IPR2019-00207
`Patent Owner Response
`
`
`
`
`IN THE 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
`_______________
`
`PATENT OWNER’S RESPONSE TO
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`Patent Owner Response
`
`
`
`
`IN THE 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
`_______________
`
`PATENT OWNER’S RESPONSE TO
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`
`IPR2019-00207
`Patent Owner Response
`
`
`TABLE OF CONTENTS
`
`Page
`PATENT OWNER’S EXHIBIT LIST ..................................................................... v
`I.
`INTRODUCTION .......................................................................................... 1
`II.
`THE ʼ219 PATENT ........................................................................................ 3
`III.
`SCOPE AND CONTENT OF THE PRIOR ART CONCERNING
`ACNE AND ROSACEA TREATMENTS .................................................... 6
`A. Acne ...................................................................................................... 6
`B.
`Prior Art Acne Treatments ................................................................... 9
`1.
`First-Line Treatments ................................................................... 9
`2. Combination Therapies .............................................................. 10
`3. Emerging Treatments ................................................................. 13
`Rosacea ............................................................................................... 14
`C.
`IV. SCOPE AND CONTENT OF THE PRIOR ART CONCERNING
`DAPSONE AND DAPSONE/ADAPALENE COMPOSITIONS FOR
`THE TREATMENT OF DERMATOLOGICAL CONDITIONS ............... 15
`A.
`Topical Dapsone for Treatment of Acne or Rosacea ......................... 15
`B.
`Formulation of Topical Dapsone Products ........................................ 18
`C.
`Adapalene Combination Products ...................................................... 26
`POSA ............................................................................................................ 27
`V.
`VI. CLAIM CONSTRUCTION ......................................................................... 28
`VII. THE PRIOR ART OF PETITIONERS’ GOUNDS DOES NOT
`RENDER OBVIOUS THE CHALLENGED CLAIMS OF THE
`ʼ219 PATENT ............................................................................................... 28
`
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`Patent Owner Response
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`TABLE OF CONTENTS
`(Continued)
`
`Page
`
`B.
`
`C.
`
`D.
`
`A. A POSA Had No Genuine Reason to Treat Acne or Rosacea
`with a New Dapsone Topical Formulation ........................................ 30
`A POSA Would Not Reasonably Have Considered Garrett a
`Motivation to Make a New Topical Dapsone Formulation for
`Treatment of Acne or Rosacea ........................................................... 33
`1. By 2012, a POSA Would Not Have Desired a Product
`Containing Undissolved Dapsone .............................................. 33
`2. Garrett Itself Teaches Dapsone Is Not Effective ....................... 39
`3. Closer Art Teaches that Dapsone Is Not Effective .................... 41
`Petitioners Fail to Show Motivation to Increase Dapsone
`Concentration to the Claimed About 7.5% ........................................ 43
`The Prior Art Taught That Adapalene/Dapsone Combinations
`Were Superior to Dapsone-Only Topicals ......................................... 45
`No Motivation to Use the Claimed Polymeric Viscosity Builder ...... 47
`1.
`Petitioners Have Not Demonstrated A Credible Motivation
`to Combine with Nadau-Fourcade ............................................. 51
`Petitioners Have Not Demonstrated A Credible Motivation
`to Combine with Bonacucina ..................................................... 54
`Neither Nadau-Fourcade Nor Bonacucina Teaches the Claimed
`Concentrations of Polymeric Viscosity Builder Comprising
`A/SA Copolymer for Use With the Dapsone Topical Formulations
`Allegedly Disclosed in Garrett ........................................................... 58
`G. Objective Indicia of Non-Obviousness Further Support Denial
`of the Petition ..................................................................................... 60
`VIII. CONCLUSION ............................................................................................. 64
`
`E.
`
`F.
`
`2.
`
`ii
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`IPR2019-00207
`Patent Owner Response
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`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Altana Pharma AG v. KUDCo,
`No. 04-2355-JLL, 2010 WL 10804666 (D.N.J. Jul. 15, 2010) .......................... 42
`Altana Pharma AG v. Teva Pharm. USA, Inc.,
`566 F.3d 999 (Fed. Cir. 2009) ............................................................................ 41
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .......................................................................................... 29, 64
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .................................................................... 29, 48
`Intendis GMBH v. Glenmark Pharms. Inc., USA,
`822 F.3d 1355 (Fed. Cir. 2016) .......................................................................... 53
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 29
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 29
`Optivus Tech., Inc. v. Ion Beam Applications S.A.,
`469 F.3d 987 (Fed. Cir. 2006) ............................................................................ 48
`Ortho-McNeil Pharm., Inc. v. Mylan Labs, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 41
`Polaris Indus. Inc. v. Arctic Cat, Inc.,
`882 F.3d 1056 (Fed. Cir. 2018) .......................................................................... 36
`Süd-Chemie, Inc. v. Multisorb Techs., Inc.
`554 F.3d 1001 (Fed. Cir. 2009) .......................................................................... 46
`
`iii
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`IPR2019-00207
`Patent Owner Response
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`TABLE OF AUTHORITIES
`(Continued)
`
`Page(s)
`
`
`STATUTES AND RULES
`35 U.S.C. § 316(e) ................................................................................................... 28
`OTHER AUTHORITIES
`37 C.F.R. § 42.1(d) .................................................................................................. 28
`
`
`iv
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`PATENT OWNER’S EXHIBIT LIST
`
`Exhibit No.
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`Description
`International Patent Application Publication No. WO 2009/108147
`(“Garrett II”)
`International Patent Application Publication No. WO 2010/105052
`(“Hani”)
`Redline Comparison of Petitions in IPR2018-00608 and
`IPR2019-00207
`Redline Comparison of Michniak-Kohn Declarations in
`IPR2018-00608 and IPR2019-00207
`Redline Comparison of Gilmore Declarations in IPR2018-00608
`and IPR2019-00207
`Petitioner’s Notice of Paragraph IV Certification to Patent Owner
`(February 22, 2019) (truncated)
`Declaration of Elizabeth B. Hagan in Support of Patent Owner
`Almirall, LLC’s Motion for Admission Pro Hac Vice
`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. Dermtol. 56 (2008) (“Collier”)
`Loren Cordain et al., Acne Vulgaris: A Disease of Western
`Civilization, 138 Arch Dermatol. 2584 (2002) (“Cordain”)
`
`v
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`IPR2019-00207
`Patent Owner Response
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`
`Exhibit No.
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`Description
`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”)
`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”)
`Michael Ghods et al., The Role of Dapsone Gel in the Acne
`Armamentarium, The Dermatologist (June 10, 2010) (“Ghods”)
`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”)
`
`vi
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`IPR2019-00207
`Patent Owner Response
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`
`Exhibit No.
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`Description
`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
`approaches to treatment of rosacea, 23 J. Eur. Acad. of
`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”)
`Warren W. Piette et al., Hematologic Safety of Dapsone Gel, 5%,
`for Topical Treatment of Acne Vulgaris, 144 Arch. Dermatol. 1564
`(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”).
`MaryAnn Steiner, Dapsone Topical Gel for Acne, 12 J Pharm Soc.
`Wisc. 67 (2009) (“Steiner”)
`
`vii
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`IPR2019-00207
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`
`Exhibit No.
`2032
`
`2033
`
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`2039
`2040
`
`Description
`John S. Strauss, Biology of the Sebaceous Gland and the
`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”).
`Physicians’ Desk Reference (2011) (excerpt)
`Physicians’ Desk Reference (2012) (excerpt)
`
`viii
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`
`Exhibit No.
`2041
`
`2042
`2043
`
`2044
`2045
`2046
`2047
`
`2048
`2049
`
`2050
`2051
`2052
`
`2053
`
`Description
`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)
`Aczone 5% Clinical Pharmacology and Biopharmaceutics
`Review(s)
`2008 Aczone 5% label
`2005 Aczone 5% approval letter
`2008 Aczone 5% approval letter
`Siripen Puavilai et al., Incidence of Anemia in Leprosy Patients
`Treated with Dapsone, J. Med. Assoc. Thailand 67(7): 404-407
`(1984) (“Puavilai”)
`World Health Organization Alert No. 117
`Boyd Poulsen, Development Process in Topical Dosage Forms,
`AAPS/FDA Joint Workshop on Topical Product Development:
`Principles and Criteria for the Development and Optimization of
`Topical Therapeutic Products, Arlington, VA (Mar. 26, 1990)
`(“Poulsen”).
`FDA Inactive Ingredient Database (September 2012)
`FDA Inactive Ingredient Database (December 2012)
`European Commission’s Scientific Committee on Consumer
`Safety, Opinion on Diethylene Glycol Monoethyl Ether (DEGEE)
`(2010)
`U.S. Patent Application Publication No. 2007/0122435
`(“Osborne III”)
`
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`IPR2019-00207
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`
`Exhibit No.
`2054
`2055
`2056
`2057
`2058
`2059
`
`2060
`
`2061
`
`2062
`
`2063
`
`2064
`
`
`
`Description
`
`2005 Aczone 5% label
`Declaration of Leon H. Kircik, M.D.
`Curriculum Vitae of Leon H. Kircik, M.D.
`Declaration of David W. Osborne, Ph.D.
`Curriculum Vitae of David W. Osborne, Ph.D.
`Ryan Gamble et al., Topical Antimicrobial Treatment of Acne
`Vulgaris, 13 Am. J. Clin. Dermatol. 3 (2012) (“Gamble”).
`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”)
`Transcript of Deposition of Elaine S. Gilmore, M.D., Ph.D., dated
`July 25, 2019
`Transcript of Deposition of Bozena B. Michniak-Kohn, Ph.D.,
`FAAPS, M.R.Pharm.S., dated July 30, 2019
`Rong-Kun Chang et al., Generic Development of Topical
`Dermatological Products: Formulation Development, Process
`Development, and Testing of Topical Dermatological Products, 15
`AAPS J. 41 (2012) (“Chang”)
`
`x
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`IPR2019-00207
`Patent Owner Response
`
`
`Patent Owner Almirall, LLC (“Almirall”) hereby submits this Patent Owner
`
`Response to the Petition filed by Amneal Pharmaceuticals LLC and Amneal
`
`Pharmaceuticals of New York, LLC (collectively, “Amneal” or “Petitioner”) in
`
`Case IPR2019-00207 for review of U.S. Patent No. 9,517,219 (“the ʼ219 patent”).
`
`I.
`
`INTRODUCTION
`Disposition of this inter partes review is controlled by two fundamental
`
`principles of the law of obviousness, and their faithful application to the Petition
`
`compel the same conclusion reached by the Examiner at the close of prosecution:
`
`the claims of the ʼ219 patent are not obvious.
`
`The first principle is that the hypothetical POSA, presumed to know all
`
`pertinent prior art, must consider the art as a whole as of the eve of the date of
`
`invention. Put in consequential terms, the perspective of the hypothetical skilled
`
`artisan is only credibly proffered when oriented around the state of the art as it
`
`existed at that time, however it may have evolved to that point. The second
`
`principle is that hindsight may never be employed in a proper obviousness
`
`assessment. A failure to mind the first principle is, quite logically, a hallmark of
`
`violating the second. The Petition presents the epitome of this dynamic: when the
`
`universe of prior art concerning topical treatment of acne and rosacea with dapsone
`
`is fairly read and considered as a whole, the only reasonable explanation for
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`1
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`IPR2019-00207
`Patent Owner Response
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`selecting the references of the Counts is hindsight.
`
`From the evidence of record it is virtually undeniable that by November
`
`2012, the peculiar microparticulate design of the topical dapsone formulations
`
`described in Petitioners’ lead reference, Garrett—a design already generally
`
`avoided by formulators, no matter the drug or condition to be treated—had long
`
`proved inefficient, impractical, unnecessary, and accordingly irrational, not least
`
`because the design inherently retarded potential efficacy of dapsone. As such, the
`
`suggestion that any skilled artisan in 2012 would reasonably pursue a novel
`
`method of treating acne and rosacea using a topical dapsone formulation
`
`employing this same microparticulate design of Garrett is simply not credible. But
`
`the posture of Garrett as the premise of Petitioner’s challenges does not just betray
`
`hindsight in this regard; more fatally, it completely undermines the suggestion that
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`there existed any motivation to combine Garrett (and its peculiar microparticulate
`
`embodiments) with the secondary references of the Counts,
`
`It is (or will be) no response for Petitioner to posit that, even if conceded that
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`dapsone topicals of the Garrett/microparticulate design were disfavored by 2012,
`
`its burden is not to show the claims reflect the best possible advance in the art of
`
`dapsone topical treatment, but only that it was obvious that what is claimed would
`
`simply work, however well, to treat acne or rosacea. The Board should not be
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`distracted by, let alone entertain, any such argument. The facts are that the
`
`Petitioner deliberately advanced Garrett as the lead reference in all Counts of its
`
`Petition, and the secondary references, Nadeau-Fourcade (Count 1) and
`
`Buonocucina (Count 2) do not teach, suggest, or even tacitly imply in any way that
`
`their respective disclosures even remotely bear on, let alone provide any solution to
`
`some problem with, or are even compatible with, the microparticulate-type
`
`dapsone topical embodiments disclosed in, described in, and core to Garrett.
`
`Whether because riddled with hindsight, or because the proffered bridge
`
`between Garrett and the secondary references falls short of evidencing the requisite
`
`motivation to combine—under a preponderance or any other standard—the Counts
`
`should be dismissed, and the Petition should be denied.
`
`II. THE ʼ219 PATENT
`The ʼ219 patent issued on December 13, 2016, from an application filed
`
`October 16, 2015. The application was a division of U.S. Patent Application No.
`
`14/082,955 (now U.S. Patent No. 9,161,926), filed on November 18, 2013. The
`
`patent claims priority to provisional applications filed on November 20, 2012, and
`
`February 28, 2013. Ex. 1001 at 1:8-14.1
`
`The pertinent art to which the ʼ219 patent is directed is broad:
`
`
`1 Citations to patents are to column and line number.
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`3
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`“compositions useful for treating a variety of dermatological conditions.”
`
`Ex. 1001 at 1:18-21. The specification provides that particular embodiments
`
`“relate to dapsone and dapsone/adapalene compositions and methods for use
`
`thereof.” Id. at 1:21-23.
`
`The ʼ219 patent has eight claims, all to methods of treatment. Specifically,
`
`it claims methods for treating the dermatological conditions acne vulgaris or
`
`rosacea by administering topical pharmaceutical compositions comprising
`
`(1) dapsone as the active pharmaceutical ingredient (“API”); (2) the solvent
`
`diethylene glycol monoethyl ether (“DGME”); (3) a polymeric viscosity builder
`
`(or “thickener”) comprising acrylamide/sodium acryloyldimethyl taurate
`
`copolymer (“A/SA copolymer”); and water. In addition, the claims are expressly
`
`limited to exclude adapalene from the formulations recited in the claimed methods.
`
`Independent claim 1 recites:
`
`1. A method for treating a dermatological condition selected
`from the group consisting of acne vulgaris and rosacea
`comprising administering to a subject having the
`dermatological condition selected from the group consisting of
`acne vulgaris and rosacea a topical pharmaceutical composition
`comprising:
`about 7.5% w/w dapsone;
`
`4
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`about 30% w/w to about 40% w/w diethylene glycol
`monoethyl ether;
`about 2% w/w to about 6% w/w of a polymeric viscosity
`builder comprising acrylamide/sodium acryloyldimethyl
`taurate copolymer; and
`water;
`wherein the composition does not comprise adapalene.
`
`Ex. 1001. Claims 2-5 depend from claim 1. Claim 2 limits the concentration of
`
`DGME to “about 30% w/w.” Id. Claim 3 limits the concentration of polymeric
`
`viscosity builder to “about 4% w/w.” Id. Claim 4 requires that the topical
`
`pharmaceutical composition further comprise the preservative methyl paraben. Id.
`
`Claim 5 limits the dermatological condition to acne vulgaris. Id.
`
`Independent claim 6 recites:
`
`6. A method for treating a dermatological condition selected
`from the group consisting of acne vulgaris and rosacea
`comprising administering to a subject having the
`dermatological condition selected from the group consisting of
`acne vulgaris and rosacea a topical pharmaceutical composition
`comprising:
`about 7.5% w/w dapsone;
`about 30% w/w diethylene glycol monoethyl ether;
`
`5
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`IPR2019-00207
`Patent Owner Response
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`
`about 4% w/w of a polymeric viscosity builder comprising
`acrylamide/sodium acryloyldimethyl taurate copolymer;
`and
`water;
`wherein the composition does not comprise adapalene.
`
`Id. Claims 7 and 8 depend from claim 6. Claim 7 requires that the topical
`
`pharmaceutical composition further comprise the preservative methyl paraben. Id.
`
`Claim 8 limits the dermatological condition to acne vulgaris. Id.
`
`III. SCOPE AND CONTENT OF THE PRIOR ART CONCERNING
`ACNE AND ROSACEA TREATMENTS
`A. Acne
`Acne is a prevalent skin disease most common in adolescents, but also
`
`occurring in adults. Physical symptoms of the blemishes associated with acne
`
`include soreness, itching, pain, redness, inflammation, and scarring. Because of its
`
`visible nature, acne can also cause low self-esteem, social inhibition, anxiety,
`
`depression, and suicidal ideation. Ex. 2055 ¶¶ 23-25.
`
`Acne affects the pilosebaceous unit. There are thousands of pilosebaceous
`
`units throughout the skin, but most are found in the face, back and chest. A
`
`pilosebaceous unit is composed of a hair follicle (the cavity from which a hair
`
`grows) and sebaceous gland, as shown below.
`
`6
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`Patent Owner Response
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`
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`Ex. 2055 ¶ 26. The sebaceous glands secrete an oily substance called sebum,
`
`which travels up the hair follicle, out through the pores, and onto the surface of the
`
`skin to keep the skin and hair lubricated. The hair follicles, which regulate hair
`
`growth, routinely shed dead skin cells, which sebum carries out of the body.
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`Ex. 2055 ¶ 27 .
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`As of 2012, it was understood that acne is a multifactorial condition with
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`four underlying causes: (1) increased sebum production; (2) excess shedding of
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`skin cells in and around the follicle (perifollicular hyperkeratinization); (3)
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`colonization with Propionibacterium acnes bacteria (also known as P. acnes); and
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`(4) inflammation. Ex. 2055 ¶ 28; Ex. 1024 at 1.
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`Excess sebum production was understood to create or contribute to blockage
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`of the follicles/pores. Perifollicular hyperkeratinization is characterized by
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`excessive development of dead skin cells in hair follicles. When the number of
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`cells increases too rapidly for the dead cells to be carried out efficiently by sebum,
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`dead skin blocks the follicle and results in what ultimately become visible
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`comedones, i.e., whiteheads and blackheads. Ex. 2055 ¶¶ 29-30.
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`P. acnes thrives in areas that are high in lipid content and lack oxygen,
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`including the pilosebaceous glands. this bacterium colonizes the obstructed
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`follicle, causing some comedones to worsen and become more inflamed. P. acnes
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`causes an inflammatory response. Ex. 2055 ¶ 31-32. By 2012, however, it was
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`understood that inflammatory events localized to the pilosebaceous unit begin
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`early in the lesion development, rather than just in response to bacterial presence.
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`Ex. 2055 ¶ 32; Ex. 2020 at 1; Ex. 2034 at 2; Ex. 2036 at 5-6.
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`There are different types of acne lesions, which can be classified by whether
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`or not they are considered clinically inflamed. However, as by 2012 it was
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`understood that subclinical inflammation is involved in development of the so-
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`called “noninflammatory” lesions, this terminology can seem a misnomer to
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`laypeople. See Ex. 2055 ¶ 33; Ex. 2034 at 2. Lesions termed “noninflammatory”
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`are the comedones (whiteheads and blackheads), while those termed
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`“inflammatory” are papules, pustules, and nodules. Ex. 2055 ¶ 33. As of 2012,
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`acne was generally categorized through assessment of the number, type, and
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`distribution of lesions, and could be characterized in terms of severity. Id. ¶ 34.
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`B.
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`Prior Art Acne Treatments
`1.
`First-Line Treatments
`As of 2012, first-line acne treatments included topical retinoids, topical
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`benzoyl peroxide, topical and oral antibiotics, and oral isotretinoin. Ex. 2055 ¶¶
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`37-41, 43. Topical retinoids—including tretinoin, tazarotene, and notably
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`adapalene—were widely used as first-line treatments. They were believed to have
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`multiple mechanisms of
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`action,
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`including
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`comedolysis,
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`reduction of
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`hyperkeratinization, and were also understood to have some anti-inflammatory
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`effect. Ex. 2055 ¶¶ 37-38; Ex. 2003 at 3-4; Ex. 2030 at 2; Ex. 2036 at 6-7; Ex.
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`2019 at 2; Ex. 2037 at 1–3. Topical adapalene in particular was known to be
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`effective and well tolerated. Ex. 2055 ¶ 38; Ex. 2037 at 6-7. Benzoyl peroxide
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`was another mainstay topical acne treatment, and was “the oldest and most widely
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`used topical agent for the treatment of non-inflammatory and inflammatory acne.”
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`Ex. 2055 ¶ 39; Ex. 2019 at 2. It was understood to have both anti-bacterial and
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`anti-inflammatory properties, but unlike other antibacterial agents was not
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`associated with antibiotic resistance. Ex. 2055 ¶ 39. Topical antibiotics, including
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`erythromycin and clindamycin, were well-tolerated and had been shown to reduce
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`inflammatory lesions by up to 70%. Antibiotics also reduced inflammation by
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`reducing the number of P. acnes organisms. Id. ¶ 40.
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`Oral antibiotics were used to treat moderate to severe inflammatory acne,
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`and were understood to have antibacterial and secondary anti-inflammatory
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`properties. Id. ¶ 41. Another orally administered compound, isotretinoin, was
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`considered unique in that it targeted all four pathogenic factors of acne. While
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`highly effective, oral isotretinoin was associated with serious side effects and was
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`therefore typically prescribed only to patients with severe acne. Id. ¶ 43.
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`Hormonal treatments were also available, and acted by reducing sebum production.
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`Id. ¶ 42.
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`Combination Therapies
`2.
`As of 2012, it was understood that no topical acne treatment was effective in
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`targeting all four pathogenic factors contributing to acne. As the chart below
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`shows, only isotretinoin affects all four, and different agents have different
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`strengths:
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`Ex. 1025 at 4; Ex. 2055 ¶ 44. For example, retinoids are particularly effective at
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`addressing hyperfollicular keratinization, but have very little effect against P.
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`acnes. In contrast, benzoyl peroxide is particularly potent against P. acnes.
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`In order to effectively target multiple pathogenic factors, recommended
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`treatments as of 2012 included therapies combining multiple agents. For example,
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`the American Academy of Dermatology’s Global Alliance Acne Treatment
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`Algorithm recommended combinations of therapies as the first-line treatment for
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`all but the mildest or most severe cases of acne. Ex. 2036 at 7; Ex. 2055 ¶ 45.
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`Other guidelines similarly recommended combination therapies. See, e.g., Ex.
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`2025 at 4.
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`By 2012, therapies combining multiple agents in a single product were
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`commonly being used. Ex. 2055 ¶ 46. “Due to their convenience and efficacy,”
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`practitioners in the field were interested in using “combination therapies that
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`address multiple mechanisms in acne pathogenesis” as “standard first-line agents.”
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`Ex. 2019 at 7. Not only were combination products understood to be more
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`effective because they address multiple mechanisms, but it was understood that
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`they would achieve better compliance in patient use, which itself leads to increased
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`efficacy. A patient is more likely to comply with use instructions for a
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`conveniently applied single product than for a burdensome multiple product
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`regimen. Ex. 2055 ¶ 46; Ex. 2036 at 10-11, 17.
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`As of 2012, several combination products were available and being
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`prescribed. For example, EpiDuo Gel, a combination product containing both the
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`retinoid adapalene and benzoyl peroxide, was frequently prescribed. Ex. 2055 ¶
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`46; Ex Ex. 2041 at 1; Ex. 1012 at 3. The combination of the two APIs in EpiDuo
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`was understood to have a synergistic effect, increasing to degrees exceeding
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`expectation based on the known efficacy of adapalene and benzoyl peroxide when
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`these agents are administered alone, as monotherapies. Ex. 2055 ¶ 46; Ex. 2022,
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`Abstract. And there were multiple products available that combined clindamycin
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`and benzoyl peroxide. Ex. 2055 ¶¶ 47-48.
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`Emerging Treatments
`3.
`In addition, new molecules were being investigated for their efficacy as
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`topical acne treatments. See Ex. 2055 ¶ 53; Ex. 2014 (resveratrol); Ex. 2060
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`(picolinic acid); Ex. 2061 (taurine bromamine).In 2012, the prevalent challenges
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`that artisans in the field faced and sought to address included antibiotic resistance,
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`effective treatment without the side effects of oral isotretinoin, and developing
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`combinations of agents that would more effectively target the multiple pathways of
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`acne and improve user compliance. Ex. 2055 ¶ 54, n.2; Ex. 2019 at 3; Ex. 1025 at
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`8; Ex. 2033 at 6-7; Ex. 2025 at 4-5.
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`By 2012, the use of topical and other antibiotics (in disciplines across
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`medicine) were increasingly giving rise to concerns of growing antibiotic
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`resistance. This prospect was and remains true no matter the bacterium targeted.
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`Use of antibiotics even against P. acnes may impact other, more pathogenic
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`organisms, creating a “significant public health concern in virtually all parts of the
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`world.” Ex. 2055 ¶ 40; Ex. 2036, at 6-8; Ex. 1024 at 5; Ex. 2059, at 145-46 .
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`Numerous publications warned against potential antibiotic resistance, and by 2012
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`studies had shown that antibiotic-resistant strains of P. acnes were rapidly
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`increasing in patient populations. Ex. 2055 ¶¶ 54 n.2; Ex. 2019 at 3; Ex. 2025 at 3;
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`Ex. 1025 at 8. Given the real concern with increasing antibacterial resistance not
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`just in P. acnes, but in any organism that comes in contact with a topical product, a
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`clinician would have been wary if not unwilling to add an additional antibiotic to
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`their armamentarium for long-term use. Ex. 2055 ¶ 97.
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`Patient compliance is key to any successful treatment. Simply put, if a drug
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`is not used, it is not effective. Patients are more likely to comply if the regimen is
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`simple and straightforward: a regimen of a single product applied once a day will
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`result in greater compliance as compared to a regimen of multiple products applied
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`either sequentially with time allowed for the first to soak in, or multiple times
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`during the day. Ex. 2055 ¶ 55.
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`A POSA would have understood that a number of existing and potential
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`options f
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