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`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 No.: IPR2017-00190
`Patent No. 7,214,506 B2
`_______________
`
`
`REPLY DECLARATION OF KENNETH A. WALTERS, PH.D. IN SUPPORT
`OF PETITION FOR INTER PARTES REVIEW OF PATENT NO. 7,214,506
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`Page 1 of 97
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`ACRUX DDS PTY LTD. et al.
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`EXHIBIT 1509
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
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`
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`TABLE OF CONTENTS
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`I.
`
`II.
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`INTRODUCTION ........................................................................................... 1
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`SUMMARY ..................................................................................................... 2
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`III. ATTEMPTS TO NARROW CLAIM SCOPE LACK MERIT ....................... 3
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`IV. DR. ELEWSKI MISCHARACTERIZES JP ’639, THE ’367 PATENT,
`AND HAY ..................................................................................................... 16
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`A. Dr. Elewski’s Attacks on JP ’639 are Baseless .................................... 18
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`B.
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`C.
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`Dr. Elewski’s Attacks on the ’367 Patent are Baseless ....................... 20
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`Dr. Elewski’s Attacks on the Hay Reference are Baseless .................. 23
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`V.
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`DR. ELEWSKI MISCHARACTERIZES THE KAKEN
`ABSTRACTS ................................................................................................ 30
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`VI. DR. ELEWSKI MISCHARACTERIZES OGURA ...................................... 43
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`VII. TOPICAL ONYCHOMYCOSIS TREATMENTS WERE KNOWN ........... 53
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`VIII. DR. ELEWSKI’S ATTACKS ON THE MOLECULAR WEIGHT OF
`EFINACONAZOLE LACK MERIT ............................................................ 61
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`IX.
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`IT WAS KNOWN THAT KP-103 IS NOT INACTIVATED BY
`KERATIN UNLIKE OTHER TOPICAL ANTIFUNGAL AGENTS ........... 69
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`X. DR. ELEWSKI’S ARGUMENT THAT HYDROPHILIC
`MOLECULES WERE DISFAVORED LACKS MERIT .............................. 75
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`XI. DR. ELEWSKI’S OTHER ARGUMENTS ARE ALSO
`CONTRADICTED BY THE PRIOR ART .................................................... 77
`
`XII. EFINACONAZOLE WAS ALREADY A KNOWN POTENT
`TOPICAL ANTIFUNGAL COMPOUND BY 1999 ..................................... 81
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`XIII. POSAS WERE MOTIVATED TO TREAT ONYCHOMYCOSIS
`TOPICALLY WITH POTENT ANTIFUNGAL AGENTS SUCH AS
`EFINACONAZOLE ...................................................................................... 88
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`ii
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`XIV. PATENT OWNER’S ATTACKS ON MY EXPERTISE LACK
`MERIT ........................................................................................................... 91
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`XV. CONCLUSIONS ........................................................................................... 93
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`iii
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`Page 3 of 97
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`iv
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`iV
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`Page 4 of 97
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`Page 4 of 97
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`I, Kenneth A. Walters, Ph.D., hereby state the following:
`
`I.
`
`INTRODUCTION
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`1.
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`In this declaration, I am providing my expert opinions in support of
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`Petitioners’ Petition for Inter Partes Review of Patent No. 7,214,506 (the “’506
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`patent”) and in reply to Patent Owner’s Response, including the Declaration of
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`Boni E. Elewski, M.D., pursuant to 37 C.F.R. § 42.120.
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`2.
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`I previously provided a declaration dated October 28, 2016, as part of
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`the petition filed by Petitioners that led to this proceeding. My previous
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`declaration is Ex. 1005. I am competent to make this declaration based upon my
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`personal knowledge and technical expertise.
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`3.
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`All of the exhibits I have considered and on which I have relied in this
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`proceeding are the kinds of documents on which I typically rely when forming
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`scientific opinions, including the opinions I have offered in this proceeding.
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`4.
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`I reserve the right to supplement my opinions to address any
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`information obtained, or positions taken, based on any new information that comes
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`to light throughout this proceeding.
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`5.
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`I have read the Declaration of Boni E. Elewski, M.D. (Ex. 2027). Her
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`declaration does not change my previous opinions.
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`6.
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`In forming my opinions, I considered and relied on my knowledge,
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`education, experience, the references identified in Ex. 1005 and in this declaration.
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`I have also considered Patent Owner’s Response, Dr. Elewski’s declaration and
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`documents referenced therein, and Dr. Elewski’s deposition transcript (Ex. 1508).
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`II.
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`SUMMARY
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`7.
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`In this Reply Declaration, I discuss the following issues:
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`a) The term “onychomycosis” as used in the’506 patent and claims
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`includes any type of onychomycosis. Dr. Elewski’s attempts to
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`narrow this term lack merit. See Section III.
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`b) As acknowledged in her deposition, the term “onychomycosis”
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`includes white superficial onychomycosis, which a POSA would have
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`known to treat topically. Ex. 1508, 158:16-159:2. See Section VII.
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`c) The term “nail” as used in the’506 patent and claims includes the
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`various skin structures such as the hyponychium, eponychium, nail
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`bed, nail matrix, further side nail wall, and posterial nail wall. The
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`prior art taught that efinaconazole treats fungal infections of skin
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`structures. See Section III.
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`d) As acknowledged in her deposition, the term “onychomycosis”
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`includes distal subungual onychomycosis, which a POSA would have
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`known invades the hyponychium, and could be treated topically. Ex.
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`1508, 109:6-110-5. See Section VII.
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`2
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`e) In evaluating the prior art, Dr. Elewski incorrectly equates lack of
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`FDA approval with lack of efficacy. See Sections III and IV.C.
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`f) Dr. Elewski overlooked the fact that the basis for institution is
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`obviousness, not anticipation, and therefore views the prior art
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`references in isolation. Therefore, and for the reasons discussed
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`below, Dr. Elewski’s attacks on the prior art references lack merit. See
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`Sections IV-VI.
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`g) Dr. Elewski mischaracterizes the Kaken Abstracts and Ogura, and, in
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`forming her declaration opinions, did not see the expanded Kaken
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`Abstracts (Ex. 2036, Ex. 2037, Ex. 2038) that Patent Owner filed with
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`its POR. See Sections V and VI. Ex. 1508, 38:3-19.
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`III. ATTEMPTS TO NARROW CLAIM SCOPE LACK MERIT
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`8.
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`Throughout her Declaration, Dr. Elewski relies on interpretations of
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`the claims of the ’506 patent that are inconsistent with and narrower than the
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`definitions and uses of those terms in the ’506 patent. As a consequence, in my
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`opinion, she disregards or misapplies the prior art discussed in my previous
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`declaration, Ex. 1005.
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`9.
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`“Onychomycosis”: As explained in my previous declaration (Ex.
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`1005, ¶¶ 48 and 61), the ’506 patent defines the term onychomycosis as follows:
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`“Onychomycosis means a kind of the above-mentioned superficial mycosis, in the
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`other word a disease which is caused by invading and proliferating in the nail of
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`human or an animal. Trichophyton rubrum and Trichophyton
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`mentagrophytes mainly cause onychomycosis in human.” Ex. 1001, col. 9:32-36;
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`see also Institution Decision at p. 8. Throughout her Declaration, Dr. Elewski
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`bases her analysis on an interpretation of this term that requires that the nail plate
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`and the nail bed both be infected “in the deeper structures of the nail” and
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`excluding onychomycosis of the skin structures that are part of the nail (as “nail
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` is defined in the ’506 patent), as well as superficial white onychomycosis, which
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`is an infection on the top surface of the nail plate. Ex. 1508, 82:9-18, 158:16-
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`159:8. See, e.g., Ex. 2027, ¶¶ 81-85 (quote from ¶ 84). I also note that the Patent
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`Owners’s Response incorrectly alleges that “[i]n the institution decision, the Board
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`construed the term ‘nail,’ but did not construe the term ‘onychomycosis.’” Dr.
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`Elewski and Patent Owner’s attempts to narrow the definition of the term
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`“onychomycosis” that is provided in the ’506 patent result in their misapplication
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`of the prior art to the ’506 patent claims and their mischaracterization of the state
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`of the art relating to topical treatment of onychomycosis at the time of the alleged
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`invention.
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`10.
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`“Nail”: As explained in my previous declaration (Ex. 1005, ¶ 49), the
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`’506 patent clearly and explicitly defines the term nail as follows: “The term ‘nail’
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`includes nail plate, nail bed, nail matrix, further side nail wall, posterial nail wall,
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`4
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`eponychium and hyponychium which make up a tissue around thereof.” Ex. 1001,
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`col. 4:65-67; see also Institution Decision at p. 8. Throughout her declaration, Dr.
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`Elewski bases her analysis on an interpretation of the term nail as either meaning
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`the nail plate exclusively, or sometimes the combination of the nail plate and the
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`nail bed. See, e.g., Ex. 2027, ¶¶ 81-85. Dr. Elewski acknowledged during her
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`deposition that she used a different definition for the term “nail” than the definition
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`provided in the ’506 patent and applied in the Institution Decision on pages 7-8.
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`Ex. 1508, 60:12-65:17.
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`11. Dr. Elewski also introduces a new term, “nail unit,” that does not
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`appear in the ’506 patent. Ex. 2027, ¶¶ 30, 35, 81, 85. As Dr. Elewski uses the
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`term, “nail unit” is narrower than the term “nail” that is defined in the ’506 patent
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`and is used in the claims. Dr. Elewski’s and Patent Owner’s attempts to narrow the
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`definition of the term “nail,” as with their narrowing of the definition of
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`“onychomycosis,” result in their misapplication of the prior art to the’506 patent
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`claims and their mischaracterization of the state of the art relating to topical
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`treatment of onychomycosis at the time of the alleged invention. I have read the
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`transcript of Dr. Elewski’s deposition and note that to support her narrow
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`definition of “nail,” she argues that the express definition in the ’506 patent is
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`unclear. Ex. 1508, 64:1-18. She then proposes to rewrite it to comport with the
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`narrow definition that she and the Patent Owner adopt for purposes of
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`distinguishing the prior art. Ex. 1508, 64:19-6. I disagree that anything is unclear
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`about the definition of “nail” provided in the ’506 patent. Specifically, that
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`definition includes the eponychium and hyponychium.
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`12. Breadth of chemical compounds covered by claim 1: Throughout her
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`Declaration, Dr. Elewski bases her attacks on an interpretation of the claims as
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`being limited to triazoles. See, e.g., Ex. 2027, ¶¶ 109, 110, 115-119, 121, 123, 125,
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`127, 129-131. Dr. Elewski appears to have overlooked that claim 1 of the ’506
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`patent, as well as the descriptive formulas in the specification, recite that “X is
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`nitrogen atom or CH,” which means that claim 1 encompasses both triazoles and
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`imidazoles. At her deposition, Dr. Elewski was unaware of what X meant in claim
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`1 of the ’506 patent and when asked if the claim covered both triazoles and
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`imidazoles, she stated that the claim “had a picture of what I thought was a
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`triazole.” Ex. 1508, 68:19-69:5. Dr. Elewski appears to have conceded this point
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`later in her deposition. Ex. 1508, 69:21-70:3 (“Q. So back to my original question,
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`the 506 patent covers the use of both triazoles and imidazoles, correct? A. It might,
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`yes.”). Moreover, such attacks also lack merit because Dr. Elewski published in
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`1995 that “[t]he triazole ring may be responsible for increased potency, decreased
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`toxicity, and a wider spectrum of action than the azoles1, 2, 22). Ex. 1502, 2. These
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`are the same advantageous properties of KP-103 that the Kaken Abstracts (Ex.
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`1015, Ex. 2036, Ex. 2037, Ex. 2038) and Ogura (Ex. 1012) reported, i.e., that it
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`had broad-spectrum potent antifungal activity against the main causes of
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`onychomycosis as defined in the ’506 patent (Trichophyton
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`rubrum and Trichophyton mentagrophytes). See, e.g., Ex. 1012, Ex. 1015, Ex.
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`2036, Ex. 2037, and Ex. 2038. Thus, it would have been obvious to improve the
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`topical onychomycosis treatment formulations and methods of JP ’639 (Ex. 1011),
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`the ’367 patent (Ex. 1013) and Hay (Ex. 1014) by using a potent, broad-spectrum
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`antifungal compound that is not inactivated by keratin.
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`13. Administering Step: The ’506 patent claims recite treating a subject
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`having onychomycosis wherein the method comprises topically administering the
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`compounds. I understand the term “comprises” is synonymous with “including,”
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`“containing,” or “characterized by,” is inclusive or open-ended and does not
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`exclude additional, unrecited elements or method steps. In contrast, throughout her
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`declaration Dr. Elewski bases her analysis on an interpretation of the claims as
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`being limited to a “stand-alone” therapy, i.e., topical-only monotherapy. Ex. 2027,
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`¶ 75. In her deposition, Dr. Elewski has conceded that the ’506 patent claims do
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`not exclude the concomitant administration of other therapies, including oral drugs
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`as well as debridement. Ex. 1508, 72:7-13. Further, Dr. Elewski acknowledged
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`during her deposition that she uses combination therapies of oral therapy with
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`Jublia in her own practice and that podiatrists often conduct debridement together
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`with efinaconazole therapy. Id., 221:20-222:15.
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`14. Moreover, in many arguments, Dr. Elewski attempts to distinguish the
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`prior art by relying on elements that are not recited in the claims such as FDA
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`approval, efficacy in toenails, efficacy for human use, extent of therapeutic effect,
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`short length of therapy, and effects of the Jublia® formulation. See, e.g., Ex. 2027,
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`¶¶ 74, 75, 112, 119, 122. See also Ex. 1508, 96:17-97:6 (“Q. So you're
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`distinguishing between approved drugs in the U.S. and approved drugs elsewhere?
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`A. Yes.”). The claims of the ’506 patent do not require FDA approval, any
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`particular length of therapy, any minimum level of nail involvement (Ex. 1508,
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`47:13-16), that the nail be a toenail or a fingernail (Ex. 1508, 47:5-12), that the
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`subject be a human, any particular level of therapeutic effect (Ex. 1508, 50:15-21),
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`or use of the Jublia® formulation.
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`15. Dr. Elewski argues that “[t]he eponychium and hyponychium alone do
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`not make up the nail unit, as they are simply skin structures that accompany the
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`other components of the nail unit.” Ex. 2027, ¶ 35. I note that the Board already
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`addressed this argument on page 8 of the Institution Decision in finding that it
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`“lacks merit.” A person of ordinary skill in the art (“POSA”) would have been
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`motivated to treat the infection at any part of the nail unit that is infected.
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`16. While ignoring the definition of “nail” in the ’506, Dr. Elewski
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`focuses her arguments on distinguishing the nail plate from skin and hair. For
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`example, Dr. Elewski states that “[w]hile keratin also appears to some extent in
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`skin and hair, in nail it has a very different concentration, density, and
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`arrangement. See, e.g., Ex. 2012, 366-67; Ex. 1028, 278.” Ex. 2027, ¶ 36. In view
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`of such statements and similar arguments throughout her Declaration, Dr. Elewski
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`used the term “nail” to mean “nail plate” rather than the definition of nail explicitly
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`provided in the ’506 patent. Ex. 1001, col. 4:65-67.
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`17. Dr. Elewski argues that “[t]he properties of the nail, particularly its
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`thickness and relatively compact construction, make it a formidable barrier to the
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`entry of topically applied agents, as compared to skin and hair.” Ex. 2027, ¶ 39.
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`Here, again, Dr. Elewski fails to consider the term “nail” as it is defined in the ’506
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`patent and focuses her opinions on a narrow definition of nail requiring that the
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`nail plate and the nail bed both must be infected “in the deeper structures of the
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`nail” and excluding onychomycosis of the skin structures that make up the nail
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`unit, as well as white superficial onychomycosis, see Ex. 2027, ¶¶ 81-85 (quote
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`from ¶8 4), which she acknowledged was simple to treat with any topical agent
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`(Ex. 1508, 158:16-159:2).
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`18.
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`In ignoring the definition of “onychomycosis” provided in the ’506
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`patent at col. 9, lines 32-391, and attempting to create a new, narrow definition, Dr.
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`1 (“Onychomycosis means a kind of the above-mentioned superficial mycosis, in
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`the other word a disease which is caused by invading and proliferating in the nail
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`9
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`Elewski further exacerbates the problem by creating a definition in her Declaration
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`that is internally inconsistent. For example, in paragraphs 81 and 84, Dr. Elewski
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`relies on an extrinsic reference that states that “onychomycosis refers to a fungal
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`infection of the nail unit - the nail matrix, bed, or plate,” but then she argues that
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`the term onychomycosis should be construed for purposes of this review to mean
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`an infection of the nail plate and the nail bed, Ex. 2027, ¶ 82.
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`19. Dr. Elewski also ignores the fact that numerous prior art references
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`disclosed that onychomycosis includes fungal infections “at the hyponychium,” or
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`“via the proximal nail fold through the cuticle area,” or at “superficial layers of the
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`nail plate directly,” including “infection beginning at the paronychia.” (Ex. 2010,
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`5-7; Ex. 2078; 5-6.) See also Ex. 2072, 2-3. “[Distal subungual onychomycosis]
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`DSO is the most common type and starts by invasion of the stratum corneum of the
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`hyponychium and distal nail bed.” Ex. 2075, 17; “[o]nychomycosis accounts for
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`one-third of all fungal skin infections and one-half of all nail disease.” Ex. 2007, 3
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`(emphasis added). Stratum corneum is a component of skin, a point that Dr.
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`Elewski conceded in her deposition. Ex. 1508, 86:12-18. Thus, the prior art
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`of human or an animal. Trichophyton rubrum and Trichophyton mentagrophytes
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`mainly cause onychomycosis in human”). See also Institution Decision at p. 8.
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`makes clear that the early stages of the most common form of onychomycosis
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`involve fungal infection of the skin structure—the hyponychium.
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`20. Dr. Elewski’s own publications define the various forms of
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`onychomycosis similar to the ’506 patent, i.e., including infection of the skin
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`structures, rather than limiting it to only a deep infection of the nail plate and nail
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`bed as Dr. Elewski proposes in her declaration. Ex. 2010, 5-6 (“Distal subungual
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`onychomycosis (DSO) is the most common form of onychomycosis. It is
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`characterized by invasion of the nail bed and underside of the nail plate beginning
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`at the hyponychium (Fig. 2). The infecting organism migrates proximally through
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`the underlying nail matrix.”); Ex. 1512,2-3 (“Onychomycosis commonly begins as
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`tinea pedis before extending to the nail bed, where its eradication is more
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`difficult….Clinically, four types of onychomycosis are distinguished: (1) distal
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`lateral subungual onychomycosis (Figure 3), with invasion via the hyponychium;
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`(2) proximal subungual onychomycosis, with invasion under the proximal nail fold
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`(common in immunocompromised hosts); (3) white superficial onychomycosis,
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`with direct invasion of the dorsal plate; and (4) total dystrophic onychomycosis,
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`which results from the progression of any of the other subtypes or a combination of
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`two or more of them.”) (emphasis added).
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`21. Furthermore, Dr. Elewski admitted during her deposition that the term
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`“onychomycosis” in the ’506 patent claims includes superficial white
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`onychomycosis, for which “treatment is fairly simple, you can scrape it off and that
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`would cure it or you can put any topical antifungal on it.” Ex. 1508, 158:16-159:2
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`(emphasis added).
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`22. Dr. Elewski also acknowledged that the nail bed is a skin structure
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`and in some cases of onychomycosis, the nail bed is exposed when the nail plate
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`separates from the nail bed. Ex. 1508, 92:17-93:7. In some cases of
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`onychomycosis, topical therapy can be applied directly to the exposed nail bed.
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`Ex. 1508, 93:8-11, 94:9-12.
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`23. Even setting aside the fact that all of the structures of the nail unit
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`other than the nail plate are skin structures, the prior art nevertheless contradicts
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`Dr. Elewski’s attempts to distinguish keratin in nail plate from hair and skin in this
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`regard. For example, it was known that “[t]he main chemical constituent of the
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`human nail is keratin . . . . [b]oth epidermal- and hair-type keratins are present,
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`although the latter make up more than 90% of the protein content” and “the content
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`of glycine and half-cystine in human nails is similar to that of human hair.” Ex.
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`2012, 366. Further, “[t]he main form of keratin present in all mammalian hairs,
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`wool, horns, claws, nails, and quills is α-keratin.” Id. (emphasis added). “[T]here
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`is striking similarity in the physical and chemical properties of hair and nail,
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`although there are some clear differences” and “[h]air and nails are also quite
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`similar in their capacity to absorb water at varying relative humidities.” Ex. 1028,
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`276 (emphasis added). Thus, contrary to Dr. Elewski’s opinion, these references
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`actually disclose that the keratin in human nails is highly similar to the keratin in
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`human hair. Thus, the prior art teachings of Ogura (Ex. 1012) and the Kaken
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`Abstracts (Ex. 1015, Ex. 2036, Ex. 2037, Ex. 2038) that efinaconazole had potent
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`and broad-spectrum activity against the fungal species primarily responsible for
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`onychomycosis and that it was not inactivated by keratin (e.g., in the form of
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`human hair or a keratin solution in Ex. 2037) would have motivated a person
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`skilled in the art to use it topically to treat onychomycosis with a reasonable
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`expectation of success.
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`24. Most importantly, the prior art disclosed that “the activities of most
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`topical antifungal agents are greatly reduced by adsorption to keratin,13) which is a
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`major constituent of the keratinized tissue where fungi reside . . . . [t]hese results
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`indicated that 4-methylpiperidino triazole derivative (40) had low affinity to
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`keratin and could retain a high level of activity in the keratinized tissue.14).” Ex.
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`1012, 4-5. Cited reference 13 in the quoted sentence was published in 1990. Ex.
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`1513. Reference 14 in the quoted sentence is a citation to the Kaken Abstracts. Ex.
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`1015, Ex. 2036, Ex. 2037, Ex. 2038. Thus, Ogura is also evidence of what was
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`known by the POSA during the 1990s regarding the importance of testing
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`antifungal compounds for inactivation by keratin and the fact that KP-103 is not
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`inactivated by keratin and could retain a high level of activity in the keratinized
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`tissue.
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`25. Also, it was known from the Kaken Abstracts that KP-103 has “a
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`broad antifungal spectrum and a potent activity” and “showed the most potent
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`activity,” (Ex. 1015, F78), “a broad antifungal spectrum and could keep a high
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`activity in the horny layer where fungi reside,” (Ex. 1015, F79), “has a low affinity
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`with keratin,” “showed low adsorption to keratin and high release from keratin as
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`compared with LCZ and BTF (Table 7 and Figure 3),” and “has a broad antifungal
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`spectrum and could keep a high activity in the horny layer where fungi reside.”).
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`Ex. 2037, 3-4. Thus, the Kaken Abstracts are also evidence of what was known by
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`the POSA during the 1990s regarding the importance of testing antifungal
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`compounds for adsorption to keratin and the fact that KP-103 had uniquely low
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`adsorption to keratin, has a broad antifungal spectrum and could keep a high
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`activity in the horny layer where fungi reside. See, e.g., Ex. 1012, Ex. 1015, Ex.
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`2036, Ex. 2037, and Ex. 2038.
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`26. Dr. Elewski argues that efinaconazole’s low keratin affinity would
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`actually have led a skilled person away from using it as an onychomycosis
`
`treatment. Ex. 2027, ¶¶ 52, 97, 130. In making this argument, Dr. Elewski ignores
`
`the role of keratin affinity for oral therapies (on which she relies) and the effect of
`
`keratin inactivation on topical antifungals. Moreover, Dr. Elewski’s arguments are
`
`14
`
`Page 18 of 97
`
`
`
`contrary to Kaken and Valeant’s retrospective explanation of how the use of
`
`efinaconazole as a topical therapy for onychomycosis came about. Ex. 2055,
`
`sponsored by Valeant, concisely summarizes the rationale that a POSA would have
`
`had a reasonable expectation of success in treating onychomycosis with
`
`efinaconazole based on the prior art:
`
`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 [Ogura
`
`1999-Ex. 1012] Since the activities of many antifungal
`
`drugs are inhibited with keratin binding,27 [Ref. 27 is by
`
`Arika et al. 1990-Ex. 1513] 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. In addition, it showed
`
`the highest efficacy compared to other drugs against T.
`
`mentagrophytes in a guinea pig model of tinea corporis and
`
`showed better penetration via both the transfollicular and
`
`transepidermal routes.18 [Ref. 18 is Ogura-Ex. 1012]
`
`15
`
`Page 19 of 97
`
`
`
`Efinaconazole was subsequently shown to have excellent in
`
`vitro activity against T. rubrum and T. mentagrophytes,
`
`surpassing that of the reference drugs neticonazole and
`
`clotrimazole but less so than lanoconazole and butenafine. A
`
`similar effect was seen for the organisms, Trichophyton
`
`violaceum, Trichophyton
`
`ajelloi, Microsporum
`
`canis, Microsporum
`
`gypseum,
`
`and Epidermophyton
`
`floccosum. Efinaconazole was also more active against C.
`
`albicans, other Candida spp., and Malassezia furfur than the
`
`reference drugs. In addition, efinaconazole was the only
`
`agent whose activity against T. mentagrophytes was
`
`unaffected by the presence of serum or keratin.
`
`Ex. 2055, 3 [The results summarized in the second quoted paragraph were
`
`disclosed in 1996 in the Kaken Abstracts. See Ex. 2037, 3-4.].
`
`IV. DR. ELEWSKI MISCHARACTERIZES JP ’639, THE ’367 PATENT,
`AND HAY
`
`27.
`
`In an attempt to downplay the importance of these references, Dr.
`
`Elewski refers to Hay, the ’367 Patent and JP ’639 as “the Secondary Art” in
`
`Section VII.B of her Declaration. As evidenced by the Petition and Institution
`
`Decision, each of Hay, the ’367 Patent and JP ’639 are primary references
`
`providing a method for treating a subject having onychomycosis wherein the
`
`16
`
`Page 20 of 97
`
`
`
`method comprises topically administering to a nail of said subject having
`
`onychomycosis a therapeutically effective amount of an antifungal compound. See
`
`Pet. 22–23, 30–31, 35–36 and Institution Decision at 16. A POSA would have
`
`been motivated to improve the compositions and topical application method of
`
`each of JP ’639, Hay and the ’367 patent by using potent azole antifungal
`
`compounds that are effective against the microorganisms that cause
`
`onychomycosis and that are not inactivated by keratin.
`
`28. The gist of paragraphs 107-122 of Dr. Elewski’s Declaration is that
`
`because none of Hay, the ’367 Patent and JP ’639 discloses topical application of
`
`efinaconazole to a patient having onychomycosis and because the topical
`
`antifungals discussed in those references were not FDA-approved, then a POSA
`
`would not have expected to be able to deliver efinaconazole topically with any of
`
`the formulations disclosed in those references. It is my understanding that Dr.
`
`Elewski’s argument would be more appropriate if the grounds for unpatentability
`
`were based on anticipation by Hay, the ’367 Patent or JP ’639. But I understand
`
`that the grounds on which the review were instituted are obviousness over the
`
`combined teachings of the prior art. Moreover, Dr. Elewski’s argument
`
`demonstrates the common theme of her declaration that she considered FDA
`
`approval to be the standard to be met before a POSA would have had any
`
`reasonable expectation of success for treating onychomycosis as claimed in the
`
`17
`
`Page 21 of 97
`
`
`
`’506 patent. As discussed further below, the topical formulation described by the
`
`’367 patent and Hay was approved in the United Kingdom. See Ex. 1503, 4. Dr.
`
`Elewski has acknowledged that the United Kingdom requires proof of safety and
`
`efficacy as a condition for approval of a new prescription drug. Ex. 1508, 116:7-
`
`12. Dr. Elewski has ignored that each of Hay, the ’367 Patent and JP ’639
`
`provides a method for treating a subject having onychomycosis by topically
`
`administering to a nail of said subject having onychomycosis a therapeutically
`
`effective amount of an antifungal compound, including various azole compounds,
`
`as well as the motivations of a POSA to improve on those formulations using
`
`potent, broad-spectrum antifungal compounds that are not inactivated by keratin
`
`and have high retention and activity in the keratinized tissues.
`
`A. Dr. Elewski’s Attacks on JP ’639 are Baseless
`
`29. Dr. Elewski focuses on one example in JP ’639 (amorolfine) rather
`
`than considering the reference and the prior art as a whole. Ex. 2027, ¶¶ 108-110.
`
`She then proceeds to attack the efficacy of amorolfine with unsupported and
`
`irrelevant statements, see id. at ¶¶ 111-112, and by doing so completely misses the
`
`mark as to the issues involved in this case, i.e., whether a POSA would have been
`
`motivated to improve JP ’639’s method and topical formulation for treating a
`
`subject having onychomycosis by topically administering to a nail of said subject
`
`having onychomycosis by using efinaconazole. In evaluating its formulation, JP
`
`18
`
`Page 22 of 97
`
`
`
`’639 concludes that, by using its topical formulation to deliver an antifungal agent,
`
`“it is possible to effectively treat trichophytosis, especially, tinea unguium.” Ex.
`
`1011 at ¶ [0073]. JP ’639 teaches that the antifungal agent of the composition may
`
`be selected from among various azole and other antifungal agents, including
`
`amorolfine hydrochloride, terbinafine hydrochloride, miconazole nitrate,
`
`isoconazole nitrate, sulconazole nitrate, oxiconazole nitrate, econazole nitrate,
`
`croconazole nitrate, neticonazole nitrate, and similar compounds. Id., [0017]. JP
`
`’639 discloses that “the amount of the antifungal agent is 0.1 to 10 w/v%,” id.,
`
`[0018], which is the same preferred effective range for the antifungal agents in the
`
`’506 patent, Ex. 1001, 9:50-51, as well as Patent Owner’s prior art efinaconazole
`
`patents, Ex. 1007, 9:26-27, Ex. 1505,10:28-29.
`
`30. Thus, JP ’639 teaches using azole antifungal drugs in a formulation
`
`for effectively treating tinea unguium (onychomycosis of the nail). A POSA
`
`would have been motivated to improve the topical formulation and application
`
`method of JP ’639 by using potent azole antifungal compounds that are effective
`
`against the microorganisms that cause onychomycosis and that are not inactivated
`
`by keratin such as KP-103.
`
`31.
`
`In paragraph 113, Dr. Elewski makes an argument based on the
`
`comparative testing provided in the ’506 patent, but her argument misses the mark
`
`because she not only views JP ’639 in isolation from the rest of the prior art, but
`
`19
`
`Page 23 of 97
`
`
`
`she also views the amorolfine teaching of JP ’639 divorced from the rest of its
`
`teachings of numerous azole antifungal compounds. Dr. Elewski fails to recognize
`
`that the issue here is not whether a POSA would have been led to efinaconazole by
`
`amorolfine, but rather whether the POSA would have been motivated by the
`
`combination of disclosures of JP ’639 and the Kaken Abstracts or Ogura, as a
`
`whole, to improve the topical formulation and method of JP ’639 by using
`
`efinaconazole, a highly potent antifungal compound with broad spectrum activity
`
`that is not inactivated by keratin and has high retention in the horny layer, in the
`
`topical formulation and method of JP ’639.
`
`B. Dr. Elewski’s Attacks on the ’367 Patent are Baseless
`
`32. Dr. Elewski focuses her arguments on the fact that the active
`
`ingredient in the topical formulation of the ’367 Patent was tioconazole instead of
`
`efinaconazole. Ex. 2027, ¶¶ 114-117. She then proceeds to attack t
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