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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ACRUX DDS PTY LTD. & ACRUX LIMITED
`Petitioners,
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`v.
`
`KAKEN PHARMACEUTICAL CO., LTD. and
`VALEANT PHARMACEUTICALS INTERNATIONAL, INC.
`Patent Owner and Licensee.
`
`
`
`Case: IPR2017-00190
`U.S. Patent No. 7,214,506
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`
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`DECLARATION OF BONI E. ELEWSKI, M.D.
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`TABLE OF CONTENTS
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`Page(s)
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`Introduction ...................................................................................................... 1
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`I.
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`A.
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`B.
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`C.
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`Professional Qualifications and Expertise ............................................ 1
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`Compensation ........................................................................................ 4
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`Review and Use of Documents and Other Materials ............................ 5
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`II.
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`Summary of Opinions ...................................................................................... 6
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`III. Applied Legal Standards ................................................................................. 7
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`A.
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`B.
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`C.
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`Claim Construction................................................................................ 8
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`Person of Ordinary Skill ........................................................................ 9
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`Prior Art and Priority ...........................................................................10
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`D. Obviousness .........................................................................................11
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`IV. Technical Background ...................................................................................13
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`A. Onychomycosis ...................................................................................13
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`B.
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`The Morphology of the Nail ................................................................16
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`C. Unique Challenges of Treating Fungal Infections of the Nail ............18
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`D. Uncertainty in the Art Regarding the Factors Contributing to
`the Effectiveness of a Topical Treatment Hindered
`Development .......................................................................................21
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`E. Many Antifungal Agents were Available Prior to the ’506
`Patent but Lacked Proven Efficacy in Treating Onychomycosis
`Topically ..............................................................................................24
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`V.
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`The Discovery of Efinaconazole was a Breakthrough for the Field .............30
`
`A.
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`The Claimed Invention and the ’506 Specification ............................30
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`ii
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`B.
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`C.
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`D.
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`Efinaconazole displays superior efficacy ............................................34
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`Relevant Field and the Person of Ordinary Skill in the Art ................35
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`Claim Construction..............................................................................37
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`VI. Priority Date of the ’506 Patent .....................................................................39
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`VII. The Claims of the ’506 Patent are Not Obvious ...........................................40
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`A.
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`The Primary References Only Relate to the Use of
`Efinaconazole in Skin ..........................................................................41
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`1.
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`2.
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`The Kaken Abstracts Test Efinaconazole In Vitro and In
`a Guinea Pig Model of Skin Infection ......................................41
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`Ogura is Not Available as Prior Art and Regardless It
`Does not Add Anything to What the Kaken Abstracts
`Disclose .....................................................................................46
`
`B.
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`The Secondary Art Cited by Petitioner Only Discussed the Nail
`Penetrance of Unrelated Compounds ..................................................49
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`1.
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`2.
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`3.
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`4.
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`5.
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`JP ’639 Only Evaluates the Structurally Unrelated
`Compound Amorolfine .............................................................49
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`Amorolfine’s Underwhelming Efficacy Is Further
`Evidende of Unpredictability ....................................................50
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`The ’367 Patent and Hay Only Evaluate Another
`Structurally Unrelated Compound, Tioconazole ......................52
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`The ’367 Patent Fails to Offer Any Data Establishing
`Efficacy for Tioconazole, Let Alone Any Other
`Compounds ...............................................................................53
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`Hay Likewise Fails to Offer any Data Establishing
`Efficacy for Tioconazole Because of Poor Study Design ........53
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`C. No Motivation to Apply the Claimed Triazole Compounds to
`Nail with a Reasonable Expectation of Successfully Treating
`Onychomycosis ...................................................................................55
`iii
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`D. Neither Claim 1 Nor Claim 2 of the ’506 Patent is Obvious ..............58
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`VIII. Objective Indicia of Nonobviousness ............................................................58
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`IX. CONCLUSION ..............................................................................................63
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`iv
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`
`I.
`
`Introduction
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`1.
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`I Dr. Boni E. Elewski, M.D., have been retained by Finnegan,
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`Henderson, Farabow, Garrett & Dunner, L.L.P., to provide the following
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`declaration on behalf of Kaken Pharmaceutical Co., Ltd. and Valeant
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`Pharmaceuticals International, Inc. (collectively, “Patent Owner”) for inter partes
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`review Case No. IPR2017-00190 regarding U.S. Patent No. 7,214,506 (“the ’506
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`patent”). I understand that this IPR resulted from a petitioned filed by Acrux DDS
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`PTY LTD. and Acrux Limited (collectively, “Petitioner”).
`
`A.
`2.
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`Professional Qualifications and Expertise
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`I am currently the Chair of the Department of Dermatology and the
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`James E. Elder M.D. Endowed Professor for Graduate Medical Education in
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`Dermatology at the University of Alabama at Birmingham. I have worked in the
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`Department of Dermatology at the University of Alabama since December 1999.
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`Prior to that, from 1982 through December 1999, I was a faculty member at Case
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`Western Reserve University School of Medicine and my responsibilities there
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`included teaching dermatology residents.
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`3.
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`I hold an M.D. from The Ohio State University College of Medicine
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`(1978) and completed a residency in dermatology at the University of North
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`Carolina Memorial Hospital from 1979-1982.
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`1
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`4.
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`Throughout my career I have specialized in mycology, which is the
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`study of fungi, and other diseases of the nail. Beginning in 1981, I completed a
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`graduate course in medical mycology at Duke University. While at Case Western
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`Reserve University School of Medicine, I initiated a Dermatopharmacology
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`Fellowship that focused on Medical Mycology. I was the founder and Medical
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`Director of the Center for Medical Mycology at Case Western from 1995-1999,
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`where among other efforts I researched dermatophytes and other fungi, which are
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`the primary cause of onychomycosis.
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`5.
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`From 1989-1992, I was a member of the Task Force on Mycology of
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`the American Academy of Dermatology, and became its chairperson in 1993.
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`From 1991-1995, I ran the American Academy of Dermatology course on
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`“Clinical and Laboratory Mycology.” I have also served as Chair of the American
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`Academy of Dermatology panel developing Guidelines on Treatment of Mycoses
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`from 1992-1998 and on the Guidelines Task Force: Onychomycosis from 1992-
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`1996, among other positions. I was an advisor to the Food and Drug
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`Administration for Onychomycosis Guidelines in 1994 and Tinea Capitis
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`Guidelines in 1998.
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`6.
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`I have over 40 years of experience in treating patients with
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`onychomycosis, including as a dermatology resident at the University of North
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`Carolina School of Medicine, and as a faculty member at Northeastern Ohio
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`2
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`University College of Medicine and Case Western Reserve University School of
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`Medicine, and as a Professor at the University of Alabama at Birmingham. My
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`expertise includes examining, diagnosing, and treating patients with fungal
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`infections of the skin, hair, and nail.
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`7.
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`I also have many years of experience working with pharmaceutical
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`companies designing, conducting, and evaluating clinical studies for the treatments
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`of onychomycosis and other fungal infections. Since 1981, I have received grants
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`to conduct over 100 clinical trials. I have been a principal investigator in most of
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`these clinical trials. In many instances, I contributed to study protocols and
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`inclusion/exclusion criteria, organized and managed treatment centers, and
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`evaluated the resulting data for these studies. In this context, I have been involved
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`in several of the integral clinical studies on oral treatments for onychomycosis,
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`including terbinafine, itraconazole, and fluconazole, and topical treatments
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`including terbinafine, econazole, ciclopirox, amorolfine, butenafine, efinaconazole,
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`and tavaborole, among others.
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` I have also evaluated devices to treat
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`onychomycosis, including lasers, nail patches, PDT (photodynamic therapy), and
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`iontophoresis. I have also been involved in and advised on clinical trials relating to
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`other fungal infections (i.e., tinea capitis, tinea corporis, tinea cruris, tinea pedis),
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`acne, eczema, psoriasis, rosacea, alopecias, and other dermatological issues.
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`3
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`8.
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`I served as the Vice President of The American Academy of
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`Dermatology from 2001-2002 and then as the President of The American Academy
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`of Dermatology from 2004-2005. Among other awards, I have been voted a Top
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`Doctor in Dermatology for many years.
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`9.
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`I have served on the editorial boards of many different publications.
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`Notably, I was appointed to two 5-year terms as a member of the Editorial Board
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`of the Journal of the American Academy of Dermatology. I was on the editorial
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`board for Mycoses and the Mycology Observer for several years, among others.
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`10.
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`I have more than 200 peer-reviewed publications and over 40 books
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`and book chapters most of which are related to onychomycosis and topical
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`antifungal agents, as well as psoriasis. Since 1990, I have been invited to over 70
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`lectures and international conferences, where I have regularly spoken on issues
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`related to onychomycosis and treatment of other fungal infections.
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`11. My background and qualifications are more fully set out in my
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`curriculum vitae, which is attached as Appendix A.
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`B. Compensation
`I am being compensated for my work on this case at my customary
`12.
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`rate of $700 per hour plus expenses. My compensation does not depend in any
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`way on my opinions, my performance, or the outcome of the case.
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`4
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`13.
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`I am active and experienced in the research and treatment of
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`onychomycosis. As a result, I have consulted and/or advised a number of
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`companies evaluating treatments for onychomycosis, as well as for other diseases
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`such as psoriasis. This includes consulting and advising Valeant Pharmaceuticals
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`International, Inc., with respect to Jublia® (efinaconazole). These consulting
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`activities have led to several publications describing the results of clinical trials
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`related to Jublia® where I am named as lead author. I am currently the principal
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`investigator for two ongoing investigator-initiated clinical trials using Jublia®. I
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`have also led clinical trials and published papers relating to a number of other
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`antifungals to treat onychomycosis, including for example Lamisil®, Penlac®,
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`Kerydin® , and Sporanox®. The funding provided for these clinical trial activities,
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`including those from Valeant Pharmaceutical International, Inc., for Jublia®, were
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`paid in my professional capacity as a faculty member of the University of Alabama
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`at Birmingham. I will not receive personal financial benefit in any way for any
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`particular outcome in this case.
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`C. Review and Use of Documents and Other Materials
`In providing the opinions and conclusions in this declaration, I
`14.
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`considered the ’506 patent, Petitioner’s IPR Petition, Patent Owner’s Preliminary
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`Response, and the Board’s Institution Decision, as well as the materials referenced
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`5
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`in this declaration.1 I also relied on my education, knowledge, and experience in
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`treating onychomycosis, and I took into consideration the knowledge of a person of
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`ordinary skill in the art at the time the ’506 patent was filed.
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`II.
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`Summary of Opinions
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`15. After my review of the art and the other materials mentioned in
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`section I(c) above, I conclude that claims 1 and 2 of the ’506 patent would not have
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`been obvious to one of ordinary skill in the art at the time of the claimed invention
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`over any of the references cited in the Petition and relied on by the Board in the
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`Institution Decision, either alone or in combination. I understand those
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`combinations to be:
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`a. Japanese Patent Application Publication No. 10-226639,
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`published August 25, 1998 (“JP ’639,” Ex. 1011) in view of
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`“Synthesis and Antifungal Activities of (2R,3R)-2-Aryl-1-
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`1 The vast majority of the materials I considered are peer-reviewed articles or other
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`treatises commonly considered by those in the art. In my experience, peer-review
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`ensures scientific accuracy and veracity by subjecting an author's scholarly work,
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`research, or ideas to the scrutiny of others in the same field, before a paper
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`describing this work is published. I view the cited materials as reliable sources of
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`accurate information and have relied on similar articles from the same journals and
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`similar text books treatises in my own research.
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`6
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`azolyl-3-(substituted amino)-2-butanol Derivatives as Topical
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`Antifungal Agents,” by Ogura, H. et al., Chem. Pharm. Bull.,
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`47(10) 1417-1425 (allegedly October 1999) (“Ogura,” Ex.
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`1012);
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`b. U.S. Patent No. 5,391,367 to DeVincentis et al. (issued
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`February 21, 1995) (“the ’367 patent,” Ex. 1013) in view of
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`Ogura;
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`c. “Tioconazole nail solution—an open study of its efficacy in
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`onychomycosis,” by Hay, R.J., et al., Clinical and Experimental
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`Dermatology, 10:111-115 (1985) (“Hay”, Ex. 1014) in view of
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`Ogura;
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`d. JP ’639 in view of Abstracts F78, F79 and F80 from Abstracts
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`of the Interscience Conference on Antimicrobial Agents and
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`Chemotherapy (ICAAC), 36th ICAAC, held on September 15-18
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`(1996) (“the Kaken Abstracts,” Ex. 1015);
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`e. The ’367 patent in view of the Kaken Abstracts; and
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`f. Hay in view of the Kaken Abstracts.
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`III. Applied Legal Standards
`I am not a lawyer or legal expert, and do not offer any opinions
`16.
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`regarding the law. I have, however, been informed by counsel for Patent Owner of
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`7
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`the legal standards applicable to the issues I have been asked to examine. The
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`legal standards that were provided to me are set forth below.
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`17. For the purpose of my analysis, I understand that there are two types
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`of claims: independent claims and dependent claims. I understand that an
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`independent claim stands alone and includes only the limitations it recites. I also
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`understand that a dependent claim is a claim that depends on another claim. A
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`dependent claim includes all of its own recited limitations as well as any
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`limitations included in the corresponding claim from which it depends.
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`A. Claim Construction
`I understand from Patent Owner’s counsel that in this inter partes
`18.
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`review (IPR) I should give claim terms their broadest reasonable interpretation
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`consistent with the specification. I also understand that under the broadest
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`reasonable interpretation standard, the words of a claim are generally given their
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`ordinary and customary meaning as understood by a person of ordinary skill in the
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`art in question at the time of the invention in the context of the entire disclosure.
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`19.
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`I understand that the intrinsic evidence, which is the claim language,
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`patent specification, and the prosecution history, should be considered first in
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`determining the meaning of a disputed claim term, before looking to additional
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`material from the time of the invention if the intrinsic evidence does not address
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`the dispute. I also understand that although there is a presumption in favor of
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`applying the ordinary and customary meaning of a term, a patentee may provide a
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`different meaning if the patentee does so with reasonable clarity, deliberateness
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`and precision.
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`B.
`20.
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`Person of Ordinary Skill
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`I have been informed that factors such as the education level of those
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`working in the field, the sophistication of the technology, the types of problems
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`encountered in the art, the prior art solutions to those problems, and the speed at
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`which innovations are made may help establish the level of skill in the art. One
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`with ordinary skill has the ability to understand the technology and make modest
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`adaptations or advances. A person of ordinary skill in the art is also a person of
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`ordinary creativity, not an automaton.
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`21.
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`I understand that the Board defined a person of ordinary skill in the
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`relevant field at the time of the invention claimed in the ’506 patent as someone
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`having (i) a bachelor’s or master’s degree in medicinal chemistry, biochemistry,
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`pharmacology, and/or biology, and at least 3-5 years of experience working with
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`topical antifungal agents, or (ii) an M.D., Pharm.D., or Ph.D. in medicinal
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`chemistry, biochemistry, pharmacology, and/or biology and at least one year of
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`experience working with topical antifungal agents. Paper 12, 10.
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`9
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`22.
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`I consider myself someone who had at least the level of ordinary skill
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`in the art of the subject patent at the time of the claimed invention and does still
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`have at least that level of skill today.
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`C.
`23.
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`Prior Art and Priority
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`I understand that a patent or other publication must first qualify as
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`prior art before it can be used to invalidate a patent claim. I have been informed
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`that documents qualifying as prior art can render a claim unpatentable as
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`anticipated or obvious.
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`24.
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`I have been informed that the “priority date” of a patent is the date on
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`which the disclosure supporting the claimed invention was first filed. It is my
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`understanding that the priority date is significant because published information
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`prior to that date may be prior art that can render a patent claim unpatentable.
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`25.
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`I have been informed that the ’506 patent claims a priority date of July
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`28, 1999. I have also been informed that Petitioner disputes this date and alleges a
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`priority date of July 28, 2000. For purposes of this declaration, I have therefore
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`evaluated the art and level of skill in the field as of this later date. In my opinion,
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`however, the invention claimed in the ’506 patent is not obvious regardless of
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`which priority date is used.
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`10
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`D. Obviousness
`26. Once the terms of a patent claim have been construed, I understand
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`that the next step is to determine whether a patent is obvious. I have been
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`informed that a claim is considered obvious when the differences between the
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`claimed subject matter and the prior art are such that the claimed subject matter as
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`a whole would have been obvious to a person of ordinary skill in the pertinent art
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`at the time the invention was made. I further understand that a person of ordinary
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`skill in the art provides a reference point from which the prior art and the claimed
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`invention should be viewed. I also understand that only the knowledge and skill of
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`the ordinary artisan at the time of the invention should be considered. This
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`reference point prevents one from using his or her own later insight or hindsight in
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`deciding whether a claim is obvious. Thus, “hindsight reconstruction” cannot be
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`used to combine references together to reach a conclusion of obviousness.
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`27.
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`I have also been informed that an obviousness determination takes
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`into account various factors such as (1) the scope and content of the prior art, (2)
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`the differences between the prior art and the claims, (3) the level of ordinary skill
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`in the pertinent art, (4) a motivation to combine the prior art with a reasonable
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`expectation of success, and (5) the existence of secondary considerations of non-
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`obviousness.
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`11
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`28.
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`I understand that an obviousness analysis requires a comparison of the
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`claim language to the prior art to determine whether the claimed subject matter as a
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`whole would have been obvious. I have been told that a claimed invention is not
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`obvious when, for example, there is no teaching, suggestion, or motivation in the
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`prior art that would have led one of ordinary skill to modify the prior art reference
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`or to combine the teachings in prior art references to arrive at the claimed
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`invention.
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`29.
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`I also understand that secondary considerations of non-obviousness
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`are part of the inquiry, and that some examples of secondary considerations
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`include:
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`(1) any long-felt and unmet need in the art that was satisfied by the invention
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`claimed in the patent;
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`(2) any failure of others to achieve the results of the invention;
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`(3) any commercial success or lack thereof of the products and
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`processes covered by the invention;
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`(4) any deliberate copying of the invention by others in the field;
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`(5) any taking of licenses under the patent by others;
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`(6) any expressions of disbelief or skepticism by those skilled in the art at
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`the time of the invention;
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`(7) any unexpected results achieved by the invention;
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`12
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`(8) any praise of the invention by others skilled in the art; and
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`(9) any lack of contemporaneous and independent invention by others.
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`IV. Technical Background
`A. Onychomycosis
`30. Onychomycosis is a fungal infection of the nail unit, more commonly
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`found in toenails than fingernails, affecting about 10% of the U.S. population. The
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`most common causes are
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`the dermatophytes Trichophyton rubrum and
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`Trichophyton mentagrophytes, and sometimes Epidermophyton floccosum; these
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`dermatophyte infections are also referred to as tinea unguium. Ex. 2009, 284; Ex.
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`2010, 416; Ex. 2012, 363; Figure 1, Ex. 2075, 2352 (showing a patient with
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`onychomycosis). The defining feature of onychomycosis is the location of the
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`infection. The fungal infection resides in the nail bed and/or nail plate, and can
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`also reside in the nail matrix. Ex. 2007, 3 (“[O]nychomycosis refers to a fungal
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`infection of the nail unit - the nail matrix, bed, or plate.”); Figure 4 (showing the
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`histology of the nail unit); see also Ex. 2048, 2628.
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`
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`FIGURE 1
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`13
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`31. There are several types of onychomycosis, all generally involving the
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`nail bed and/or nail plate. Overwhelmingly, the most common form is distal
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`subungual onychomycosis (DSO, also known as distal
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`lateral subungual
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`onychomycosis, or DLSO). This form of onychomycosis is characterized by
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`fungal invasion of the distal nail bed and underside of the nail plate, migrating
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`from there through the nail matrix. Ex. 2010, 417-18. All of the drugs specifically
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`approved to treat onychomycosis, including Jublia®, have been tested for efficacy
`
`against DSO. Ex. 2055, 167-68, 171. The other, less common, types of
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`onychomycosis include proximal subungual onychomycosis (PSO, also known as
`
`proximal white subungual onychomycosis, or PWSO), white superficial
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`onychomycosis (WSO), and Candida yeast infections (CMCC). Ex. 2010, 418-19.
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`The types are differentiated based on the initial site and spread of the infection
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`(although all implicate the nail bed and/or nail plate) and the pathogen causing the
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`infection. See id. For example, Candida infections occur in patients with chronic
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`mucocutaneous candidiasis (CMCC), with C. albicans invading the entire nail
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`plate. Id., 419.
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`32. Onychomycosis should not be confused with fungal infections of
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`other tissues. Those infections include, for example, tinea capitis (a fungal
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`infection of the scalp), tinea corporis (a fungal infection of the body skin), and
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`tinea pedis (a fungal infection of the skin on a foot). See Figure 2 (showing from
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`14
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`

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`left to right images of tinea capitis, tinea corporis, and tinea pedis), Ex. 2075, 2344,
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`2346, 2349. Similarly, paronychia refers to an infection of the skin around the
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`fingernail or toenail and is predominantly by bacteria or the yeast fungus C.
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`albicans. Ex. 2078, 568-69.
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`
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`
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`FIGURE 2
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`33. These infections have different clinical presentations. Carefully
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`distinguishing between different types of infections is particularly important
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`because “the site of infection is critical in selecting therapy.” Ex. 2075, 2738. An
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`infection on the skin is superficial, unlike the nail plate and nail bed infection seen
`
`in onychomycosis. Dermatophyte infections of the scalp are generally referred to
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`as tinea capitis, where the hair follicles themselves involve fungal invasion of
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`highly complex tissue having a very different anatomy from the nail. Similarly,
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`paronychia is a distinct infection; only if the infection spreads to the nail bed and
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`nail plate would it become onychomycosis. Ex. 2078, 568-69.
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`34.
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`In the late 1990s, like today, doctors treated each of these types of
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`infection differently. Paronychia, when caused by yeast fungal infection rather
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`15
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`than bacteria, was usually treated with an oral drug, such as itraconazole or
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`fluconazole. Likewise, I prescribed and still prescribe oral treatments such as
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`fluconazole to treat tinea capitis, whereas topical treatments, such as topical
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`terbinafine, work for tinea corporis or tinea pedis. But those drugs had not been
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`reported to work when applied topically to treat onychomycosis in the late 1990s.
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`Thus, each of these distinct diseases required different treatments. See Ex. 2075,
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`2737-39 (describing treatments for various infections and stating that the “two
`
`most important factors” for treating fungal infections are the “type of the pathogen
`
`and the site of the infection”). Nail in particular is a specialized and unique tissue
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`structure, with distinct requirements for treatment as compared to infections in
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`other tissues.
`
`The Morphology of the Nail
`
`B.
`35. The nail unit is complex, having several specialized structures,
`
`including a nail plate, nail bed, nail matrix, and nail folds (including the lateral and
`
`posterior nail folds), as well as the eponychium, and hyponychium surrounding
`
`these other structures. Ex. 1001, 4:65-67; see also Ex. 2012, 365; Ex. 2013, 239-
`
`43. See Figure 3 below. The eponychium and hyponychium alone do not make up
`
`the nail unit, as they are simply skin structures that accompany the other
`
`components of the nail unit.
`
`16
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`

`

`FIGURE 3
`
`
`
`36. The nail plate contains several layers, with the upper dorsal layer of
`
`being only a few cell layers thick but consisting of hard keratin, constituting the
`
`main barrier for drug diffusion through the nail plate. Ex. 2012, 364-367; see also
`
`Ex. 2049, 3837. See Figure 4 below. While keratin also appears to some extent in
`
`skin and hair, in nail it has a very different concentration, density, and
`
`arrangement. See, e.g., Ex. 2012, 366-67; Ex. 1028, 278. Other components of the
`
`nail include carbohydrates, lipids, water, and trace elements. Ex. 2012, 366-67;
`
`Ex. 2013, 242. The nail plate contains less than 5% lipid content, much lower than
`
`skin or hair. Ex. 2012, 367.
`
`37. The nail plate acts as an effective barrier to the permeation of drugs.
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`Ex. 2012, 364, 368-69. Each layer of the nail plate “possesses unique
`
`physicochemical properties and drug permeabilities through the layers may be
`
`different.” Ex. 2082, 69. This uniquely layered structure contributes to the
`
`difficulty of identifying effective treatments for onychomycosis, even for
`
`antifungal agents that otherwise work well in other keratinized tissue such as skin.
`
`17
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`

`

`FIGURE 4
`
`
`
`C. Unique Challenges of Treating Fungal Infections of the Nail
`38. Nail is unlike skin and hair structurally, producing distinct interactions
`
`with antifungal agents. Even if infection is caused by the same pathogen, the
`
`differences between skin, hair, and nail may still require different types of
`
`treatment. See Ex. 2075, 2737-39. For example, terbinafine works topically but
`
`not orally to treat Candida infections in skin. Ex. 2074, 16; Ex. 2013, 292.
`
`39. Treating nail infections presents distinct challenges. Due to the
`
`difficulty of penetrating and combating infection in the nail plate and nail bed, the
`
`standard of care for many years had been oral treatment. The properties of the nail,
`
`particularly its thickness and relatively compact construction, make it a formidable
`
`barrier to the entry of topically applied agents, as compared to skin and hair. See
`
`Ex. 2012, 369; see also Ex. 2049, 3837. In fact, a nail infected with a fungus
`
`becomes unusually thick, making it even more difficult for a topical agent to reach
`
`the site of infection within the nail plate and nail bed.
`
`18
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`

`

`40. Given the structural and functional differences between hair, skin, and
`
`nail, and the distinct types of dermatophyte infections commonly seen in these
`
`tissues, they also require different treatment strategies. See Ex. 2075, 2738-39.
`
`Skin infections reside in the superficial layers of the stratum corneum (also known
`
`as the horny layer or material), making them easily accessible by topical means,
`
`often more easily than through oral routes. But these same topical agents are often
`
`less effective in nail.
`
`41. Nail infections commonly reside in or below layers of keratinous nail
`
`plate, making them far less accessible topically. The presence of fungal infections
`
`in the nail plate and deeper in the underlying nail bed, as well as the inaccessibility
`
`of those structures, contributed to the serious difficulty identifying effective topical
`
`agents. An effective treatment for onychomycosis generally must penetrate the
`
`nail plate and/or nail bed before providing long-term therapeutic efficacy. See Ex.
`
`2012, 365, 369. While oral agents showed some promise achieving these functions
`
`by the late 1990s, they also had recognized side effects. Ex. 2010, 422; see also
`
`Ex. 2075, 2847-52. Yet alternatives were in short supply and indeed the general
`
`recommendation for many years was to consider avoiding treatment altogether.
`
`42. Topically treating onychomycosis, like most mycotic infections,
`
`requires an agent capable of providing antifungal activity against
`
`the
`
`microorganism causing the infection. But, unlike other mycoses, in order to
`
`19
`
`

`

`effectively treat onychomycosis, the agents must also (1) effectively reach the
`
`fungal infection in the nail bed, nail plate, and/or nail matrix, and (2) persist as an
`
`active antifungal agent to effectively combat the underlying infection in these
`
`structures. Ex. 2010, 422-23; Ex. 2012, 369; Ex. 2015, Abstract; Ex. 2048, 2628
`
`(explaining the challenges in treating onychomycosis derive in part from the fact
`
`that it is “difficult for a topically applied antifungal drug to achieve a
`
`therapeutically effective level in the inner ventral layer, let alone the nail bed”);
`
`Ex. 2007, 3 (“fungal infections of the nail are notoriously difficult to treat.”); Ex.
`
`2076, Abstract; Ex. 2049, 3839-3841. For example, oral itraconazole was thought
`
`to be effective because it persisted over long periods of time in the nail at levels
`
`sufficient to combat the fungal infection, thereby reducing the need for continuous
`
`and prolonged treatment, with its concomitant side effects and drug-drug
`
`interactions. Ex. 2010, 424-25; see also Ex. 2065, Abstract, 456 (terbinafine
`
`likewise has promise because it persists in nail for longer than 252 days due to high
`
`keratin binding).
`
`43. Drug transport and retention in and under the nail plate are also
`
`influenced by the physicochemical properties of the chosen compound (i.e., size,
`
`shape, charge, and hydrophilicity), formulation characteristics, and delivery
`
`vehicle, as well as individual nail properties (thickness and hydration). Ex. 2051,
`
`20
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`

`

`2. These properties interact differently with the distinct structures in nail, skin, and
`
`hair.
`
`44.
`
`In short, nails are unique, specialized structures that differ in many
`
`respects from hair and skin in ways that ultimately affect drug diffusion and
`
`efficacy. Ex. 2019, 775. The art is replete with examples of agents that effectively
`
`treated fungal infections in skin but did not translate to efficacy in nail. Ex. 2010,
`
`422; Ex. 2075, 2739; Ex. 2052, 291-92.
`
`D. Uncertainty in the Art Regarding t