAMA Derm, vol. 75, pp. 720-28 (1957).
`Zhdankin et al., Synthesis and Structure of Benzoxaboroles: Novel
`Organoboron Heterocycles, Tetrahedron Lett., vol. 40, pp. 6705-08
`(1999)
`Triggle, Pharmacological Receptors: A Century of Discovery—and
`More, Pharm. Acta Helvetiae, vol. 74, pp. 79-84 (2000)
`Larsen et al., The Prevalence of Onychomycosis in Patients with
`Psoriasis and Other Skin Diseases, Acta Derm. Venereol., vol 83,
`pp. 206-09 (2003)
`Tatsumi et al., Therapeutic Efficacy of Topically Applied KP-103
`Against Experimental Tinea Unguium in Guinea Pigs in
`Comparison with Amorolfine and Terbinafine, Antimicrobial
`Agents and Chemotherapy, vol. 46, no. 12, pp. 3797-3801 (2002)
`Osborne et al., Antifungal Drug Response in an In Vitro Model of
`Dermatophyte Nail Infection, Med. Mycol., vol. 42, pp. 159-63
`(2004)
`Favre et al., Comparison of In Vitro Activities of 17 Antifungal
`Drugs Against a Panel of 20 Dermatophytes by Using a
`Microdilution Assay, J. Clin. Microbiol., vol. 41, no. 10, pp. 4817-
`19 (2003)
`Sangster, Octanol-Water Partition Coefficients of Simple Organic
`Compounds, J. Phys. Chem. Ref. Data, vol. 18, pp. 1111-1227
`(1989)
`Powers et al., Structure-Based Approach for Binding Site
`Identification on AmpC β-Lactamase, J. Med. Chem., vol. 45, pp.
`3222-34 (2002)
`Boric Acid, R.E.D. Facts, EPA-738-F-93-006 (Sept. 1993),
`http://archive.epa.gov/pesticides/reregistration/web/pdf/0024fact.pdf
`Vander Straten et al., Cutaneous Infections: Dermatophytosis,
`Onychomycosis, and Tinea Versicolor, Infect. Dis. Clinics N. Am.,
`vol. 17, pp. 87-112 (2003)
`
`- ii -
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`

`
`IPR2015-01776
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION .......................................................................................... 1
`
`BACKGROUND ............................................................................................ 6
`
`A. Anacor’s Surprising Discovery That Tavaborole Treats
`Onychomycosis .................................................................................... 6
`
`B.
`
`2005 State of the Art: Boron-containing Compounds Are Toxic ........ 7
`
`III. LEVEL OF ORDINARY SKILL IN THE ART .......................................... 15
`
`IV. CLAIM CONSTRUCTION ......................................................................... 16
`
`A.
`
`B.
`
`C.
`
`1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole ......................... 17
`
`Therapeutically Effective Amount ..................................................... 18
`
`Tinea Unguium ................................................................................... 18
`
`D. Dermatological Diseases and Tinea Pedis ......................................... 18
`
`V.
`
`THE PETITION FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CLAIM OF THE ’621 PATENT IS
`UNPATENTABLE ....................................................................................... 19
`
`A. Ground 1: The Petition Fails to Demonstrate That Claims 1-12
`Are Unpatentable Over Austin in View of Brehove .......................... 19
`
`1.
`
`2.
`
`A POSA would not have started with a compound
`selected from Austin ................................................................ 20
`
`A POSA would not have selected tavaborole from among
`Austin’s millions of compounds .............................................. 23
`
`a)
`
`b)
`
`c)
`
`Austin’s preferred boron-containing industrial
`biocides include millions of compounds ....................... 24
`
`Austin prefers other benzoxaboroles over
`tavaborole ...................................................................... 26
`
`Tavaborole’s molecular weight does not support its
`preference over other compounds ................................. 27
`
`- iii -
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`

`
`IPR2015-01776
`
`3.
`
`The Petition provides no credible reason to combine
`Austin and Brehove .................................................................. 29
`
`a)
`
`b)
`
`c)
`
`d)
`
`Brehove does not demonstrate that its
`dioxaborinanes, or the oxaboroles of Austin, are
`not toxic ......................................................................... 30
`
`Brehove’s dioxaborinanes are structurally different
`from Austin’s oxaboroles, including tavaborole ........... 32
`
`Brehove does not make tavaborole, one of Austin’s
`millions of compounds, obvious to try .......................... 35
`
`Brehove does not supply a reasonable expectation
`of success ....................................................................... 37
`
`4.
`
`The Petition fails to provide articulated reasoning
`supported by evidence for treating onychomycosis and
`other infections requiring nail penetration (claims 4, 6, 8,
`9, and 11) .................................................................................. 38
`
`B.
`
`Ground 2: The Petition Fails to Demonstrate That Claims 1-12
`Are Unpatentable Over Austin in View of Freeman .......................... 45
`
`1.
`
`2.
`
`A POSA would not have selected any compound from
`Austin, and certainly not tavaborole ........................................ 46
`
`The petition provides no credible reason to combine
`Austin and Freeman ................................................................. 47
`
`a)
`
`b)
`
`c)
`
`d)
`
`Freeman does not remedy the expectation that
`Austin’s benzoxaboroles would be toxic ....................... 47
`
`Freeman’s phenyl boronic acids are structurally
`different from Austin’s benzoxaboroles, including
`tavaborole ...................................................................... 48
`
`Freeman does not supply a reasonable expectation
`that any of Austin’s compounds would succeed ........... 51
`
`Freeman does not make tavaborole, one of
`Austin’s millions of compounds, obvious to try ........... 54
`
`- iv -
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`

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`IPR2015-01776
`
`3.
`
`The Petition fails to provide articulated reasoning
`supported by evidence for treating onychomycosis and
`other infections requiring nail penetration (claims 4, 6, 8,
`9, and 11) .................................................................................. 55
`
`C.
`
`Ground 3: The Petition Fails to Demonstrate That Claim 9 Is
`Unpatentable Over Austin in View of Freeman and Sun................... 58
`
`- v -
`
`

`
`TABLE OF AUTHORITIES
`
`IPR2015-01776
`
` Page(s)
`
`Cases
`Apple, Inc. v. ContentGuard Holdings, Inc.,
` IPR2015-00441, Paper No. 11 (PTAB July 13, 2015) ........................................ 4
`
`Coalition for Affordable Drugs VI LLC v. Celgene Corp.,
` IPR2015-01169, Paper No. 22 (PTAB Nov. 16, 2015) ........................... 5, 35, 51
`
`Eli Lilly & Co., v. Teva Pharm. USA, Inc.,
`619 F.3d 1329 (Fed. Cir. 2010) ...................................................................... 6, 38
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .......................................................................... 35
`
`Ex parte Sobajima,
`Appeal 2012-003087, 2014 WL 664007 (PTAB Feb. 18, 2014) ....................... 36
`
`Genetics Inst., LLC v. Novartis Vaccines and Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .......................................................................... 29
`
`Grain Processing Corp. v. Am.–Maize Prods. Co.,
`840 F.2d 902 (Fed. Cir. 1988) .............................................................................. 4
`
`In re Bigio,
`381 F.3d 1320 (Fed. Cir. 2004) .......................................................................... 23
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015), reh’g en banc denied, 793 F.3d
`1297 (Fed. Cir. 2015) .......................................................................................... 17
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 36
`
`In re ICON Health and Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) .................................................................... 17, 18
`
`In re Johnston,
`435 F.3d 1381 (Fed. Cir. 2006) .......................................................................... 47
`
`- vi -
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`IPR2015-01776
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) .......................................................................... 17
`
`InTouch Techs., Inc. v. VGO Commc’ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 54
`
`K-TEC, Inc. v. Vita-Mix Corp.,
`696 F.3d 1364 (Fed. Cir. 2012) .......................................................................... 23
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ...................................................................................... 29, 36
`
`MacDermid Printing Solutions LLC v. E.I. DuPont de Nemours &
`Co., Appeal 2014-001756, 2015 WL 1456091 (PTAB Mar. 27,
`2015) ............................................................................................................. 36, 54
`
`Otsuka Pharm. Co., Ltd. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ............................................................................ 21
`
`Pfizer Inc. v. Teva Pharm. USA, Inc.,
`555 F. App’x 961 (Fed. Cir. 2014) ..................................................................... 21
`
`Schering Corp. v. Geneva Pharm.,
`339 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 31
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .................................................................... 20, 21
`
`Torrent Pharm. Ltd. v. Merck Frosst Canada & Co.,
` IPR2014-00559, Paper No. 8 (PTAB Oct. 1, 2014) .................................... 29, 47
`
`Statutes & Regulations
`
`35 U.S.C. § 103(a) ................................................................................................... 19
`
`37 C.F.R. § 42.100(b) .............................................................................................. 16
`
`Other Authorities
`
`Bradford J. Duft, “Preparing the Patent Application,”
`UNDERSTANDING BIOTECHNOLOGY LAW: PROTECTION, LICENSING,
`AND INTELLECTUAL PROPERTY POLICIES 87 (Gale R. Peterson ed.,
`1993) ................................................................................................................... 32
`
`- vii -
`
`

`
`Manual of Patent Examining Procedure § 608.01(p) ............................................. 32
`
`Office Patent Trial Practice Guide,
`77 Fed. Reg. 48,756, 48,764, 48,766 (Aug. 14, 2012) ....................................... 17
`
`IPR2015-01776
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`
`
`- viii -
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`

`
`IPR2015-01776
`
`Patent Owner Anacor Pharmaceuticals, Inc. (“Patent Owner” or “Anacor”)
`
`provides the following Preliminary Response to the Petition filed by Coalition for
`
`Affordable Drugs X LLC (“Petitioner”) on August 20, 2015, requesting inter
`
`partes review of claims 1-12 of U.S. Patent No. 7,582,621 (“the ’621 Patent”) (Ex.
`
`1001). This Preliminary Response is timely filed within three months of the
`
`August 27, 2015, mailing date of the Notice of Filing Date Accorded to Petition
`
`(Paper No. 4). For at least the reasons set forth below, Patent Owner requests that
`
`the Patent Trial and Appeal Board (“PTAB”) deny inter partes review as to all
`
`grounds presented in the Petition.
`
`I.
`
`INTRODUCTION
`
`The ’621 Patent claims the use of tavaborole (5-fluoro-1,3-dihydro-1-
`
`hydroxy-2,1-benzoxaborole) – a single species of the large class of boron-
`
`containing benzoxaborole compounds − for treating fungal and other infections,
`
`and for inhibiting the growth of a fungus, in humans and animals. The commercial
`
`embodiment of the ’621 Patent is KERYDIN®, which was approved by the Food
`
`and Drug Administration in 2014 for the treatment of onychomycosis of the
`
`toenails due to Trichophyton rubrum or Trichophyton mentagrophytes, which are
`
`species of the dermatophyte type of fungus. See FDA Approved Label for
`
`KERYDIN®, Section 1 (Rev. 3/2015) (Ex. 2001). It is the first and only approval
`
`of tavaborole, or any oxaborole, for human or animal use.
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`1
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`IPR2015-01776
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`Try as it might, Petitioner cannot overcome the overwhelming evidence that,
`
`as of the early-2005 priority date of the ’621 Patent, a person of ordinary skill in
`
`the art (“POSA”) would have expected boron-containing compounds to be toxic to
`
`humans and other animals, and therefore not suitable for therapeutic use.
`
`Petitioner’s own references, and its own expert, confirm this expectation. A POSA
`
`would have had no reason to select tavaborole for development for human or
`
`animal use; and there was no basis for a reasonable expectation that tavaborole
`
`could be therapeutically effective, let alone safe. Petitioner cannot satisfy its
`
`burden of demonstrating a reasonable likelihood that one or more of the claims of
`
`the ’621 Patent are unpatentable.
`
`Austin (Ex. 1002) is entitled “Oxaboroles and Salts Thereof, and Their Use
`
`as Biocides,” and describes the application of oxaboroles solely for industrial
`
`purposes, such as “the protection of plastics materials.” See Ex. 1002 at Abstract.
`
`Biocides are poisons and other compounds designed to kill living organisms. The
`
`direction to use biocides for industrial purposes would not have provided a POSA
`
`with any reasonable expectation that the biocides would be safe and effective for
`
`the therapeutic human and animal uses claimed in the ’621 Patent. A POSA would
`
`not have consulted Austin in searching for therapeutically effective and safe
`
`pharmaceutical compounds.
`
`Brehove (Ex. 1003) expressly states that boron-containing compounds have
`
`2
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`IPR2015-01776
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`been found to be “very toxic.” Against this, Brehove provides only present-tense
`
`(prophetic) examples of the treatment of five individuals with a structurally distinct
`
`class of compounds. Brehove does not disclose any pharmacokinetic, safety, nail
`
`or skin permeability, toxicity or other actual clinical data. The reference purports
`
`to show that a dioxaborinane biocide used in diesel and jet fuel, and registered as a
`
`pesticide with the EPA, had in vitro activity against one specific fungal species that
`
`rarely causes onychomycosis. Brehove, however, provides no reason for a POSA
`
`to have selected a compound from Austin for development, or reasonably to have
`
`expected that tavaborole, a boron-containing industrial biocide from a structurally
`
`different class, would be non-toxic and therapeutically effective.
`
`The compounds of Freeman (Ex. 1004) – phenyl boronic acids – define
`
`another large class of compounds quite different from the oxaboroles of Austin that
`
`include tavaborole. Moreover, Freeman only explains how to conduct in vivo tests
`
`for efficacy and toxicity; and provides no actual results of any in vivo efficacy,
`
`toxicity, pharmacokinetic, pharmacodynamic or any other tests indicating that any
`
`of the compounds it discloses would be therapeutically effective or non-toxic. In
`
`fact, Freeman discloses that toxicity data on its compounds are “incomplete” and
`
`that those compounds are “harmful if swallowed.” Ex. 1004 at ¶ [0028]. Thus,
`
`Freeman would not change a POSA’s expectation that boron-containing biocides
`
`would be toxic to humans and other animals.
`
`3
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`IPR2015-01776
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`Petitioner’s own expert, Dr. Stephen Kahl, a chemist at the University of
`
`California, San Francisco, contributed to a POSA’s expectation of toxicity. Dr.
`
`Kahl’s declaration focuses on toxicology. Well before the 2005 priority date, he
`
`co-authored a paper emphasizing the toxicity of boron-containing compounds.
`
`Fairchild et al., In Vitro Determination of Uptake, Retention, Distribution,
`
`Biological Efficacy, and Toxicity of Boronated Compounds for Neutron Capture
`
`Therapy: A Comparison of Porphyrins with Sulfhydryl Boron Hydrides, Cancer
`
`Res., vol. 50, pp. 4860-65, at 4864 (1990) (reporting the “overt toxicity” of boron-
`
`containing compounds) (Ex. 2002).
`
`The only plausible explanation for Petitioner’s selection of Austin as a
`
`starting point is that Petitioner first looked to the claims of the ’621 Patent,
`
`searched the prior art for tavaborole, found Austin’s disclosure of the compound as
`
`one of millions of oxaborole (boron-containing) industrial biocides, and then
`
`through impermissible hindsight used “the [’621 Patent] as a guide through the
`
`maze of prior art references, combining the right references in the right way so as
`
`to achieve the result of the claims in suit.” Apple, Inc. v. ContentGuard Holdings,
`
`Inc., IPR2015-00441, Paper No. 11, at 14 (PTAB July 13, 2015) (quoting Grain
`
`Processing Corp. v. Am.–Maize Prods. Co., 840 F.2d 902, 907 (Fed. Cir. 1988))
`
`(further citations and internal quotation marks omitted). Along this hindsight-
`
`driven route, Petitioner committed further error by relying on compounds having
`
`4
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`IPR2015-01776
`
`very different structures with severe or at best untested toxicity, in the face of a
`
`POSA’s expectation in 2005 that boron-containing compounds, like tavaborole,
`
`would be toxic.
`
`The Petition does not provide articulated reasoning with rational
`
`underpinning to explain why a POSA, without the benefit of the claims and
`
`specification of the ’621 Patent, would have selected Austin as the starting point.
`
`Nor does the Petition provide any explanation, let alone with rational
`
`underpinning, of why a POSA, without guidance from the claims and specification
`
`of the ’621 Patent, would have selected tavaborole, a single species from among
`
`the millions disclosed by Austin or even characterized by Austin as preferred.
`
`The Petition also does not provide articulated reasoning with rational
`
`underpinning to explain why a POSA would have combined Austin with Brehove
`
`or Freeman or Sun. The PTAB recently confirmed what numerous courts have
`
`held: “even minor structural modifications to a chemical compound can have
`
`significant and highly unpredictable effects on functionality.” Coalition for
`
`Affordable Drugs VI LLC v. Celgene Corp., IPR2015-01169, Paper No. 22, at 17
`
`(PTAB Nov. 16, 2015) (denying inter partes review) (“CFAD VI”). The structural
`
`differences between the compounds of Austin, Brehove and Freeman are far from
`
`minor. In fact, they are substantial, making it impossible to extrapolate the
`
`functions and properties of one to the others. And the well-known toxicity of
`
`5
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`IPR2015-01776
`
`boron-containing compounds would have deprived a POSA of any expectation of
`
`success. See, e.g., Eli Lilly & Co. v. Teva Pharm. USA, Inc., 619 F.3d 1329, 1336-
`
`37 (Fed. Cir. 2010) (widely reported concerns about prior art compound defeat
`
`reasonable expectation of success).
`
`Petitioner’s use of hindsight is transparent. The Petition should be denied.
`
`II. BACKGROUND
`A. Anacor’s Surprising Discovery That Tavaborole Treats
`Onychomycosis
`
`Onychomycosis is a fungal infection of the nail. The dermatophyte
`
`Trichophyton rubrum is the major cause of onychomycosis. Ex. 1004 at ¶¶ [002],
`
`[008]; Charif et al., A Historical Perspective on Onychomycosis, Dermatol. Ther.
`
`vol. 3, pp. 43-45, at 43 (1997) (Ex. 2003). In February 2005, physicians typically
`
`treated onychomycosis with oral antifungals. See Ex. 1005 at 1:21-25. Topical
`
`antifungals were rarely effective, mainly due to the inability of topical drugs to
`
`penetrate the nail to the sites of infection. See id. at 1:18-21; Ex. 1028 at 2
`
`(“topical treatment of onychomycosis remains a drug delivery problem”).
`
`Anacor was founded in 2000 by researchers with the bold idea that boron-
`
`containing pharmaceuticals could be used to treat human disease, despite industry-
`
`wide concerns about the toxicity of boron-containing compounds. See, e.g., Heath
`
`et al., Fatty Acid Biosynthesis as a Target for Novel Antibacterials, Curr. Opin.
`
`Invest. Drugs, vol. 5, pp. 146-53, at 146 (2004) (Ex. 2004) (describing a class of
`
`6
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`

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`IPR2015-01776
`
`boron-containing compounds with good antimicrobial activity as “toxic due to the
`
`presence of boron atoms”). Over the next few years, scientists at Anacor refined
`
`their boron chemistry platform and amassed a substantial library of boron-
`
`containing structures.
`
`Anacor’s 2004 breakthrough with tavaborole was the result of serendipity.
`
`An Anacor scientist synthesized a different class of boron-containing compounds
`
`and identified an undesired byproduct in a reaction. On no more than a hunch and
`
`scientific curiosity, Anacor scientists decided to isolate and test it. They
`
`discovered that it possessed antifungal potency, and ultimately synthesized
`
`tavaborole. Surprisingly, it had the right combination of anti-fungal potency,
`
`safety, nail permeability, and clinical efficacy for development as a drug candidate
`
`for the treatment of onychomycosis. Anacor successfully developed tavaborole
`
`and in 2014 received FDA approval to market tavaborole solution (brand name
`
`KERYDIN®) for the topical treatment of onychomycosis due to the dermatophytes
`
`T. rubrum or T. mentagrophytes.
`
`2005 State of the Art: Boron-containing Compounds Are Toxic
`
`B.
`A POSA in early 2005 would have understood that boron-containing
`
`compounds were toxic, and thus unsuitable for use as pharmaceuticals. See, e.g.,
`
`Ex. 1003 at ¶¶ [0013]-[0014]; Ex. 2004 at 146; Baldock et al., A Mechanism of
`
`Drug Action Revealed by Structural Studies of Enoyl Reductase, Science, vol. 274,
`
`7
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`

`
`IPR2015-01776
`
`pp. 2107-10, at 2109 (1996) (Ex. 2005); Boric Acid, R.E.D. Facts, EPA-738-F-93-
`
`006 at 2-3 (Sept. 1993) (Ex. 2026) (boric acid, first registered as a pesticide in
`
`1948, has “moderate acute toxicity,” including “dermal toxicity”).
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`For decades prior to the filing of the ’621 Patent, scientists had failed in their
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`efforts to develop boron-containing pharmaceuticals. See, e.g., Grassberger et al.,
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`Preparation and Antibacterial Activities of New 1,2,3-Diazaborine Derivatives and
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`Analogs, J. Med. Chem., vol. 27, no. 8, pp. 947-53, at 952 (1984) (Ex. 2008).
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`Nearly every drug program based on a boron-containing compound failed due to
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`toxicity. See, e.g., Lefkovits et al., Direct Thrombin Inhibitors in Cardiovascular
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`Medicine, Circulation, vol. 90, pp. 1522-36, at 1525 (1994) (Ex. 2007).
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`By February 2005, the prior art was replete with examples of scientists
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`achieving excellent biological potency with organoboron drugs, but at the price of
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`unacceptable toxicity. See, e.g., id. (disclosing “adverse liver toxicity, believed to
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`be related to the boron constituent” in a series of thrombin inhibitors); Ex. 2008 at
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`952 (disclosing toxicity of diazaborines); Baldock et al., Mechanism of Action of
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`Diazaborines, Biochem. Pharm., vol. 55, pp. 1541-49, at 1541 (1998) (Ex. 2009)
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`(disclosing “the inherent toxicity of boron-containing compounds”); Ex. 2004 at
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`146 (disclosing that diazaborines “are toxic due to the presence of boron atoms”);
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`Ex. 2005 at 2109 (disclosing boron’s “inherent toxic potential”); Heindel et al.,
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`The Developmental Toxicity of Boric Acid in Mice, Rats, and Rabbits, Environ.
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`Health Perspect., vol. 102, suppl. 7, pp. 107-12, at Abstract (1994) (Ex. 2010)
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`(disclosing that boric acid is a “developmental toxicant”).1
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`Indeed, severe toxicity warnings surround the only other boron-containing
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`drug approved by FDA before February 2005 or since. Bortezomib (VELCADE®)
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`is a proteasome inhibitor (not an oxaborole) whose serious adverse effects are only
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`acceptable because the drug treats late-stage cancers. See Richardson, Clinical
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`Update: Proteasome Inhibitors in Hematologic Malignancies, Cancer Treatment
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`Rev., vol. 29, suppl. 1, pp. 33-39, at 36 (2003) (Ex. 2011). Medicinal chemists in
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`early 2005 viewed bortezomib as a cautionary tale of the severe toxicity associated
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`with boron-containing compounds. A POSA would have known that
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`“[b]ortezomib was poorly tolerated when administered daily, even at very low
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`doses.” Bross et al., Approval Summary for Bortezomib for Injection in the
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`Treatment of Multiple Myeloma, Clin. Cancer Res., vol. 10, pp. 3954-64, at 3956
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`(2004) (Ex. 2012). Toxicological studies of bortezomib in monkeys and rats
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`showed that it caused cardiotoxicity, neurotoxicity, and drug-related deaths in both
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`species. Id. at 3957. Bortezomib was also considered “likely to have an adverse
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`effect on pregnancy” based on a significant loss of fetuses in rabbit toxicity
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`studies. Id. A POSA in 2005 also would have known of clinical trials that had
`
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`1 A POSA also would have understood that effective treatment of onychomycosis
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`often requires months of antifungal treatment. See, e.g., Ex. 1028 at 6.
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`revealed that bortezomib causes adverse events, many serious, at all dose levels in
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`humans. Ex. 2011 at 35; see also Adams, Proteasome Inhibitors as Therapeutic
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`Agents, Expert Opin. Ther. Patents, vol. 13, no. 1, pp. 45-57, at Abstract (2003)
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`(Ex. 2013).
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`The references relied on by Petitioner – Austin, Brehove and Freeman – in
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`no way alter a POSA’s expectation in 2005 that boron-containing compounds
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`would be toxic. The very title of Austin, “Oxaboroles and Salts Thereof, and Their
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`Use as Biocides,” conveys this common expectation of toxicity. The defining
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`feature of a “biocide” is its ability to kill living organisms. See, e.g., Dorland’s
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`Illustrated Medical Dictionary, p. 211 (29th ed. 2000) (defining “biocide” as “an
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`agent that kills living organisms”) (Ex. 2014); Stedman’s Medical Dictionary, p.
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`204 (27th ed. 2000) (defining “biocidal” as “destructive of life; particularly
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`pertaining to microorganisms”) (Ex. 2015); Random House Webster’s Unabridged
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`Dictionary, p. 209 (2nd ed. 2001) (defining “biocide” as “any chemical that
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`destroys life by poisoning, esp. a pesticide, herbicide, or fungicide”) (Ex. 2016).
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`Even Brehove, relied upon by Petitioner, explicitly warns that boron-
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`containing compounds are “very toxic” and are “industrial poison[s].” See Ex.
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`1003 at ¶¶ [0013]-[0014]. The only class of compounds suggested by Brehove as
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`non-toxic is dioxaborinanes, and Brehove provides no actual data to support this
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`suggestion. Even if a POSA were to accept the teachings of Brehove at face value
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`(despite its very serious limitations as discussed in Section V.A.3 below), those
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`teachings would not change the POSA’s general expectation that, absent reliable
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`data showing otherwise, boron-containing compounds are toxic.
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`Freeman does nothing to change this expectation of toxicity. Freeman
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`reports that “[d]ata on [phenyl boronic acid’s] toxicity are incomplete” and that
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`phenyl boronic acid “is considered harmful if swallowed.” See Ex. 1004 at ¶
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`[0028]. Moreover, Freeman focuses on only one structurally distinct class out of
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`the myriad of classes of boron-containing compounds, and the Freeman class of
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`compounds is in any event structurally quite different from tavaborole, as well as
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`functionally different.
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`Medicinal chemists in early 2005 were also fully aware that boric acid is a
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`toxin produced by the body’s metabolism of boron-containing compounds. See
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`Ex. 1027 at 322 (explaining that “no matter whether a boronic acid-based
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`therapeutic agent is actively metabolized or simply undergoes chemical
`
`degradation in vivo, the production of boric acid is not to be unanticipated”).
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`Scientists with the National Toxicology Program at the National Institute of
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`Environmental Health Sciences warned that boric acid is a “developmental
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`toxicant” in three pre-clinical species. Ex. 2010 at Abstract. These authors also
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`noted “a report of increased malformations (especially congenital cataracts) among
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`children of pregnant women who used boric acid as a topical antimicrobial agent.”
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`Id. at 107. Topical application of boric acid for as little as 14 days can kill a
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`human. Jordon et al., Boric Acid Poisoning: A Report of a Fatal Adult Case from
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`Cutaneous Use. A Critical Evaluation of the Use of This Drug in Dermatologic
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`Practice, JAMA Derm., vol. 75, pp. 720-28 (1957) (Ex. 2017).
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`Petitioner’s own expert, Dr. Stephen Kahl, has contributed to creating the
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`expectation in early 2005 that boron-containing compounds are toxic. Dr. Kahl
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`has experience in the field of boron neutron capture therapy (“NCT”), which deals
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`with the treatment of often-inoperable cancers. He, too, has expressed concerns
`
`about the toxicity of boron-containing compounds. For example, an article he co-
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`authored in 1990 about the use of boronated compounds for NCT states, “[I]n vivo
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`toxicity is too complicated to be uniquely established by an in vitro test and …
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`ultimately, toxicity must be evaluated in animals. However, it should be noted that
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`the majority of [boronated] compounds synthesized for possible use in NCT
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`cannot be successfully administered because of overt toxicity.” Ex. 2002 at 4864
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`(emphasis added).
`
`Contradicting his own research and countless references describing the
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`toxicity of organoboron compounds, Dr. Kahl declares – without any citation
`
`support – that “[b]oron-containing compounds are generally considered safe.” Ex.
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`1006 at ¶ 30. Dr. Kahl references Austin, Brehove and Freeman to support this
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`broad generalization, but not one of these references provides any actual data
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`supporting the notion that a boron-containing compound could be safely and
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`effectively used in humans or other animals. As highlighted above and discussed
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`below, Dr. Kahl does not and cannot provide articulated reasoning supported by
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`rational underpinning to explain why a POSA would have combined the noted
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`references with a reasonable expectation that an industrial biocide of Au