`
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
` AMNEAL PHARMACEUTICALS LLC AND
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC,
`Petitioners,
`
`v.
`
`ALMIRALL, LLC,
`Patent Owner.
`
`___________________
`
`Case IPR2018-00608
`U.S. Patent No. 9,161,926 B2
`___________________
`
`PETITIONERS’ REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`Case IPR2018-00608
`Patent No. 9,161,926 B2
`
`TABLE OF CONTENTS
`
`INTRODUCTION .................................................................................................... 1 
`
`ARGUMENT ............................................................................................................ 4 
`
`I. 
`
`ALMIRALL’S LEGALLY IRRELEVANT ARGUMENTS. ....................... 4 
`
`A. 
`
`B. 
`
`The existence of alternatives is not a “teaching away,” and
`does not negate obviousness of the claimed compositions. .................. 4 
`
`There is no need to construe “dapsone” because its meaning
`is not in dispute in this case. .................................................................. 8 
`
`II. 
`
`ALMIRALL HAS NOT REBUTTED AMNEAL’S
`PRIMA FACIE OBVIOUSNESS CASE. ...................................................... 10 
`
`A. 
`
`The Sepineo® disclosures in Nadau-Fourcade (Ground 1)
`and Bonacucina (Ground 2) meet the “polymeric viscosity
`builder consisting of A/SA” limitation. .............................................. 10 
`
`B. 
`
`Garrett does not teach away from the challenged claims. ................... 12 
`
`1. 
`
`2. 
`
`3. 
`
`Garret does not teach away from compositions
`containing 7.5% dapsone. ........................................................ 12 
`
`Garrett does not teach away from either 30%-40%
`w/w or 30% w/w ethoxydiglycol. ............................................ 15 
`
`from excluding
`teach away
`Garrett does not
`adapalene. ................................................................................. 18 
`
`C. 
`
`is not
`incompatible with Nadau-Fourcade
`Garrett
`(Ground 1). .......................................................................................... 20 
`
`1. 
`
`2. 
`
`3. 
`
`Compositions containing dissolved API would not
`have dissuaded a POSA. .......................................................... 20 
`
`Carbopol® and A/SA copolymers are interchangeable
`thickeners. ................................................................................ 21 
`
`The claimed range of A/SA would have been obvious. .......... 23 
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`D. 
`The combination of Garrett and Bonacucina (Ground 2)
`renders the challenged claims obvious. ............................................... 24 
`
`1. 
`
`2. 
`
`A POSA had multiple reasons to combine Garrett
`with Bonacucina. ...................................................................... 24 
`
`Bonacucina renders 2% to 6% polymeric viscosity
`builder consisting of A/SA obvious. ........................................ 26 
`
`III.  ALMIRALL WAIVED OBJECTIVE INDICIA ARGUMENTS. .............. 27 
`
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`
`
`TABLE OF AUTHORITIES
`
`CASES
`Accord Healthcare Inc. v. Daiichi Sankyo Co., Ltd.,
`
`(IPR2015-00865) ................................................................................................ 14
`
`Allergan, Inc. v. Sandoz Inc.,
` 726 F.3d 1286, 1292 (Fed. Cir. 2013) ................................................................. 25
`
`Almirall LLC v. Taro Pharm. Indus. LTD.,
` C.A. No. 17-00663 (D. Del.) ............................................................................... 21
`
`Conopco, Inc. v. Proctor & Gamble Co.
`
`(IPR2013-00505) ................................................................................................. 21
`
`Daiichi Sankyo Co., Ltd. v. Apotex, Inc.,
` 501 F.3d 1254, 1257-58 (Fed. Cir. 2007) ............................................................ 22
`
`DuPont de Nemours & Co. v. Synvina C.V.,
` 904 F.3d 996, 1006(Fed. Cir. 2018) .................................................................... 13
`
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
` 904 F.3d 996, 1007 .............................................................................................. 15
`
`Galderma Laboratories, L.P. v. Tolmar, Inc.,
` 737 F.3d 731, 738-39 (Fed. Cir. 2013) ................................................................ 27
`
`In re Boesch,
` 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) ....................................... 16
`
`In re Crish,
` 393 F.3d 1253, 1257 (Fed. Cir. 2009) ................................................................. 11
`
`In re Fulton,
` 391 F.3d 1195, 1201 (Fed. Cir. 2004) ................................................................... 7
`
`In re Geisler,
` 116 F.3d 1465, 1469 (Fed. Cir. 1997) ................................................................. 15
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`In re Heck,
` 699 F.2d 1331, 1333 (Fed. Cir. 1983) ................................................................. 13
`
`In re Mouttet,
` 686 F.3d 1322, 1334 (Fed. Cir. 2012) ................................................................... 4
`
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
` 868 F.3d 1013, 1017 (Fed. Cir. 2017) ................................................................... 8
`
`Pfizer, Inc. v. Apotex, Inc.,
` 480 F.3d 1348 (Fed. Cir. 2007)............................................................................ 26
`
`Shire Dev., LLC v. Watson Pharmas., Inc.,
` 848 F.3d 981, 984 (Fed. Cir. 2017) ..................................................................... 12
`
`SightSound Techs., LLC v. Apple Inc.,
` 809 F.3d 1307, 1320 (Fed. Cir. 2015) ................................................................... 4
`
`Süd-Chemie, Inc. v. Multisorb Techs., Inc.,
` 554 F.3d 1001 (Fed. Cir. 2009)............................................................................ 19
`
`Unigene Labs., Inc. v. Apotex, Inc.,
` 655 F.3d 1352 (Fed. Cir. 2011)............................................................................ 22
`
`Upsher-Smith Labs., Inc. v. Pamlab, LLC,
` 412 F.3d 1319, 1322 (Fed. Cir. 2005) ................................................................. 19
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
` 683 F.3d 1356, 1364-65 (Fed. Cir. 2012) ............................................................ 22
`
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`
`INTRODUCTION
`Almirall’s1 Response (“POR”) has not overcome the strong obviousness
`
`case presented in Amneal’s Petition. Almirall’s inconsistent and shifting positions
`
`undermine the credibility of its arguments. Desperate to escape obviousness,
`
`Almirall makes statements to this Board that are completely contradicted by prior
`
`statements to other agencies and a district court.
`
`For example, first, alleging “unexpected results” during prosecution,
`
`Almirall told the USPTO that dapsone compositions containing Sepineo® P 600 (a
`
`commercial brand of the claimed A/SA2 polymeric thickener) were within the ’926
`
`patent’s scope. But confronted with certain obviousness in this IPR, Almirall
`
`panics and tells this Board the exact opposite—that Sepineo®-containing
`
`compositions are outside the scope of the claims. The prosecution history exposes
`
`Almirall’s misrepresentation, but so do admissions by Almirall’s retained expert,
`
`Dr. Alexander Klibanov, who testified that Sepineo®-containing dapsone
`
`formulations have a nexus to the ’926 patent claims. EX2003, ¶203; AMN1058,
`
`25:97:23-29:113:9.
`
`Second, and equally egregious, Almirall told the Delaware District Court in
`
`1 “Almirall” includes its predecessor-in-interest Allergan.
`
`2 Following Almirall’s convention, “A/SA” means “acrylamide/sodium
`
`acryloyldimethyl taurate.”
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`a parallel infringement action over a related patent that Carbopol® 980 (the
`
`polymeric thickener taught in Garrett) and Sepineo® are “equivalent” for
`
`infringement purposes. Yet Almirall argues here that these thickeners are not
`
`interchangeable.
`
`In a third example, Almirall tells this Board that Garrett’s omission of any
`
`mention of adapalene is insufficient to meet the “no adapalene” negative limitation
`
`of the claims. But during prosecution, Almirall pointed to the same omission in the
`
`’926 patent specification for §112 support for this limitation.
`
`
`
`Almirall’s blatantly inconsistent statements are inexcusable, and standing
`
`alone warrant revocation of the ’926 patent. But Almirall’s remaining arguments
`
`on the merits also fail to overcome Petitioner’s obviousness showing. The prior art
`
`teachings are remarkably clear. Garrett, the primary reference in both Grounds,
`
`specifically taught every limitation of the challenged claims, except the A/SA
`
`polymeric viscosity builder (“PVB”) thickener. Garrett expressly taught topical
`
`compositions containing:
`
`
`
`
`
`
`
`
`
`
`
`5% to 10% w/w dapsone;
`
`about 30% ethoxydiglycol;
`
`water, and
`
`methyl paraben;
`
`with no adapalene.
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`Regarding the PVB limitation, Garrett teaches 0.2% to 4% w/w of Carbopol®.
`
`Nadau-Fourcade, the second reference for Ground 1, taught that Sepineo® was a
`
`“preferred” PVB that was interchangeable with Carbopol®. A POSA would have
`
`combined these teachings to arrive at the claimed compositions.
`
`Moreover, Almirall has not rebutted that a POSA would have been
`
`separately motivated to replace Carbopol® in Garrett’s formulation with Sepineo®
`
`because using Carbopol® required a neutralization step, and also because
`
`Carbopol® yielded a gritty texture (as in the prior art ACZONE® Gel, 5%). So a
`
`POSA would have combined Garrett with Bonacucina (Ground 2), which showed
`
`that Sepineo® was a “prime candidate” for use as a thickener in topical
`
`compositions that created stiff and stable gel-compositions and did not require
`
`neutralization. AMN1015, 2.
`
`Unable to rebut the overwhelming obviousness on the merits, Almirall
`
`resorts to manufacturing its so-called “Five Assumptions,” through which Almirall
`
`alleges that Amneal did not establish whether a POSA would have: (1) looked to
`
`dapsone, (2) considered Garrett, (3) used 7.5% w/w dapsone, (4) used 30% to 40%
`
`w/w ethoxydiglycol, and (5) used an A/SA thickener. These are not “assumptions.”
`
`Each finding is expressly supported by the art.
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`
`ARGUMENT
`
`I.
`
`ALMIRALL’S LEGALLY IRRELEVANT ARGUMENTS.
`
`Hemmed-in by the clear prior art, Almirall’s POR advances various legally
`
`irrelevant arguments that serve only to distract from the actual merits. The Board
`
`should reject them.
`
`A. The existence of alternatives is not a “teaching away,” and does
`not negate obviousness of the claimed compositions.
`
`Almirall throughout its POR argues that the existence of alternatives to the
`
`claimed features—(i) dapsone, (ii) ethoxydiglycol, and (iii) A/SA—would have
`
`“dissuaded” a POSA from selecting those features, rendering them not obvious.
`
`That is wrong as a matter of law. The “mere disclosure of more than one
`
`alternative does not amount to teaching away from one of the alternatives where
`
`the [prior art] does not ‘criticize, discredit, or otherwise discourage the solution
`
`claimed.’” SightSound Techs., LLC v. Apple Inc., 809 F.3d 1307, 1320 (Fed. Cir.
`
`2015) (citation omitted); see also In re Mouttet, 686 F.3d 1322, 1334 (Fed. Cir.
`
`2012) (“This court has further explained that just because better alternatives exist
`
`in the prior art does not mean that an inferior combination is inapt for obviousness
`
`purposes.”).
`
`Almirall’s argument also finds no support in the factual record:
`
`Dapsone: Almirall purports three reasons why a POSA would not have been
`
`“motivated” to considered dapsone: it is (1) not a first-line acne treatment; (2)
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`ineffective against rosacea; and (3) less effective than other dapsone derivatives.
`
`POR, 33, 35-38, 40-41. Each of these arguments fails on the facts and the law.
`
`First, Garrett expressly explains that ACZONE® Gel 5%, which contained
`
`the exact 4,4’-diaminodiphenyl sulfone dapsone compound claimed in the ’926
`
`patent, was “developed to deliver therapeutic concentrations of dapsone to the
`
`skin,” and resulted in a 44% and 5% reduction in inflammatory and non-
`
`inflammatory acne lesions respectively. AMN1004, 3:9-15, 9:4-12, 29:2-27;
`
`AMN1034, ¶10. Additionally, ACZONE® Gel, 5% was FDA approved to treat
`
`acne vulgaris. AMN1007, ¶[0003]; AMN1010, 1; AMN1018, ¶¶26, 35, 38;
`
`AMN1034, ¶¶8-11; EX2005, 8:16-17. Moreover, the art is replete with statements
`
`that topical dapsone gel is a common and effective acne treatment, regardless of
`
`being “second-line.” AMN1018, ¶¶22-29; AMN1034, ¶¶6-11; AMN1008, ¶[0004];
`
`EX2013, 3-4; EX2016, 5; EX2040, 1 EX2041, 1-2. Indeed, Almirall’s expert Dr.
`
`Harper3 published an article in 2012 saying that ACZONE® Gel, 5% “is an
`
`effective topical treatment for patients with acne vulgaris.” AMN1035, 1.
`
`Second, Garrett also discloses that topical dapsone is effective at treating
`
`rosacea. AMN1004, 3:13-15, 3:23-24 ; AMN1034, ¶12. Almirall’s argument is
`
`3 Dr. Harper admitted receiving between $213,344.70 and $232,342.70 in pay
`
`and benefits from Allergan since July 2011 for, inter alia, promotional activities
`
`for ACZONE® Gel 5%. AMN1049, 39:151:2-42:163-19; AMN1041-AMN1047.
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`legally misguided—dapsone does not need to be the “most obvious” rosacea
`
`treatment to still be obvious. SightSound, 809 F.3d at 1320; Mouttet, 686 F.3d at
`
`1334. Third, while some in vitro data shows that certain dapsone derivatives may
`
`be more “effective” than dapsone, only dapsone’s efficacy is supported by reliable
`
`in vivo clinical data. AMN1050, ¶12, n.2. A POSA, thus, would have been
`
`motivated to formulate a topical dapsone formulation.
`
`Almirall’s argument resembles a “lead compound” analysis for “structural
`
`obviousness.” But the alleged invention here has nothing to do with arriving at a
`
`new or inventive compound. The issue is whether it would have been obvious to
`
`combine known topical excipients with dapsone, a known topically-administered
`
`treatment for acne and rosacea. Using dapsone is not based on “hindsight,” as
`
`Almirall repeatedly states, but instead explicitly instructed by art. See, e.g.,
`
`AMN1004, 3:9-15, 4:25-31, 10:4-12, 12:1-4, 28:10-29:5, 29:24-25; AMN1007,
`
`¶¶[0003], [0017]; AMN1010, 3, 8-9; AMN1008, ¶[0004]; AMN1018, ¶¶22-29;
`
`AMN1034, ¶¶6-11; AMN1035, 1, 4, 8; EX2005, 3:10-24; EX2013, 3-4; EX2016,
`
`5; AMN2017, 1; AMN2024, 5; EX2040, 1; EX2041, 1-2.
`
`Ethoxydiglycol: Almirall suggests that “dozens” of possible solvents for
`
`dapsone existed. POR, 21-22. But this is irrelevant because Garrett specifically
`
`informs a POSA that ethoxydiglycol is “preferred,” and a POSA would have
`
`known that it was successfully used in the FDA-approved prior art ACZONE® Gel
`
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`Case IPR2018-00608
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`5%. AMN1050, ¶35; AMN1004, 14:13-14; AMN1010, 1; EX2005, 8:19-24;
`
`EX2006, 23:7-8. Additionally, Almirall’s expert Dr. Harper wrote in 2012 that
`
`ethoxydiglycol itself may have anti-acne activity, rendering it even more obvious
`
`for use in the treatment of acne. AMN1035, 5-6. Far from any “hindsight,” the art
`
`instructed a POSA to use ethoxydiglycol. See, e.g., AMN1002, ¶¶23-25, 41, 44,
`
`51; see also EX2003, ¶72.
`
`A/SA thickener: Almirall contends that the existence of thickeners would
`
`have led a POSA away from Sepineo®. POR, 46-48. But the mere disclosure of
`
`other thickeners is not a teaching away. In re Fulton, 391 F.3d 1195, 1201 (Fed.
`
`Cir. 2004). In any event, obviousness requires only that a POSA have a reason to
`
`use a prior art feature, not a reason to “rule out” all others. Cf. Mouttet, 686 F.3d at
`
`1334.
`
`Almirall’s argument that nothing in the art “suggested the need to use a
`
`polymeric viscosity builder other than those disclosed in Garrett” is also factually
`
`wrong. POR, 47. Almirall identifies nothing that “criticizes, discredits, or
`
`discourages” using thickeners not identified in Garrett. Rather, Garrett taught that
`
`suitable thickeners include “those known to one skilled in the art” and explicitly
`
`identifies well-known hydrophilic thickeners. AMN1050, ¶¶38, 44; AMN1004,
`
`13:3-6. Nadau-Fourcade teaches that Sepineo® and Simulgel® (both commercial
`
`brands of A/SA copolymer) are “preferred” hydrophilic thickeners, and also that
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`they were interchangeable with Carbopol®. AMN1050, ¶39; AMN1005, 47:16-17,
`
`34. And separately, Bonacucina informs a POSA that Sepineo® is a “prime
`
`candidate” for topical applications. AMN1002, ¶71; AMN1015, 7. There was no
`
`“teaching away” from using any thickeners not explicitly disclosed in Garrett, as
`
`Almirall erroneously contends.
`
`B.
`
`There is no need to construe “dapsone” because its meaning is not
`in dispute in this case.
`
`Almirall asserts that “dapsone” should be construed as “the compound also
`
`known as 4,4’-diaminodiphenyl sulfone.” POR, 31. But its meaning is not in
`
`controversy, so there is no need for claim construction.4 Nidec Motor Corp. v.
`
`Zhongshan Broad Ocean Motor Co., 868 F.3d 1013, 1017 (Fed. Cir. 2017).
`
`Almirall repeats the vacuous mantra that “dapsone” in Garrett “refer[s] to a family
`
`of thousands of distinct chemical compounds” from which a POSA would not
`
`envisage dapsone. POR, 40. Almirall is wrong.
`
`
`4 Almirall’s construction also incorrectly omits other names for the specific
`
`dapsone compound “4,4’-diaminodiphenyl sulfone.” POR, 8. Almirall also has not
`
`demonstrated lexicography because the intrinsic record fails to “clearly set forth a
`
`definition of the disputed claim term, and clearly express an intent to define the
`
`term.” GE Lighting Sol’ns, LLC v. AgiLight, Inc., 750 F.3d 1304, 1309 (Fed. Cir.
`
`2014).
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`Patent No. 9,161,926 B2
`First, Garrett’s use of “dapsone” includes only three categories of
`
`compounds (AMN1004, 8:18-27):
`
`
`
`the exact 4,4’-diaminodiphenyl sulfone “dapsone compound” that is
`
`claimed in the ’926 patent, and synonyms of that chemical name, see
`
`AMN1050, ¶¶4-6; POR, 7-8; AMN1010, 1;
`
`
`
`
`
`“dapsone analogues”; and
`
`“dapsone-related compounds.”
`
`Dr. Klibanov agreed at his deposition. AMN1059, 17:65:6-9. Far from being the
`
`“thousand-compound” maze that Almirall misleadingly suggests, Garrett’s
`
`disclosure readily and explicitly directs a POSA to the claimed specific “dapsone
`
`compound”: 4,4’-diaminodiphenyl sulfone.
`
`Moreover, Garrett conspicuously distinguishes between “dapsone” versus
`
`“dapsone analogs” and “dapsone-related compounds.” AMN1004, 10:4-12; 10:28-
`
`34; 11:1-12. Garrett says that ACZONE Gel, 5% is “a topical formulation of
`
`dapsone” that is FDA-approved. AMN1050, ¶¶7, 13; AMN1004, 10:6-12. Garrett
`
`subsequently distinguishes “dapsone analogs” and “dapsone-related compounds,”
`
`which a POSA would not confuse with 4,4’-diaminodiphenyl sulfone, the only
`
`compound in an FDA-approved product discussed in Garrett, so a POSA would
`
`understand that Garrett’s 5% to 10% range applies to it. AMN1050, ¶¶5-10;
`
`AMN1004, 11:1-12. Garrett also says that “dapsone analogs and related
`
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`Case IPR2018-00608
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`compounds” “have “activity similar to dapsone and would be expected to have
`
`similar treatment efficacy.” AMN1004, 11:10-12. Even under Almirall’s
`
`interpretation, Garrett teaches “dapsone” and Garrett’s concentration ranges would
`
`be understood to apply to it. AMN1050, ¶¶7-8.
`
`II. ALMIRALL HAS NOT REBUTTED AMNEAL’S PRIMA FACIE
`OBVIOUSNESS CASE.
`A. The Sepineo® disclosures in Nadau-Fourcade (Ground 1) and
`Bonacucina (Ground 2) meet the “polymeric viscosity builder
`consisting of A/SA” limitation.
`
`Desperate to escape obviousness, Almirall tries mightily to argue that
`
`Sepineo® is not a “polymeric viscosity builder consisting of [A/SA],” as recited in
`
`the claims. Using only attorney argument, Almirall contends that because
`
`Sepineo® has two other ingredients— isohexadecane and polysorbate 80—it
`
`somehow does not “consist” solely of A/SA as required by the claims. POR, 3, 34-
`
`35. Almirall is wrong.
`
`First, the claims’ preambles recite the “comprising” transitional phrase, thus
`
`allowing for un-recited features to fall within their scope. AMN1001, 15:21, 16:14.
`
`The “consisting of” language only limits the universe of “polymeric viscosity
`
`builders” to A/SA copolymers, but does not, as a matter of law, foreclose any un-
`
`recited features that are not PVBs. AMN1050, ¶¶59-61; In re Crish, 393 F.3d
`
`1253, 1257 (Fed. Cir. 2009) (holding that “consists” language in the body of a
`
`claim limits only the limitation in which it appears). Neither isohexadecane (a
`
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`solvent) nor polysorbate 80 (a surfactant) are PVBs, they are not excluded by the
`
`“consisting of” term. AMN1050, ¶61; AMN1015, 1-2. Even according to Dr.
`
`Klibanov, there is a “nexus” between Dr. Warner’s dapsone/Sepineo compositions
`
`and the claims. EX2003, ¶203.
`
`Second, the patent specification expressly contemplates Sepineo®’s use with
`
`the claimed compositions by prominently states that the viscosity builder “further
`
`includes isohexadecane, … and polysorbate 80,” thus. AMN1001, 5:35-38.
`
`Similarly, the specification discusses embodiments containing Sepineo®.
`
`AMN1050, ¶62; AMN1001, Examples 1-5. These disclosures definitively debunk
`
`Almirall’s argument; no wonder that neither of Almirall’s experts opined in
`
`support of it. Sepineo® is not excluded from the claims. AMN1050, ¶62.
`
`Third, Almirall’s argument directly contradicts its representations to the
`
`USPTO. Co-inventor Dr. Warner submitted a declaration during prosecution
`
`showing alleged “unexpected results” for what he called “dapsone/Sepineo
`
`compositions,” which standing alone negates any presumption that “consisting of”
`
`excludes Sepineo®. AMN1017, 349-355; id., 504-506; see also AMN1031, 29-30;
`
`see Shire Dev., LLC v. Watson Pharmas., Inc., 848 F.3d 981, 984 (Fed. Cir. 2017)
`
`(presumption that “consisting of” is closed is overcome when the prosecution
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`history “unmistakably manifest[s] an alternative meaning”). Almirall cannot have
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`it both ways: if its new position is correct that the claims do not encompass
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`Sepineo®, then the ’926 patent should never have issued because the alleged
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`unexpected results had no nexus to the challenged claims.
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`Additionally, the ’926 patent is listed in the FDA’s Orange Book as covering
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`ACZONE 7.5%.5 AMN1033, 2. ACZONE 7.5% contains isohexadecane and
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`polysorbate 80. AMN1050, ¶63; EX2039, 5. A POSA would have understood that
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`Sepineo® was covered by the claims. AMN1050, ¶¶63-64.
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`B. Garrett does not teach away from the challenged claims.
`1. Garret does not teach away from compositions containing
`7.5% dapsone.
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`Almirall incorrectly argues that a POSA would have ignored Garrett because
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`“the FDA itself had long since confirmed that the commercial dapsone product did
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`not in fact carry the very concern that Garrett set out to address.” POR, 38-39. This
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`makes no sense. Myopically focusing on Garrett’s alleged “objective,” Almirall
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`misapplies obviousness law. “The use of patents as references is not limited to
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`what the patentees describe as their own invention or to the problems with which
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`they are concerned. They are part of the art, relevant for all they contain.” In re
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`Heck, 699 F.2d 1331, 1333 (Fed. Cir. 1983). Garrett teaches that (1) dapsone
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`topical compositions are known for treating acne, (2) dapsone compositions result
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`5 Seeking to somehow save its patent, Almirall has now requested that FDA
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`“delist” the ’926 patent from the Orange Book. This request is too little, too late.
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`Patent No. 9,161,926 B2
`in a greater reduction of acne lesions than vehicle, and (3) and were FDA-approved
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`to treat acne, providing extensive formulation information and working examples.
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`AMN1050, ¶¶11-15; AMN1010, 2; AMN1004, 10:6-12, 28:11-29:5.
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`Next, Almirall argues that using 7.5% w/w dapsone was not obvious for two
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`reasons: (1) alleged risk of increased side-effects; and (2) prior optimization as
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`ACZONE Gel 5%. POR, 41-43. Almirall is wrong on the law and facts.
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`The law is settled: a prior art range renders obvious claimed amounts within
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`that range, absent a showing of unexpected results, teaching away, that the
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`parameter is not results-effective, or that the prior art range was too broad to invite
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`optimization. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006
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`(Fed. Cir. 2018). It is undisputed that the 7.5% w/w concentration was
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`encompassed by Garrett. AMN1058, 30:116:9-16. Almirall’s POR does not assert
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`any unexpected results, and does not argue that the 7.5% w/w amount is somehow
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`critical. Almirall also does not dispute that the amount of dapsone is a results-
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`effective variable, or argue that a range of 5% to 10% w/w is too broad to
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`optimize.
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`As this Board recently explained, concern over side-effects without more
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`does not negate obviousness: “caution is not a prohibition.” Accord Healthcare
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`Inc. v. Daiichi Sankyo Co., Ltd., IPR2015-00865, Paper 104, 17 (Sept. 12, 2016).
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`Almirall has not identified any side-effect concerns that criticize, discredit, or
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`Patent No. 9,161,926 B2
`otherwise teach away from using 7.5% w/w dapsone. AMN1050, ¶16; EX2014, 2.
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`In fact, Garrett taught that 5% to 10% dapsone compositions “do[] not induce
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`hemolytic anemia” or “adverse hematologic events.” AMN1050, ¶17; AMN1004,
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`4:2-5; 6:5-8; 42:25-32.
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`Garrett found the level of systemic exposure of topically-administered 5%
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`dapsone to be far below the levels associated with oral dosing that were associated
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`with hematological changes. AMN1050, ¶¶18-20; AMN1004, 38:2-15. Far from
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`being dissuaded, a POSA would have understood that a 7.5% w/w concentration
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`would only increase marginally (if at all) systemic dapsone levels. AMN1050,
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`¶¶19-20; AMN1004, 39:2-15. The ACZONE Gel, 7.5% label is consistent with
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`this understanding; it states that exposure was “expected” to be 1% of an oral dose.
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`AMN1050, ¶¶19-20; EX2034, 6; EX2039, 5; AMN1010, 1.
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`Almirall’s second argument against motivation—that ACZONE® 5% was
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`already optimized—is wrong. A more accurate reading of Osbourne I (AMN1009)
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`is that only the ratio of dissolved-to-undissolved dapsone, as opposed to the
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`amount, had been optimized. AMN1050, ¶¶21-22; AMN1009, 4, AMN1017, 353.
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`Even if the 5% was “optimized,” that does not render other formulations “inapt for
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`obviousness purposes.” Mouttet, 686 F.3d at 1334. Nevertheless, Garrett discloses
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`5% to 10% w/w dapsone and informs a POSA that dapsone compositions are
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`typically applied “once or twice daily.” AMN1004, 23:8-12. Knowing that
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`ACZONE® 5% was dosed twice-daily (AMN1010, 8-9), a POSA would have had
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`reason to increase the dapsone concentration to achieve once-daily dosing.
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`AMN1050, ¶¶23-25; AMN1018, ¶¶30-36, 41-43; AMN1004, 23:8-12. Dr. Harper
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`agreed. AMN1049, 39:149:23-39:150:10; EX2022, 152. And Garrett also taught a
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`POSA that the amount of dapsone was a results-effective variable because it
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`teaches that the amounts of dissolved and undissolved dapsone in the composition
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`could be modified to provide minimum (or maximum) reservoir capacity and
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`thereby maintain sustained drug delivery. AMN1050, ¶¶24-25; AMN1004, 12:20-
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`13:2, 22:28-23:7. Thus, the claimed dapsone amount was obvious.
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`2. Garrett does not teach away from either 30%-40% w/w or
`30% w/w ethoxydiglycol.
`Almirall again misstates the law,6 as it is undisputed that Garrett’s range of
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`“about” 30% w/w ethoxydiglycol overlaps with the claimed “about 30% w/w to
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`about 40% w/w” limitation, and therefore is obvious. DuPont, 904 F.3d at 1006.
`
`
`6 Almirall incorrectly states that In re Geisler is inapplicable to IPRs. POR, 45.
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`DuPont reaffirms Geisler’s applicability to IPR proceedings, and that prior art
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`ranges render obvious points falling within that range. E.I. DuPont de Nemours &
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`Co. v. Synvina C.V., 904 F.3d 996, 1007 (“The same basic framework is also
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`applicable to examination at the United States Patent & Trademark Office”) (citing
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`In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997).
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`Almirall neither asserts unexpected results or criticality of the ethoxydiglycol
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`concentration, nor does it dispute that the ethoxydiglycol concentration is a results-
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`effective variable, or that Garrett’s range is too broad to optimize. And the art does
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`not teach away.
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`Arguing without support that 25% ethoxydiglycol was somehow the magic
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`amount, Almirall asserts that a POSA would not want to “compromise” the
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`allegedly “optimized” ratio of dissolved-to-undissolved dapsone in ACZONE®
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`5%. POR, 43-44. But there is no such “dissolved-to-undissolved” limitation in the
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`claims; they require only “about 7.5% w/w dapsone.” AMN1050, ¶¶26-27.
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`In any event, Garrett informs a POSA that the ratio of dissolved-to-
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`undissolved dapsone could be adjusted and optimized, and teaches a POSA how it
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`optimize this ratio. AMN1050, ¶¶27-28; AMN1004, 3:26-27, 12:20-13:2, 14:29-
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`31, 18:17-20; In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980)
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`(“[D]iscovery of an optimum value of a result effective variable in a known
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`process is ordinarily within the skill of the art.”). Nor would the non-linear
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`solubility curve of dapsone in ethoxydiglycol have given a POSA difficulty. The
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`solubility curve, although non-linear, was known and was easily understandable to
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`a POSA. AMN1050, ¶¶27-28. Indeed, Dr. Klibanov agreed such non-linear
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`solubility curves are common. EX2003, ¶57; AMN1059, 10:34:18-10:35:1.
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`Finally, assuming Almirall’s position that a POSA sought to use the
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`“optimized” ratio of one-third dissolved to two-thirds undissolved dapsone
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`(disclosed in AMN1009, 4), it would have been even more obvious to use the
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`claimed 30% to 40% concentration of ethoxydiglycol to dissolve 2.5% w/w
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`dapsone (one third of 7.5%), as shown below.
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`
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`AMN1050, ¶28; AMN1009, 3.
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`Next, Almirall argues teaching away by alleging that increasing the
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`ethoxydiglycol concentration above 25% would exceed the highest FDA-approved
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`concentration. POR, 44-45. This is not teaching away.
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`First, Garrett explicitly teaches the use of “about 30%.” AMN1050, ¶¶29-
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`31, 34; AMN1004, 4:2-5; AMN1053, 3. Almirall ignores this.
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`Case IPR2018-00608
`Patent No. 9,161,926 B2
`Second, Almirall’s reliance on EX2020 (a European Union scientific
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`committee opinion) is misplaced. POR, 44-45. The opinion was not directed to
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`prescription pharmaceuticals; if it were, it would have similarly lead away from
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`using the 25% ethoxydiglycol concentration in the FDA-approved ACZONE Gel,
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`5%—which cannot be correct. AMN1050, ¶¶32-34; EX2020, 5, 8, 47. Regardless,
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`EX2020 teaches, and later art confirms, that commercially available
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`ethoxydiglycol in 2012 was highly pure (containing less than 0.062% ethylene
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`glycol) and was not associated with any safety concerns. AMN1050, ¶¶31-34;
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`EX2020, 5, 8, 47; AMN1053, 9. Thus, the claimed ethoxydiglycol concentration
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`was obvious.
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`3. Garrett does not teach away from excluding adapalene.
`Remarkably, Almirall tells this Board that “Garrett [does not] suggest that
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`dapsone …must be used as the sole API.” POR, 49. This is a brazen statement
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`given that Almirall told the USPTO the exact opposite—that support for this claim
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`limitation existed in Table 1 of the ’926 patent because it showed “only dapsone
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`and no adapalene is used in the formulation.” AMN1017, 315-316. But that is
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`exactly what