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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC and AMNEAL
`PHARMACEUTICALS OF NEW YORK, LLC,
`Petitioners
`
`v.
`
`ALMIRALL, LLC,
`Patent Owner
`
`Case IPR2019-00207
`Patent 9,517,219
`
`DECLARATION OF LEON H. KIRCIK, M.D. IN SUPPORT OF PATENT
`OWNER’S RESPONSE TO PETITION FOR INTER PARTES REVIEW
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`Almirall EXHIBIT 2055
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`Amneal v. Almirall
`IPR2019-00207
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`IPR2019-00207
`Declaration of Dr. Leon H. Kircik
`
`
`TABLE OF CONTENTS
`
`
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`A.
`Background and Qualifications ............................................................. 1
`B. Materials Considered ............................................................................. 5
`SUMMARY OF OPINIONS ........................................................................... 9
`II.
`III. THE ’219 PATENT .......................................................................................10
`IV. PERSON OF ORDINARY SKILL IN THE ART ........................................11
`V.
`THE SCOPE AND CONTENT OF THE PRIOR ART AS OF
`
`NOVEMBER 20, 2012 ..................................................................................12
`A. Acne Vulgaris and Rosacea .................................................................12
`1.
`Acne Pathogenesis ....................................................................12
`2.
`Prior Art Acne Treatments ........................................................19
`a.
`First-Line Treatments .....................................................19
`b.
`Combination Therapies ...................................................22
`c.
`Second-Line Treatments .................................................27
`d.
`Emerging Treatments .....................................................29
`Rosacea ................................................................................................32
`B.
`C. Dapsone and Dapsone/Adapalene Compositions ...............................36
`1.
`Dapsone .....................................................................................36
`2.
`Adapalene Combinations ..........................................................42
`VI. Petitioner’s Prior Art References ...................................................................45
`A. WO 2009/061298 (“Garrett”) (Ex. 1004) ...........................................45
`B.
`International Publ. No. WO 2010/072958 A2
`(“Nadau-Fourcade”) (Ex. 1005) ..........................................................48
`C. Giulia Bonacucina et al., Characterization and stability of
`emulsion gels based on acrylamide/sodium acryloyldimethyl
`taurate copolymer, 10 AAPS PharmSciTech 368 (2009)
`(“Bonacucina”) (Ex. 1015) ..................................................................48
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`IPR2019-00207
`Declaration of Dr. Leon H. Kircik
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`TABLE OF CONTENTS
`(continued)
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`
`
`Page
`
`VII. THE CLAIMS OF THE ’219 PATENT WOULD NOT HAVE
`
`BEEN OBVIOUS ..........................................................................................49
`A. A POSA Would Not Have Been Motivated to Select Dapsone ..........49
`B. A POSA Would Not Be Motivated to Select the Concentration
`of Dapsone to 7.5% .............................................................................55
`If a POSA Had Selected Dapsone for an Acne or Rosacea
`Treatment, It Would Be Combined with Adapalene ...........................58
`VIII. CONCLUSION ..............................................................................................61
`
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`C.
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`IPR2019-00207
`Declaration of Dr. Leon H. Kircik
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`I, Dr. Leon H. Kircik, declare as follows:
`
`I.
`
`INTRODUCTION
`
`
`
`1.
`
`I am Leon H. Kircik, M.D., and I submit this declaration on behalf of
`
`Almirall, LLC (“Almirall”), the patent owner of United States Patent No.
`
`9,517,219 (the “’219 patent”), the subject matter of the above-referenced petition
`
`for
`
`inter partes review by Amneal Pharmaceuticals LLC and Amneal
`
`Pharmaceuticals of New York, LLC (“Amneal” or “Petitioner”). Specifically, I
`
`submit this declaration in response to the declaration of Dr. Elaine S. Gilmore
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`proffered by Petitioner, and in support of Almirall’s Patent Owner Response.
`
`A. Background and Qualifications
`
`2.
`
`I am an expert in the field of dermatology and in the treatment of
`
`patients suffering from dermatological disorders, including acne and rosacea.
`
`3.
`
`I earned a Bachelor of Arts in chemistry from New York University,
`
`magna cum laude, in 1985, where I was a member of the Phi Beta Kappa honor
`
`society. I subsequently earned my M.D. cum laude in 1989 from the State
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`University of New York Health Sciences Center at Brooklyn, and was a member of
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`the Alpha Omega Alpha Honor Medical Society. I completed an internship in
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`internal medicine from 1989 to 1990 at New York Medical College, and completed
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`a residency in dermatology from 1990 to 1993 at the State University of New York
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`Health Sciences Center at Buffalo, and was chief resident during the last year. I
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`have been certified by the American Board of Dermatology since December 1993.
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`
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`I also completed a Mohs micrographic surgery and cutaneous oncology fellowship
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`at the University of Wisconsin in 1994. I am currently licensed to practice in New
`
`York, Wisconsin, Kentucky, Indiana, and Virginia.
`
`4.
`
`I have served on faculties at State University of New York Health
`
`Sciences Center at Buffalo, State University of New York Health Sciences Center
`
`at Brooklyn, and currently hold appointments as Associate Clinical Professor of
`
`Dermatology at Indiana University Medical Center and at Mount Sinai Medical
`
`Center in New York, where I have been faculty since 2005 and 2008, respectively.
`
`5.
`
`Throughout my career, I have published widely in peer-reviewed
`
`journals, with over 200 publications to my name. I have also presented hundreds
`
`of posters at industry meetings, and am frequently invited to give talks on new and
`
`emerging treatments in dermatology, including acne and rosacea treatments. In my
`
`career, I have given hundredsof talks at industry meetings and symposia as well as
`
`local seminars.
`
`6.
`
`I was named one of the Stars of the Academy by the American
`
`Academy of Dermatology in 2016 and 2017. I serve on the editorial board of
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`several key journals in the field, including the Journal of Drugs in Dermatology,
`
`the Journal of Clinical & Aesthetic Dermatology, Skin & Ageing, and Practical
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`Dermatology. I have served as Medical Monitor for Kamedis Pharmaceuticals and
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`Merk, and have in the past served as a Data Safety Monitoring Committee Member
`
`
`
`for Ethica. I am also sought out by and serve as a consultant for Phase II–IV
`
`clinical trial design and marketing for numerous pharmaceutical companies with
`
`dermatological products or product pipelines, including Merck, Amgen, Allergan,
`
`Almirall, Dr. Reddy’s Lab, Taro, Galderma, Valeant, and Genentech.
`
`7.
`
`In addition to my academic appointments, I see patients in private
`
`dermatology practice. I have been the Medical Director of Physicians Skin Care,
`
`PLLC in Louisville, Kentucky since 2000, and oversee clinical trials of
`
`dermatology-related treatments as the Medical Director of Skin Sciences, PLLC
`
`since 2016 and DermResearch, PLLC since 2005, both also in Louisville. I am the
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`founder of DREAM—a medical education meeting in Canada targeting young
`
`dermatology graduates to prepare them for real-world practice—and president of
`
`the
`
`International Dermatology Education Foundation,
`
`Inc.—a non-profit
`
`organization whose principal mission is to raise awareness and improve
`
`dermatology through education around the world, especially in underserved areas.
`
`8. My background and qualifications are more fully set forth in my
`
`curriculum vitae, attached as Exhibit 2056.
`
`9.
`
`I have been practicing dermatology since I completed my fellowship
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`in 1995. In my 24 years of practice, I have seen thousands of patients, including
`
`several hundred acne and rosacea patients each year.
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`10.
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`I am familiar with, and have prescribed to my patients, appropriate
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`therapies to treat the various dermatological conditions that they present. These
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`therapies include agents in topical, oral, and biologics dosage formulations, as well
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`as surgical treatment, chemical peels, light therapy, and Mohs Micrographic
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`Surgery. I am familiar with, and have prescribed, both monotherapies, therapies
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`where multiple active agents are administered concurrently, and therapies where
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`two active agents are combined in a single dosage form (combination therapies) for
`
`my patients. I am also familiar with, and have prescribed, topical dermatological
`
`therapies with a variety of dosing regimens, e.g., for application once a day (Q.D.)
`
`or for twice a day (B.I.D.).
`
`11.
`
`I have served as a clinical investigator in trials leading to multiple
`
`approved drugs, including Embrel, Skyrizi, Duobrii, Soolantra, Rhofade, and
`
`Aczone 7.5%. I also currently am or have been an investigator of Phase III trials
`
`on drugs undergoing FDA approval, including lebikizumab, tralokinumab, TYK2
`
`inhibitor, JAK inhibitor, roflumilast, and numerous others.
`
`12. From my service in the aforementioned capacities, I have extensive
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`experience assessing and opining on clinical data underlying dermatological drugs
`
`and drug candidates, both during development and post-approval.
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`IPR2019-00207
`Declaration of Dr. Leon H. Kircik
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`B. Materials Considered
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`
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`13. The opinions that I express in this declaration are based on the
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`information and evidence currently available to me. The following table lists the
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`materials that I considered in forming my opinions set forth in this declaration. I
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`have also relied on my education, knowledge, and experience that I have acquired
`
`over 24 years as a practicing dermatologist.
`
`Exhibit
`No.
`1001
`
`Materials
`
`United States Patent No. 9,517,219
`
`1004
`
`1005
`
`1007
`
`International Patent Application Publication No. WO 2009/061298
`(“Garrett”)
`International Patent Application Publication No. WO 2010/072958
`(“Nadau-Fourcade”)
`U.S. Patent Application Publication No. 2006/0204526 (“Lathrop”)
`
`1008
`
`U.S. Patent Application Publication No. 2010/0029781 (“Morris”)
`
`1012
`
`Epiduo Product Label
`
`1015
`
`1018
`
`Giulia Bonacucina et al., Characterization and stability of emulsion
`gels based on acrylamide/sodium acryloyldimethyl taurate
`copolymer, 10 AAPS PharmSciTech 368 (2009) (“Bonacucina”)
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`
`1022 Wozel, D., “Innovative Use of Dapsone” Dermatol. Clin. 28: 599–
`610 (2010) (“Wozel 2010”)
`Thiboutot, D., et al., “Pharmacokinetics of Dapsone Gel, 5% for the
`Treatment of Acne Vulgaris” Clin. Pharmacokinet. 46: 697-712
`
`1023
`
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`Declaration of Dr. Leon H. Kircik
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`Exhibit
`No.
`
`Materials
`
`
`
`1024
`
`1027
`
`1032
`
`(2007) (“Thiboutot 2007”)
`Nguyen, R. and Su, J., “Treatment of Acne Vulgaris” Pediatrics and
`Child Health 21: 119-125 (2011) (“Nguyen”)
`1025 Williams, H., et al., “Acne vulgaris” Lancet 379: 361–72 (2012)
`(“Williams”)
`Barclay, L., “Use of Topical Corticosteroids for Dermatologic
`Conditions Reviewed” Medscape - Jan 21, 2009, accessed from
`https://www.medscape.com/viewarticle/587159_print (“Barclay”)
`Piskin, S. et al. “A review of the use of adapalene for the treatment
`of acne vulgaris,” Therapeutics and Clinical Risk Management 3(4):
`621–624 (2007) (“Piskin”)
`2001 WO 2009/108147 (“Garrett II”)
`
`International Patent Application Publication No. WO 2011/014627
`(“Ahluwalia”)
`Dina Anderson, Finding a Place for Topical Anti-inflammatory Acne
`Therapy, Practical Dermatology 17 (July 2009) (“Anderson”)
`Christin N. Collier et al., The prevalence of acne in adults 20 years
`and older, 58 J. Am. Acad. Dermatol. 56 (2008) (“Collier”)
`Loren Cordain et al., Acne Vulgaris: A Disease of Western
`Civilization, 138 Arch Dermatol. 2584 (2002) (“Cordain”)
`Barry Coutinho, Dapsone (Aczone) 5% Gel for the Treatment of
`Acne, Am. Family Physician (2010) (“Coutinho”)
`James Q. Del Rosso, Newer Topical Therapies for the Treatment of
`Acne Vulgaris, 80 Cutis 400 (2007) (“Del Rosso 2007”)
`Gabriella Fabbrocini et al., Resveratrol-Containing Gel for the
`Treatment of Acne Vulgaris: A Single-Blind, Vehicle-Controlled,
`Pilot Study, 12 Am. J. Clin. Dermatol. 133 (2011) (“Fabbrocini”)
`Zoe D. Draelos et al., Two randomized studies demonstrate the
`efficacy and safety of dapsone gel, 5% for the treatment of acne
`vulgaris, 46 J. Am. Acad. Dermatol. 439.e1 (2007) (“Draelos”)
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
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`Declaration of Dr. Leon H. Kircik
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`Materials
`
`Exhibit
`No.
`2016
`
`A. B. Fleischer et al., Dapsone Gel 5% in Combination with
`Adapalene Gel 0.1%, Benozoyl Peroxide Gel 4% or Moisturizer for
`the Treatment of Acne Vulgaris: A 12-Week, Randomized, Double-
`Blind Study, 9 J. Drugs Dermatol. 33 (2010) (“Fleischer”)
`2017 Michael Ghods et al., The Role of Dapsone Gel in the Acne
`Armamentarium, The Dermatologist (June 10, 2010) (“Ghods”)
`2018 William D. James, Acne, 352 New Eng. J. Medicine 463 (2005)
`(“James 2005”)
`Kirk A. James et al., Emerging Drugs for Acne, 14 Expert Opinions
`on Emerging Drugs 649 (2009) (“James 2009”)
`Leon H. Kircik, Harnessing the Anti-inflammatory Effects of Topical
`Dapsone for Management of Acne, 9 J. Drugs Dermatol. 667 (2010)
`(“Kircik 2010”)
`Leon Kircik and Adam Friedman, Optimizing Acne Therapy With
`Unique Vehicles, 9 J. Drugs Dermatol. S53 (2010) (“Kircik 2010a”)
`Leon H. Kircik, Synergy and Its Clinical Relevance in Topical Acne
`Therapy, 4 J. Clin. Aethet. Dermatol. 30 (2011) (“Kircik 2011”)
`Leon H. Kircik, Microsphere Technology: Hype or Help?, 4 J. Clin.
`Aesthet. Dermatol. 27 (2011) (“Kircik 2011a”)
`H.C. Korting & C. Schöllmann, Current topical and systemic
`treatment of rosacea, 23 J. Eur. Acad. of
`approaches
`to
`Dermatology and Venereology 876, 876 (2009) (“Korting”)
`John Kraft & Anatoli Freiman, Management of acne, 183 Canadian
`Med. Assoc. J. E430 (2011) (“Kraft”)
`Evgenia Makrantonaki et al., An update on the role of the sebaceous
`gland in the pathogenesis of acne, 3 Dermato-Endocrinology 41
`(2011) (“Makrantonaki”)
`Otto H. Mills et al., Comparing 2.5%, 5%, and 10% Benzoyl
`Peroxide on Inflammatory Acne Vulgaris, 25 Int’l J. Dermatology
`664 (1986) (“Mills”)
`2028 Warren W. Piette et al., Hematologic Safety of Dapsone Gel, 5%, for
`Topical Treatment of Acne Vulgaris, 144 Arch. Dermatol. 1564
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
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`Declaration of Dr. Leon H. Kircik
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`Exhibit
`No.
`
`Materials
`
`
`
`2029
`
`2030
`
`2032
`
`2033
`
`2034
`
`(2008) (“Piette”)
`Frank C. Powell, Rosacea, 352 New Eng. J. Med. 793 (2005)
`(“Powell”)
`Thierry Simonart, Newer Approaches to the Treatment of Acne
`Vulgaris, 13 Am. J. Clin. Dermatol. 357 (2012) (“Simonart”)
`2031 MaryAnn Steiner, Dapsone Topical Gel for Acne, 12 J Pharm Soc.
`Wisc. 67 (2009) (“Steiner”)
`John S. Strauss, Biology of
`the
`the Sebaceous Gland and
`Pathophysiology of Acne Vulgaris, Chapter 13 in Pathophysiology of
`Dermatologic Diseases, Second Edition, N. A. Soter and H. Baden
`eds., McGraw-Hill, New York (1991) (“Strauss 1991”)
`John S. Strauss et al., Guidelines of care for acne vulgaris
`management, 56 J. Am. Acad. Dermatol. 651 (2007) (“Strauss
`2007”)
`Emil Tanghetti et al., Clinical Evidence for the Role of a Topical
`Anti-Inflammatory Agent in Comedonal Acne: Findings From a
`Randomized Study of Dapsone Gel 5% in Combination With
`Tazarotene Cream 0.1% in Patients With Acne Vulgaris, 10 J. Drugs
`Dermatol. 783 (2011) (“Tanghetti”)
`Diane Thiboutot et al., An aqueous gel fixed combination of
`clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the
`once-daily
`treatment of moderate
`to severe acne vulgaris:
`Assessment of efficacy and safety in 2813 patients, 59 J. Am. Acad.
`Dermatol. 792 (2008) (“Thiboutot 2008”)
`Diane Thiboutot et al., New insights into the management of acne:
`An update from the Global Alliance to Improve Outcomes in Acne
`Group, 60 J. Am. Acad. Dermatol. S1 (2009) (“Thiboutot 2009”)
`Anja Thielitz and Harald Gollnick, Topical Retinoids in Acne
`Vulgaris – Update on Efficacy and Safety, 9 Am. J. Clin. Dermatol.
`369 (2008) (“Thielitz”)
`Stephen Titus & Joshua Hodge, Diagnosis and Treatment of Acne,
`86 Am. Family Physician 734 (2012) (“Titus”)
`
`2035
`
`2036
`
`2037
`
`2038
`
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`IPR2019-00207
`Declaration of Dr. Leon H. Kircik
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`
`
`Materials
`
`Exhibit
`No.
`2039
`
`Physicians’ Desk Reference (2011) (excerpt)
`
`2040
`
`Physicians’ Desk Reference (2012) (excerpt)
`
`2041
`
`2042
`
`Epiduo Press Release (Dec. 15, 2011), available at
`https://www.galderma.com/us/news/1-branded-topical-acne-product-
`epiduo-gel-recieves-fda-approval-new-convenient-pump-dispenser
`Aczone 5% Medical Review(s) (excerpt)
`
`2043
`
`Aczone 5% Clinical Pharmacology and Biopharmaceutics Review(s)
`
`2044
`
`2008 Aczone 5% label
`
`2045
`
`2005 Aczone 5% approval letter
`
`2046
`
`2008 Aczone 5% approval letter
`
`2059
`
`Ryan Gamble et al., Topical Antimicrobial Treatment of Acne
`Vulgaris, 13 Am. J. Clin. Dermatol. 3 (2012) (“Gamble”)
`2060 M. P. Heffernan et al., A Pilot Study of the Safety and Efficacy of
`Picolinic Acid Gel in the Treatment of Acne Vulgaris, 156 British J.
`Dermatol. 548 (2006) (“Heffernan”)
`Janusz Marcinkiewicz et al., Topical Taurine Bromamine, a New
`Candidate in the Treatment of Moderate Inflammatory Acne
`Vulgaris - A Pilot Study, 18 Eur. J. Dermatol. 433 (2008)
`(“Marcinkiewicz”)
`
`2061
`
`
`
`II.
`
`SUMMARY OF OPINIONS
`
`14.
`
`I have reviewed the Declaration of Dr. Elaine S. Gilmore (the
`
`“Gilmore Declaration”), Amneal’s Petition for inter partes review of the ’219
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`patent, and the specification and claims of the ’219 patent. I disagree with a
`
`
`
`number of the opinions expressed in the Gilmore Declaration and the positions
`
`taken in the Petition regarding the obviousness of the challenged claims of the ’219
`
`patent.
`
`15.
`
`In my opinion, a POSA would not have found it obvious to arrive at
`
`the challenged claims of the ’219 patent at least because at the time of the
`
`invention, a POSA would not have been motivated to treat patients for acne and
`
`rosacea with any novel topical formulation of dapsone, and less motivated still to
`
`treat with such a formulation having a design as described in the lead prior art
`
`reference relied on by Petitioner, Garrett. Moreover, had the POSA resolved to
`
`treat with a newly-formulated dapsone, he or she would not be motivated to do so
`
`specifically at a concentration of 7.5%. Finally, it is my opinion that had a POSA
`
`selected dapsone for an improved acne or rosacea treatment, it would only have
`
`been obvious combine adapalene in, not exclude adapalene from, the composition.
`
`III. THE ’219 PATENT
`
`16. The ʼ219 patent is entitled “Topical Dapsone and Dapsone/Adapalene
`
`Compositions and Methods for Use Thereof” and pertains to methods of treating
`
`acne vulgaris and rosacea by administering to a patient having one of those
`
`conditions a topical pharmaceutical compound.
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`17. The field of art, according to the ʼ219 patent, is generally
`
`
`
`“compositions useful for treating a variety of dermatological conditions,” and more
`
`specifically “dapsone and dapsone/adapalene compositions and methods for use
`
`thereof.” Ex. 1001 at 1:19–23. The patent’s eight claims are all directed
`
`specifically to “method[s] for treating a dermatological condition selected from the
`
`group consisting of acne vulgaris and rosacea” by administering topical
`
`pharmaceutical compositions. Id. at Claims 1, 6.
`
`18. Claims 5 and 8, which are dependent on Claims 1 and 6, respectively,
`
`specify that the dermatological condition treated is acne vulgaris. Id. at Claims.
`
`19. The topical pharmaceutical compounds used in the claimed methods
`
`contain about 7.5% dapsone, as well as particular amounts of specified excipients,
`
`and specifically exclude adapalene. However, the claims of the ʼ219 patent are not
`
`concerned with
`
`the method of manufacturing
`
`the
`
`topical pharmaceutical
`
`compounds, but only with methods of treating the dermatological conditions. Id. at
`
`Claims.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`
`20.
`
`In have been informed that during prosecution of the application that
`
`issued as the ʼ219 patent, the examiner stated that “the level of skill in the art is
`
`high and is at least that of a medical doctor with several years of experience in the
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`art.” I agree with the examiner, insofar as this would encompass other skilled
`
`
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`artisans.
`
`21.
`
`I understand that another expert, Dr. David Osborne, will address the
`
`relevant issues.
`
`V. THE SCOPE AND CONTENT OF THE PRIOR ART AS OF
`NOVEMBER 20, 20121
`
`22. The prior art as of 2012 contained several methods of treating acne
`
`and a few methods of treating rosacea.
`
`A. Acne Vulgaris and Rosacea
`1.
`Acne Pathogenesis
`23. Acne vulgaris is likely the most prevalent skin disease in Western
`
`civilization. See Ex. 2011, Loren Cordain et al., Acne Vulgaris: A disease of
`
`Western civilization, 138 Arch. Dermatol. 2584 (2002) (“Cordain”) at 1; Ex. 1025,
`
`Hywel C. Williams et al., Acne vulgaris, 379 Lancet 361 (2012) (“Williams”) at 1.
`
`“Vulgaris” simply means “common,” and my reference to “acne” in this
`
`declaration refers to acne vulgaris.
`
`24. Acne commonly affects adolescents, and may persist into adulthood
`
`or may have an initial presentation in adulthood. In adults, acne is more common
`
`
`1 I have used the effective filing date of the ʼ219 patent of November 20, 2012 for
`
`the purposes of my opinions.
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`in women than in men. See Williams at 1; Ex. 2010, Christin N. Collier et al., The
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`
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`prevalence of acne in adults 20 years and older, 58 J. Am. Acad. Dermatol. 56
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`(2008) (“Collier”) at 1.
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`25. Acne is characterized by skin lesions of varying degrees, and may
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`result in scarring. See Ex. 2010, Collier at 1; Ex. 2019, Kirk A. James et al.,
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`Emerging drugs for acne, 14 Expert Opinions on Emerging Drugs 649 (2009)
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`(“James 2009”) at 1. Because of its visible nature, acne can cause low self-esteem,
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`social inhibition, anxiety, depression, and suicidal ideation. Ex. 1025, Williams at
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`3; Ex. 2019, James 2009 at 1; Ex. 2025, John Kraft & Anatoli Freiman,
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`Management of acne, 183 Canadian Med. Assoc. J. E430 (2011) (“Kraft”) at 1;
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`Ex. 2036, Diane Thiboutot et al., New insights into the management of acne: an
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`update from the Global Alliance to Improve Outcomes in Acne Group, 60 J. Am.
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`Acad. Dermatol. S1 (2009) (“Thiboutot 2009”) at 2–3.
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`26. Acne is a disease of the pilosebacous unit. Pilosebaceous units are
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`present across the skin, but are clustered most densely in the areas where acne is
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`common—the face, neck, upper chest, shoulders, and back. Ex. 1025, Williams
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`at 1; Ex. 2019, James 2009 at 1. Each unit is composed of a hair follicle and
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`sebaceous gland, as shown below:
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`27. The sebaceous gland secretes an oily substance called sebum, which
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`travels up the hair follicle and through the pore to the skin surface, keeping the
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`skin and hair from drying out. See Ex. 2026, Evgenia Makrantonaki et al., An
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`Update on the Role of the Sebaceous Gland in the Pathogenesis of Acne, 3
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`Dermato-Endocrinology 41 (2011) (“Makrantonaki”) at 1. The sebum also carries
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`dead skin cells shed by the hair follicle out through the pore.
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`28. As of 2012, it was understood that there were four primary pathogenic
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`mechanisms of acne:
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`inflammation,
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`increased sebum production,
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`faulty
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`keratinization, and bacterial colonization by Propioniumbacterium acnes. See Ex.
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`1025, Williams at 2; Ex. 1024, Rebecca Nguyen and John Su, Treatment of acne
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`vulgaris, 21 Paediatrics and Child Health 119 (2011) (“Nguyen”) at 1; Ex. 2019,
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`James 2009 at 1, 3–4; Ex. 2030, Thierry Simonart, Newer Approaches to the
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`Treatment of Acne Vulgaris, 13 Am. J. Clin. Dermatol. 357 (2012) (“Simonart”)
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`at 1.
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`29. Sebum is the oily substance produced by the sebaceous glands in the
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`pilosebaceous unit. See, e.g., Ex. 2019, James 2009 at 1; Ex. 2036, Thiboutot 2009
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`at 5. Increased sebum production in acne is understood to contribute to blockage
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`of the pores, leading to lesion formation. See, e.g., Ex. 2026, Makrantonaki at 1.
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`In addition, the lipid composition of the sebum of acne patients differs from that of
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`people without acne. Id. at 1–2.
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`30. As
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`for
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`faulty
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`keratinization,
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`also
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`called
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`perifollicular
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`hyperkeratinization, the keratinocytes (skin cells) surrounding and in the follicles
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`proliferate rapidly. See, e.g., Ex. 1024, Nguyen at 1. Hyperproliferation may
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`narrow the pore, and the increased number of dead cells cannot be removed from
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`the follicle efficiently by sebum. The blocked follicle ultimately results in visible
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`comedones, i.e., whiteheads and blackheads. See, e.g., Ex. 2032, John S. Strauss,
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`Biology of the Sebaceous Gland and the Pathophysiology of Acne Vulgaris,
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`Chapter 13 in Pathophysiology of Dermatologic Diseases, Second Edition, N. A.
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`Soter and H. Baden eds., McGraw-Hill, New York (1991) (“Strauss 1991”) at 3–
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`18, 3, 7; Ex. 2019, James 2009 at 3. Whiteheads are clogged follicles closed off
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`from the air, while blackheads are clogged follicles exposed to air. See, e.g.,
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`Ex. 2032, Strauss 1991 at 8; Ex. 2025, Kraft at 1; Ex. 1024, Nguyen at 2.
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`Comedones generally occur in areas with more sebaceous glands, particularly the
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`
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`face, shoulders, upper chest and back. See, e.g., Ex. 2016, James I at 1; Ex. 1024,
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`Nguyen at 1, 2; Ex. 2025, Kraft at 1; Ex. 2032, Strauss 1991 at 8; Ex. 2038,
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`Stephen Titus & Joshua Hodge, Diagnosis and Treatment of Acne, 86 Am. Family
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`Physician 734 (2012) (“Titus”) at 1.
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`31. Propionibacterium acnes is a bacterium that thrives in areas that are
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`high in lipid content and lack oxygen, including the pilosebaceous glands. See,
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`e.g., Ex. 1025, Williams at 3; Ex. 2019, James 2009 at 4; Ex. 2032, Strauss 1991
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`at 8. This bacteria was and is understood to colonize the obstructed follicle,
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`causing some comedones to worsen and change into larger and more inflamed
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`lesions. See, e.g., Ex. 2032, Strauss 1991 at 8; Ex. 1025, Williams at 3.
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`32. Acne was understood
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`to be an
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`inflammatory disease, with
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`inflammation localized to the pilosebaceous units. The inflammation in acne is the
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`result of complex cellular signaling processes involving both the innate and
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`adaptive immune responses. While the timing and interaction of the four
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`pathogenic factors of acne remain unclear, by 2012 it was understood that immune
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`changes and inflammatory events begin early in the lesion development, and not
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`just in response to bacterial presence. See Ex. 2036, Thiboutot 2009 at 5–6; Ex.
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`2034, Emil Tanghetti et al., Clinical Evidence for the Role of a Topical Anti-
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`Inflammatory Agent in Comedonal Acne: Findings from a Randomized Study of
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`Dapsone Gel 5% in Combination with Tazarotene Cream 0.1% in Patients with
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`
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`Acne Vulgaris, 10 J. Drugs Dermatol. 783 (2011) (“Tanghetti”) at 2. However, the
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`presence of P. acnes in the follicles also contributes to the inflammatory response
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`by stimulating production of proinflammatory cytokines. See Ex. 2036, Thiboutot
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`2009 at 5–6; see also Ex. 2020, Leon H. Kircik, Harnessing the Anti-Inflammatory
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`Effects of Topical Dapsone for Management of Acne, 9 J. Drugs Dermatol. 667
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`(2010) (“Kircik 2010”) at 1; Ex. 2034, Tanghetti at 2.
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`33. While acne
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`lesions are classified as not clinically
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`inflamed
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`(comedones—whiteheads and blackheads) or clinically
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`inflamed (papules,
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`pustules, and nodules), by 2012 it was understood that subclinical inflammation is
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`involved
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`in development of comedones, which are
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`traditionally called
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`“noninflammatory” lesions. Ex. 2034, Tanghetti at 2:
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`34. As of 2012, acne was generally categorized through assessment of the
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`number, type, and distribution of lesions. See, e.g., Ex. 2033, John S. Strauss et al.,
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`Guidelines of care for acne vulgaris management, 56 J. Am. Acad. Dermatol. 651
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`(2007) (“Strauss 2007”) at 2. A typical example of such categorization is in the
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`table below:
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`(Ex. 2018, William D. James, Acne, 352 New Eng. J. Medicine 463 (2005)
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`(“James 2005”) at 1–2).
`2.
`Prior Art Acne Treatments
`35. As of 2012, a variety of acne treatment options existed. The
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`treatments targeted the four pathogenic bases of acne discussed above, and various
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`treatment courses were recommended depending on the type and severity of the
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`acne. See, e.g., Ex. 2019, James 2009 at 2.
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`36. Treatments for mild to moderate acne included topical therapies, oral
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`antibiotics, and hormonal therapies, while treatments for severe acne further
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`included oral isotretinoin. See Ex. 1024, Nguyen, at 5–6; Ex. 1025, Williams, at 5.
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`Less common treatments included light therapy, steroidal injections, comedo
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`removal, chemical peels, and alternative medicines like tea tree oil. See, e.g.,
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`Ex. 1024, Nguyen at 6; Ex. 2033, Strauss 2007 at 7–8.
`a.
`First-Line Treatments
`37. As of 2012, topical retinoids were widely used as a first-line treatment
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`for mild to moderate acne. Ex. 2033, Strauss 2007 at 3–4; Ex. 2030, Simonart at 2;
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`Ex. 2036, Thiboutot 2009 at 6–7. Topical retinoids in the United States included
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`tretinoin, adapalene, and tazarotene. Ex. 2019, James 2009 at 2; Ex. 2037, Anja
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`Thielitz and Harald Gollnick, Topical Retinoids in Acne Vulgaris – Update on
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`Efficacy and Safety, 9 Am. J. Clin. Dermatol. 369 (2008) (“Thielitz”) at 2.
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`38. Retinoids are potent acne treatments with multiple mechanisms of
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`action. They are comedolytic and reduce hyperkeratinization. In addition,
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`retinoids were known to be anti-inflammatory, and have been shown to be
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`effective in reducing both non-inflammatory and inflammatory lesions. Ex. 2019,
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`James 2009 at 2; Ex. 2037, Thielitz at 2–3. Topical adapalene in particular was
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`known to be effective and well tolerated. See Ex. 2037, Thielitz at 6–7.
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`39. Benzoyl peroxide is another mainstay in topical acne treatments. See
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`Ex. 2019, James 2009 at 2 (“It is the oldest and most widely used topical agent for
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`the treatment of non-inflammatory and inflammatory acne vulgaris.”). It is
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`understood to be comedolytic and to kill bacteria via production of free radicals.
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`Id. The free radicals further exfoliate the skin and clear clogged pores. Id. It is
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`well tolerated and efficacious, but is also a potent bleaching agent. Id.; Ex. 2025,
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`Kraft at 2–3. Because benzoyl peroxide kills P. acnes through oxidative damage
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`rather than by binding a specific target, it is not associated with antibiotic
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`resistance. See Ex. 2019, James 2009 at 2.
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`40. Topical antibiotics also reduce inflammation and kill bacteria. See
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`Ex. 2019, James 2009 at 2. Specific topical antibiotics as of 2012 included
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`erythromycin and clindamycin. See, e.g, id. Erythromycin and clindamycin were
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`regarded as well tolerated and had been shown to reduce inflammatory lesions by
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`up to 70%. See, e.g., Ex. 2025, Kraft at 3. However, antibiotic treatment is
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`associa