`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC,
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC,
`and MYLAN PHARMACEUTICALS INC.,
`Petitioners
`
`
`v.
`
`ALMIRALL, LLC,
`Patent Owner
`
`
`Case IPR2019-002071
`Patent 9,517,219
`
`
`
`
`
`PATENT OWNER’S SUR-REPLY
`
`
`1 Cases IPR2019-00207 and IPR2019-01095 have been joined in this
`proceeding.
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`II.
`
`B.
`
`C.
`
`Introduction ........................................................................................................ 1
`The Board Has Not Considered Almirall’s Arguments in
`Prior Proceedings ............................................................................................... 3
`III. Petitioners Have Not Met Their Burden to Prove Obviousness
`According to the Grounds .................................................................................. 4
`A. Garrett Would Not Have Motivated a POSA to Develop
`a Treatment with New Topical Dapsone Formulations
`Recited in the ʼ219 Patent Claims ........................................................... 4
`Garrett’s teachings are limited to compositions with
`1.
`both dissolved and undissolved dapsone ....................................... 5
`Garrett does not teach that dapsone treats acne or
`rosacea ........................................................................................... 7
`A POSA would not have been motivated to increase
`dapsone to the recited concentration of 7.5% ............................... 8
`Garrett does not teach using dapsone compositions
`without adapalene .......................................................................... 9
`In view of the prior art as a whole, Garrett would not
`suggest to a POSA the recited DGME concentrations
`of the claims .................................................................................. 9
`Petitioners Failed to Show Motivation to Combine Garrett
`with the Other Asserted Art ................................................................... 11
`A POSA would not have been motivated to combine
`1.
`Garrett with Nadau-Fourcade ...................................................... 11
`A POSA would not have been motivated to combine
`Garrett with Bonacucina .............................................................. 16
`The Claimed Dapsone and DGME Concentrations Are Not
`Obvious .................................................................................................. 18
`
`2.
`
`3.
`
`4.
`
`5.
`
`2.
`
`i
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`TABLE OF CONTENTS
`(Continued)
`
`Page
`
`
`IV. Objective Indicia of Non-Obviousness Further Support Denial
`of the Petition ................................................................................................... 23
`Conclusion ........................................................................................................ 24
`
`V.
`
`
`
`
`
`ii
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) ....................................................................... 18, 19
`Almirall LLC v. Taro Pharm. Indus. Ltd.,
`C.A. No. 17-00663 (D. Del. June 6, 2018), ECF No. 87 ........................................ 2
`Dynamic Drinkware LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ............................................................................... 1
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) ................................................................... 19, 20, 22
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................... 22
`In re Baird,
`16 F.3d 380 (Fed. Cir. 1994) ................................................................................. 14
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) ..................................................................... 1, 2, 13
`In re Patel,
`566 F. App’x 1005 (Fed. Cir. 2014) ...................................................................... 13
`Inphi Corp. v. Netlist, Inc.,
`805 F.3d 1350 (Fed. Cir. 2015) ............................................................................... 9
`Insite Vision, Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ............................................................................... 15
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ............................................................................. 17
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................. 21
`Warner-Jenkinson Co. v. Hilton Davis Chem. Co.,
`520 U.S. 17 (1997) .................................................................................................. 3
`iii
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`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`TABLE OF AUTHORITIES
`(Continued)
`
`Page(s)
`
`
`STATUTES
`35 U.S.C. § 316(e) ........................................................................................................ 1
`35 U.S.C. § 103(a) (2006) ............................................................................................ 3
`OTHER AUTHORITIES
`37 C.F.R. § 42.104(b)(4) .............................................................................................. 4
`
`
`
`iv
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`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
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`
`
`
`
`PATENT OWNER’S EXHIBIT LIST
`
`Exhibit No.
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`
`
`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”)
`Barry Coutinho, Dapsone (Aczone) 5% Gel for the Treatment of
`Acne, Am. Family Physician (2010) (“Coutinho”)
`
`v
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`
`
`Exhibit No.
`2013
`
`Description
`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”)
`Leon H. Kircik, Synergy and Its Clinical Relevance in Topical
`Acne Therapy, 4 J. Clin. Aethet. Dermatol. 30 (2011) (“Kircik
`2011”)
`
`vi
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`
`
`Exhibit No.
`2023
`
`Description
`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”)
`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”)
`
`vii
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`
`
`Exhibit No.
`2033
`
`Description
`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)
`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)
`
`viii
`
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`2039
`2040
`2041
`
`2042
`
`
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
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`
`
`
`Exhibit No.
`2043
`
`Description
`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”)
`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.
`
`ix
`
`2044
`2045
`2046
`2047
`
`2048
`2049
`
`2050
`2051
`2052
`
`2053
`
`2054
`2055
`2056
`2057
`
`
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`
`
`Exhibit No.
`2058
`2059
`
`Description
`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”)
`Supplemental Declaration of David W. Osborne, Ph.D. (served
`August 30, 2019)
`Erick H. Turner, How to access and process FDA drug approval
`packages for use in research, BMJ (2013) ("Turner 2013") (served
`August 30, 2019)
`Manual of Policies and Procedures - Center for Drug Evaluation
`and Research (served August 30, 2019)
`Transcript of Deposition of Bozena B. Michniak-Kohn, Ph.D.,
`FAAPS, M.R.Pharm.S., dated December 6, 2019
`
`x
`
`2060
`
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`2066
`
`2067
`
`2068
`
`
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
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`
`
`
`Exhibit No.
`2069
`
`Description
`Transcript of Deposition of Elaine S. Gilmore, M.D., Ph.D., dated
`December 12, 2019
`
`
`
`
`
`
`
`xi
`
`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
`
`
`I.
`
`
`INTRODUCTION
`Petitioners’ Reply fails to remedy the deficiencies of their Petition, and runs
`
`no less replete with hindsight. Petitioners have not shown that a person of ordinary
`
`skill in the art, considering the art of the Grounds, and as a whole, on the eve of the
`
`date of invention, would have been motivated to treat acne or rosacea with a new
`
`dapsone topical formulation as taught by the primary reference of both Grounds,
`
`Garrett. Certainly, Petitioners provide nothing in reply to cure the infirmity of their
`
`asserted evidence that there existed a credible motivation to use the claimed A/SA
`
`copolymer-based polymeric viscosity builder (“PVB”), let alone to combine either
`
`Nadau-Fourcade or Bonacucina with Garrett.
`
`Preliminarily, Petitioners’ Reply is littered with arguments completely
`
`unsupported by the record or in law. See, e.g., Reply at 1–3. Notably contrary to
`
`propositions set forth in their Reply, Petitioners retain the burden to prove
`
`obviousness throughout the entire inter partes review proceeding. In re Magnum Oil
`
`Tools Int'l, Ltd., 829 F.3d 1364, 1375 (Fed. Cir. 2016) (“‘In an inter partes review,
`
`the burden of persuasion is on the petitioner to prove ‘unpatentability by a
`
`preponderance of the evidence,’ and that burden never shifts to the patentee.’”
`
`(quoting Dynamic Drinkware LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378
`
`(Fed. Cir. 2015) and 35 U.S.C. § 316(e)). Even where a prima facie case is made the
`
`“burden-shifting framework” of the prosecution context does not apply to an inter
`1
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`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
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`
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`partes review. Id. Petitioners bear the burden of proof at all times, and Petitioners
`
`have never met that burden.
`
`Petitioners also factually misrepresent Almirall’s arguments in other
`
`proceedings—and only to make a point that is decidedly without any legal force.
`
`Petitioners contend that Almirall argued in a district court patent infringement
`
`litigation against a non-party that Carbopol is “equivalent” to Sepineo. Reply at 2,
`
`20–21. These are quite distorted facts and not of record. Petitioners’ source is a
`
`citation to the district court’s claim construction report and recommendation, which
`
`merely republished that non-party’s position in its opening claim construction
`
`brief—not Almirall’s position in that dispute. Report and Recommendation at 2,
`
`Almirall LLC v. Taro Pharm. Indus. Ltd., C.A. No. 17-00663 (D. Del. June 6, 2018),
`
`ECF No. 87 (“Taro’s proposed generic version of Aczone uses Carpobol® 980 as the
`
`PVB.” (citing ECF No. 56)). While true that Almirall claimed infringement under
`
`the doctrine of equivalents (“DOE”) in that unrelated proceeding, Petitioners have no
`
`factual basis to assert what Almirall there contended to be the PVB in the accused
`
`product at issue, the composition of which remains confidential and thus necessarily
`
`not on the record in this Petition. And as this Board has noted, for purposes of an
`
`inter partes review, “[i]f it’s not in the record, it doesn't exist.” See IPR2018-00608,
`
`Paper 48 at 46:7 (June 5, 2019) (Hearing Transcript). Dispositive of the issue in any
`
`
`
`2
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`IPR2019-00207
`Patent Owner’s Sur-Reply
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`
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`event, these representations—even if true—amount to no legal consequence, for it is
`
`well-settled that interchangeability for purposes of DOE is determined as of the time
`
`of infringement, whereas in assessing validity interchangeability is determined as of
`
`the date of invention. Warner-Jenkinson Co. v. Hilton Davis Chem. Co., 520 U.S.
`
`17, 37 (1997); 35 U.S. § 103(a) (2006).
`
`Petitioners moreover serially mischaracterize Almirall’s expert evidence as
`
`inconsistent with Almirall’s Response. Not so. The out-of-context phrases cited
`
`hardly constitute contradictory statements. The weight and credibility of the expert
`
`evidence proffered by Almirall properly must be considered as a whole, and not
`
`merely in regard of Petitioners’ conveniently selected excerpts.
`
`For these and reasons detailed further below, at this close of briefing,
`
`Petitioners still fail to have shown, even by preponderance, that the challenged
`
`claims of the ʼ219 patent are obvious over Garrett combined with either Nadau-
`
`Fourcade or Bonacucina.
`
`II. THE BOARD HAS NOT CONSIDERED ALMIRALL’S ARGUMENTS
`IN PRIOR PROCEEDINGS
`Petitioners misconstrue the Board’s Final Written Decision in IPR2018-
`
`00608. That proceeding regarded a different patent—the ʼ926 patent—and its
`
`composition claims that are not at issue in this proceeding. The Board found that
`
`Petitioners failed to show that the prior art of the Grounds (identical to the Grounds
`
`
`
`3
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`

`

`IPR2019-00207
`Patent Owner’s Sur-Reply
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`of this Petition) disclosed the limitation there at issue that claimed compositions
`
`comprise about 2% w/w to about 6% w/w of a polymeric viscosity builder consisting
`
`of A/SA copolymer. IPR2018-00608 Paper 50 at 17–21. For Petitioners’ failure to
`
`make this threshold showing, see 37 C.F.R. § 42.104(b)(4), the Board proceeded no
`
`further and did not address Almirall’s remaining arguments, including those
`
`Petitioners represent as similar to certain arguments Almirall presents in defense of
`
`this Petition. From arguments never addressed by the Board, it does not—and
`
`cannot—follow that the same arguments were “rejected” by it.
`
`III. PETITIONERS HAVE NOT MET THEIR BURDEN TO PROVE
`OBVIOUSNESS ACCORDING TO THE GROUNDS
`A. Garrett Would Not Have Motivated a POSA to Develop a
`Treatment with New Topical Dapsone Formulations Recited in the
`ʼ219 Patent Claims
`This IPR must be decided by adherence to the record in this proceeding. The
`
`corollary to that indisputable requirement is that Petitioners are bound by the
`
`Grounds as they have elected to construct them. It follows that Petitioners are
`
`likewise bound by the theories they have elected to advance as to the existence of a
`
`motivation for the relevant skilled artisan—armed with knowledge of not merely the
`
`universe of pertinent prior art, but the evolution of that art to the time of invention—
`
`to combine Garret with one or both of the secondary references asserted. The
`
`fundamental infirmity of both Grounds is that the clear and genuine thrust of what
`
`
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`4
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`IPR2019-00207
`Patent Owner’s Sur-Reply
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`
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`Garrett teaches is a specific design critical to delivering dapsone in the described
`
`topical compositions to achieve treatment of acne or rosacea. So long as this
`
`principal thesis of Garrett is minded as the premise from which all of Petitioners’
`
`arguments flow, there can be little question that proscribed hindsight infects every
`
`building-block assumption that the Board must find as fact to reach the ultimate
`
`conclusion of obviousness, from the plausibility of developing a new dapsone topical
`
`in the first place, to the most contrived final step of combining Garrett with
`
`references that conveniently disclose A/SA copolymer as a thickening agent (or
`
`PVB). For the following reasons, none of these component assumptions merits
`
`crediting.
`
`1.
`
`Garrett’s teachings are limited to compositions with both
`dissolved and undissolved dapsone
`
`Petitioners have not met their burden to prove a POSA would have been
`
`motivated to develop a dapsone composition as claimed.1 First, Petitioners assert
`
`that Garrett disclosed compositions with completely dissolved dapsone, as well as
`
`compositions with completely undissolved dapsone or mixtures of the two. Reply at
`
`1 Petitioners assert that the ʼ219 patent claims do not require dapsone to be in any
`
`particular state of dissolution. But as Petitioner’s expert admits, the dapsone in the
`
`claimed compositions is necessarily “a mixture of dissolved and undissolved
`
`dapsone.” Ex. 2068 at 88:21–89:19; 98:11–102:12.
`
`
`
`5
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`

`IPR2019-00207
`Patent Owner’s Sur-Reply
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`
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`19. But Petitioners cite to one single sentence of Garrett and ignore the might of
`
`Garrett’s teachings. Its abstract, description of “the invention” under “summary of
`
`the invention,” and at least twenty other disclosures within Garrett make clear that
`
`Garrett’s purpose is a dermatological composition “wherein dapsone is dissolved in
`
`the gel such that the dapsone has the capacity to cross the stratum corneum layer of
`
`the epidermis and become available systemically, and wherein the composition also
`
`contains dapsone in a microparticulate state that does not readily cross the stratum
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`corneum of the epidermis”—that is, a composition containing dapsone in both
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`dissolved and undissolved states. Ex. 1004 at 3:20–27 (describing “the present
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`invention”); id. at Abstract, 4:18–24, 6:10–16, 6:34–7:6, 11:15–18, 11:23–27, 12:5–
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`6:2, 13:15–2, 13:29–33, 15:3–14, 16:25–16:1, 16:3–17:2, 24:31–34.
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`Almirall’s evidence demonstrates that at the time of the invention, it was
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`known in the industry that formulations containing both undissolved, particulate API
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`and dissolved API led to stability issues and uneven distribution of the API particles.
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`Ex. 2057 ¶¶42, 123–125; Ex. 2049 at 18; Ex. 2064 at 5, 9. Indeed, art more recent
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`than Garrett—Ahluwalia (Ex. 2008) and Lathrop (Ex. 1007)—taught that the
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`preferred formulation comprised completely dissolved dapsone. The record is
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`accordingly clear—as Petitioners do not meaningfully rebut—that at the time of the
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`invention the prior art taught away from dual-state dapsone formulations, and the
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`industry had skepticism over undissolved dapsone formulations. Nonetheless,
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`Petitioners assert Garrett, with a contrary dual-state design central to its teaching, as
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`the lead reference in both Grounds.
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`2.
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`Garrett does not teach that dapsone treats acne or rosacea
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`Petitioners’ primary obviousness reference, Garrett, does not teach that
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`dapsone is effective to treat acne.2 The data presented in Garrett shows that for acne
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`treatment, the composition with no dapsone in it was just as good as, and in some
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`cases better than, the composition containing dapsone. Garrett’s sole example states
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`that “vehicle treatment in this study resulted in a better reduction in non-
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`inflammatory lesion counts while the percentage reduction in total lesion count was
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`similar between Aczone™ [containing 5% dapsone] and vehicle.” Ex. 1004 at
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`29:20–24. And the “vehicle gel consisted of the same inactive ingredients as the
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`dapsone gel.” Id. at 24:12–13. While a POSA may conclude from Garrett that
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`Aczone® Gel, 5%—i.e., vehicle plus dapsone—is more effective at treating acne
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`than no therapy at all, a POSA would not conclude from reading Garrett that the
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`dapsone in that composition had any effect.
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`2 Petitioners incorrectly assert that Almirall equates “treating” with demonstrated
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`effectiveness sufficient to warrant FDA approval. Reply at 11. Not so; nor can
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`Petitioners point to where Almirall asserts such a construction in its briefing.
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`Similarly, a POSA would not have understood that dapsone is effective to
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`treat rosacea. Petitioners reply that Garrett II provides “all treatment groups”—that
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`is, vehicle treatment as well as Aczone™ Gel, 5% treatment—showed decreased
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`lesion counts. Reply at 13. But from this reference, a POSA would readily
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`understand that dapsone’s presence made no difference in the lesion count
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`improvement. Ex. 2001 at 35:16–23; see also id. at 24:18–24 (vehicle contains
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`identical ingredients to Aczone™ Gel, 5%, but minus the dapsone); Ex. 2055 ¶¶ 31–
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`82, 96.
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`3.
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`A POSA would not have been motivated to increase dapsone to
`the recited concentration of 7.5%
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`Petitioners clearly assume that a POSA would increase dapsone concentration
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`in any effort to develop a new topical formulation of the drug. See Reply at 13.
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`Petitioners have not rebutted Almirall’s argument that decreasing active agent is
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`desirable to decrease the likelihood of adverse events. Ex. 1013 at [0292] (“[I]t is
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`possible to use less of the active agent that in current commercial or clinically tested
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`products, thereby lessening the likelihood of adverse reactions, irritation, or other
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`side effects.”). Nor have they responded at all to the evidence that new topical
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`dermatological compositions showed a trend towards decreasing API concentration
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`while maintaining, or increasing, efficacy. Ex. 2055 ¶ 47–48; see also Ex. 2035 at 2,
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`8–9. With that understanding, the prior art could not so obviously have motivated a
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`POSA to increase the concentration of dapsone, an assumption core to both Grounds.
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`4.
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`Garrett does not teach using dapsone compositions without
`adapalene
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`Petitioners only reiterate in their Reply that the absence of adapalene in prior
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`art means that the prior art expressly teaches no adapalene. See Reply at 15.
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`Petitioners newly distract by reference to a portion of an unrelated applicant
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`response to a §112 objection during prosecution. This Board knows well that §103
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`and §112 are interpreted under different legal standards and analyses. Relevant to
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`the applicant response, the law of written description provides that disclosure of
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`multiple alternatives—as in the ʼ219 patent’s specification—is sufficient to support
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`the exclusion of one such via a negative claim limitation. Inphi Corp. v. Netlist, Inc.,
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`805 F.3d 1350, 1355 (Fed. Cir. 2015). But this does not touch on the obviousness
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`analysis. As such, the record evidence remains explicit and unanswered that prior art
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`published closely in time to the invention date taught that dapsone should be used in
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`combination with another API, and with adapalene specifically. See PO Response at
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`45–47.
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`5.
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`In view of the prior art as a whole, Garrett would not suggest to
`a POSA the recited DGME concentrations of the claims
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`Almirall’s evidence of record demonstrates that a POSA would not have been
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`motivated to increase DGME concentrations relative to the only prior art commercial
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`embodiment of a dapsone topical (which doubles as the only non-prophetic example
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`disclosed in Garrett). This is so not least because increasing the amount of solvent
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`(here, DGME) forces the reduction of other components in the composition. See
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`Ex. 2063 at 217:14–21. To this, Petitioners reply with a non-sequitur: the claims of
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`the ʼ219 patent “do not require any specific water amount.” See Reply at 17-18.
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`The issue is whether a POSA would be motivated to increase DGME concentration,
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`thus forcing the decision of which other components, among which water is just one,
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`to reduce in concentration, and to what extent. On this question of the obviousness
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`of increasing DGME, Petitioners notably do not dispute in reply that the highest
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`concentration of DGME in an FDA-approved product as of 2012 was just 25%.
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`Petitioners cite instead to general disclosures of “solvation mediums” at hypothetical
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`ranges up to 99% are a classic reach-by-necessity typical of obviousness challenged
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`constructed with hindsight. See Reply at 2 (citing Lathrop, Ex. 1007).
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`So postured, Petitioners deflect to the dapsone-DGME solubility curve
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`disclosed in the Osborne I reference, with the benefit of which, according to
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`Petitioners, a POSA could easily have predicted the increase in DGME that would be
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`necessitated by a given increase in dapsone concentration. If anything, reference to
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`Osborne I epitomizes the unconvincing nature of the Grounds: if a POSA
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`developing a new topical dapsone treatment turned to this figure in that reference, it
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`reasonably could only be in order to avoid deviating from the dissolved-to-
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`undissolved ratio of the dual-state design taught in Garrett. See Ex. 1009 at 4
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`(discussing the “optimization” of the ratio of dissolved dapsone to particulate
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`dapsone). And if that were the POSA’s objective, it only further confirms that
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`POSA would have no motivation to combine Garrett with a secondary reference like
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`Nadau-Fourcade that is directed specifically to deviating from the dual-state design
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`of Garrett. See infra § B.1.
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`B.
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`Petitioners Failed to Show Motivation to Combine Garrett with the
`Other Asserted Art
`1.
`A POSA would not have been motivated to combine Garrett
`with Nadau-Fourcade
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`Petitioners’ contention that a POSA at the time of the invention would have
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`combined Garrett with Nadau-Fourcade is perhaps the chief fallacy of this entire
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`proceeding, and it lays bare the hindsight ingrained in the Grounds in remarkable
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`fashion. Garrett concerns dapsone compositions wherein the dapsone, a water-
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`sensitive API, exists simultaneously in both a dissolved and undissolved state.
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`Ex. 1004 at Abstract, 11:15–27, 12:5–32. Nadau-Fourcade, on the other hand,
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`concerns compositions wherein the goal is to completely dissolve the water-sensitive
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`API. Ex. 2057 ¶¶ 101, 119–122; Ex. 1005 at 40:27–29, 41:13–15. Laying these
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`unambiguous, central teachings side-by-side, there can be no serious question that
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`these two goals articulated in the respective references are beyond just
`
`incompatible—they are diametrically opposed. As such, no artisan of even marginal
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`skill could have been motivated to combine them. Garrett eviscerates the principle
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`of operation taught by Nadau-Fourcade, and vice-versa.
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`a.
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`A POSA would not have been motivated to combine Garrett
`with a reference that requires completely dissolved API
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`A POSA would not be motivated to combine Garrett with Nadau-Fourcade
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`because