`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`v.
`ALMIRALL, LLC
`Patent Owner
`
`Case: IPR2019-01095
`U.S. Patent No. 9,517,219
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,517,219
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, Virginia 22313–1450
`
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`TABLE OF CONTENTS
`
`2.
`3.
`
`INTRODUCTION ........................................................................................... 1
`I.
`GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................. 6
`II.
`PRECISE RELIEF REQUESTED AND SUPPORTING REASONS ........... 6
`III.
`IV. OVERVIEW OF LEVEL OF SKILL AND PRIOR ART .............................. 7
`A.
`Person of ordinary skill in the art (“POSA”). ....................................... 7
`B.
`Scope and content of the art before November 20, 2012. ..................... 8
`Dapsone was known for treating both inflammatory and
`1.
`non-inflammatory acne and rosacea. .......................................... 8
`Topical dapsone compositions were well-known. ...................... 9
`Petitioners’ grounds rely specifically on the following
`prior art publications. ................................................................ 13
`(a) Garrett (MYLAN1004) ................................................... 13
`(b) Nadau-Fourcade (MYLAN1005) ................................... 15
`(c) Bonacucina (MYLAN1015) ........................................... 16
`OVERVIEW OF THE ’219 PATENT .......................................................... 18
`1.
`The Claims ................................................................................ 18
`2.
`Prosecution history .................................................................... 19
`CLAIM CONSTRUCTION .......................................................................... 20
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ................. 22
`A. GROUND 1: Claims 1-8 are obvious over Garrett in view of
`Nadau-Fourcade. ................................................................................. 23
`1.
`Claims 1 and 6 ........................................................................... 23
`
`V.
`
`VI.
`VII.
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`(c)
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`(a) Garrett teaches treating acne vulgaris and rosacea with
`topical dapsone formulations. ......................................... 26
`(b) Garrett also teaches a composition having “about 7.5%
`w/w dapsone,” “water,” and “about 30% w/w to about
`40% w/w ethoxydiglycol” “wherein the composition
`does not comprise adapalene.” ....................................... 27
`It would have been obvious to a POSA to substitute the
`“acrylamide copolymer” in Nadau-Fourcade for the
`thickening agent in Garrett. ............................................ 33
`(d) Using “about 4% w/w” of the acrylamide copolymer as
`recited in claim 6 would have been obvious. ................. 38
`(e) A POSA would have had a reasonable expectation of
`successfully combining the components of the claimed
`topical dapsone formulations. ......................................... 38
`Claim 2 ...................................................................................... 41
`2.
`Claim 3 ...................................................................................... 41
`3.
`Claims 4 and 7 ........................................................................... 42
`4.
`Claims 5 and 8 ........................................................................... 42
`5.
`B. GROUND 2: Claims 1-8 are obvious over Garrett in view of
`Bonacucina. ......................................................................................... 43
`1.
`Claims 1 and 6 ........................................................................... 43
`(a) Garrett discloses methods of administering dapsone
`formulations to patients with acne vulgaris and
`rosacea. ........................................................................... 47
`(b) Garrett also teaches a composition having “about 7.5%
`w/w dapsone,” “water,” and “about 30% w/w to about
`40% w/w ethoxydiglycol” “wherein the composition
`does not comprise adapalene.” ....................................... 47
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`(c) A POSA would have had a reason to use the claimed
`acrylamide copolymer in a 7.5% w/w dapsone
`compositions. .................................................................. 49
`(d) The claimed “about 4% w/w” copolymer limitation
`would have been obvious as a routine optimization. ...... 54
`(e) A POSA would have had a reasonable expectation of
`successfully combining the components of the claimed
`topical dapsone formulations. ......................................... 55
`Claim 2 ...................................................................................... 57
`2.
`Claim 3 ...................................................................................... 57
`3.
`Claims 4 and 7 ........................................................................... 57
`4.
`Claims 5 and 8 ........................................................................... 58
`5.
`There are no objective indicia that could overcome the strong
`obviousness showing here. .................................................................. 59
`Allergan’s “unexpected” compatibility and smaller
`1.
`particle size arguments would have been expected. ................. 60
`There are no other objective indicia of non-obviousness. ........ 65
`The prior art did not teach away from combining the
`claimed components in the claimed amounts. .......................... 66
`VIII. THERE IS NO BASIS TO DENY THE PETITION UNDER 35
`U.S.C. §§ 314(a) or 325(d) ............................................................................ 66
`CONCLUSION .............................................................................................. 68
`IX.
`X. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) .................................... 68
`
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`2.
`3.
`
`C.
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Labs. v. Andrx Pharm., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) ............................................................................ 7
`Amneal Pharmas. LLC et al. v. Almiral, LLC,
`IPR2018-00608, Paper 10 (P.T.A.B. Aug. 29, 2018) ..................................... 1, 19
`Amneal Pharms. v. Supernus Pharms.,
`IPR2013-00368, Paper 8 (P.T.A.B. Dec. 17, 2013) ........................................... 59
`Conopco, Inc. v. Procter & Gamble Co.,
`IPR2013-00505, Paper 69 (P.T.A.B. Feb. 10, 2015) .......................................... 35
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 20
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 66
`E.I. DuPont de Nemours & Co. v. Synvina C. V.,
`2018 WL 4390796 (Fed. Cir. September 17, 2018) ....................................passim
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .....................................................................passim
`Great Atl. & Pac. Tea Co. v. Supermarket Equip. Corp.,
`340 U.S. 147 (1950) ...................................................................................... 41, 57
`Hotchkiss v. Greenwood,
`52 U.S. 248 (1850) .......................................................................................... 3, 31
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ........................................................ 31, 38, 49, 55
`In re Boesch,
`617 F.2d 272 (C.C.P.A.1980) ........................................................... 31, 38, 49, 55
`In re Fout,
`675 F.2d 297 (C.C.P.A. 1982) ............................................................................ 35
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) ...................................................................passim
`In re GPAC Inc.,
`57 F.3d 1573 (Fed. Cir. 1995) ............................................................................ 61
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) .......................................................................... 64
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ...................................................................passim
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) ............................................................................ 35
`In re Woodruff,
`919 F.2d 1575 (Fed. Cir. 1990) ...................................................................passim
`Iron Grip Barbell Co., Inc. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) .......................................................................... 64
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .....................................................................................passim
`Leapfrog Enterprises, Inc. v Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 59
`Medichem, S.A. v. Rolabo,
`S.L., 437 F.3d 1157 (Fed. Cir. 2006) ............................................................ 38, 55
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ............................................................................ 59
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 39
`Senju Pharm. Co. v. Apotex, Inc.,
`717 F. Supp. 2d 404 (D. Del. 2010)........................................................ 39, 40, 56
`Sud-Chemie, Inc. v. Multisorb Techs., Inc.,
`554 F.3d 1001 ..................................................................................................... 33
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`Statutes
`35 U.S.C. § 102(b) ....................................................................................... 13, 15, 16
`35 U.S.C. § 103(a) ................................................................................................. 1, 6
`35 U.S.C. §§ 311-319................................................................................................. 6
`35 U.S.C. §§ 314(a) ................................................................................................. 66
`35 U.S.C. § 325(d) ............................................................................................. 67, 68
`Other Authorities
`37 C.F.R. §§ 42.1-.80 and 42.100-42.123 ................................................................. 6
` (37 C.F.R. § 42.8(a)(1)) .......................................................................................... 68
` (37 C.F.R. § 42.8(b)(1)) .......................................................................................... 68
` (37 C.F.R. § 42.8(b)(2)) .......................................................................................... 68
` (37 C.F.R. § 42.8(b)(3)) .......................................................................................... 69
`37 C.F.R. §§42.8(b)(3) and 42.10(a) ....................................................................... 69
`37 C.F.R. § 42.10(b) and § 42.63(e) ........................................................................ 69
`37 C.F.R. § 42.24(a) ................................................................................................. 70
` (37 C.F.R. § 42.104(a)) ............................................................................................. 6
` (37 C.F.R. § 42.104(b)) ........................................................................................... 22
`37 C.F.R. § 42.106(a) ............................................................................................... 69
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`iii
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`I.
`
`INTRODUCTION
`Claims 1-8 of U.S. Patent No. 9,517,219 (MYLAN1001) (“the ’219 patent)
`
`should be cancelled as unpatentable under pre-AIA 35 U.S.C. § 103(a). The ’219
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`patent, assigned to Almirall, LLC, (“Almirall”),1 simply claims known methods of
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`treating rosacea or acne vulgaris using known topical dapsone compositions.2 This
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`does not entitle Almirall to patent protection.
`
`A Motion for Joinder is filed herewith requesting joinder with IPR2019-
`
`00207. IPR2019-00207 was filed by Amneal Pharmaceuticals Inc. on November 6,
`
`2018 and inter partes review of Claims 1-8 was instituted May 10, 2019. See
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`IPR2019-00207, Paper 13. The instant Petition is identical to the petition filed by
`
`Amneal, challenging the same claims of the ’219 patent on the same grounds and
`
`relying on identical expert testimony.
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`1 According to the Assignment Database at the USPTO, the ‘219 patent was
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`recently assigned from Allergan, Inc. to Almirall.
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`2 The compositions recited in the ’219 patent are claimed in the related U.S.
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`Patent No. 9,161,926 (“’926 patent”). Review of the ’926 patent was instituted on
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`August 29, 2018. See Amneal Pharmas. LLC et al. v. Almiral, LLC,
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`IPR2018-00608, Paper 10 (P.T.A.B. Aug. 29, 2018).
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`The challenged claims generally recite methods of treating acne vulgaris or
`
`rosacea with a topical pharmaceutical composition of:3
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`
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`
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`about 7.5% w/w dapsone, a known drug at a known concentration;
`
`about 30% w/w to about 40% w/w of diethylene glycol monoethyl
`
`ether (“ethoxydiglycol”), a known preferred solubilizing agent at a
`
`known concentration;
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`
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`about 2% w/w to about 6% w/w of acrylamide/sodium
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`acryloyldimethyl taurate copolymer (“acrylamide copolymer”), a
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`known thickening agent described as preferred in the prior art for
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`topical formulations at known concentrations;
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`water, a well-known and commonly used solvent, which was used in
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`prior art dapsone gel formulations; and
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`wherein the composition does not include adapalene, a negative
`
`limitation that existed in various prior art teachings, including
`
`
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`
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`Aczone® Gel 5%.
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`The ’219 patent merely claims the administration of obvious compositions of a
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`known amount of dapsone combined with known amounts of excipients previously
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`
`3 Throughout this petition, all emphasis to quotation is added, except where
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`otherwise indicated.
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`known for use with dapsone and topical compositions. This is the work of an
`
`ordinary laborer, not an inventor. See Hotchkiss v. Greenwood, 52 U.S. 248, 267
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`(1850) (finding claims unpatentable where “the improvement is the work of the
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`skilful [sic] mechanic, not that of the inventor.”); KSR International Co. v. Teleflex
`
`Inc., 550 U.S. 398, 427 (2007).
`
`Nor is the claimed use—treatment of acne vulgaris and rosacea—innovative.
`
`The prior art taught topical dapsone compositions to treat both rosacea and
`
`inflammatory and non-inflammatory acne. Indeed, Allergan—Almirall’s
`
`predecessor in interest—sold a prior art topical dapsone composition (Aczone®
`
`Gel 5%) indicated for the treatment of acne vulgaris.
`
`It is no wonder that the examiner repeatedly found the challenged claims
`
`obvious during prosecution. Notably, the examiner never found any claim
`
`limitation to be missing from the prior art or not prima facie obvious, and allowed
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`the claims only after Allergan submitted alleged unexpected results evidence. As
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`discussed below, there were no “unexpected” results.
`
`This petition demonstrates that all challenged claims of the ’219 patent are
`
`unpatentable as obvious under at least two separate and independent grounds:
`
`Ground 1. The challenged claims are unpatentable over Garrett in view of
`
`Nadau-Fourcade. Dapsone was a well-known medicament, already approved by
`
`the FDA as a 5% gel for treating acne vulgaris. Garrett discloses topical dapsone
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`compositions having 5% to 10% w/w dapsone, and further expressly teaches each
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`and every limitation of the challenged claims, except the specific claimed
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`acrylamide copolymer thickening agent. Garrett, however, teaches the use of other
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`thickening agents, identifying five of them that were widely-accepted: Carbopol®,
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`Hypan®, Natrosol®, Klucel®, and Stabileze®. Garrett also teaches using topical
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`dapsone compositions to treat acne vulgaris and rosacea.
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`A POSA by 2012 would have known that Garrett’s thickening agents were
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`interchangeable with the claimed acrylamide copolymer thickening agent in view
`
`of at least the disclosure in Nadau-Fourcade, which specifically teaches the
`
`claimed acrylamide copolymer as a “preferred” thickening agent for water
`
`insoluble drugs like dapsone.
`
`Ground 2. The challenged claims also would have been obvious over
`
`Garrett in view of Bonacucina. The prior art Aczone® Gel 5% was known to be
`
`“gritty with visible drug particles present,” which a POSA would have wanted to
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`reduce. (MYLAN1010, 3). Given that it was known that Aczone® Gel 5% used
`
`Carbopol® 980 as its thickening agent, topical dapsone compositions using
`
`Carbopol® like that disclosed in Garrett were expected to be gritty. Another
`
`drawback of Carbopol® 980 is that it required neutralization with a base (e.g.,
`
`sodium hydroxide) to function as a thickening agent.
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`In view of those drawbacks, a POSA would have had a reason to modify
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`Garrett to improve texture and feel in view of Bonacucina, which teaches that
`
`“Sepineo P 600 [a commercial grade of the claimed acrylamide copolymer] is a
`
`prime candidate for use in the formulation of gels and emulsion gels with
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`rheological properties suitable for topical administration.” (MYLAN1015, 7). The
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`claimed acrylamide copolymer, in contrast to Carbopol® 980, was known to
`
`render topical formulations “stable” with “a perfectly uniform appearance,” and be
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`“very pleasant for the touch and spread on the skin.” (MYLAN1026, 2;
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`MYLAN1034, 5). Further, the claimed acrylamide copolymer did not require
`
`neutralization with a base, unlike Carbopol® 980. (MYLAN1026, 1;
`
`MYLAN1034, 5).
`
`Based on either Ground 1 or 2, all challenged claims would have been
`
`obvious. Neither Nadau-Fourcade nor Bonacucina were before the examiner
`
`during prosecution. Had the examiner considered these references, the ’219 patent
`
`should not have issued. This petition demonstrates that a POSA would have had
`
`reason to substitute the thickening agent taught in the dapsone composition of
`
`Garrett with the acrylamide copolymer taught in either Nadau-Fourcade or
`
`Bonacucina, for multiple and independent reasons, any of which compels finding
`
`obviousness. Because (1) each component of the claimed composition was known
`
`for use in topical compositions (including the prior art Aczone® Gel 5%) for its
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`intended purpose and in its intended concentration, and (2) such a composition was
`
`known to treat acne vulgaris or rosacea, a POSA would have had a reasonable
`
`expectation of successfully arriving at the claimed composition. This is a textbook
`
`case of obviousness: “the combination of familiar elements according to known
`
`methods is likely to be obvious when it does no more than yield predictable
`
`results.” KSR, 550 U.S. at 416.
`
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(A))
`The ’219 patent is available for IPR and that Petitioners are not barred or
`
`estopped from requesting IPR of any of the challenged claims.
`
`III. PRECISE RELIEF REQUESTED AND SUPPORTING REASONS
`The Office should institute IPR under 35 U.S.C. §§ 311-319 and 37 C.F.R.
`
`§§ 42.1-.80 and 42.100-42.123, and cancel claims 1-8 of the ’219 patent as
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`unpatentable under pre-AIA 35 U.S.C. § 103(a). This Petition is supported by the
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`declaration of Audra L. Stinchcomb, Ph.D. (MYLAN1002/1035),4 an expert in the
`
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`4 As explained in the accompanying Motion for Joinder, Audra L.
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`Stinchcomb’s, Ph.D. declaration in support of these grounds is identical to that of
`
`Dr. Bozena Michniak Kohn, Ph.D., submitted in the Amneal IPR. Dr. Marc
`
`Serota’s declaration is similarly identical to Dr. Elaine Gilmore’s. The
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`field of topical pharmaceutical compositions and topical drug delivery
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`(MYLAN1002/1035, ¶¶1-12), and the declaration of Marc Serota, M.D.
`
`(MYLAN1018/1037), a practicing dermatologist and expert in the clinical use of
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`topical compositions, including topical dapsone compositions.
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`(MYLAN1018/1037, ¶¶1-18). Petitioner’s detailed, full statement of the reasons
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`for relief requested is provided, infra, at §VII.
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`IV. OVERVIEW OF LEVEL OF SKILL AND PRIOR ART
`A.
`Person of ordinary skill in the art (“POSA”).
`A POSA is presumed to be aware of all pertinent art prior to November 20,
`
`2012, the earliest priority date to which the ’219 patent could be entitled. The
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`POSA thinks along conventional wisdom in the art, and is a person of ordinary
`
`creativity. See Abbott Labs. v. Andrx Pharm., Inc., 452 F.3d 1331, 1336 (Fed. Cir.
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`2006) (stating that a POSA possesses the “understandings and knowledge reflected
`
`in the prior art”).
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`Here, a POSA would draw upon the knowledge and experience of related
`
`disciplines of a multi-disciplinary team that might lie outside the POSA’s primary
`
`training. A POSA relevant to the ’219 patent would have the knowledge of both a
`
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`corresponding declarations are cited in tandem herein, e.g., MYLAN1002/1035
`
`and MYLAN1018/1037, respectively.
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`formulator of topical pharmaceutical compositions and clinician with experience
`
`treating dermatological diseases.
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`The formulator POSA would possess a Ph.D. or equivalent degree in
`
`pharmaceutics, chemistry or a related discipline such as pharmacology, who also
`
`has practical experience (at least two years) of formulating topical drug delivery
`
`products, or the POSA could possess a Bachelors or Masters degree in one of the
`
`preceding disciplines with a greater level (at least four years) of the same
`
`formulating experience. (MYLAN1002/1035, ¶¶16-18).
`
`The clinical POSA would possess an M.D. with a board certification in
`
`dermatology with at least two years of experience in dermatology, or otherwise
`
`treating skin conditions. It is also possible that an M.D. without a certification in
`
`dermatology (i.e., a primary care physician, or a pediatrician) may qualify as a
`
`clinical POSA, assuming that they have more than two years of knowledge and
`
`experience treating skin conditions. (MYLAN1018/1037, ¶¶9 -2 1).
`
`B.
`
`Scope and content of the art before November 20, 2012.
`1.
`Dapsone was known for treating both inflammatory and
`non-inflammatory acne and rosacea.
`Dapsone is not a new compound. It is “a well-known medicament
`
`possessing several beneficial medicinal activities.” (MYLAN1002/1035, ¶¶19-20;
`
`MYLAN1007, [0002]; MYLAN1004, 2:7-10, 9:28-30; MYLAN1018/1037,
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`¶¶27-28). While orally administered dapsone had been used to treat leprosy,
`8
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`topical dapsone compositions were known and used to treat dermatological
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`conditions such as inflammatory and non-inflammatory acne and rosacea prior to
`
`the invention date. (MYLAN1002/1035, ¶¶20-22; MYLAN1004, 3:9-15, 22:6-11;
`
`MYLAN1007, [0002]-[0007], MYLAN1018/1037, ¶¶29-31; MYLAN1033, 2?;
`
`MYLAN1010, 3). Indeed, before the priority date, FDA had approved a topical
`
`dapsone 5% formulation (Aczone® Gel 5%) for treatment of acne vulgaris.
`
`(MYLAN1002/1035, ¶21; MYLAN1010, 3; MYLAN1018/1037, ¶31). The art
`
`also reflected a preference for topical administration of dapsone over oral
`
`administration because of the reduced likelihood of systemic side effects.
`
`(MYLAN1018/1037, ¶¶30; MYLAN1024,5).
`
`2.
`Topical dapsone compositions were well-known.
`Several topical dapsone compositions were known in the prior art and shared
`
`various common features:
`
`First, the art taught using a solubilizing agent to address dapsone’s known
`
`insolubility in water and in oils. (MYLAN1002/1035, ¶23; MYLAN1007,
`
`[0004]-[0005]; MYLAN1004, 13:10-14:19). Organic solvents that would either
`
`completely dissolve the dapsone in the composition, or enable the dapsone to
`
`dissolve in a water-solvent combination, were common solubilizing agents.
`
`(MYLAN1002/1035, ¶23; MYLAN1007, [0048-49]). Of all the possible
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`solubilizing agents, the prior art favored one above others: ethoxydiglycol, which
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`is recited in the challenged claims.
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`Garrett taught that ethoxydiglycol was one of two “preferred solvents for use
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`in [] topically applied dermatological composition[s].” (MYLAN1002/1035, ¶24;
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`MYLAN1004, 14:13-14; MYLAN1007, [0055]-[0057]; MYLAN1010, 4). Not
`
`surprisingly, the prior art Aczone® Gel 5% successfully employed ethoxydiglycol
`
`as a solubilizing agent. (MYLAN1002/1035, ¶24; MYLAN1010, 4). Indeed,
`
`dapsone’s solubility in ethoxydiglycol was so well understood that a solubility
`
`curve had been established to correlate the amount of ethoxydiglycol needed to
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`dissolve various amounts of dapsone. (MYLAN1002/1035, ¶25; MYLAN1009,
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`3-4).
`
`Second, dapsone compositions most often were water-based compositions,
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`with several working formulations having been disclosed, including those taught
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`by both Lathrop and Garrett. (MYLAN1002/1035, ¶21; MYLAN1007, [0018],
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`[0086], [0093], [0100], [0109], [0111], [0118], [0127], [0134], [0142];
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`MYLAN1004, 4:2-15; MYLAN1010, 4; MYLAN1008, Abstract; MYLAN1016,
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`Examples 2-6). Artisans were also well aware that the prior art Aczone® Gel 5%
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`was water-based. (MYLAN1002/1035, ¶21; MYLAN1010, 4).
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`Third, dapsone compositions, like most topical compositions, utilized a
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`preservative. Preservatives in topical formulations were used to inhibit growth of
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`bacteria in the composition. (MYLAN1002/1035, ¶29; MYLAN1004, 13:26-33;
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`MYLAN1028, 20-21). Preservatives thereby maintain the integrity of the
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`compositional components, increase the shelf-life of the composition, and
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`generally make the composition safer for use. (MYLAN1002/1035, ¶29;
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`MYLAN1028, 20-21). Prior art topical dapsone compositions were known to use
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`methyl paraben—the preservative recited in the challenged claims—as the
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`preservative. (MYLAN1002/1035, ¶29; MYLAN1007, [0082]; MYLAN1004,
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`13:26-14:18). Unsurprisingly, methyl paraben had been successfully employed in
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`the prior art Aczone Gel 5%. (MYLAN1002/1035, ¶29; MYLAN1010, 4).
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`Fourth, dapsone compositions often utilized a “thickening agent” to
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`increase viscosity. (MYLAN1002/1035, ¶26; MYLAN1004, 12:5-13:25;
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`MYLAN1016, 4:7-19, 6:7-16; MYLAN1008, [0004]). Thickening agents were
`
`known to impart a smooth texture and feel. (MYLAN1002/1035, ¶26;
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`MYLAN1007, [0009], [0068]; MYLAN1013, [0176], [0200]-[0202]). Thickening
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`agents were also known to disperse or suspend particles or globules.
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`(MYLAN1002/1035, ¶57; MYLAN1007, [009], [0068]; MYLAN1013, [0176],
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`[200]-[202]). Although solubilizing agents, such as ethoxydiglycol, were used to
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`enhance the dissolution of dapsone in topical compositions, it was known that
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`complete dissolution was not always possible. (MYLAN1002/1035, ¶23;
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`MYLAN1004, 11:15-33; MYLAN1007, [0049]-[0051]). By 2012, it was well
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`known that some portion of dapsone in a composition may not dissolve in the
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`organic solvent, or that some portion of the dissolved dapsone would precipitate
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`out of the dissolved state into the undissolved state. (MYLAN1007, [0049-50];
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`MYLAN1004, 3:20-4:24, 11:20-33). When not fully dissolved, dapsone manifests
`
`as solid particles in the composition. (MYLAN1007, [0049]; MYLAN1004,
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`9:8-14).
`
`Artisans further understood that the ratio of dissolved to undissolved
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`dapsone was important. (MYLAN1002/1035, ¶22; MYLAN1004, 11:15-12:2).
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`The dissolved dapsone crosses the stratum corneum of the epidermis and is
`
`absorbed into the lower layers of the skin. (MYLAN1004, Abstract). The
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`undissolved dapsone, on the other hand, can either be delivered to and act on the
`
`upper layers of the skin, or act as a reservoir of slowly absorbed dapsone.
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`(MYLAN1004, 11:15-27). However, because the undissolved dapsone was
`
`dispersed or suspended in the composition, artisans understood that the
`
`undissolved drug particles needed to be controlled to maintain homogeneity of the
`
`drug particles, i.e., to prevent aggregation and clumping of the drug particles.
`
`(MYLAN1002/1035, ¶26; MYLAN1011, 3:7-12).
`
`By 2012, formulators had good reason to avoid aggregation and clumping of
`
`the drug particles, including to avoid compromising the stability of the overall
`
`composition and to avoid impairing the clinical efficacy of the drug because larger
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`drug particles dissolve or disperse more slowly due to their lower surface
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`area:volume ratio when compared to smaller particles of a similar shape.
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`(MYLAN1002/1035, ¶26; MYLAN1008, [0004]). The known solution to these
`
`problems by 2012 was to use thickening agents, specifically crosslinked acrylic
`
`acid polymers. Such agents, sold under various Carbopol® trade names, were
`
`known and used specifically in dapsone compositions. (MYLAN1002/1035, ¶27;
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`MYLAN1007, [0079], [0093], [0100], [0109], [0118], [0134], [0142];
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`MYLAN1004, 13:3-25). Other thickening agents were known to be
`
`interchangeable with Carbopol® and suitable for dapsone (and other water
`
`insoluble drugs), including, the acrylamide/sodium acryloyldimethyl taurate
`
`copolymer (referred to herein as “acrylamide copolymer” for simplicity) that is
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`claimed in the ’219 patent, such as Simulgel® 600 and Sepineo® P 600.
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`(MYLAN1005, 47:12-33 48:1-7; MYLAN1004, 13:3-25; MYLAN1015, 1).
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`3.
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`Petitioners’ grounds rely specifically on the following prior
`art publications.
`(a) Garrett (MYLAN1004)
`International Patent Application Publication No. WO 2009/061298, “Topical
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`Treatment With Dapsone in G6PD-Deficient Patients,” (“Garrett”) published on
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`May 14, 2009, and qualifies as prior art under pre-AIA 35 U.S.C. § 102(b).
`
`Garrett teaches treatments “directed to dermatological conditions and the
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`treatment is provided by a topical dapsone composition,” including where “the
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`dermatological condition to be treated is inflammatory acne, non-inflammatory
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`acne or rosacea.” (MYLAN1004, 3:10-15; MYLAN1018/1037, ¶¶35-36). Garrett
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`teaches a “dermatological composition that is a semi-solid aqueous gel, wherein
`
`dapsone is dissolved in the gel such that the dapsone has the capacity to cross the
`
`stratum corneum layer of the epidermis, and wherein the composition also contains
`
`[some] dapsone in a microparticulate state that does not readily cross the stratum
`
`corneum of the epidermis.” (MYLAN1004, Abstract, 3:20-26;
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`MYLAN1002/1035, ¶40).
`
`Garrett discloses compositions having about 5% to 10% w/w dapsone, which
`
`encompasses the claimed 7.5% w/w amount. (MYLAN1004, 3:33-4:15;
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`MYLAN1002/1035, ¶41). Garrett’s dapsone compositions are water-based
`
`compositions. (MYLAN1004, Abstract, 3:33-4:15). Garrett also teaches topical
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`dapsone compositions having about 10% to 30% w/w ethoxydiglycol, which
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`overlaps with the claimed range of ethoxydiglycol. (MYLAN1004, 3:33-4:15;
`
`14:6-15:18). Garrett also teaches the use of preservatives in the topical dapsone
`
`compositions to prevent m