IPR2018-00608
`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 IPR2018-00608
`Patent 9,161,926
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`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 IPR2018-00608
`Patent 9,161,926
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`IPR2018-00608
`Patent Owner Response
`
`
`TABLE OF CONTENTS
`
`
`Page
`Introduction ...................................................................................................... 1
`I.
`The ’926 Patent ................................................................................................ 4
`II.
`III. Background of the Invention and State of the Relevant Art ........................... 7
`A. Dapsone ................................................................................................. 7
`B. Acne ....................................................................................................... 9
`1.
`Acne Has Multiple Causes .......................................................... 9
`2.
`Prior Art Acne Treatments ........................................................ 13
`C. Rosacea ................................................................................................ 20
`IV. Scope and Content of the Prior Art Concerning Topical Dapsone
`Compositions and treatments ......................................................................... 21
`Person of Ordinary Skill in the Art ................................................................ 28
`V.
`VI. Claim Construction: “DAPSONE” ................................................................ 30
`VII. The Prior Art of Petitioner’s Grounds doES not render obvious the
`CHALLENGED claims of the ’926 patent ................................................... 32
`A.
`The State of the Art in 2012 Provided No Motivation to Develop a
`New Dapsone Formulation .................................................................. 35
`B. Only Hindsight Can Explain Why a Skilled Artisan Would Look to
`Garrett in Developing a Novel Dapsone Formulation ........................ 38
`C. Garrett Neither Discloses All Elements of the Claimed Dapsone
`Formulation Nor Provides Motivation to Derive Them ...................... 40
`
`
`i
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`IPR2018-00608
`Patent Owner Response
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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Garrett Teaches Away from Using the Claimed Dapsone
`Compound ................................................................................. 40
`Garrett Provides No Motivation or Teaching to Use an
`Increased Dapsone Concentration of 7.5% ............................... 41
`Garrett Provides No Motivation or Teaching to Use an
`Increased DGME Concentration of at Least 30% .................... 43
`Garrett Provides No Motivation or Teaching to Use A/SA
`Copolymer as the Polymeric Viscosity Builder ........................ 46
`Garrett Provides No Motivation or Teaching to Exclude
`Adapalene .................................................................................. 48
`D. A Skilled Artisan Would Not Have Been Motivated to Substitute
`Garrett’s Polymeric Viscosity Builder with One of Nadau-Fourcade or
`Bonacucina, Nor Would Either Combination Disclose All Claim
`Limitations ........................................................................................... 50
`1.
`No Credible Motivation Existed to Combine Garrett with
`Nadau-Fourcade and Less than All Claim Limitations are
`Disclosed Even Upon Combination .......................................... 51
`No Credible Motivation Existed to Combine Garrett with
`Bonacucina and Less than All Claim Limitations are
`Disclosed Even Upon Combination .......................................... 56
`VIII. CONCLUSION .............................................................................................. 60
`
`2.
`
`
`
`
`ii
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`IPR2018-00608
`Patent Owner Response
`
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`TABLE OF AUTHORITIES
`
`
`Page(s)
`
`CASES
`Conopco, Inc. v. Procter & Gamble Co.,
`IPR 2013-00505 .................................................................................................. 54
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 32
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 45
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) .......................................................................... 45
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .................................................................... 33, 51
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .....................................................................................passim
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .............................................................. 33, 35, 48
`Multilayer Stretch Cling Film Holdings, Inc. v. Berry Plastics Corp.,
`831 F.3d 1350 (Fed. Cir. 2016) .................................................................... 54, 58
`Nestle USA, Inc. v. Steuben Foods, Inc.,
`686 F. App’x 917 (Fed. Cir. 2017) ..................................................................... 30
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 30
`Polaris Indus., Inc. v. Arctic Cat, Inc.,
`882 F.3d 1056 (Fed. Cir. 2018) .................................................................... 39, 40
`PPC Broadband, Inc. v. Corning Optical Commc’ns. RF, LLC,
`815 F.3d 747 (Fed. Cir. 2016) ............................................................................ 30
`
`
`iii
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`IPR2018-00608
`Patent Owner Response
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`
`TABLE OF AUTHORITIES
`(continued)
`
`
`Page(s)
`
`Randall Mfg. v. Rea,
`733 F.3d 1355 (Fed. Cir. 2013) .............................................................. 41, 43, 46
`Süd-Chemie, Inc. v. Multisorb Techs., Inc.
`554 F.3d 1001 (Fed. Cir. 2009) .......................................................................... 49
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .......................................................................... 54
`STATUTES
`35 U.S.C. § 103 ........................................................................................................ 50
`35 U.S.C. § 316(e) ............................................................................................... 5, 32
`OTHER AUTHORITIES
`37 C.F.R. § 42.1(d) .................................................................................................. 32
`37 C.F.R. § 42.100(b) .............................................................................................. 30
`37 C.F.R. § 42.104(b)(4) .......................................................................................... 50
`83 Fed. Reg. 51,340 (Oct. 11, 2018) ........................................................................ 30
`
`
`
`iv
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`IPR2018-00608
`Patent Owner Response
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`PATENT OWNER’S EXHIBIT LIST
`
`
`Exhibit No.
`
`Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`Patent Assignment Agreement dated October 10, 2018
`
`Hagan declaration in support of pro hac vice application
`
`Declaration of Professsor Alexander M. Klibanov
`
`Curriculum Vitae for Professor Alexander M. Klibanov
`
`International Patent Application Publication No. WO
`2011/014627 (“Ahluwalia”)
`
`International Patent Application Publication No. WO
`2009/108147 (“Garrett I”)
`
`International Patent Application Publication No. WO
`2010/105052 (“Hani”)
`
`U.S. Patent No. 4,829,058 (“Seydel I”)
`
`U.S. Patent No. 4,912,112 (“Seydel II”)
`
`Wayback Machine Results for David Pascoe, Aczone Fails to
`Impress for Rosacea, Rosacea Support Group (July 23, 2012),
`available at https://rosacea-support.org/aczone-fails-to-
`impress-for-rosacea.html
`
`S. 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, Antimalarial
`chlorproguanil-dapsone (LapDap™) withdrawn following
`demonstration of post-treatment haemolytic anaemia in G6PD
`deficient patients in a Phase III trial of chlorproguanil-
`dapsone-artesunate (Dacart™) versus artemether-lumefantrine
`(Coartem®) and confirmation of findings in a comparative trial
`of LapDap™ versus Dacart™ (Mar. 4, 2008)
`
`v
`
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`IPR2018-00608
`Patent Owner Response
`
`
`Exhibit No.
`
`Description
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`MaryAnn Steiner, “Dapsone Topical Gel for Acne,” J. Pharm.
`Soc. Wisc. 12(6): 67–71 (2009) (“Steiner”)
`
`ACZONETM Gel, 5% Prescribing Information (2008) (“2008
`Aczone 5% PI”)
`
`Robert Lott et al., “Medication adherence among acne
`patients: A review.” J. Cosmetic Dermatology 9: 160–166
`(2010) (“Lott”)
`
`Kirk A. James et al., “Emerging drugs for acne,” Expert Opin.
`Emerging Drugs 14(4): 649–659 (2009) (“James I”)
`
`Barry Coutinho, “Dapsone (Aczone) 5% Gel for the Treatment
`of Acne,” American Family Physician (Dec. 2010)
`(“Coutinho”)
`
`Food and Drug Administration Inactive Ingredient Database
`(September, 2012)
`
`H.C. Korting & C. Schöllmann, “Current topical and systemic
`approaches to treatment of rosacea,” JEADV 23: 876–882
`(2009) (“Korting”)
`
`European Commission’s Scientific Committee on Consumer
`Safety, Opinion on Diethylene Glycol Monoethyl Ether
`(DEGEE) (2010)
`
`Food and Drug Administration Inactive Ingredient Database
`(December, 2012)
`
`Declaration of Julie Harper, M.D.
`
`Curriculum Vitae of Julie Harper, M.D.
`
`John Kraft & Anatoli Freiman, Management of acne,
`183 Canadian Med. Assoc. J. E430–E435 (2011) (“Kraft”)
`
`vi
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`IPR2018-00608
`Patent Owner Response
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`
`Exhibit No.
`
`Description
`
`2025
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`Meghan I. Dubina & Alan B. Fleisher Jr., Interaction of
`Topical Sulfacetamide and Topical Dapsone with Benzoyl
`Peroxide, 145 JAMA Dermatology 1027–1029 (2009)
`(“Dubina”)
`
`Stephen Titus & Joshua Hodge, Diagnosis and Treatment of
`Acne, 86 Am. Family Physician 734–740 (2012) (“Titus”)
`
`John S. Strauss, Biology of the Sebaceous Gland and the
`Pathophysiology of Acne Vulgaris, in Pathophysiology of
`Dermatologic Diseases, Second Edition, N. A. Soter and H.
`Baden eds., McGraw-Hill, New York 195–210 (1991)
`(“Strauss”)
`
`William D. James, Acne, 352 New Eng. J. Medicine
`1463–1472 (2005) (“James II”)
`
`Ayumi Naito et al., Topical retinoids for acne vulgaris
`(Protocol), 3 The Cochrane Library (John Wiley & Sons
`2008) (“Naito”)
`
`Physicians’ Desk Reference 2967–2969 (2011) (excerpt)
`
`Physicians’ Desk Reference 2765–2767 (2012) (excerpt)
`
`Gabriella Fabbrocini et al., Resveratrol-Containing Gel for the
`Treatment of Acne Vulgaris, 12 Am. J. of Clinical
`Dermatology 131–141 (2011) (“Fabbrocini”)
`
`James Q. Del Rosso, The Use of Sodium Sulfacetamide
`10%-Sulfur 5% Emollient Foam in the Treatment of Acne
`Vulgaris, 2 J. Clinical and Aesthetic Dermatology 26–29
`(2009) (“Del Rosso”)
`
`Janusz Marcinkiewicz et al., Topical taurine bromamine, a
`new candidate in the treatment of moderate inflammatory acne
`vulgaris—A pilot study, 18 Eur J. Dermatology 433–439
`(2008) (“Marcinkiewicz”)
`
`vii
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`IPR2018-00608
`Patent Owner Response
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`
`Exhibit No.
`
`Description
`
`2035
`
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`Yuko Takenaka et al., Glycolic acid chemical peeling
`improves inflammatory acne eruptions through its inhibitory
`and bactericidal effects on Propionibacterium acnes, 39 J.
`Dermatology 350–354 (2012) (“Takenaka”)
`
`P. Marazzi et al., Clinical evaluation of Double Strength
`IsotrexinTM versus Benzamycin® in the topical treatment of
`mild to moderate acne vulgaris, 13 Journal of Dermatological
`Treatment 111–117 (2002) (“Marazzi”)
`
`N. Kellett et al., Conjoint analysis: a novel, rigorous tool for
`determining patient preferences for topical antibiotic
`treatment for acne. A randomized controlled trial, 154 British
`Journal of Dermatology 524–532 (2006) (“Kellett”)
`
`Frank C. Powell, Rosacea, 352 New Eng. J. Med. 793–803
`(2005) (“Powell”)
`
`Aczone 7.5% PI (“Aczone 7.5% PI”)
`
`Dina Anderson, Finding a Place for Topical Anti-
`inflammatory Acne Therapy, Practical Dermatology 17–18
`(July 2009) (“Anderson”)
`
`Michael Ghods et al., The Role of Dapsone Gel in the Acne
`Armamentarium, The Dermatologist (June 10, 2010), available
`at https://www.the-dermatologist.com/content/role-dapsone-
`gel-acne-armamentarium (“Ghods”)
`
`David Pascoe, Aczone Fails to Impress for Rosacea, Rosacea
`Support Group (July 23, 2012), available at https://rosacea-
`support.org/aczone-fails-to-impress-for-rosacea.html
`(“Pascoe”)
`
`viii
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`IPR2018-00608
`Patent Owner Response
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`
`Exhibit No.
`
`Description
`
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`2050
`
`2051
`
`2052
`
`Clinical Study Report—ACZ ROS 01, A phase II,
`randomized, partial-blind, parallel-group, active- and vehicle-
`controlled, multicenter study of the safety and efficacy of
`Aczone™ (dapsone) Gel, 5% in subjects with papulopustular
`rosacea, QLT Inc. (Feb. 5, 2007)
`
`AZC ROS 01 Web Results Summary, A phase II, randomized,
`partial-blind, parallel-group, active- and vehicle-controlled,
`multicenter study of the safety and efficacy of Aczone™
`(dapsone) Gel, 5% in subjects with papulopustular rosacea,
`available at http://www.allerganclinicaltrials.com/
`pdfs/medical_aesthetics/Results_Web_PostingACZ-ROS-
`01.pdf
`
`Otto H. Mills et al., Comparing 2.5%, 5%, and 10% Benzoyl
`Peroxide on Inflammatory Acne Vulgaris, 25 Int’l J.
`Dermatology 664–667 (1986) (“Mills”)
`
`John V. Ashurst et al., Pathophysiological Mechanisms,
`Diagnosis, and Management of Dapsone-Induced
`Methemoglobinemia, 110 J. Am. Osteopathic Assoc. 16–20
`(2010) (“Ashurst”)
`
`J.S. Chun et al., Dapsone hypersensitivity syndrome with
`circulating 190-kDA and 230-kDA autoantibodies, 34 Clinical
`and Experimental Dermatology e798–e801 (2009) (“Chun”)
`
`U.S. Patent Publication No. 2011/0135584 (“Mallard”)
`
`U.S. Patent Publication No. 2011/0003894 (“Louis”)
`
`NDA 21-794 FDA approval letter (July 7, 2005)
`
`NDA 21-794 FDA approval letter (March 14, 2008)
`
`Deposition of Elaine S. Gilmore, M.D., Ph.D., taken
`November 16, 2018
`
`ix
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`IPR2018-00608
`Patent Owner Response
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`Exhibit No.
`
`Description
`
`2053
`
`Deposition of Bozena B. Michniak-Kohn, Ph.D., taken
`November 20, 2018
`
`
`
`
`
`
`
`
`x
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`
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`IPR2018-00608
`Patent Owner Response
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`Patent Owner Almirall, LLC (“Almirall”)1 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 IPR2018-00608 for review of U.S. Patent No. 9,161,926 (“the ’926 patent”).
`
`I.
`
`INTRODUCTION
`The ’926 patent describes topical dapsone and dapsone/adapalene
`
`compositions useful for treating dermatological conditions including acne and
`
`rosacea. See Ex. 1001 at 1:15–2:2. The patent claims topical pharmaceutical
`
`compositions that contain 7.5% w/w dapsone; certain concentrations of diethylene
`
`glycol monoethyl ether (“DGME”); certain concentrations of a specific polymeric
`
`viscosity builder, acrylamide/sodium acryloyldimethyl taurate copolymer (“A/SA
`
`copolymer”); and do not contain adapalene. Petitioner asserts that the claims of
`
`the ’926 patent are invalid as obvious over Garrett (Ex. 1004) in view of either of
`
`two additional references, Nadau-Fourcade (Ex. 1005) or Bonacucina (Ex. 1015).
`
`Not so. For this Board to conclude otherwise would require crediting no less than
`
`five contingent assumptions as obvious. Whereas if even one such assumption is
`
`
`1 Patent Owner’s mandatory notices were updated to reflect a change in ownership
`
`of U.S. Patent No. 9,161,926 on October 12, 2018. Paper 13.
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`1
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`IPR2018-00608
`Patent Owner Response
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`unsupported the Petition should be denied; Patent Owner submits not even one is
`
`in fact supported by the evidence of record.
`
`First, Petitioner’s assumed starting point that a person of ordinary skill in the
`
`art as of 2012 would be motivated to formulate a novel dapsone topical
`
`pharmaceutical composition to begin with is not credible. Dapsone was not a
`
`reasonable compound on which to focus given its relatively poor performance and
`
`associated concerns with side effects in the attendant treatment field, and the art
`
`was bare of any problem, concern, or suggested improvement that a new topical
`
`dapsone formulation might address.
`
`Second, even assuming that it was reasonable to formulate a new dapsone
`
`composition, Petitioner provides no credible evidence of any motivation to
`
`pinpoint Garrett as a suggestive source for developing a new formulation of it.
`
`Garrett addressed—and resolved—side effect concerns with the then-existing 5%
`
`ACZONE® Gel product, such that they were no longer concerns by 2008, much
`
`less by 2012.
`
`Third, even accepting Garrett as a primary reference, Petitioner inexplicably
`
`assumes that it would have been obvious to increase dapsone concentration over
`
`the already-commercialized 5% formula, which coincidentally (or not) is the sole
`
`example of a dapsone formulation disclosed in Garrett. Nothing in Garrett
`
`2
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`IPR2018-00608
`Patent Owner Response
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`suggests an opportunity or need for a formulation with an increased concentration
`
`of dapsone.
`
`Fourth, even assuming Garrett suggests a formulation with a dapsone
`
`concentration increased to 7.5% as claimed, Petitioner fails to show any teaching
`
`or motivation to increase, in parallel, the solvent concentration to the claimed
`
`amounts. This omission is glaring, particularly in light of the art, including
`
`Osborne I, which taught that a particular ratio of dissolved to microparticulate
`
`dapsone in topical formulations was desirable, but also that achieving such ratio
`
`was unpredictable in the event one increased the solvent concentration.
`
`Fifth, even crediting the assumed starting points of dapsone and Garrett, and
`
`the further assumed motivation for, and guidance as to, increasing dapsone and
`
`solvent concentrations, Petitioner’s proffered motivation to use a polymeric
`
`viscosity builder other than one of the many disclosed by Garrett itself is truly a
`
`bridge too far, bringing an already-contrived theory clear across the threshold of
`
`objective hindsight. A skilled artisan would not reasonably have looked beyond
`
`Garrett, and even less reasonably would one instead have looked directly to the
`
`specific references of either Nadau-Fourcade or Bonacucina for a suggestion of
`
`suitable polymeric viscosity builder. The disclosed polymeric viscosity builders in
`
`these two secondary references in any event do not disclose a polymeric viscosity
`
`builder consisting of A/SA copolymer.
`
`3
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`IPR2018-00608
`Patent Owner Response
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`The full record demonstrates that Petitioner has not met its burden of
`
`proving unpatentability by a preponderance of the evidence as required under 35
`
`U.S.C. § 316(e). Accordingly, Patent Owner respectfully requests that this Board
`
`confirm the patentability of claims 1–6 of the ’926 patent.
`
`II. THE ’926 PATENT
`The ’926 patent issued on October 20, 2015, from an application filed on
`
`November 18, 2013. The patent claims priority to provisional applications filed on
`
`November 20, 2012, and February 28, 2013. Ex. 1001 at 1:8–12.2
`
`The’926 patent is directed to topical pharmaceutical compositions for
`
`treating dermatological conditions, including acne and rosacea, that utilize dapsone
`
`as an active pharmaceutical ingredient (“API”). The specification of the ’926
`
`patent provides that the compositions are “useful for treating a variety of
`
`dermatological conditions.” Ex. 1001 at Abstract, 1:13–19. It describes various
`
`forms of acne and other dermatological conditions, including rosacea, and
`
`addresses the “continuing need for compositions and methods used in a treatment
`
`of a variety of skin conditions, such as acne, in which topical application is
`
`potentially effective.” Id. at 1:65–2:1.
`
`
`2 In keeping with the Petition, citations to the ’926 patent (Ex. 1001) and to other
`
`United Stated patents are to column and line number to avoid confusion.
`
`4
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`IPR2018-00608
`Patent Owner Response
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`
`The ’926 patent claims “topical pharmaceutical compositions” comprising
`
`(1) dapsone as the API; (2) the solvent diethylene glycol monoethyl ether
`
`(“DGME”); (3) the polymeric viscosity builder (or “thickener”) A/SA copolymer;
`
`and water. In addition, the claimed compositions expressly exclude the API
`
`adapalene.
`
`Specifically, the patent includes six claims, two of which are independent.
`
`Independent claim 1 recites:
`
`1. A topical pharmaceutical composition comprising:
`about 7.5% w/w dapsone;
`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 consisting of acrylamide/sodium
`acryloyldimethyl taurate copolymer;
`and water; wherein the composition does not comprise
`adapalene.
`
`Ex. 1001. Dependent claim 2 limits the concentration of DGME to “about 30%
`
`w/w.” Id. Dependent claim 3 limits the concentration of polymeric viscosity
`
`builder to “about 4% w/w.” Id. Dependent claim 4 limits the composition of claim
`
`1 to compositions further comprising the preservative methyl paraben. Id.
`
`Independent claim 5 recites:
`
`5. A topical pharmaceutical composition comprising:
`
`5
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`IPR2018-00608
`Patent Owner Response
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`about 7.5% w/w dapsone;
`about 30% diethylene glycol monoethyl ether;
`about 4% w/w of a polymeric viscosity builder consisting
`of acrylamide/sodium acryloyldimethyl taurate
`copolymer;
`and water; wherein the composition does not comprise
`adapalene.
`Id. Dependent claim 6 limits the composition of claim 5 to compositions further
`
`comprising methyl paraben. Id.
`
`The application that issued as the ’926 patent was examined over several
`
`years. During prosecution, the inventors narrowed their claims to limit the claimed
`
`concentration of dapsone, to limit the claimed concentration of DGME, to
`
`specifically exclude adapalene, and both to specify that the polymeric viscosity
`
`builder consists of A/SA copolymer and to limit its concentration. See Ex. 1017 at
`
`241–242, 280–281, 314–315, 345–346. The inventors also distinguished the
`
`claimed compositions from prior art topical dermatological compositions,
`
`including other prior art by Garrett, the author of the primary reference of both
`
`Grounds. See id. at 347–348.
`
`In addition, the inventors also pointed to unexpected results in overcoming
`
`the examiner’s obviousness rejection. As detailed in the declaration of Dr. Kevin
`
`Warner, development of a topical 7.5% dapsone formulation with a higher
`
`percentage of the solvent DGME, as compared to the otherwise identical original
`
`6
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`IPR2018-00608
`Patent Owner Response
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`ACZONE® Gel, 5% formulation unexpectedly resulted in “undesirable”
`
`aggregation of the polymeric viscosity builder, Carbopol 980, used in the
`
`ACZONE® Gel, 5% formulation. The inventors discovered, however, that use of
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`A/SA copolymer as the polymeric viscosity builder eliminated that previously
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`unrecognized problem, and also beneficially decreased the particle size of dapsone.
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`Id. at 350–355.
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`The ’926 patent is listed in the FDA’s Orange Book as a drug product patent
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`related to the now-approved ACZONE® Gel, 7.5% product. Ex. 1033.
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`III. BACKGROUND OF THE INVENTION AND STATE OF THE
`RELEVANT ART
`A. Dapsone
`Dapsone is a sulfone compound active against a wide range of bacteria. As
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`an antibiotic, dapsone works by inhibiting bacterial synthesis of dihydrofolic acid,
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`which is a necessary building block for bacterial nucleic acid biosynthesis. The
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`chemical structure for dapsone, also known as 4,4´-diaminodiphenyl sulfone, is
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`depicted below:
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`Ex. 2003 ¶ 44. Dapsone (4,4´-diaminodiphenyl sulfone) is also known by several
`additional chemical names, e.g., bis-(4-aminophenyl)sulfone, 4,4´-
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`sulfonyldianiline, and diaminodiphenyl sulfone. Id. ¶ 47; Ex. 1004 at 8:12–22.
`
`Historically, dapsone has been used as an oral treatment for leprosy and
`
`other diseases. However, dapsone has many potentially severe side effects. For
`
`example, a significant number of patients treated with dapsone suffer hemolysis—
`
`rupture of red blood cells—when it is administered orally. This dangerous side
`
`effect is more frequent and severe in patients deficient in the enzyme glucose-6-
`
`phosphate dehydrogenase (“G6PD”), a condition known as G6PD deficiency. Ex.
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`2003 ¶ 45; Ex. 2011 at 7; Ex. 2012. The concerns regarding systemic toxicity and
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`topical use. Ex. 2003 ¶ 46; Ex. 2013 at 2.
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`hemolysis of oral dapsone led to the view that dapsone would not be safe for
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`In addition to the dapsone (4,4´-diaminodiphenyl sulfone) compound itself,
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`dapsone analogs and related compounds were known in the art to have
`
`antimicrobial effects. See Ex. 1004 at 11:1–12; Ex. 2003 ¶ 86. For example, in
`
`patents issued in 1989 and 1990, certain dapsone derivative compounds were
`
`shown to be more effective, either alone or in combination with dapsone, than
`
`dapsone itself. Ex. 2003 ¶ 86; Ex. 2008 at 9:1–43; Ex. 2009 at 4:27–52; 17:40–50.
`
`dapsone (4,4´-diaminodiphenyl sulfone), for topical treatment of acne vulgaris.
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`In July of 2005, the FDA approved ACZONE® Gel, 5%, containing 5%
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`See Ex. 2050 at 1, 4. The initially approved package insert required that G6PD
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`levels “should be obtained in all patients prior to initiating therapy with
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`ACZONETM Gel, 5%.” Ex. 1010 at 3. It also cautioned that patients with G6PD
`
`deficiency needed to be monitored more closely, including by obtaining their
`
`baseline blood counts and routine follow-up work, as a result of hemolysis risk. Id.
`
`at 3-4. In 2008, however, the FDA approved a change in labeling, removing these
`
`screening and monitoring requirements for G6PD deficiency. See Ex. 2051 at 1, 4;
`
`Ex. 2014.
`
`B. Acne
`1.
`Acne Has Multiple Causes
`Acne is a skin disease consisting of blemishes that can occur on the face,
`
`neck, chest, shoulders, and back. It is commonly observed during adolescence, but
`
`may persist from adolescence into adulthood or even present for the first time
`
`during adulthood. In adults, acne is more common among women than men. Acne
`
`can have both physical and psychological consequences. 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. 2022
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`¶¶ 40–41.
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`Acne is a multifactorial disease of the pilosebaceous unit. There are
`
`thousands of pilosebaceous units throughout the skin, but most are found in the
`
`face, back and chest—the areas most commonly affected by acne. A
`
`pilosebaceous unit is composed of a hair follicle (the cavity from which a hair
`
`grows) and sebaceous gland, as shown below.
`
`
`
`Id. ¶¶ 42–43. 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,
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`routinely shed dead skin cells, which sebum carries out of the body. Id. ¶¶ 44–45.
`
`As of 2012, it was understood that acne is a multifactorial condition with
`
`four underlying causes: “(1) Increased sebum production; (2) Perifollicular
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`hyperkeratinization and follicular obstruction; (3) Colonization with
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`Propionibacterium acnes; [and] (4) Release of enzymes which induce humoral and
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`cell mediated inflammations.” Id. ¶ 46; Ex. 1024 at 1.
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`As to the first factor, increased sebum production was (and still is)
`
`understood to create or contribute to blockages in the hair follicles and skin pores.
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`In particular, increased sebum production by the sebaceous glands during puberty
`
`leads to a greater incidence of acne during adolescence. Ex. 2022 ¶¶ 46–47.
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`The second factor, perifollicular hyperkeratinization, is a skin condition
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`characterized by excessive development of dead skin cells in hair follicles. As the
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`number of cells increases too rapidly for the dead cells to be carried out efficiently
`
`by sebum, dead skin blocks the follicle and results in what ultimately become
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`visible comedones, i.e., whiteheads and blackheads. Whiteheads are clogged
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`follicles closed off from the air, while blackheads are clogged follicles exposed to
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`air. Comedones generally occur in areas with more sebaceous glands, particularly
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`the face, shoulders, upper chest, and back. Id. ¶ 48.
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`As to the third factor, Propionibacterium acnes is a bacterium that thrives in
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`areas that are high in lipid content and lack oxygen, including the pilosebaceous
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`glands. This bacterium 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. The presence of P. acnes generates an inflammatory response in the body.
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`Id. ¶ 49.
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`Finally, as to humoral- and cell-mediated inflammation, the proliferation of
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`P. acnes was understood to release enzymes that produce an immune, and thus
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`inflammatory, response. It was also understood that the rupture of acne lesions
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`could exacerbate inflammation, thereby worsening acne. Id. ¶ 50.
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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. Lesions not clinically inflamed are
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`the comedones (whiteheads and blackheads):
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`Lesions that are clinically inflamed are papules, pustules, and nodules:
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`As of 2012, the degree to which an individual experienced acne was generally
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`assessed by the number, type, and distribution of lesions, and could be
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`characterized in terms of severity from mild to severe. Id. ¶¶ 51–54.
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`2.
`Prior Art Acne Treatments
`As of 2012, there were several methods of acne treatment. These treatments
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`targeted “one or more of the four traditional pathogenic factors involved in acne”
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`and were designed to address “both the severity and type of lesions.” Id. ¶ 55; Ex.
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`2016 at 2. Common treatments for mild to moderate acne included topical
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`therapies, oral antibiotics, and hormonal therapies. For severe acne, treatment
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`could also include an oral retinoid, isotretinoin. Less common treatments included
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`light therapy, steroidal injections, comedo extraction, chemical peels, and
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`alternative medicines like tea tree oil. Ex. 2022 ¶ 56.
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`a. Oral Treatments
`Some acne treatments were oral. For example, oral antibiotics were used to
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`treat moderate to severe inflammatory acne, and were understood to have
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`antibacterial and anti-inflammatory properties. Another orally administered
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`compound, isotretinoin, was considered unique in that it targeted all four
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`pathogenic factors of acne. While highly effective, oral isotretinoin was associated
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`with serious side effects and was therefore typically prescribed only to patients
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`with severe acne. Ex. 2022 ¶¶ 62–63. Female acne patients were also sometimes
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`prescribed hormonal treatments such as oral contraceptives, spironolactone,
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`flutamide, or oral corticosteroids. These generally reduced testosterone or other
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`androgen levels, thereby reducing sebum production. Id. ¶ 64.
`
`b.
`Topical Treatments
`Topical acne treatments were well known and often prescribed by
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`dermatologists. Common topical agents used to treat acne in 2012 included
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`retinoids, benzoyl peroxide, and antibiotics. Retinoids—including adapalene,
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`tretinoin, and tazarotene—were a first-line treatment for mild to moderate acne and
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`more severe inflammatory acne. They were believed to have several mechanisms
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`of action, including induction of comedo lysis, inhibition of inflammation, and
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`reduction of hyperkeratinization. Id. ¶¶ 57–58.
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