UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC and AMNEAL
`PHARMACEUTICALS OF NEW YORK, LLC
`
`Petitioners
`
`v.
`
`ALMIRALL, LLC
`
`Patent Owner
`________________________
`
`Case: IPR2019-00207
`
`
`
`
`
`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
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
`
`TABLE OF CONTENTS
`
`INTRODUCTION .......................................................................................... 1
`
`GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................ 5
`
`
`
`I.
`
`II.
`
`III.
`
`PRECISE RELIEF REQUESTED AND SUPPORTING REASONS .......... 6
`
`IV. OVERVIEW OF LEVEL OF SKILL AND PRIOR ART ............................. 6
`
`A.
`
`
`B.
`
`
`Person of ordinary skill in the art (“POSA”). ....................................... 6
`
`Scope and content of the art before November 20, 2012. ..................... 7
`
`1.
`
`2.
`
`3.
`
`Dapsone was known for treating both inflammatory
`and non-inflammatory acne and rosacea. .................................. 7
`
`Topical dapsone compositions were well-known. ..................... 8
`
`Petitioners’ grounds rely specifically on the following
`prior art publications. ............................................................... 12
`
`(a) Garrett (AMN1004) ....................................................... 12
`
`(b) Nadau-Fourcade (AMN1005)........................................ 14
`
`(c) Bonacucina (AMN1015) ............................................... 15
`
`V. OVERVIEW OF THE ’219 PATENT ......................................................... 16
`
`1.
`
`2.
`
`The Claims ............................................................................... 17
`
`Prosecution history ................................................................... 18
`
`VI. CLAIM CONSTRUCTION ......................................................................... 19
`
`VII.
`
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ................ 20
`
`
` GROUND 1: Claims 1-8 are obvious over Garrett in view of A.
`Nadau-Fourcade. .................................................................................21
`
`1.
`
`Claims 1 and 6 .......................................................................... 21
`
`(a) Garrett teaches treating acne vulgaris and
`rosacea with topical dapsone formulations. .................. 24
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`(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.” ............................................... 25
`
`(c)
`
`It would have been obvious to a POSA to
`substitute
`the “acrylamide copolymer”
`in
`Nadau-Fourcade for the thickening agent in
`Garrett. ........................................................................... 31
`
`(d) Using “about 4% w/w” of the acrylamide
`copolymer as recited in claim 6 would have
`been obvious. ................................................................. 35
`
`(e) A POSA would have had a reasonable
`expectation of successfully combining
`the
`components of the claimed topical dapsone
`formulations. .................................................................. 36
`
`Claim 2 ..................................................................................... 38
`
`Claim 3 ..................................................................................... 39
`
`Claims 4 and 7 .......................................................................... 39
`
`Claims 5 and 8 .......................................................................... 40
`
`2.
`
`3.
`
`4.
`
`5.
`
`B.
`
`
`GROUND 2: Claims 1-8 are obvious over Garrett in view of
`Bonacucina. .........................................................................................40
`
`1.
`
`Claims 1 and 6 .......................................................................... 41
`
`(a) Garrett discloses methods of administering
`dapsone formulations to patients with acne
`vulgaris and rosacea. ...................................................... 44
`
`(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.” ............................................... 44
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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. ................................................... 46
`
`(d)
`
`The claimed “about 4% w/w” copolymer
`limitation would have been obvious as a routine
`optimization. .................................................................. 51
`
`(e) A POSA would have had a reasonable
`expectation of successfully combining
`the
`components of the claimed topical dapsone
`formulations. .................................................................. 52
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 2 ..................................................................................... 54
`
`Claim 3 ..................................................................................... 54
`
`Claims 4 and 7 .......................................................................... 54
`
`Claims 5 and 8 .......................................................................... 55
`
`C.
`
`
`There are no objective indicia that could overcome the
`strong obviousness showing here. .......................................................55
`
`1.
`
`2.
`
`3.
`
`Allergan’s “unexpected” compatibility and smaller
`particle size arguments would have been expected. ................ 56
`
`indicia of non-
`There are no other objective
`obviousness. ............................................................................. 61
`
`The prior art did not teach away from combining the
`claimed components in the claimed amounts. ......................... 62
`
`VIII. THERE IS NO BASIS TO DENY THE PETITION UNDER 35 U.S.C. §§
`314(a) or 325(d) ............................................................................................ 63
`
`IX. CONCLUSION ............................................................................................. 64
`
`X. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ................................... 64
`
`
`
`
`
`iii
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Labs. v. Andrx Pharm., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) ............................................................................ 6
`
`Amneal Pharmas. LLC et al. v. Almiral, LLC,
`IPR2018-00608, Paper 10 (P.T.A.B. Aug. 29, 2018) ..................................... 1, 18
`
`Amneal Pharms. v. Supernus Pharms.,
`IPR2013-00368, Paper 8 (P.T.A.B. Dec. 17, 2013) ........................................... 56
`
`Conopco, Inc. v. Procter & Gamble Co.,
`IPR2013-00505, Paper 69 (P.T.A.B. Feb. 10, 2015) .......................................... 32
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 19
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 62
`
`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) ...................................................................................... 38, 53
`
`Hotchkiss v. Greenwood,
`52 U.S. 248 (1850) .......................................................................................... 2, 29
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ........................................................ 28, 35, 45, 51
`
`In re Boesch,
`617 F.2d 272 (C.C.P.A.1980) ........................................................... 28, 35, 45, 51
`
`In re Fout,
`675 F.2d 297 (C.C.P.A. 1982) ............................................................................ 32
`
`iv
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
`
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) ...................................................................passim
`
`In re GPAC Inc.,
`57 F.3d 1573 (Fed. Cir. 1995) ............................................................................ 57
`
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) .......................................................................... 60
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ...................................................................passim
`
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) ............................................................................ 32
`
`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) .......................................................................... 60
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 ................................................................................................passim
`
`Leapfrog Enterprises, Inc. v Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 56
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .................................................................... 36, 52
`
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ............................................................................ 55
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 36
`
`Senju Pharm. Co. v. Apotex, Inc.,
`717 F. Supp. 2d 404 (D. Del. 2010).............................................................. 37, 52
`
`Sud-Chemie, Inc. v. Multisorb Techs., Inc.,
`554 F.3d 1001 (Fed. Cir. 2009) .......................................................................... 30
`
`v
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
`
`
`Statutes
`
`35 U.S.C. § 102(b) ....................................................................................... 12, 14, 15
`
`35 U.S.C. § 103(a) ................................................................................................. 1, 6
`
`35 U.S.C. §§ 311-319................................................................................................. 6
`
`35 U.S.C. §§ 314(a) ................................................................................................. 62
`
`35 U.S.C. § 325(d) ............................................................................................. 63, 64
`
`Other Authorities
`
`37 C.F.R. §§ 42.1-.80 and 42.100-42.123 ................................................................. 6
`
` (37 C.F.R. § 42.8(a)(1)) .......................................................................................... 64
`
` (37 C.F.R. § 42.8(b)(1)) .......................................................................................... 64
`
` (37 C.F.R. § 42.8(b)(2)) .......................................................................................... 64
`
` (37 C.F.R. § 42.8(b)(3)) .......................................................................................... 64
`
`37 C.F.R. §§42.8(b)(3) and 42.10(a) ....................................................................... 64
`
`37 C.F.R. § 42.10(b) and § 42.63(e) ........................................................................ 65
`
`37 C.F.R. § 42.24(a) ................................................................................................. 65
`
` (37 C.F.R. § 42.104(a)) ............................................................................................. 5
`
` (37 C.F.R. § 42.104(b)) ........................................................................................... 20
`
`37 C.F.R. § 42.106(a) ............................................................................................... 65
`
`
`
`
`
`
`
`vi
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
`
`INTRODUCTION
`
`
`
`I.
`
`Claims 1-8 of U.S. Patent No. 9,517,219 (AMN1001) (“the ’219 patent)
`
`should be cancelled as unpatentable under pre-AIA 35 U.S.C. § 103(a). The ’219
`
`patent, assigned to Almirall, LLC, (“Almirall”),1 simply claims known methods of
`
`treating rosacea or acne vulgaris using known topical dapsone compositions.2 This
`
`does not entitle Almirall to patent protection.
`
`The challenged claims generally recite methods of treating acne vulgaris or
`
`rosacea with a topical pharmaceutical composition of: 3
`
`•
`
`•
`
`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
`
`
`1 According to the Assignment Database at the USPTO, the ’219 patent was
`
`recently assigned from Allergan, Inc. to Almirall.
`
`2 The compositions recited in the ’219 patent are claimed in the related U.S.
`
`Patent No. 9,161,926 (“’926 patent”). Review of the ’926 patent was instituted on
`
`August 29, 2018. See Amneal Pharmas. LLC et al. v. Almiral, LLC, IPR2018-
`
`00608, Paper 10 (P.T.A.B. Aug. 29, 2018).
`
`3 Throughout this petition, all emphasis to quotation is added, except where
`
`otherwise indicated.
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`1
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`known concentration;
`
`•
`
`about 2% w/w to about 6% w/w of acrylamide/sodium
`
`acryloyldimethyl taurate copolymer (“acrylamide copolymer”), a
`
`known thickening agent described as preferred in the prior art for
`
`topical formulations at known concentrations;
`
`water, a well-known and commonly used solvent, which was used in
`
`prior art dapsone gel formulations; and
`
`wherein the composition does not include adapalene, a negative
`
`limitation that existed in various prior art teachings, including
`
`•
`
`•
`
`Aczone® Gel 5%.
`
`The ’219 patent merely claims the administration of obvious compositions of a
`
`known amount of dapsone combined with known amounts of excipients previously
`
`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
`
`(1850) (finding claims unpatentable where “the improvement is the work of the
`
`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
`
`2
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`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
`
`the claims only after Allergan submitted alleged unexpected results evidence. As
`
`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
`
`compositions having 5% to 10% w/w dapsone, and further expressly teaches each
`
`and every limitation of the challenged claims, except the specific claimed
`
`acrylamide copolymer thickening agent. Garrett, however, teaches the use of other
`
`thickening agents, identifying five of them that were widely-accepted: Carbopol®,
`
`Hypan®, Natrosol®, Klucel®, and Stabileze®. Garrett also teaches using topical
`
`dapsone compositions to treat acne vulgaris and rosacea.
`
`A POSA by 2012 would have known that Garrett’s thickening agents were
`
`interchangeable with the claimed acrylamide copolymer thickening agent in view
`
`3
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`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
`
`reduce. (AMN1010, 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.
`
`In view of those drawbacks, a POSA would have had a reason to modify
`
`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
`
`rheological properties suitable for topical administration.” (AMN1015, 7). The
`
`claimed acrylamide copolymer, in contrast to Carbopol® 980, was known to
`
`render topical formulations “stable” with “a perfectly uniform appearance,” and be
`
`“very pleasant for the touch and spread on the skin.” (AMN1026, 2; AMN1034, 5).
`
`Further, the claimed acrylamide copolymer did not require neutralization with a
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`base, unlike Carbopol® 980. (AMN1026, 1; AMN1034, 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
`
`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.
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`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
`
`unpatentable under pre-AIA 35 U.S.C. § 103(a). This Petition is supported by the
`
`declaration of Dr. Bozena Michniak-Kohn, Ph.D. (AMN1002), an expert in the
`
`field of topical pharmaceutical compositions and topical drug delivery (AMN1002,
`
`¶¶1-12), and the declaration of Dr. Elaine Gilmore, M.D., Ph.D (AMN1018), a
`
`practicing dermatologist and expert in the clinical use of topical compositions,
`
`including topical dapsone compositions. (AMN1018, ¶¶1-18). Petitioners’ detailed,
`
`full statement of the reasons for relief requested is provided, infra, at §VII.
`
`IV. OVERVIEW OF LEVEL OF SKILL AND PRIOR ART
`Person of ordinary skill in the art (“POSA”).
`A.
`
`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
`
`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.
`
`2006) (stating that a POSA possesses the “understandings and knowledge reflected
`
`in the prior art”).
`
`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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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`formulator of topical pharmaceutical compositions and clinician with experience
`
`treating dermatological diseases.
`
`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. (AMN1002, ¶¶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. (AMN1018, ¶¶19-21).
`
`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.” (AMN1002, ¶¶19-20;
`
`AMN1007, [0002]; AMN1004, 2:7-10, 9:28-30; AMN1018, ¶¶27-28). While
`
`orally administered dapsone had been used to treat leprosy, topical dapsone
`
`7
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`compositions were known and used to treat dermatological conditions such as
`
`inflammatory and non-inflammatory acne and rosacea prior to the invention date.
`
`(AMN1002, ¶¶20-22; AMN1004, 3:9-15, 22:6-11; AMN1007, [0002]-[0007],
`
`AMN1018, ¶¶29-31; AMN1033, 2?; AMN1010, 3). Indeed, before the priority
`
`date, FDA had approved a topical dapsone 5% formulation (Aczone® Gel 5%) for
`
`treatment of acne vulgaris. (AMN1002, ¶21; AMN1010, 3; AMN1018, ¶31). The
`
`art also reflected a preference for topical administration of dapsone over oral
`
`administration because of the reduced likelihood of systemic side effects.
`
`(AMN1018, ¶¶30; AMN1024,5).
`
`Topical dapsone compositions were well-known.
`
`2.
`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. (AMN1002, ¶23; AMN1007, [0004]-[0005];
`
`AMN1004, 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. (AMN1002, ¶23;
`
`AMN1007, [0048-49]). Of all the possible solubilizing agents, the prior art favored
`
`one above others: ethoxydiglycol, which is recited in the challenged claims.
`
`Garrett taught that ethoxydiglycol was one of two “preferred solvents for use
`
`8
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`in [] topically applied dermatological composition[s].” (AMN1002, ¶24;
`
`AMN1004, 14:13-14; AMN1007, [0055]-[0057]; AMN1010, 4). Not surprisingly,
`
`the prior art Aczone® Gel 5% successfully employed ethoxydiglycol as a
`
`solubilizing agent. (AMN1002, ¶24; AMN1010, 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 dissolve various amounts of
`
`dapsone. (AMN1002, ¶25; AMN1009, 3-4).
`
`Second, dapsone compositions most often were water-based compositions,
`
`with several working formulations having been disclosed, including those taught
`
`by both Lathrop and Garrett. (AMN1002, ¶21; AMN1007, [0018], [0086], [0093],
`
`[0100], [0109], [0111], [0118], [0127], [0134], [0142]; AMN1004, 4:2-15;
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`AMN1010, 4; AMN1008, Abstract; AMN1016, Examples 2-6). Artisans were also
`
`well aware that the prior art Aczone® Gel 5% was water-based. (AMN1002, ¶21;
`
`AMN1010, 4).
`
`Third, dapsone compositions, like most topical compositions, utilized a
`
`preservative. Preservatives in topical formulations were used to inhibit growth of
`
`bacteria in the composition. (AMN1002, ¶29; AMN1004, 13:26-33; AMN1028,
`
`20-21). Preservatives thereby maintain the integrity of the compositional
`
`components, increase the shelf-life of the composition, and generally make the
`
`composition safer for use. (AMN1002, ¶29; AMN1028, 20-21). Prior art topical
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`dapsone compositions were known to use methyl paraben—the preservative recited
`
`in the challenged claims—as the preservative. (AMN1002, ¶29; AMN1007,
`
`[0082]; AMN1004, 13:26-14:18). Unsurprisingly, methyl paraben had been
`
`successfully employed in the prior art Aczone Gel 5%. (AMN1002, ¶29;
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`AMN1010, 4).
`
`Fourth, dapsone compositions often utilized a “thickening agent” to
`
`increase viscosity. (AMN1002, ¶26; AMN1004, 12:5-13:25; AMN1016, 4:7-19,
`
`6:7-16; AMN1008, [0004]). Thickening agents were known to impart a smooth
`
`texture and feel. (AMN1002, ¶26; AMN1007, [0009], [0068]; AMN1013, [0176],
`
`[0200]-[0202]). Thickening agents were also known to disperse or suspend
`
`particles or globules. (AMN1002, ¶57; AMN1007, [009], [0068]; AMN1013,
`
`[0176], [200]-[202]). Although solubilizing agents, such as ethoxydiglycol, were
`
`used to enhance the dissolution of dapsone in topical compositions, it was known
`
`that complete dissolution was not always possible. (AMN1002, ¶23; AMN1004,
`
`11:15-33; AMN1007, [0049]-[0051]). By 2012, it was well known that some
`
`portion of dapsone in a composition may not dissolve in the organic solvent, or that
`
`some portion of the dissolved dapsone would precipitate out of the dissolved state
`
`into the undissolved state. (AMN1007, [0049-50]; AMN1004, 3:20-4:24, 11:20-
`
`33). When not fully dissolved, dapsone manifests as solid particles in the
`
`composition. (AMN1007, [0049]; AMN1004, 9:8-14).
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`Artisans further understood that the ratio of dissolved to undissolved
`
`dapsone was important. (AMN1002, ¶22; AMN1004, 11:15-12:2). The dissolved
`
`dapsone crosses the stratum corneum of the epidermis and is absorbed into the
`
`lower layers of the skin. (AMN1004, Abstract). The 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. (AMN1004, 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. (AMN1002, ¶26; AMN1011, 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
`
`drug particles dissolve or disperse more slowly due to their lower surface
`
`area:volume ratio when compared to smaller particles of a similar shape.
`
`(AMN1002, ¶26; AMN1008, [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. (AMN1002, ¶27; AMN1007, [0079], [0093],
`
`[0100], [0109], [0118], [0134], [0142]; AMN1004, 13:3-25). Other thickening
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`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 claimed in the ’219 patent, such as Simulgel® 600 and
`
`Sepineo® P 600. (AMN1005, 47:12-33 – 48:1-7; AMN1004, 13:3-25; AMN1015,
`
`1).
`
`3.
`
`Petitioners’ grounds rely specifically on the following prior
`art publications.
`(a) Garrett (AMN1004)
`International Patent Application Publication No. WO 2009/061298, “Topical
`
`Treatment With Dapsone in G6PD-Deficient Patients,” (“Garrett”) published on
`
`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
`
`treatment is provided by a topical dapsone composition,” including where “the
`
`dermatological condition to be treated is inflammatory acne, non-inflammatory
`
`acne or rosacea.” (AMN1004, 3:10-15; AMN1018, ¶¶35-36). Garrett 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.” (AMN1004, Abstract, 3:20-26; AMN1002, ¶40).
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`Garrett discloses compositions having about 5% to 10% w/w dapsone, which
`
`encompasses the claimed 7.5% w/w amount. (AMN1004, 3:33-4:15; AMN1002,
`
`¶41). Garrett’s dapsone compositions are water-based compositions. (AMN1004,
`
`Abstract, 3:33-4:15). Garrett also teaches topical dapsone compositions having
`
`about 10% to 30% w/w ethoxydiglycol, which overlaps with the claimed range of
`
`ethoxydiglycol. (AMN1004, 3:33-4:15; 14:6-15:18). Garrett also teaches the use of
`
`preservatives in the topical dapsone compositions to prevent microbial
`
`contamination, including the claimed methyl paraben, and discloses working
`
`examples. (AMN1004, 3:33-4:15, 13:26-33, 14:6-15:18; AMN1002, ¶43).
`
`Garrett next discloses the use of polymeric thickening agents from 0.2% to
`
`4% w/w in the dapsone compositions. (AMN1004, 13:3-16). Garrett teaches that
`
`“[t]hickening agents include polymer thickeners” and further states “[p]olymer
`
`thickeners that may be used include those known to one skilled in the art, such as
`
`hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic and
`
`pharmaceutical industries.” (AMN1004, 13:3-16; AMN1002, ¶42). The claimed
`
`acrylamide copolymer was a well-known, preferred hydrophilic thickening agent
`
`in the prior art. Garrett teaches methods for producing dapsone gel compositions
`
`based on the teachings above. (AMN1002, ¶44).
`
`Finally, Garrett’s topical dapsone compositions do not contain adapalene,
`
`exactly as claimed in the ’219 patent. (AMN1018, ¶¶41-42).
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`Petition for Inter Partes Review of U.S. Patent No. 9,517,219
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`(b) Nadau-Fourcade (AMN