Paper No. ___
`Filed: November 1, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`ACRUX DDS PTY LTD. & ACRUX LIMITED
`Petitioners,
`
`v.
`
`KAKEN PHARMACEUTICAL CO., LTD. and VALEANT
`PHARMACEUTICALS INTERNATIONAL, INC.,
`Patent Owner and Licensee
`
`
`
`Case: IPR2017-00190
`U.S. Patent No. 7,214,506
`
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`I.
` 
`
`II.
` 
`
`ARGUMENT SUMMARY .............................................................................. 1 
`
`THE PRIMARY REFERENCES DISCLOSE TREATING
`ONYCHOMYCOSIS BY ENHANCING DELIVERY OF
`ANTIFUNGALS .............................................................................................. 6 
`
`A. 
`
`B. 
`
`JP ’639 Discloses Methods for Effective Topical Treatment of
`Onychomycosis ...................................................................................... 7 
`
`The ’367 Patent and Hay Teach Methods for Effectively
`Topically Treating Onychomycosis ....................................................... 10 
`
`III.
` 
`
`PO MISCHARACTERIZES THE KAKEN ABSTRACTS AND
`OGURA ............................................................................................................ 11 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`E. 
`
`Efinaconazole’s Properties Were Known .............................................. 11 
`
`Efinaconazole’s Properties Were Desirable for Topically
`Treating Onychomycosis ........................................................................ 13 
`
`PO’S Arguments are Contrary to Kaken’s and Valeant’s
`Retrospective Explanations .................................................................... 14 
`
`Efinaconazole Was Known to Not Be Inactivated By Keratin .............. 15 
`
`PO’S Arguments Ignore The ’506 Patent’s Definitions ........................ 16 
`
`IV.
`
`  POSAS WERE MOTIVATED TO DEVELOP NEW TOPICAL
`ONYCHOMYCOSIS THERAPIES WITH A REASONABLE
`EXPECTATION OF SUCCESS ...................................................................... 17 
`
`V.
`
` 
`
`THERE IS NO CREDIBLE EVIDENCE OF SECONDARY
`CONSIDERATIONS OR THE NECESSARY NEXUS ................................. 18 
`
`A. 
`
`B. 
`
`PO’s Blocking Patents Render its Evidence Insufficient ....................... 19 
`
`PO’s Arguments that Jublia was a “Breakthrough” and a
`“Discovery” are Wrong and Contradicted by the Evidence .................. 19 
`
`C. 
`
`Alleged Industry Praise Has No Nexus and is Insufficient .................... 20 
`
` 
`
`ii
`
`

`

`D.  Alleged Commercial Success Has No Nexus and is Based on
`Improper, Unsupported Expert Testimony ............................................ 21 
`
`E. 
`
`PO’s Claims of Failure of Others and Long-felt, Unmet Need
`are Based on Improper Standards and Contradicted by its
`Expert’s and FDA’s Contemporaneous Statements ............................... 23 
`
`VI.
`
`  PO’S ALLEGED EVIDENCE OF PRIOR INVENTION IS
`LEGALLY AND FACTUALLY DEFICIENT................................................ 25 
`
`A. 
`
`B. 
`
`PO Impermissibly Relies on Uncorroborated Inventor
`Testimony ............................................................................................... 25 
`
`Even if it had Been Corroborated, PO’s Evidence of Alleged
`Prior Invention is Factually Deficient .................................................... 27 
`
`
`
`  CONCLUSION ................................................................................................. 28 VII.
`
`
`
`
`
`
`
` 
`
`
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases 
`
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) .............................................................................. 18
`
`Allergan, Inc. v. Teva Pharm. USA, Inc.,
`No. 15-1455, 2017 WL 4803941 (E.D. Tex. Oct. 16, 2017) ......................... 19, 23
`
`AstraZeneca LP v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2010) .............................................................................. 7
`
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) ............................................................................ 20
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) .............................................................................. 19
`
`Callaway Golf Co. v. Acushnet Co.,
`576 F.3d 1331 (Fed. Cir. 2009) ............................................................................ 17
`
`Cubist Pharms., Inc. v. Hospira, Inc.,
`805 F.3d 1112 (Fed. Cir. 2015) ............................................................................ 24
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) .......................................................................................... 16
`
`Genzyme Therapeutic Prods. Ltd. P'ship v. Biomarin Pharm. Inc.,
`825 F.3d 1360 (Fed. Cir. 2016) ............................................................................ 12
`
`Hahn v. Wong,
`892 F.2d 1028 (Fed. Cir. 1989) ............................................................................ 26
`
`In re Copaxone Consol. Cases,
`No. 14-1171-GMS, 2017 WL 401943 (D. Del. Jan. 30, 2017) ........................... 14
`
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996) .............................................................................. 23
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) ............................................................................ 26
`
` 
`
`iv
`
`

`

`In re Sasse,
`629 F.2d 675 (C.C.P.A. 1980) ................................................................................ 7
`
`In re Skoll,
`523 F.2d 1392 (C.C.P.A. 1975) ............................................................................ 20
`
`Insite Vision Inc. v Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) .............................................................................. 17
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................................ 7
`
`Mahurkar v. C. R. Bard, Inc.,
`79 F.3d 1572 (Fed. Cir. 1996) .............................................................................. 26
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) ..................................................................... 25, 27
`
`Merck & Cie v. Gnosis S.p.A.,
`808 F.3d 829 (Fed. Cir. 2015) .............................................................................. 18
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................ 19
`
`Mylan Labs. Ltd. v. Aventis Pharma S.A.,
`IPR2016-00712, Paper No. 99 (PTAB Sept. 21, 2017) .......................................... 7
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 13484 (Fed. Cir. 2007) .......................................................................... 10
`
`Pharmastem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ............................................................................ 20
`
`Reese v. Hurst,
`661 F.2d 1222 (C.C.P.A. 1981) ............................................................................ 26
`
`Shu-Hui Chen v. Bouchard,
`347 F.3d 1299 (Fed. Cir. 2003) ............................................................................ 26
`
`Tokai Corp. v. Easton Enters.,
`632 F.3d 1358 (Fed. Cir. 2011) ............................................................................ 24
`
`Other Authorities 
`
` 
`
`v
`
`

`

`Fed. R. Evid. 801 ..................................................................................................... 14
`
`Fed. R. EVid. 801 ..................................................................................................... 14
`
`
`
`
`
` 
`
`
`
`vi
`
`Vi
`
`

`

`
`I.
`
`ARGUMENT SUMMARY
`
`This Reply responds to Patent Owner’s Response (“POR”). Patent Owner
`
`(“PO”) confuses the bases for this IPR and the grounds on which it was instituted:
`
` The primary references are JP ’639 (Ex. 1011), the ’367 patent (Ex.
`
`1013), and Hay (Ex. 1014)—each of which taught topical application
`
`of antifungal compound(s) in a therapeutically effective amount for
`
`treating onychomycosis.
`
` The Kaken Abstracts, including the ICAAC abstracts belatedly
`
`produced by PO (Ex. 1015, Ex. 2036, Ex. 2037, Ex. 2038), and Ogura
`
`(Ex. 1012) taught that efinaconazole (“KP-103”) has broad-spectrum
`
`antifungal activity, has potent activity against the fungal species that
`
`were well-known causes of onychomycosis, and is not inactivated by
`
`keratin, which is ideal for topically treating infections of keratinized
`
`tissues.
`
` It would have been obvious to use an antifungal having
`
`efinaconazole’s properties to improve the primary references’ topical
`
`treatment methods.
`
` PO addresses the references in isolation and directs its arguments to
`
`anticipation, not the obviousness grounds on which this IPR was
`
`instituted.
`
` 
`
`1
`
`

`

`To support its arguments, PO must distort the ’506 patent’s express
`
`definitions of “onychomycosis” and “nail.”
`
` “Onychomycosis means a kind of the above-mentioned superficial
`
`mycosis, in the other word a disease which is caused by invading and
`
`proliferating in the nail of human or an animal. Trichophyton
`
`rubrum and Trichophyton mentagrophytes mainly cause
`
`onychomycosis in human.” Ex. 1001, 9:32-39.
`
` “The term ‘nail’ includes nail plate, nail bed, nail matrix, further side
`
`nail wall, posterial nail wall, eponychium and hyponychium which
`
`make up a tissue around thereof.” Id., 4:65-67.
`
` PO and its expert argue that “onychomycosis” should be limited to
`
`infection of both the nail plate and nail bed “in the deeper structures
`
`of the nail” and to exclude onychomycosis of skin structures of the
`
`nail, and white superficial onychomycosis (“WSO” or “SWO”). Ex.
`
`2027, ¶¶ 81-85 (quoting ¶ 84).
`o Contrary to PO’s litigation arguments, Dr. Elewski published
`
`in 1998 (Ex. 2010, 5) that distal subungal onychomycosis
`
`(“DSO” or “DLSO”)—the most common type of
`
`onychomycosis—begins at the hyponychium, with invasion of
`
`the stratum corneum. Ex. 1508, 86:12-18.
`
` 
`
`2
`
`

`

`o She admitted that SWO is a form of onychomycosis
`
`encompassed by the ’506 patent claims and for which
`
`“treatment is fairly simple, you can scrape it off and that would
`
`cure it or you can put any topical antifungal on it.” Id., 158:16-
`
`159:2. (emphasis added).
`
` Dr. Elewski criticizes and re-writes the ’506 patent’s definition of
`
`“nail” and admits her declaration opinions are based on her revised
`
`definition. Ex. 1508, 64:19-6.
`o She introduces the term “nail unit” to mean nail plate, matrix
`
`and bed, Ex. 2027, ¶¶ 81-85, even though “nail unit” is found
`
`nowhere in the ’506 patent.
`o She thereby excludes the skin structures that are included in the
`
`patent’s definition of “nail.” Ex. 1001, 4:65-67.
`
`PO’s arguments that efinaconazole was a “breakthrough” and that prior art
`
`topical agents did not work are contradicted by the evidence.
`
` By 1999, efinaconazole was a known antifungal and PO held patents
`
`covering the compound itself, and compositions and methods for
`
`treating mycoses by administering efinaconazole. Ex. 1007, 18:28-33,
`
`43-45, 55-57.
`
` 
`
`3
`
`

`

` Jublia® provided only a marginal improvement over prior art
`
`therapies—an improvement that was obvious and predictable in view
`
`of efinaconazole’s published properties.
`
` In contrast to her litigation-inspired opinions, Dr. Elewski published
`
`in 1995 that, due to new topical antifungals (amorolfine, tioconazole,
`
`and ciclopirox), “onychomycosis is no longer considered incurable,”
`
`Ex. 1502, 3.
`
` To support their arguments, PO and Dr. Elewski contend that a prior
`
`art antifungal cannot be considered a “success” unless it was FDA-
`
`approved, and argue that tioconazole (’367 patent and Hay) and
`
`amorolfine were therefore “failures.”
`
` The prior art reported successful cures of patients with topical
`
`antifungals, which were approved by 1999 in many countries
`
`including the U.K. (Trosyl® (tioconazole) and Loceryl®
`
`(amorolfine)). It is undisputed that the U.K. requires proof of safety
`
`and efficacy for approval. Ex. 1508, 116:7-12.
`
` The prior art is presumed to be enabling—PO submitted no evidence
`
`to rebut that presumption.
`
` 
`
`4
`
`

`

`Persons of ordinary skill in the art (“POSAs”) would have had a reasonable
`
`expectation of success in treating onychomycosis by topically administering a
`
`therapeutically effective amount of efinaconazole.
`
` The claims encompass any type of onychomycosis including early-
`
`stage DSO beginning with infection of the hyponychium (skin), as
`
`well as SWO. Ex. 1508, 92:17-93:11. Dr. Elewski admitted that the
`
`claims also include treating SWO, and that “treatment is fairly
`
`simple” by putting “any topical antifungal on it.” Id., 158:16-159:2.
`
` Efinaconazole’s known properties would have informed POSAs that it
`
`would penetrate the nail plate in an appropriate formulation. Ex. 1509,
`
`§§ VIII-X.
`
`PO’s attempt to remove Ogura as prior art fails.
`
` PO improperly relies solely on uncorroborated inventor testimony to
`
`prove earlier reduction to practice (“RTP”).
`
` PO relies on a document that it argues existed before the Ogura
`
`publication, but fails to provide testimony from the document’s
`
`alleged author, even though he is still employed by PO. Instead, PO
`
`improperly relies solely on uncorroborated inventor testimony in an
`
`effort to authenticate the document and establish its existence on the
`
`alleged date.
`
` 
`
`5
`
`

`

` Even had it been corroborated, the document is insufficient to prove a
`
`RTP.
`
`PO’s secondary considerations arguments fail on both factual and legal
`
`grounds.
`
` PO failed to prove a nexus between the alleged secondary factors and
`
`the claims.
`
` PO failed even to address that its own blocking patents negate its
`
`secondary considerations arguments. Ex. 1007; Ex. 1505; Ex. 1508,
`
`197:18-198:2.
`
` PO’s commercial success expert relied only on information provided
`
`to him by PO’s counsel and that he did not independently analyze. He
`
`failed to consider crucial relevant information, and based his opinions
`
`in part on prescription sales resulting from Valeant’s questionable
`
`business practices.
`
` THE PRIMARY REFERENCES DISCLOSE TREATING
`II.
`ONYCHOMYCOSIS BY ENHANCING DELIVERY OF
`ANTIFUNGALS
`
`PO incorrectly refers to JP ’639, the ’367 patent and Hay as “secondary art,”
`
`POR, 47. The instituted grounds are that it would have been obvious to improve
`
`topical antifungal therapies described in those references by using efinaconazole
`
` 
`
`6
`
`

`

`(described by Ogura and the Kaken Abstracts) as the antifungal agent. Institution
`
`Decision, 25.
`
`PO also addresses the references in isolation, arguing that each primary
`
`reference discloses drug(s) other than efinaconazole, and improperly equates
`
`“success” with FDA approval. POR, 47-56. AstraZeneca LP v. Apotex, Inc., 633
`
`F.3d 1042, 1064–65 (Fed. Cir. 2010) (lacking FDA approval does not demonstrate
`
`lack of drug utility); Mylan Labs. Ltd. v. Aventis Pharma S.A., IPR2016-00712,
`
`Paper No. 99, 37 (PTAB Sept. 21, 2017) (“FDA approval is not the
`
`appropriate standard for measuring success.”).
`
`A.
`
`JP ’639 Discloses Methods for Effective Topical Treatment of
`Onychomycosis
`
`Rather than considering the prior art as a whole, PO focuses on one example
`
`that used amorolfine as the antifungal agent. PO then argues that amorolfine was a
`
`“failure” because JP ’639 does not describe clinical testing and amorolfine lacks
`
`FDA approval. POR, 48-53. PO ignores that JP ’639 discloses methods of
`
`enhancing topical delivery of various antifungal compounds to treat
`
`onychomycosis, and the obviousness standard to be applied, i.e., what the
`
`references as a whole would teach one skilled in the art, KSR Int’l Co. v. Teleflex
`
`Inc., 550 U.S. 398, 418 (2007). PO also ignores that prior art is presumed
`
`enabling. In re Sasse, 629 F.2d 675, 681 (C.C.P.A. 1980). PO has not rebutted the
`
`presumption.
`
` 
`
`7
`
`

`

`Dr. Elewski admitted that her argument that amorolfine lacked FDA
`
`approval because it was ineffective was based on speculation. Ex. 1508, 116:21-
`
`117:17. In fact, Loceryl® (amorolfine) is a topical onychomycosis product
`
`marketed since approval in 1991 in the U.K. and 50 other countries. Ex. 2057, 7;
`
`Ex. 2008, 12-13 (discussing successful amorolfine clinical trials and stating that
`
`“topical treatment is suitable for SWO and early DLSO”). Ex. 1509, § VII; Ex.
`
`1501, § IX.
`
`The obviousness question is not whether POSAs would have been led to
`
`efinaconazole by amorolfine, but rather whether POSAs would have been
`
`motivated by combined disclosures of JP ’639 and the Kaken Abstracts or Ogura,
`
`as a whole, to improve JP ’639’s method by using efinaconazole. As explained by
`
`Dr. Walters, POSAs were motivated to treat onychomycosis topically with potent
`
`antifungal agents having efinaconazole’s properties. Ex. 1509, § XIII.
`
`PO’s arguments regarding the preferred azoles in paragraph [0017] of JP
`
`’639 and the distinction between imidazoles from triazoles are misleading. POR,
`
`49; Ex. 1509, ¶ 29. As Dr. Elewski grudgingly admitted, the ’506 patent describes
`
`and claims both triazoles and imidazoles, Ex. 1508, 69:21-70:3; Ex. 1509, ¶ 34.
`
`Moreover, she published multiple advantages of triazoles over other azoles in
`
`1995, thereby providing POSAs with strong motivation to replace imidazoles with
`
`a triazole having efinaconazole’s known advantages. Ex. 1502, 2 (“The triazole
`
` 
`
`8
`
`

`

`ring may be responsible for increased potency, decreased toxicity, and a wider
`
`spectrum of action than the azoles [footnotes omitted].”) PO’s analysis ignores
`
`known advantageous properties of triazoles, specifically efinaconazole. Ex. 1509,
`
`§ IX.
`
`JP ’639 discloses that, by using its topical formulation to deliver any one of
`
`several antifungal agents, “it is possible to effectively treat trichophytosis,
`
`especially, tinea unguium.” Ex. 1011, [0073]. JP ’639 discloses that “the amount
`
`of the antifungal agent is 0.1 to 10 w/v%” (id., [0018]), which matches the
`
`preferred range in the ’506 patent specification (Ex. 1001, 9:50-51) and in PO’s
`
`prior efinaconazole patents, (Ex. 1007, 9:26-27, Ex. 1505, 10:28-29). JP ’639 in
`
`combination with the Kaken Abstracts or Ogura would have motivated POSAs to
`
`use efinaconazole as the antifungal for its known properties. Ex. 1509, §§ IV.C.,
`
`XII-XIII.
`
`PO’s arguments—that lack of actual testing of efinaconazole in nail meant
`
`that no conclusion could be drawn and that lack of FDA approval meant prior art
`
`compounds failed—are flawed. POR, 50-53. “[I]t would be inappropriate to
`
`engraft an efficacy or FDA approval requirement onto the obviousness analysis.”
`
`Mylan, IPR2016-00712, Paper No. 99, 29.
`
` 
`
`9
`
`

`

`B.
`
`The ’367 Patent and Hay Teach Methods for Effectively Topically
`Treating Onychomycosis
`
`PO discusses each of the ’367 patent and Hay in isolation. PO criticizes the
`
`’367 patent for lack of actual testing of tioconazole. POR, 53-55. Hay provides
`
`actual human testing of tioconazole, so PO alleges a “flawed study design.” POR,
`
`55-56. Not only are PO’s arguments incorrect, but PO applies incorrect legal
`
`standards and ignores what POSAs understood from the prior art as a whole.
`
`PO argues that, without actual in vivo testing, POSAs would “struggle to
`
`expect success treating onychomycosis” using the ’367 patent composition, or that
`
`composition substituted with efinaconazole. POR, 55. Obviousness requires only
`
`a reasonable expectation of success—not actual testing. Pfizer, Inc. v. Apotex,
`
`Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). The ’367 patent concludes that its
`
`“topical tioconazole formulation is effective in the treatment of onychomycosis.”
`
`Ex. 1013, 2:27–29. Combined with the Kaken Abstracts or Ogura, this disclosure
`
`provided POSAs a reasonable expectation of success. See Section IV; Ex. 1509,
`
`IV.B.
`
`PO argues that tioconazole was not FDA-approved and alleges it “failed.”
`
`POR, 55-56. However, Dr. Elewski admitted that successful onychomycosis
`
`treatment using tioconazole was known and Trosyl® was approved in the U.K. by
`
`1999. Ex. 1503, 4; Ex. 1508, 161:2-163:1, 115:15-116:1. In 1995, she published
`
`that “topical (amorolfine, ticonazole [sic, tioconazole], ciclopirox olamine)
`
` 
`
`10
`
`

`

`antifungals formulated for onychomycosis, have excellent safety profiles and have
`
`greatly improved the prognosis of onychomycosis. Due to these agents,
`
`onychomycosis is no longer considered incurable.” Ex. 1502, 3 (emphasis
`
`added); Ex. 1508, 103:4-17; Ex. 1509, IV.B-C. Thus, PO’s attacks on tioconazole
`
`and amorolfine fail in view of what was known in the 1990s, including Dr.
`
`Elewski’s own contemporaneous publications.
`
`Further, Hay is available for all it teaches, including that “cures of
`
`onychomycosis are possible after topical therapy” and “it is possible to obtain
`
`clinical and mycological cures in onychomycosis using topical therapy alone.” Ex.
`
`1014, 1, 5; Ex. 1510, § VI.B; Ex. 1509, § IV.C.
`
`PO failed to demonstrate non-enablement. Primary reference disclosures, in
`
`combination with efinaconazole’s known properties disclosed in the Kaken
`
`Abstracts or Ogura, provided a reasonable expectation of success. Section IV; Ex.
`
`1509, § XIII.
`
` PO MISCHARACTERIZES THE KAKEN ABSTRACTS AND
`III.
`OGURA
`A. Efinaconazole’s Properties Were Known
`PO argues that the Kaken Abstracts and Ogura offer no “guidance on the
`
`therapeutic efficacy of efinaconazole when applied topically to nail.” POR, 35, 43-
`
`44. PO views references in isolation, ignores relevant disclosures, and assumes
`
`“nail” to mean “nail plate” contrary to the ’506 patent’s definitions. PO also
`
` 
`
`11
`
`

`

`ignores that, before the filing date, efinaconazole was patented for treating
`
`“mycosis,” which Dr. Elewski admitted includes onychomycosis. Ex. 1007; Ex.
`
`1508, 197:18-198:2; Ex. 1509, §§ V, VI.
`
`With its POR, PO produced more detailed versions of the Kaken Abstracts
`
`that PO published in 1996. Ex. 2036-2038.1 Dr. Elewski admitted that she did not
`
`see these publications when she wrote her opinion. Ex. 1508, 38:3-19. PO failed
`
`to disclose these publications to the Office during prosecution of the ’506 patent
`
`and failed to disclose them during the institution phase.
`
`The Kaken Abstracts disclose that efinaconazole “has a low affinity with
`
`keratin,” “showed low adsorption to keratin and high release from keratin as
`
`compared with [reference drugs] (Table 7 and Figure 3),” “has a broad antifungal
`
`spectrum and could keep a high activity in the horny layer where fungi reside” and
`
`Table 1 shows that KP-103’s antifungal activity was potent against the most
`
`common causes of onychomycosis (C. albicans, T. rubrum and T. mentagrophytes)
`
`as defined in the ’506 patent. Ex. 2037, 3-4; Ex. 1001, 9:32-39; Ex. 1509, § V.
`
`Further, the Introduction section (Ex. 2037, 4) lists numerous drugs known for
`                                                            
`1 “[T]he Board may consider a prior art reference to show the state of the art at the
`
`time of the invention, regardless of whether that reference was cited in the Board's
`
`institution decision.” Genzyme Therapeutic Prods. Ltd. P'ship v. Biomarin Pharm.
`
`Inc., 825 F.3d 1360, 1369 (Fed. Cir. 2016).
`
` 
`
`12
`
`

`

`treating onychomycosis, (cf. Ex. 2065, 5, 9, 27). Ex. 1509, ¶48. Thus, PO’s
`
`arguments that POSAs would not have connected the Kaken Abstracts’ disclosure
`
`with onychomycosis treatment are without merit.
`
`PO misleadingly asserts that tested fungal strains are “not typically found in
`
`nail infections” or “also often infect skin.” POR, 35-36, 44. PO repudiates the
`
`patent’s definitions of “nail” and “onychomycosis,” which specifically identified
`
`the same fungal strains. Ex. 1509, § V. PO’s arguments are also contradicted by
`
`contemporaneous literature, including PO’s expert’s publications, and should be
`
`rejected.
`
`B.
`
`Efinaconazole’s Properties Were Desirable for Topically Treating
`Onychomycosis
`
`Efinaconazole’s properties are in a “sweet spot” for topical onychomycosis
`
`therapeutics. Ex. 2050, 173:11-174:10. Specifically, Dr. Elewski’s argument that
`
`efinaconazole’s molecular weight and hydrophilicity would have led away from its
`
`use for treating onychomycosis is rebutted in detail by Dr. Walters—a pioneer in
`
`permeation characteristics of the nail plate and the skin. Ex. 1509, §§ VIII-X. In
`
`fact, POSAs would have understood that these properties uniquely suited
`
`efinaconazole for topical treatment of onychomycosis.
`
`
`
`In addition, the Kaken Abstracts demonstrated efinaconazole’s potent and
`
`broad-spectrum activity against microorganisms causing 90% of onychomycosis,
`
`and its high retention in the horny layer where fungi reside and low adsorption to
`
` 
`
`13
`
`

`

`keratin in contrast to other known topical antifungals. Ex. 1015; Exs. 2036-2038;
`
`Ex. 1510, § VI.D.
`
`C.
`
`PO’S Arguments are Contrary to Kaken’s and Valeant’s
`Retrospective Explanations2
`Ex. 2055 (“Efinaconazole in the treatment of onychomycosis”), sponsored
`
`by Valeant, concisely explains the rationale for Jublia® with citations to prior art
`
`on page 165:
`
`In vitro studies showed that efinaconazole had potent activity
`against C. albicans, Cryptococcus neoformans, Aspergillus fumigatus,
`and T. mentagrophytes, similar to other synthesized azoleamine
`agents.18 [Ref 18 is Ogura-Ex. 1012] Since the activities of many
`antifungal drugs are inhibited with keratin binding,27 [Ref. 27 was
`published in 1990, Ex. 1513, and cited as Ref. 13 in Ogura-Ex. 1012,
`4] efinaconazole’s activity was tested against T. mentagrophytes in the
`presence of keratin. Efinaconazole demonstrated less deactivation
`than its comparators in the presence of keratin, which was attributed
`to its 4-methylenepiperidino group. . . .
`
`Efinaconazole was subsequently shown to have excellent in vitro
`activity against T. rubrum and T. mentagrophytes, surpassing that of
`                                                            
`2 Disclosures in post-filing publications sponsored by PO can be considered party-
`
`opponent admissions and used to confirm the court’s prior art analysis. Fed. R.
`
`Evid. 801(d)(2); In re Copaxone Consol. Cases, No. 14-1171-GMS, 2017 WL
`
`401943, *20 (D. Del. Jan. 30, 2017).
`
` 
`
`14
`
`

`

`the reference drugs neticonazole and clotrimazole but less so than
`lanoconazole and butenafine. A similar effect was seen for the
`organisms . . . . In addition, efinaconazole was the only agent whose
`activity against T. mentagrophytes was unaffected by the presence of
`serum or keratin. [These results were disclosed in 1996-Ex. 2037, 4].
`
`Other PO-sponsored publications evidence that low adsorption to keratin and
`
`the reduced inactivation reported in the Kaken Abstracts and Ogura were
`
`recognized desirable properties for topical efficacy in the 1990s. Ex. 2016, Ex.
`
`2049, Ex. 2084; Ex. 1509, § IX.
`
`D. Efinaconazole Was Known to Not Be Inactivated By Keratin
`PO misleadingly confuses the known problem of keratin inactivation of
`
`topical antifungals and the desirability of keratin affinity for oral antifungals to be
`
`targeted to and persist in keratinized tissues for therapeutic effect. POR, 38-39, 45;
`
`Ex. 1509, §§ V, IX; Ex. 1012, 4 (noting that activity of KP-103 was less affected
`
`than other drugs and it “could retain a high level of activity in the keratinized
`
`tissue”). Dr. Elewski admitted that the references she cites for the proposition that
`
`keratin affinity is a desirable property all relate to orally-administered antifungals
`
`(Ex. 1508, 124:20-126:4; 185:11-22 (Ex. 2010, Table 2 discusses orally-
`
`administered drugs)). She admitted that the literature cites low keratin affinity to
`
`explain efinaconazole’s efficacy. Ex. 1508, 129:16-21 (referencing Ex. 2084).
`
`Contrary to PO’s arguments, KP-103’s lack of inactivation by keratin and the
`
` 
`
`15
`
`

`

`desirability of that property for topical efficacy were known. Ex. 1509, § IX.
`
`Thus, PO’s teaching away arguments fail.
`
`PO’S Arguments Ignore The ’506 Patent’s Definitions
`
`E.
`Dr. Elewski testified that her opinions are based on how she would have
`
`“rewritten” the definition of “nail” narrowly. Ex. 1508, 64:19-6. She admitted that
`
`her contemporaneous articles explained that onychomycosis usually begins in the
`
`hyponychium or nail fold (skin structures). Id., 81:14-82:8 (discussing Ex. 2010);
`
`88:15-90:18 (discussing Ex. 1500), 91:5-92:16 (discussing Ex. 1501). PO’s
`
`litigation-inspired attempts to narrow expressly-defined terms should be rejected.
`
`37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`
`(2016).
`
`PO’s narrowed definition of “onychomycosis” requires that the nail plate
`
`and the nail bed both must be infected “in the deeper structures of the nail” and
`
`excludes onychomycosis of skin structures that make up the nail unit, and SWO.
`
`Ex. 2027, ¶ 84. Dr. Elewski admitted that “onychomycosis” as used in the claims
`
`is broader and includes SWO, for which “treatment is fairly simple, . . .you can put
`
`any topical antifungal on it.” Ex. 1508, 158:8-159:8. Efinaconazole was a known
`
`topical antifungal with potent activity against the fungi that cause onychomycosis
`
`and is not inactivated by keratin. Thus, her admissions confirm that POSAs would
`
`have reasonably expected success in treating SWO by topically administering
`
` 
`
`16
`
`

`

`efinaconazole. Ex. 1510, ¶ 28. PO’s arguments should be rejected because they
`
`ignore the patent’s definitions and what POSAs knew at the time.
`
`IV.
`
` POSAS WERE MOTIVATED TO DEVELOP NEW TOPICAL
`ONYCHOMYCOSIS THERAPIES WITH A REASONABLE
`EXPECTATION OF SUCCESS
`
`PO’s expert admitted that POSAs were interested in finding new topical
`
`therapies in the 1990s. Ex. 1508, 84:8-85:3. Each primary reference discloses a
`
`method of treating onychomycosis by topically administering a therapeutically
`
`effective amount of an antifungal. Ex. 1509, ¶ 28. Given efinaconazole’s known
`
`characteristics, POSAs would have been motivated to improve the methods of each
`
`primary reference by using a potent, broad-spectrum antifungal agent that would
`
`not be inactivated by keratin—the main component of nail plate and skin’s horny
`
`layer.3 Ex. 1509, § XIII.
`
`PO’s reliance on Insite Vision Inc. v Sandoz, Inc., 783 F.3d 853, 860 (Fed.
`
`Cir. 2015) is misplaced because that case related to whether it would have been
`
`obvious to administer a drug topically that had previously only been administered
`
`orally. Id. at 860. In contrast, the issue here does not involve converting an oral
`
`drug to topical use: All cited references disclose topical use and efinaconazole’s
`
`                                                            
`3 PO’s argument regarding broader claim 1 on POR page 60 is unavailing.
`
`Callaway Golf Co. v. Acushnet Co., 576 F.3d 1331, 1344 (Fed. Cir. 2009).
`
`
`
` 
`
`17
`
`

`

`potent topical efficacy against onychomycotic fungi was known. POSAs would
`
`have had a reasonable expectation of success in improving known topical
`
`formulations by using efinaconazole given its known properties and topical
`
`efficacy.
`
`V.
`
` THERE IS NO CREDIBLE EVIDENCE OF SECONDARY
`CONSIDERATIONS OR THE NECESSARY NEXUS
`
`For secondary considerations to be given substantial weight, PO must
`
`present evidence and establish a nexus between the evidence and the claims. Merck
`
`& Cie v. Gnosis S.p.A., 808 F.3d 829, 837 (Fed. Cir. 2015). There is insufficient
`
`proof of either here.
`
`PO’s arguments based on failure of others, long-felt but unmet need,
`
`unexpected results,4 industry praise and commercial success are legally insufficient
`
`as not “commensurate in scope with the claims which the evidence is offered to
`
`support.” Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 965 (Fed. Cir. 2014)
`
`(quotation omitted). Even if accepted, in light of the breadth of claim 1, the
`
`evidence represents only a sliver of the claimed subject matter.
`
`                                                            
`4 PO implies that Jublia®’s clinical data reflected unexpected results, but provides
`
`no supporting evidence. POR, 61-62.
`
` 
`
`18
`
`

`

`PO’s Blocking Patents Render its Evidence Insufficient
`
`A.
`PO ignores that its prior-issued U.S. Patent 5,620,994 (“’994 patent”)
`
`covered the chemical compound genus of claim 1, fungicide compositions of those
`
`compounds, and methods of treating my