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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
`_______________
`
`
`REBUTTAL DECLARATION OF JEFFREY M. WEINBERG, M.D. IN
`SUPPORT OF PETITION FOR INTER PARTES REVIEW OF PATENT NO.
`7,214,506
`
`
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`Page 1 of 127
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`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1510
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`SCOPE OF ASSIGNMENT ............................................................................ 4
`
`I.
`
`II.
`
`III. MATERIALS CONSIDERED ........................................................................ 5
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`IV. A PERSON OF ORDINARY SKILL IN THE RELEVANT ART .................. 6
`
`V.
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`VI.
`
`A.
`
`B.
`
`Relevant Field ........................................................................................ 7
`
`Person of Ordinary Skill in the Art ....................................................... 7
`
`BACKGROUND ............................................................................................. 7
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`I DISAGREE WITH DR. ELEWSKI’S ATTACKS ON THE PRIOR
`ART REFERENCES ..................................................................................... 12
`
`A. Dr. Elewski’s Attacks on the ’367 Patent ............................................ 12
`
`B.
`
`C.
`
`Dr. Elewski’s Attacks on the Hay Reference ...................................... 14
`
`Dr. Elewski mischaracterizes the Ogura Reference ............................ 16
`
`D. Dr. Elewski Mischaracterizes the Kaken Abstracts ............................ 17
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`VII. DR. ELEWSKI MISCHARACTERIZES PARONYCHIA .......................... 21
`
`VIII. DR. ELEWSKI’S OPINIONS ARE BASED ON INCORRECT
`INTERPRETATIONS OF THE ’506 PATENT CLAIMS ............................. 23
`
`IX. EFINACONAZOLE WAS ALREADY A KNOWN POTENT
`ANTIFUNGAL COMPOUND BY 1999 ...................................................... 29
`
`X.
`
`SECONDARY CONSIDERATIONS ............................................................ 35
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`XI. CONCLUSIONS ........................................................................................... 44
`
`
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`ii
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`Page 2 of 127
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`I, Jeffrey M. Weinberg, M.D., hereby state the following:
`
`I.
`
`INTRODUCTION
`
`1.
`
`In this declaration, I am providing my expert opinions in support of
`
`Petitioners’ Petition for Inter Partes Review of Patent No. 7,214,506 (the “’506
`
`patent”) and in reply to Patent Owner’s Response (“POR”) Pursuant to 37 C.F.R. §
`
`42.120. In particular, I have been asked to address certain opinions offered by
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`Patent Owner’s expert, Boni E. Elewski, M.D.
`
`2.
`
`I am Senior Attending at Mount Sinai St. Luke’s Hospital Center in
`
`New York, New York. I have worked at Mount Sinai (formerly St. Luke’s-
`
`Roosevelt Hospital Center) since 1999. I am also a practicing dermatologist at
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`Forest Hills Dermatology Group in Forest Hills, New York and treat hundreds of
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`onychomycosis patients per year. I am also an Associate Clinical Professor of
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`Dermatology at Icahn School of Medicine at Mount Sinai.
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`3.
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`I also serve as the Acting Director, Division of Dermatology
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`Attending in the Department of Medicine and the Dermatology Clinic at the
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`Jamaica Hospital Medical Center, where I have worked since 1998. In addition, I
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`serve as senior attending at Mount Sinai Beth Israel, where I have worked since
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`2000. Jamaica Hospital Medical Center and Mount Sinai Beth Israel are both
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`located in New York, New York. My work responsibilities at these three hospitals
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`include treating patients for various dermatological diseases, investigating
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`1
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`dermatological clinical development, and overseeing all department
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`responsibilities. As part of my work, I routinely treat patients in clinical drug
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`development programs and I regularly evaluate the benefits using different
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`treatments for dermatological diseases and defects.
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`4.
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`I am also presently an Associate Clinical Professor of Dermatology in
`
`the Department of Dermatology at Columbia University College of Physicians and
`
`Surgeons in New York, New York. I have been teaching as a clinical professor of
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`dermatology at Columbia University since 2000.
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`5.
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`I am on the editorial board and a Senior Editor of Cutis. I am also an
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`Associate Editor of the Journal of the American Academy of Dermatology. I am a
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`member of the Medical Board of the National Psoriasis Foundation. I am Editor-in-
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`Chief of Current Dermatology Reports. I am the founding Editor and Editor-in-
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`Chief of Clinical, Cosmetic and Investigational Dermatology. I am also on the
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`Editorial Board of publications including Scientific Reports, Biologics in Therapy,
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`Journal of Cosmetics, Dermatological Sciences and Applications, Journal of
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`Clinical Dermatology, Journal of the American Academy of Dermatology, The
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`Open Dermatology Journal / The Open Infectious Diseases Journal, and Case
`
`Reports in Medicine. I am on the Editorial Advisory Board or Panel of publications
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`including Expert Review of Clinical Immunology, Clinical Investigation, The
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`Journal of Clinical and Aesthetic Dermatology, and BenSci Newsletter. I am a
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`2
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`member of the Honorary Editorial Board of Psoriasis: Targets and Therapy and
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`Journal of Pain Research.
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`6. My clinical research encompasses a variety of dermatology-related
`
`topics, including studies of diagnostic methods in the evaluation of
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`onychomycosis. I have been principal or co-investigator for several clinical trials.
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`In addition, I have written or co-authored numerous articles for professional
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`journals such as Cutis, the Journal of the American Academy of Dermatology, and
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`Blood, as well as reviews, book chapters and abstracts.
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`7.
`
`I served on the National Psoriasis Foundation Medical Board from
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`2011-2017. I have been a Fellow of the American Academy of Dermatology since
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`1997. I have been a member of the National Psoriasis Foundation since 2002 and
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`on its President’s Council since 2005.
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`8.
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`From 1997 to 2000, I worked as the Director of Dermatology at
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`Riverview Medical Associates in New York, New York.
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`9.
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`I developed a specialization in dermatology as dermatological resident
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`at the University of Pennsylvania School of Medicine in Philadelphia,
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`Pennsylvania from 1994 to 1997. During that time, I also worked as an Assistant
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`Instructor at the University of Pennsylvania School of Medicine.
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`10. From 1993 to 1994, I completed my first-year residency internship in
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`the Department of Medicine at the Columbia-Presbyterian Medical Center in New
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`York, New York. During that time, I was a Post-Doctoral Residency Fellow in the
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`Columbia University College of Physicians and Surgeons.
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`11. Prior to my internship and residency, I attended the University of
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`Pennsylvania School of Medicine in Philadelphia, Pennsylvania. I received a
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`Medical Degree in 1993.
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`12. Before attending medical school, in 1989, I graduated summa cum
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`laude from Columbia University in New York, New York, where I received a
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`Bachelor of Arts degree with a major in Biology. Further aspects of my
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`qualifications, background and experience are outlined in my curriculum vitae
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`attached as Exhibit A. Publications that I have authored or co-authored within the
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`preceding ten years are listed on my curriculum vitae.
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`II.
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`SCOPE OF ASSIGNMENT
`
`13.
`
`I have been engaged as an expert on this case by Rothwell, Figg, Ernst
`
`& Manbeck, P.C. I am being compensated for my time on this matter at a rate of
`
`$450 per hour. For any work that involves travel, I am being compensated at a rate
`
`of $500 per hour. I am also being reimbursed for the actual and reasonable
`
`expenses I incur in conjunction with this case. I have no personal or financial
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`stake or interest in the outcome of the Petition for Inter Partes Review or any
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`related action. My compensation in no way depends on my testimony or the
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`outcome of the Petition for Inter Partes Review.
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`4
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`14.
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`I have been advised that Rothwell Figg represents Acrux DDS Pty
`
`Ltd. and Acrux Limited (collectively, “Acrux” or “Petitioners”) in this matter and
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`that Kaken Pharmaceutical Co., Ltd. (“Kaken” or “Patent Owner”) owns the ’506
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`patent. I also understand that the ’506 patent has been licensed to Valeant
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`Pharmaceuticals International, Inc. and that its subsidiary, Valeant Pharmaceuticals
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`North America LLC, is the New Drug Application (“NDA”) holder of the Jublia®
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`NDA (collectively, “Valeant”). I have no personal or financial stake or interest in
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`Acrux, Kaken, Valeant, or the ’506 patent.
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`III. MATERIALS CONSIDERED
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`15.
`
`In forming the opinions expressed below, I considered and relied on
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`my knowledge, education, experience, the ’506 patent (Ex. 1001) and its file
`
`history (Ex. 1006) (including the prior art cited therein), and the exhibits identified
`
`throughout this declaration. I have also considered the Petition, the Patent
`
`Owner’s Preliminary Response, the Institution Decision, Patent Owner’s Response,
`
`Dr. Elewski’s declaration (Ex. 2027) and documents referenced therein, and Dr.
`
`Elewski’s deposition transcript (Ex. 1508).
`
`16. All of the exhibits I have considered and on which I have relied in this
`
`proceeding are the kinds of documents on which I typically rely when forming my
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`medical/scientific opinions, including the opinions I have offered in this
`
`proceeding.
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`5
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`17.
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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
`
`to light throughout this proceeding.
`
`18.
`
`I understand that Acrux has filed a Petition on which this Inter Partes
`
`Review was instituted and Dr. Elewski has criticized the findings of the Board. I
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`have been asked to evaluate Dr. Elewski’s arguments from the perspective of a
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`practicing dermatologist with over 20 years of experience in treating
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`onychomycosis.
`
`IV. A PERSON OF ORDINARY SKILL IN THE RELEVANT ART
`
`19.
`
`I understand that the patentability of the challenged claims of the ’506
`
`patent must be undertaken from the perspective of what would have been known or
`
`understood by someone of ordinary skill in the relevant field as of the earliest
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`priority date to which the ’506 patent is entitled, which is July 11, 2000.1
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`
`1 I understand that the Petition adequately explains why July 11, 2000 is the earliest
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`priority date for the ’506 patent.
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`6
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`Page 8 of 127
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`A. Relevant Field
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`20.
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`I understand that the field relevant to the claims of the ’506 patent is
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`treatment of fungal infections of the nail and skin.
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`B.
`
`21.
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`Person of Ordinary Skill in the Art
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`I have been informed of the Board’s definition of a person of ordinary
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`skill in the relevant field as of July 11, 2000 (sometimes referred to in this
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`declaration as a “POSA”). Institution Decision at p. 11. I have noted that Dr.
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`Elewski did not disagree with that definition. I agree with the Board’s definition
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`and have applied it in forming the opinions expressed in this declaration.
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`22. With more than 20 years of experience as a practicing dermatologist
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`and an educator of medical students in the field of dermatology, I am well
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`acquainted with the level of ordinary skill pertinent to the subject matter of the
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`’506 patent.
`
`V. BACKGROUND
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`23. The fundamental thing to understand about onychomycosis is that it
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`was difficult to treat in 1999 and it is difficult to treat today. Even today, cure rates
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`are low, patients must persist with therapy over long periods of time and there are
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`high rates of recurrence.
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`24.
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`It was known in the prior art that both “[t]opical and oral therapies
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`have high recurrence rates. Oral therapy has the added disadvantages of high cost
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`and potentially adverse side effects.” Ex. 1036, 4. Dr. Elewski’s 2015 publication
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`7
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`Page 9 of 127
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`– published after the commercial introduction of Jublia® – states that
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`“[o]nychomycosis remains a common, progressive and difficult disease to manage
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`successfully, and one where early diagnosis and treatment is important irrespective
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`of risk factors or comorbidities.” Ex. 1518, 4. See also Ex. 2087, 1 (“Fungal nail
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`infections can be difficult to treat.”). Dr. Elewski admitted during her deposition
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`that, when beginning treatment with Jublia, patients are made aware of the
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`“importance of adhering to the application on a daily basis and persisting until the
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`very end, until the nail is normal,” which can take “a long time to grow out” such
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`as “about a year.” Ex. 1508, 139:1-17.
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`25. While Jublia appears to have provided some improvement in cure
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`rates over topical therapies that had been FDA-approved in 1999, the improvement
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`was merely incremental in degree—and was not a revolutionary breakthrough, as
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`argued in Dr. Elewski’s declaration. During regulatory review, the FDA
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`concluded that Jublia does not provide “a significant improvement over existing
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`therapies,” that “[t]here are several currently approved therapies for
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`onychomycosis” and that the “efficacy response rate of about 16%, [] is similar to
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`at least one currently approved therapy. Approximately 84% of subjects would fail
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`to respond to your proposed treatment.” Ex. 1504, 3. Other topical therapies,
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`including topical tioconazole (approved in the United Kingdom and sold by Pfizer
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`as Trosyl®) and topical amorolfine (approved in the United Kingdom and sold by
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`Galderma as Loceryl®) were known to have useful therapeutic value. Ex. 1503, 4.
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`Moreover, oral terbinafine (Lamisil®) remains the “gold standard” onychomycosis
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`therapy, having a clinical cure rate of 38% and a mycological cure rate of 74%, Ex.
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`2084, 2, as opposed to Jublia’s clinical cure rates of 17.8% and 15.2% and
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`mycological cure rates of 55.2% and 53.4% (as reported in two studies), Ex. 1043,
`
`2.
`
`26. Claim 1 of the ’506 patent broadly recites:
`
`1. A method for treating a subject having onychomycosis
`wherein the method comprises topically administering to a
`nail of said subject having onychomycosis a therapeutically
`effective amount of an antifungal compound represented by
`the following formula:
`
`
`wherein, Ar is a non-substituted phenyl group or a phenyl
`group substituted with 1 to 3 substituents selected from a
`halogen atom and trifluoromethyl group,
`R1 and R2 are the same or different and are hydrogen atom,
`C1-6 alkyl group, a non-substituted aryl group, an aryl group
`substituted with 1 to 3 substituents selected from a halogen
`atom, trifluoromethyl group, nitro group and C1-16 alkyl
`group, C2-8 alkenyl group, C2-6 alkynyl group, or C7-12 aralkyl
`group,
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`9
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`m is 2 or 3,
`n is 1 or 2,
`X is nitrogen atom or CH, and
`*1 and *2 mean an asymmetric carbon atom.
`
`27. 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 as requiring 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 both onycomycosis of the skin structures that make up the nail (as
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`expressly defined in the ’506 patent) as well as white superficial onychomycosis (a
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`superficial infection of the nail plate). It is also inconsistent with Dr. Elewski’s
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`contemporaneous publication in which she described onychomycosis as beginning
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`with fungal invasion of the stratum corneum (a component of skin) of the
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`hyponychium (a skin structure that is part of the nail). Ex. 2010, 5.
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`28. At her deposition, when trying to distinguish the 1985 Hay
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`publication (Ex. 1012), Dr. Elewski acknowledged that the term “onychomycosis”
`
`in the ’506 patent claims includes white superficial onychomycosis, for which
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`10
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`“treatment is fairly simple, you can scrape it off and that would cure it or you
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`can put any topical antifungal on it.” Ex. 1508, 158:12-159:2 (emphasis added).
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`I agree with Dr. Elewski that successful treatment of superficial white
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`onychomycosis is relatively simple with topical antifungals and the same was true
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`in the late 1990s.
`
`29. The ’506 patent expressly defines the term “nail” as follows: “The
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`term ‘nail’ includes nail plate, nail bed, nail matrix, further side nail wall, posterial
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`nail wall, eponychium and hyponychium which make up a tissue around thereof.”
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`Ex. 1001, col. 4:65-67; see also Institution Decision at pp. 7-8. Throughout her
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`declaration, Dr. Elewski bases her analysis on what she refers to as the “nail unit,”
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`which she argues is limited to either the nail plate exclusively, or sometimes the
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`combination of the nail plate and the nail bed. See, e.g., Ex. 2027, ¶¶ 81-85. The
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`term “nail unit” does not appear in the ’506 patent. Dr. Elewski’s meaning of “nail
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`unit” is considerably narrower than the definition of “nail” in the ’506 patent. Dr.
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`Elewski admitted during her deposition that she used a different definition for the
`
`term “nail” than the definition provided in the ’506 patent and applied in the
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`Institution Decision on pages 7-8. Ex. 1508, 60:12-65:17. In my opinion, Dr.
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`Elewski’s narrow interpretation is not only contrary to the express definition of the
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`term “nail” in the ’506 patent, but is also contrary to the art-recognized meaning of
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`this term.
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`11
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`30.
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`In addition, Dr. Elewski’s arguments are misplaced because they
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`define “success” as a clinically effective treatment in the context of a clinical trial
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`designed for FDA approval. Ex. 2027, ¶¶ 62-63. Dr. Elewski has acknowledged,
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`however, that the ’506 patent claims do not specify any particular result or level of
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`therapeutic effect. Ex. 1508, 50:1-5, 15-21.
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`VI.
`
`I DISAGREE WITH DR. ELEWSKI’S ATTACKS ON THE PRIOR
`ART REFERENCES
`
`A. Dr. Elewski’s Attacks on the ’367 Patent
`
`31. The topical solution described in the ’367 patent comprises an
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`effective amount of the imidazole antifungal, tioconazole, water, an alcohol, and a
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`gel-forming agent, so that when the topical solution is applied to the nails of a
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`human infected with onychomycosis, it creates a reservoir from which tioconazole
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`continuously penetrates the nail. Ex. 1013 at 1:44–52. The ’367 patent concludes
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`that “[i]t has now been found by in vitro microbiological tests that a topical
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`tioconazole formulation is effective in the treatment of onychomycosis.” Id. at
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`2:27–29.
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`32.
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`In paragraph 118 of her declaration, Dr. Elewski argues that because
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`the ’367 patent does not disclose testing “tioconazole in patients with
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`onychomycosis,” i.e., clinical trial results, it should be disregarded as prior art. Dr.
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`Elewski contends that this prior art reference is “not persuasive” because it does
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`not “establish nail efficacy even for tioconazole, let alone for an entirely different
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`12
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`class of compound such as a triazole.” Ex. 2027, ¶ 118. Contrary to Dr. Elewski’s
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`analysis, the ’367 patent discloses that the topical formulation is effective in the
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`treatment of onychomycosis and there is no reason to doubt that the formulation of
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`the ’367 patent can be improved by using a potent antifungal with broad spectrum
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`activity that is not inactivated by keratin and has high retention in the horny layer,
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`as taught by the Kaken Abstracts, Ex. 1015, Ex. 2036, Ex. 2037, Ex. 2038, and
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`Ogura, Ex. 1012. Dr. Elewski’s efforts to dismiss the ’367 patent because
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`tioconazole is not a triazole are inappropriate because, as Dr. Elewski
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`acknowledged in her deposition (Ex. 1508, 69:21-70:3), the general formula of the
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`’506 patent encompasses both imidazoles and triazoles. Further, in 1995, Dr.
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`Elewski published that “[t]he triazole ring may be responsible for increased
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`potency, decreased toxicity, and a wider spectrum of action than the azoles1, 2, 22).
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`Ex. 1502, 2. Thus, in my opinion a POSA would have been motivated to replace
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`tioconazole with a potent, broad-spectrum triazole such as efinaconazole that is not
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`inactivated by keratin.
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`33. Moreover, Dr. Elewski’s dismissal of prior art topical drugs as
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`ineffective is belied by her 1995 publication, in which she stated that “the newer
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`oral antimycotics (fluconazole, itraconazole and terbinafine) and topical
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`(amorolfine, ticonazole [sic, tioconazole], ciclopirox olamine) antifungals
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`formulated for onychomycosis, have excellent safety profiles and have greatly
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`13
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`improved the prognosis of onychomycosis. Due to these agents, onychomycosis
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`is no longer considered incurable.” Ex. 1502, 3 (emphasis added). Dr. Elewski
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`admitted during her deposition that when she wrote this article, it was her intention
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`to be accurate and truthful and complete. Ex. 1508, 103:4-17. Thus, I disagree
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`with Dr. Elewski’s opinions; a POSA would have been motivated by the
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`combination of disclosures of the ’367 patent and the Kaken Abstracts or Ogura, as
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`a whole, to improve the topical formulation and method of the ’367 patent by using
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`efinaconazole, which had already been reported to be a highly potent antifungal
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`compound with broad spectrum activity that is not inactivated by keratin and has
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`high retention in the horny layer.
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`B. Dr. Elewski’s Attacks on the Hay Reference
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`34. As with the ’367 Patent, Dr. Elewski focuses her arguments on the
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`fact that the active ingredient in the human trials reported by Dr. Hay was
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`tioconazole instead of efinaconazole. Ex. 2027, ¶¶ 114-117. Because Hay
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`provides the testing of tioconazole in human patients with onychomycosis that Dr.
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`Elewki argued was missing from the ’367 Patent, she instead attacks the human
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`clinical testing in this prior art reference as being an “open study” and implies that
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`the study design negates its findings. Id. at ¶¶ 116 and 119-121. Dr. Elewski’s
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`attacks miss the mark as to what I understand to be the issues involved in this case,
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`i.e., whether a POSA would have been motivated to use efinaconazole with its
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`14
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`known high potency, broad spectrum of activity, long retention time in the horny
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`layer, and lack of inactivation by keratin to improve topical formulations for
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`treating onychomycosis.
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`35. Dr. Elewski admitted during her deposition that she knows Dr. Hay
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`and he is respected in this field and was respected in this field in 1999. Ex. 1508,
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`104:13-20. I also am acquainted with Dr. Hay and agree with Dr. Elewski’s
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`opinion of him. I disagree that the fact that Dr. Hay studied topical tioconazole in
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`an open-label study negates its value in providing a reasonable expectation of
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`success to a POSA as of the late 1990s. Indeed, I have reviewed the Hay reference
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`and find that the author employed scientifically sound procedures. While an open-
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`label study might not be accepted as proof of safety and efficacy for FDA
`
`approval, it is incorrect to conclude that valuable information cannot be derived
`
`from such a study. Indeed, such studies can sometimes provide the basis for larger
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`scale clinical trials. The ’506 patent studies, which were animal studies, were also
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`open studies, a fact admitted by Dr. Elewski during her deposition. Ex. 1508,
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`155:19-156:15. Further, she admitted that while her declaration criticizes the prior
`
`art compounds as not having been approved by the FDA as of the late 1990s, the
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`FDA also would not have approved a drug based on animal studies such as those in
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`the ’506 patent. Ex. 1508, 159:13-160:15.
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`15
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`36. Dr. Hay concludes from his studies that “[i]n some patients it is
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`possible to obtain clinical and mycological cures in onychomycosis using topical
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`therapy alone.” Ex. 1014, 115. Contrary to Dr. Elewski’s declaration, in my
`
`opinion a POSA would have been strongly motivated to improve the Hay method
`
`by using a drug like efinaconazole with its reported advantageous properties.
`
`C. Dr. Elewski mischaracterizes the Ogura Reference
`
`37.
`
`In paragraph 102 of her declaration, Dr. Elewski states that “Ogura
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`offers no suggestion to use efinaconazole on nail at all” and “Ogura did not test
`
`efinaconazole in patients with onychomycosis.” In my opinion, Dr. Elewski
`
`misses the point. Ogura discloses properties of efinaconazole (designated KP-103
`
`or compound (–)-(40)) that would have strongly motivated a POSA to use it as a
`
`topical therapy for onychomycosis as described by JP ’639, the ’367 patent and
`
`Hay. These properties included broad spectrum antifungal activity and excellent
`
`activity against the very fungal species T. rubrum and T. mentagrophytes that
`
`cause onychomycosis and little to no inactivation by keratin. Ex. 1012, 5.
`
`
`
`38.
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`In the last sentence of paragraph 103 of her declaration, Dr. Elewski
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`criticizes Ogura by stating that “many of the tested compounds demonstrated
`
`antifungal properties in the skin, which was the focus of the research, but the paper
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`draws no conclusions about other indications, particularly onychomycosis.” There
`
`are two problems with this criticism. First, while Ogura tested efinaconazole
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`16
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`Page 18 of 127
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`
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`against a wide range of fungal species to establish its broad spectrum of activity, a
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`POSA would have recognized that the authors demonstrated good activity against
`
`the species that are responsible for onychomycosis, as defined in the ’506 patent.
`
`As Dr. Elewski had published T. rubrum and T. mentagrophytes are responsible for
`
`90% of the onychomycosis. Ex. 2010, 4-5. Second, it was well-known that
`
`onychomycosis often begins by the infectious fungus invading the skin component
`
`of the nail—the hyponychium—and other skin components. This fact is confirmed
`
`by Dr. Elewski’s own publications, which explain that onychomycosis begins by
`
`fungal invasion of the stratum corneum (a component of skin) of the hyponychium.
`
`Ex. 2010, 5. Thus, treatment of onychomycosis, particularly at the early stages,
`
`would necessarily include treating an infection of a skin structure of the nail.
`
`D. Dr. Elewski Mischaracterizes the Kaken Abstracts
`
`39. Dr. Elewski argues that “[n]otably, T. mentagrophytes infection is also
`
`often found in skin infections. The use of these strains indicates to me that the
`
`abstract assessed efinaconazole’s broad spectrum of activity rather than providing
`
`any guidance on efficacy in onychomycosis specifically.” Ex. 2027, ¶ 90. As
`
`explained above in ¶ 38 in connection with Dr. Elewski’s criticism of the Ogura
`
`reference, a POSA would have recognized that the Kaken Abstracts demonstrated
`
`good antifungal activity against the organisms that were known to be responsible
`
`for 90% of onychomycosis. Ex. 2010, 4-5. Moreover, as defined in the ’506
`
`17
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`Page 19 of 127
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`
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`patent, the nail includes skin structure and onychomycosis was known to initiate
`
`with invasion of those skin structures—notably the hyponychium and
`
`eponychium—by the infectious fungi. Ex. 1001, 4:65-67; Ex. 2010, 5-6. This
`
`topical treatment of onychomycosis involves treating infection of the skin.
`
`40. The efficacy of KP-103 against the same fungal strains that cause
`
`onychomycosis was tested in the Kaken Abstracts, see, e.g., Ex. 2037, 4, published
`
`in 1996. Table 1 of Ex. 2037 shows that the antifungal activity of KP-103 was
`
`tested against the major causes of onychomycosis (C. albicans, T. rubrum and T.
`
`mentagrophytes):
`
`Ex. 2037, 4.
`
`
`
`
`41. Dr. Elewski published in 1998 that “[t]he species that most often
`
`cause onychomycosis in North America and parts of Europe are T. rubrum, T.
`
`mentagrophytes, and Epidermophyton floccosum: the first two species are much
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`18
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`Page 20 of 127
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`
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`more often implicated than E. floccosum (58). . . . Dermatophytes account for most
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`(90%) of onychomycosis of the toenails and at least 50% of fingernail
`
`infections(31). Both dermatophytes and nondermatophytes, especially Candida
`
`albicans, have been identified as sole etiologic agents of onychomycosis.” Ex.
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`2010, 4-5. See also Table 1 of Ex. 2010:
`
`Ex. 2010, 9.
`
`
`
`
`42. The Introduction section of Abstract F792 of the Kaken Abstracts
`
`listed bifonazole, terbinafine, butenafine, amorolfine, clotrimazole, fluconazole
`
`and itraconazole as known antifungal agents (Ex. 2037, 4) all of which were drugs
`
`for treating onychomycosis in the prior art (Ex. 2065, 5, 9, 27). Thus, I disagree
`
`with Dr. Elewski’s argument that a POSA would not have been motivated to treat
`
`onychomycosis using the subject antifungal agent upon reading a reference that
`
`lists onychomycosis treatments in the introduction section, and provides data
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`19
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`Page 21 of 127
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`
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`demonstrating potent, broad-spectrum antifungal activity against the
`
`microorganisms known to cause onychomycosis, unique low adsorption to keratin
`
`and high release from keratin. Based on everything that was known by 1999, a
`
`POSA would have been motivated to use KP-103, a potent, broad-spectrum
`
`antifungal compound that is not inactivated by keratin, to improve topical
`
`formulations for treating onychomycosis with a reasonable expectation of success.
`
`43.
`
`In addition, Dr. Elewski’s position that the Kaken Abstracts tested
`
`efinaconazole against fungi that do not generally infect nail is incorrect. The
`
`Kaken Abstracts disclose the potent activity of KP-103 against T. mentagrophytes,
`
`T. rubrum, and C. albicans, the major causes of onychomycosis, and that KP-103’s
`
`potent antifungal activity was not inactivated by horny materials/keratin. The fact
`
`that the authors tested against a wide variety of pathogenic fungi to establish
`
`efinaconazole’s broad spectrum of activity would not have distracted a POSA from
`
`appreciating that the reference specifically highlighted efinaconazole’s high
`
`antifungal activity against the organisms most responsible for onychomycosis. Ex.
`
`2037, 4 (Table 1).
`
`44. Moreover, Dr. Elewski failed to note that the definition of
`
`onychomycosis in the ’506 patent explicitly defines the term onychomycosis as
`
`follows: “Onychomycosis means a kind of the above-mentioned superficial
`
`mycosis, in the other word a disease which is caused by invading and proliferating
`
`20
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`Page 22 of 127
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`
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`in the nail of human or an animal. Trichophyton rubrum and Trichophyton
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`mentagrophytes mainly cause onychomycosis in human.” Ex. 1001, col. 9:32-36.
`
`45. Efinaconazole was known to be effective against fungal infections in
`
`the horny layer. Throughout her Declaration, particularly at paragraphs 89-100,
`
`Dr. Elewski ignores the fact that onychomycotic fungi invade and reside in the
`
`horny layer of the skin (also known as that stratum corneum) at the distal edge of
`
`the nail plate (hyponychium) even though her 1998 review paper stated that
`
`“[d]istal subungual onychomycosis (DSO) is the most common form of
`
`onychomycosis. It is characterized by invasion of the nail bed and underside of the
`
`nail plate beginning at the hyponychium.” Ex. 2010, 5 (emphasis added). Nothing
`
`has changed in the literature to alter the view of the anatomy of the nail since this
`
`1998 publication.
`
`VII. DR. ELEWSKI MISCHARACTERIZES PARONYCHIA
`
`46. Dr. Elewski states that “[p]aronychia is distinct from onychomycosis
`
`in its pathogens, clinical appearance, treatment, and risk factors, and is not
`
`classified as onychomycosis. See Ex. 2078, 568-69.” Ex. 2027, ¶ 83. However, the
`
`reference that she cites for this premise expressly identifies paronychia as a clinical
`
`feature of distal and lateral subungual onychomycosis. Ex. 2078, 567-568.
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`POSAs knew that there are various “types of onychomycosis, characterized
`
`according to clinical presentation and the route of invasion,” including fungal
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`21
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`infections “at the hyponychium,” o
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