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 IPR2019-00207
`U.S. Patent No. 9,517,219
`___________________
`
`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
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`

`

`Case IPR2019-00207
`Patent No. 9,517,219
`
`TABLE OF CONTENTS
`
`INTRODUCTION .................................................................................................... 1 
`
`ARGUMENT ............................................................................................................ 4 
`
`I. 
`
`II. 
`
`MOST OF ALMIRALL’S ARGUMENTS WERE ADVANCED IN THE
`RELATED ’926 PATENT IPR, NONE OF WHICH THE BOARD
`ACCEPTED IN ITS DECISION. ................................................................... 4 
`
`ALMIRALL HAS NOT REBUTTED AMNEAL’S PRIMA FACIE CASE
`OF OBVIOUSNESS. ...................................................................................... 5 
`
`A.  Under Dupont and Galderma, Almirall’s lack-of-motivation
`arguments for the claimed dapsone and ethoxydiglycol
`percentages are legally irrelevant. ......................................................... 5 
`
`B. 
`
`C. 
`
`Actual artisans before 2012 selected dapsone for product
`development, confirming a POSA’s motivation. .................................. 6 
`
`Garrett does not “teach away” or negate motivation to select
`dapsone. ................................................................................................. 9 
`
`1. 
`
`2. 
`
`Garrett’s teachings are not limited to undissolved
`dapsone. ...................................................................................... 9 
`
`Garrett (and other prior art) taught that dapsone
`“treats” acne and rosacea. ........................................................ 11 
`
`D.  A POSA had reason to use 7.5% w/w dapsone. .................................. 13 
`
`E. 
`
`F. 
`
`Garrett and other art teach using topical dapsone
`compositions without adapalene. ........................................................ 15 
`
`Garrett teaches using the claimed ethoxydiglycol amounts. ............... 17 
`
`III.  A POSA HAD REASON TO USE SEPINEO WITH GARRETT’S
`DAPSONE COMPOSITIONS. .................................................................... 19 
`
`A.  Garrett is not incompatible with Nadau-Fourcade. ............................. 19 
`
`1. 
`
`Compositions containing dissolved API would not
`have dissuaded a POSA. .......................................................... 19 
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`Case IPR2019-00207
`Patent No. 9,517,219
`2. 
`Carbopol® and Sepineo® are interchangeable. ....................... 20 
`
`3. 
`
`The claimed A/SA range would have been obvious. ............... 22 
`
`B. 
`
`Garrett combined with Bonacucina renders the challenged
`claims obvious. .................................................................................... 23 
`
`1. 
`
`2. 
`
`There were multiple reasons to combine Garrett with
`Bonacucina. .............................................................................. 23 
`
`Bonacucina renders the claimed PVB amount
`obvious. .................................................................................... 24 
`
`IV.  SECONDARY CONSIDERATIONS CANNOT RESCUE THE ’219
`PATENT. ...................................................................................................... 24 
`
`1. 
`
`2. 
`
`3. 
`
`Compatibility of Sepineo® with 40% ethoxydigycol
`was not unexpected. ................................................................. 25 
`
`The smaller particle size was not unexpected. ......................... 25 
`
`No others failed. ....................................................................... 27 
`
`CONCLUSION ....................................................................................................... 28 
`
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`Case IPR2019-00207
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`
`
`TABLE OF AUTHORITIES
`
`Cases Page(s)
`
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) .......................................................................... 12
`
`Almirall LLC v. Taro Pharm. Indus. LTD.,
`C.A. No. 17-00663 (D. Del.), D.I. 87 ................................................................. 20
`
`BTG Int’l Ltd. v. Amneal Pharm. LLC,
`923 F.3d 1063 (Fed. Cir. 2019) ...................................................................... 8, 16
`
`Daiichi Sankyo Co., Ltd. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) .......................................................................... 21
`
`Duramed Pharm., Inc. v. Watson Labs., Inc.,
`413 F. App’x 289 (Fed. Cir. 2011) ..................................................................... 12
`
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) .............................................................................. 6
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .................................................................... 5, 6, 27
`
`Healthcare Inc. v. Daiichi Sankyo Co., Ltd.,
`IPR2015-00865, Paper 104, 17 (Sept. 12, 2016) ................................................ 14
`
`Interactive Pictures Corp. v. Infinite Pictures, Inc.,
`274 F.3d 1371 (Fed, Cir. 2001) .......................................................................... 22
`
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012) ............................................................................ 7
`
`Ormco Corp. v. Align Technology, Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 28
`
`SightSound Techs., LLC v. Apple Inc.,
`809 F.3d 1307 (Fed. Cir. 2015) .......................................................................... 10
`
`Süd-Chemie, Inc. v. Multisorb Techs., Inc.,
`554 F.3d 1001 (Fed. Cir. 2009) .......................................................................... 17
`
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`Case IPR2019-00207
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`Upsher-Smith Labs., Inc. v. Pamlab, LLC,
`412 F.3d 1319 (Fed. Cir. 2005) .......................................................................... 16
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012) .......................................................................... 21
`
`Wockhardt Bio AG v. Janssen Oncology, Inc.,
`IPR2016-01582, Paper 72, 22 (PTAB Jan. 17, 2018) ........................................ 14
`
`  
`
` 
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`Case IPR2019-00207
`Patent No. 9,517,219
`
`INTRODUCTION
`Almirall’s1 Response (“POR”) does not overcome the strong obviousness
`
`showing in Amneal’s Petition. Instead, Almirall advances unsupported arguments
`
`that contradict (1) statements made by Almirall’s own declarants outside this
`
`proceeding and (2) Almirall’s positions during prosecution and in related litigation
`
`over the ’219 patent. The prior inconsistent statements by Almirall and its
`
`declarants confirm the unpatentability of the ’219 patent.
`
`For example, before the 2012 priority date, Dr. Kircik himself touted the
`
`clinical benefits of commercial dapsone (Aczone 5% Gel), stating that it
`
`“represents a valuable treatment option for patients with acne vulgaris,” which
`
`undermines Almirall’s assertion that a POSA would not have viewed dapsone as
`
`effective. EX2020, 4; see also AMN1044, ¶¶21-23; AMN1048, 1; AMN1047,
`
`Abstract. Garrett, the primary reference in both of Amneal’s Grounds, parallels Dr.
`
`Kircik’s prior statements, teaching that topical dapsone compositions are effective
`
`acne treatments. See, e.g., AMN1004, 10:6-12.
`
`Next, while Dr. Osborne tells this Board that “no reasonable” POSA would
`
`have selected dapsone for development, he—and other “reasonable” artisans—
`
`selected dapsone for development of a topical product. See AMN1007, Abstract;
`
`AMN1016, Abstract; EX2053, Abstract (all by Dr. Osborne); AMN1004, Abstract;
`
`1 “Almirall” includes its predecessor-in-interest Allergan.
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`EX2001, Abstract; EX2008, Abstract. Dr. Osborne also says that “no reasonable”
`
`POSA would have used 7.5% w/w dapsone in a topical composition. POR, 43-45.
`
`But Garrett specifically teaches that 5% to 10% w/w dapsone is preferred, and Dr.
`
`Osborne before 2012 instructed the public that 7.5% dapsone was “preferred” for
`
`topical formulations. AMN1007, ¶14; AMN1040, 19:3-20:19.
`
`Dr. Osborne also argues that a POSA would not select ethoxydiglycol
`
`amounts above 25%. But Garrett teaches that “about” 30% ethoxydiglycol should
`
`be used. Dr. Osborne (and others) also selected amounts up to “about” 30%
`
`ethoxydiglycol. AMN1007, ¶15 (Dr. Osborne describing “solvation medi[a]”
`
`ranging up to 99%, 50%, 40%, 35%, and 30%), ¶¶55-56 (describing
`
`ethoxydiglycol as a “solvation medium”); AMN1004, 4:21-26; AMN1008, ¶¶30-
`
`32; EX2001, 18:4-10; EX2008, 9 (1-50%).
`
`Perhaps most egregious, Almirall argues that Carbopol® (the thickening
`
`agent in Garrett) is not interchangeable with the claimed A/SA copolymer
`
`thickening agent (i.e., Sepineo®). Remarkably, Almirall took the exact opposite
`
`position to assert infringement of the ’219 patent in a recent district court litigation,
`
`where Almirall asserted that Carbopol® was legally and functionally equivalent to
`
`Sepineo®.
`
`Finally, Almirall tells this Board that Garrett’s omission of any mention of
`
`adapalene is insufficient to meet the “no adapalene” negative limitation of the
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`claims. But Almirall argued that a similar omission provided written description
`
`support for this negative limitation during prosecution of the parent U.S. 9,161,926
`
`(“the ’926 patent”). AMN1056, 315-316.
`
`These inconsistent statements alone warrant finding unpatentability. But
`
`even setting them aside, Almirall has not offered any legal or factual arguments to
`
`overcome the clear prima facie obviousness case here on the merits, particularly
`
`regarding reasons to combine Garrett with Nadau-Fourcade or Bonacucina. For
`
`Ground 1, Garrett teaches 0.2% to 4% w/w of Carbopol® as the polymeric
`
`viscosity builder (“PVB”) and Nadau-Fourcade taught that 0.01% to 5% of
`
`Sepineo® was a “preferred” PVB that was interchangeable with Carbopol®.
`
`AMN1005, 48:5-9. For Ground 2, a POSA would have been separately motivated
`
`to replace Carbopol® in Garrett’s formulation with Sepineo® because using
`
`Carbopol® required additional hydration and neutralization steps, and also because
`
`Carbopol® yielded an unpleasant gritty texture in the commercial Aczone 5% Gel.
`
`A POSA would use Sepineo®, which Bonacucina taught was a “prime candidate”
`
`for use as a thickener in topical gel-compositions that were smooth, and did not
`
`require hydration or neutralization.
`
`Finally, there are no objective indicia that can save the ’219 patent from the
`
`strong prima facie case of obviousness. As discussed below, Almirall’s alleged
`
`unexpected results and failure of others theories fall flat, and find no legal support.
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`
`ARGUMENT
`
`Unable to escape the prior art and long-standing Federal Circuit precedent
`
`compelling obviousness, Almirall resorts to legally irrelevant and factually
`
`unpersuasive arguments aimed to distract from the only relevant inquiry: would it
`
`have been obvious use an A/SA copolymer thickener with Garrett’s dapsone
`
`compositions. As Amneal’s Petition demonstrated, the answer is yes.
`
`I. MOST OF ALMIRALL’S ARGUMENTS WERE ADVANCED IN
`THE RELATED ’926 PATENT IPR, NONE OF WHICH THE BOARD
`ACCEPTED IN ITS DECISION.
`
`IPR2018-00608 involved the ’926 patent, which issued from the same parent
`
`application as the ’219 patent. See generally Paper 10. Whereas the ’926 patent
`
`claims dapsone topical formulations, the ’219 patent claims methods of using those
`
`formulations to treat acne or rosacea. In other material respects, the claims are
`
`nearly identical, except that the PVB in the ’926 patent “consist[s] of” A/SA
`
`copolymer, while the ’219 patent’s PVB “compris[es]” A/SA copolymer. Compare
`
`AMN1001 (claims) with AMN1076 (claims). The Board, therefore, construed the
`
`’926 patent to exclude Sepineo® (which has other inert ingredients than just
`
`A/SA). The ’219 patent does not exclude Sepineo®.
`
`That claim construction advanced by Almirall—which is presently under
`
`appeal—is the sole basis that the Board upheld the claims of the ’926 patent.
`
`IPR2018-00608, Paper 50, 17-21. Beyond that, Almirall presented many of the
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`same arguments it advances here:
`
`
`
`
`
`
`
`dapsone is less effective than other treatment options;
`
`even though the claimed ranges are expressly set forth in the art, a
`
`POSA would not have considered them; and
`
`even though omission of adapalene in the specification was sufficient
`
`to support Almirall’s “no adapalene” limitation in the claims, that
`
`same omission in Garrett is somehow insufficient for obviousness.
`
`The Board did not credit any of these arguments in upholding the ’926 patent. The
`
`only reason the ’926 patent survived was the “consisting of” language, which is not
`
`at issue in the ’219 patent. This Board should again reject these same arguments,
`
`and cancel the challenged claims of the ’219 patent.
`
`II. ALMIRALL HAS NOT REBUTTED AMNEAL’S PRIMA FACIE
`CASE OF OBVIOUSNESS.
`A. Under Dupont and Galderma, Almirall’s lack-of-motivation
`arguments for the claimed dapsone and ethoxydiglycol
`percentages are legally irrelevant.
`
`Almirall’s POR ignores settled Federal Circuit law concerning obviousness
`
`of claimed points within prior art ranges. “The point of [the Federal Circuit’s]
`
`overlapping range cases is that, in the absence of evidence indicating that there is
`
`something special or critical2 about the claimed range, an overlap suffices to show
`
`
`2 Unless otherwise indicated, all emphases are added.
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`that the claimed range was disclosed in—and therefore obvious in light of—the
`
`prior art.” E.I. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006
`
`(Fed. Cir. 2018) (collecting cases).
`
`It is undisputed that the claimed amounts of dapsone and ethoxydiglycol
`
`overlap with ranges in Garrett. AMN1040, 114:17-22; 132:11-20; AMN1039,
`
`181:23-1825. Thus, these limitations are prima facie obvious. To overcome
`
`obviousness, Almirall needed—but failed—to prove: (1) a teaching away from the
`
`range, (2) unexpected results, (3) the range is not a results-effective variable, or (4)
`
`is too large to invite optimization. See DuPont, 904 F.3d at 1006; Galderma Labs.,
`
`L.P. v. Tolmar, Inc., 737 F.3d 731, 737-38 (Fed. Cir. 2013). Almirall has not
`
`provided evidence to support any of these factors, and has not rebutted Amneal’s
`
`prima facie showing of obviousness.
`
`B. Actual artisans before 2012 selected dapsone for product
`development, confirming a POSA’s motivation.
`
`Almirall argues that a POSA would not have selected dapsone because the
`
`“art was replete with more reasonable starting points.” POR, 30-33. But the law
`
`does not require that dapsone be the “most obvious” (or most “reasonable”)
`
`choice.3 The issue is whether it would have been obvious to combine known
`
`
`3 Almirall’s argument resembles a “lead compound” analysis for “structural
`
`obviousness.” Here, the issues have nothing to do with finding a new compound or
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`topical excipients, at known amounts, with dapsone, a known topically-
`
`administered treatment for acne and rosacea. Even if other starting points were
`
`available, as Almirall posits, “just because better alternatives exist in the prior art
`
`does not mean that an inferior combination is inapt for obviousness purposes.” In
`
`re Mouttet, 686 F.3d 1322, 1334 (Fed. Cir. 2012). Almirall’s POR says nothing to
`
`reconcile its flawed arguments with Mouttet or other similar cases. In any event,
`
`Garrett is a strong primary reference since it teaches both the existing 5% and
`
`higher-strength formulations.
`
`Next, selecting dapsone is not “hindsight,” as Almirall suggests, but instead
`
`explicitly instructed by the prior art. Actual artisans, including Dr. Osborne, were
`
`actively developing dapsone topical anti-acne drugs before 2012. See AMN1007,
`
`AMN1016, and EX2053 (all Dr. Osborne); AMN1008 (Morris), and AMN1004
`
`(Garrett).
`
`Garrett explains that Aczone 5% Gel 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.4 AMN1004, 4:9-15,
`
`selecting a “more reasonable” starting compound. The claims are to a formulation
`
`comprising dapsone, a compound known and used for years prior.
`
`4 Garrett also discloses that topical dapsone is effective at treating rosacea.
`
`AMN1004, 3:13-15, 3:20-26 ; AMN1034, 10; see also AMN1044, ¶¶25-27.
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`10:4-12, 29:2-27; AMN1044, ¶¶11, 13-14. Additionally, Aczone 5% Gel was FDA
`
`approved to treat acne vulgaris. AMN1007, ¶3; AMN1010, 5; AMN1018, ¶¶26,
`
`35, 38; AMN1044, ¶¶6-12, 17; EX2055, ¶50. Moreover, the art shows that topical
`
`dapsone gel is a common and effective acne treatment, regardless of being
`
`“second-line.” AMN1018, ¶¶22-29; AMN1044, ¶¶15-16, 18; AMN1008, ¶4;
`
`EX2013, 3-4; EX2016, 5; EX2017, 1; EX2024, 5; EX2040, 1 EX2041, 1-2,
`
`AMN1035, 1. Indeed, Dr. Kircik,5 published multiple articles before 2012
`
`describing dapsone as “offer[ing] documented efficacy,” and being “a worthwhile”
`
`and “valuable treatment option for patients with acne vulgaris.” EX2020, Abstract,
`
`4; EX2034, 7; AMN1044, ¶19.
`
`Contrary to Almirall’s assertion that the field was “skeptical” of dapsone,
`
`the prior art and real-world actions by its own declarants confirm that a POSA
`
`would not have been dissuaded from developing a dapsone formulation.
`
`AMN1044, ¶¶19-24; c.f. BTG Int’l Ltd. v. Amneal Pharm. LLC, 923 F.3d 1063,
`
`1076 (Fed. Cir. 2019) (“lack of enthusiasm by a few is not equivalent to skepticism
`
`5 Dr. Kircik received more than $100,000 from Allergan for, inter alia,
`
`promotional speaking engagements to inform and educate peers on the benefits of
`
`ACZONE® Gel 5%. See EX2055, ¶6; EX2056, 2, 52; AMN1039, 194:24-195:24;
`
`AMN1062-AMN1074. Dr. Kircik was the highest-paid of all Aczone-promoting
`
`physicians during that period. AMN1039, 195:25-196:21; AMN1074, 1.
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`or failure of others such that the combination would not have been obvious to a
`
`PHOSITA.”).
`
`C. Garrett does not “teach away” or negate motivation to select
`dapsone.
`1. Garrett’s teachings are not limited to undissolved dapsone.
`Almirall creates a straw man, arguing that a POSA would have avoided
`
`compositions containing undissolved dapsone because (1) it allegedly is an unusual
`
`formulation design and (2) the undissolved dapsone did not exert antimicrobial
`
`activity. POR, 33-39. Neither was a concern for a POSA. First, Almirall’s
`
`presumption is wrong that Garrett requires undissolved dapsone only, because
`
`Garrett explicitly teaches that “the dapsone may exist as a microparticulate form, a
`
`dissolved form, or both.” AMN1004, 3:12-13, 4:30-31. Moreover, the claims of the
`
`’219 patent do not require dissolved or undissolved dapsone. AMN1043, ¶¶5-9.
`
`Second, Almirall is undermined by its own expert Dr. Osborne, who stated
`
`that the ratio of dissolved to undissolved dapsone in Aczone 5% Gel was
`
`“optimized” “[d]espite a relatively high amount of dispersed dapsone.” EX2057,
`
`¶¶44, 154, 186-187; AMN1009, 4. He also identified undissolved dapsone
`
`compositions as “preferred embodiments.” AMN1016, 3:15-4:6. Additionally, a
`
`POSA would have known that Aczone 5% Gel contained undissolved dapsone
`
`before 2012. EX1043, ¶¶7-8, 18-21, 24, 58-60; AMN1010, 2; AMN1004, 4;
`
`EX2042, 4; AMN1009, 4; AMN1016, 3:52-64; AMN1075, ¶¶96, 115, 124, 159,
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`188. Despite that, FDA approved Aczone 5% Gel as stable, safe, and effective for
`
`treating acne. EX1043, ¶7; AMN1010, 1; AMN1004, 4, 10; EX2042, 4. Thus, by
`
`2012 a POSA knew that a formulation containing undissolved dapsone was viable
`
`and obvious. EX1043, ¶¶5-9; EX1042; EX1040, 98:10-99:12.
`
`Third, regarding Almirall’s asserted lack of antimicrobial effect, a POSA
`
`knew that a primary benefit of undissolved dapsone in the composition was not its
`
`direct antimicrobial activity, but rather its ability to act as a drug reservoir, slowly
`
`disbursing dapsone, as taught by Garrett. AMN1043, ¶¶20-22; AMN1004, 11-12;
`
`AMN1016, 3:52-64. Dr. Osborne agreed. AMN1016, 3:15-4:6.
`
`Finally, Almirall argues that two references—Lathrop (AMN1007) and
`
`Ahluwalia (EX2008)—“teach away” because they purportedly prefer “completely
`
`dissolved” dapsone. POR, 36. But that is not the law: “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). Nowhere in Lathrop or Ahluwalia is there any criticism,
`
`discrediting, or discouragement from having an undissolved portion in a dapsone
`
`topical composition. See AMN1007, ¶49 (teaching partial dissolution); EX2008
`
`(no mention of undissolved dapsone); AMN1043, ¶¶8, 23, 80.
`
`Finally, Almirall argues that increasing dapsone “from 5% up to 10%, while
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`maintaining the ratio of dissolved to undissolved dapsone,” would “require a
`
`decrease in other elements (i.e., water), which would affect the delivery and
`
`behavior of the formulation.” POR, 37-38. But as Dr. Michniak-Kohn explains,
`
`this would not have concerned a POSA because the amount of water is not critical
`
`to these formulations and water is used in wide ranges. AMN1043, ¶¶33-35;
`
`AMN1004, 4-6 (identifying wide water amounts); AMN1007, ¶¶ 9 (identifying
`
`water as “optional”), 18 (identifying 0-99% water); AMN1040, 112:3-113:24.
`
`Almirall has not demonstrated that the prior art as a whole “criticized,
`
`discredited, or otherwise discouraged” the use of undissolved dapsone.
`
`2. Garrett (and other prior art) taught that dapsone “treats”
`acne and rosacea.
`
`Almirall argues that Garrett (and the art generally) shows that dapsone is not
`
`effective against acne or rosacea. POR, 39-43. This is false. As an initial matter,
`
`each challenged claim recites treatment of acne or rosacea. Therefore, showing
`
`that dapsone was known to treat acne is sufficient to render those claims obvious,
`
`because there is no legal requirement to demonstrate that dapsone is independently
`
`effective to treat both conditions.
`
`In any event, the art provides ample evidence that dapsone was effective in
`
`treating both conditions. Almirall applies an overly restrictive definition of
`
`“treating” that is tantamount to FDA approval or effectiveness proven by
`
`randomized clinical trials. “There is no requirement in patent law that the [POSA]
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`be motivated to develop the claimed invention based on a rationale that forms the
`
`basis for FDA approval.” Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1291-92
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`(Fed. Cir. 2013); see also Duramed Pharm., Inc. v. Watson Labs., Inc., 413 F.
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`App’x 289, 294 (Fed. Cir. 2011) (“there is no requirement that a teaching in the
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`prior art be scientifically tested, or even guarantee success. Rather, it is sufficient
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`that [a POSA] would perceive from the prior art a reasonable likelihood of
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`success.”).
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`In the ’219 patent, “treating” means “having a positive effect on a skin
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`condition” and “needs only to reduce the severity of a skin condition [or] reduce
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`the severity of symptoms associated therewith.” AMN1001, 5:22-35; AMN1044,
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`¶13. Both the Garrett and Garrett II references contain similar definitions.
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`AMN1004, 9:33-10:2 (“‘treating’ refers to the reduction in number and/or severity
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`of symptoms”); EX2001, 8:20-23 (“‘treating’ refers to the reduction in number
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`and/or severity of rosacea lesions”); AMN1044, ¶¶13, 27, 46. Dr. Kircik and
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`Almirall erroneously interpreted “treatment” to require statistically significant
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`improvement compared to vehicle (such as FDA requires for approval).6 See, e.g.,
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`AMN1039, 152:15-156:11. But even under Almirall’s restrictive construction,
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`6 Dr. Kircik’s admitted that he did not consider the differences between the prior
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`art and the claimed invention, further undermining his testimony. AMN1039,
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`133:20-25.
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`Case IPR2019-00207
`Patent No. 9,517,219
`dapsone 5% received FDA approval. AMN1010.
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`The art shows that dapsone was known to treat both acne and rosacea.
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`Garrett taught that “the absolute reduction in lesion counts was numerically better
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`with Aczone™ treatment for all [acne] lesion categories.” AMN1004, 29:24-25;
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`see also id., 28:11-29:2; AMN1018, ¶14. Likewise, Garrett II taught that “all
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`treatment groups [including the dapsone group] experienced a mean decrease from
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`baseline in [rosacea] lesion counts.” EX2001, 35:16-23; AMN1018, ¶¶25-28.
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`Consistent with the art, each party’s dermatologist testified that they used Aczone
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`5% Gel to treat acne pre-2012, and Dr. Kircik used dapsone to treat rosacea pre-
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`2012. AMN1018, ¶31; AMN1039, 61:18-24, 150:10-152:18. Thus, a POSA would
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`have understood that dapsone could treat acne or rosacea.
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`D. A POSA had reason to use 7.5% w/w dapsone.
`Almirall argues that a POSA would have been motivated to decrease the
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`dapsone concentration below 5%. POR, 43-45. This makes no sense and
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`contradicts the clear prior art teachings. AMN1043, ¶¶10-26. Indeed, Garrett
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`shows that one preferred embodiment is a topical composition containing “about
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`5% to 10% dapsone,” and Dr. Osborne (in Lathrop) disclosed 7.5% dapsone as a
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`“preferred” amount. AMN1043, ¶26; AMN1044, ¶¶29-30; AMN1004, 4:2-5;
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`AMN1007, ¶47. And during cross examination, Dr. Osborne admitted that 7.5%
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`was preferred. AMN1040, 19:6-20:19.
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`Case IPR2019-00207
`Patent No. 9,517,219
`Almirall’s safety concerns are irrelevant. POR, 44-45. The Board recently
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`explained that concern over side-effects without more does not negate
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`obviousness: “caution is not a prohibition.” Accord Healthcare Inc. v. Daiichi
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`Sankyo Co., Ltd., IPR2015-00865, Paper 104, 17 (Sept. 12, 2016); see also
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`Wockhardt Bio AG v. Janssen Oncology, Inc., IPR2016-01582, Paper 72, 22
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`(PTAB Jan. 17, 2018) (rejecting patent owner’s argument that the risk of side
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`effects would have dissuaded a POSA). Moreover, Garrett teaches that 5% to 10%
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`dapsone compositions “do[] not induce hemolytic anemia” or “adverse
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`hematologic events.” AMN1043, ¶10; AMN1004, 4:2-5; 6:5-8; 42:25-32. Dr.
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`Osborne agrees that topical dapsone was safe. EX2057, ¶¶49-52. No other safety
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`concerns existed. AMN1043, ¶7; EX2042, 4.
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`Next, Almirall’s speculation that occasional off-label once-daily use of
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`Aczone 5% Gel somehow means that a POSA would not use a higher
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`concentration is wrong. POR, 44-45. Garrett already informed a POSA that topical
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`compositions containing 5% to 10% w/w dapsone are typically applied “once or
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`twice daily.” AMN1004, 23:8-12; AMN1044, ¶31. Knowing that Aczone 5% Gel
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`was approved for twice-daily dosing (AMN1010, 3), a POSA would have had
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`reason to increase the dapsone concentration to achieve once-daily dosing.
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`AMN1043, ¶¶19-26; AMN1018, ¶¶45-47; AMN1004, 23:8-12; AMN1044, ¶¶29-
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`32. Dr. Kircik agreed on cross-examination. AMN1039, 49:192:11-50:194:8;
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`Case IPR2019-00207
`Patent No. 9,517,219
`AMN1035, 6; AMN1044, ¶¶31-32.
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`And Garrett also taught a POSA that the amounts of dissolved and
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`undissolved dapsone in the composition could be modified to provide minimum (or
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`maximum) reservoir capacity and thereby maintain sustained drug delivery.
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`AMN1043, ¶¶20-22; AMN1004, 12:20-13:2, 22:28-23:7.
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`Further, Almirall argues that a POSA would not increase the concentration
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`of dapsone to increase efficacy because dose-ranging studies show that dapsone
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`concentration below 5% are equally effective. POR, 45. This is not teaching away.
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`Moreover, a POSA would have understood that increasing the dapsone
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`concentration would allow for more penetration and anti-acne effects. AMN1043,
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`¶23. The opportunity to optimize the dosing and increase the efficacy of dapsone
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`compositions, the POSA would have increased rather than decreased the dapsone
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`concentration. AMN1043, ¶¶19-23; AMN1044, ¶¶29-32. The POSA would not
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`have avoided 7.5% w/w dapsone.
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`E. Garrett and other art teach using topical dapsone compositions
`without adapalene.
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`Almirall tells this Board that “Garrett [does not] suggest that dapsone must
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`be used as the sole API,” because allegedly Garrett merely omits mention of
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`adapalene and does not expressly say “no adapalene.” POR, 46. But during
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`prosecution, Almirall pointed to the exact same omission in Table 1 of the
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`specification showing “only dapsone and no adapalene is used in the formulation”
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`Case IPR2019-00207
`Patent No. 9,517,219
`as support for the no adapalene limitation. AMN1056, 315-316. That is exactly
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`what Garrett (and other art) discloses. AMN1050, ¶36; AMN1004, 3:9-15, 10:6-9;
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`AMN1008, ¶[0004]; AMN1010, 3; AMN1034, ¶¶14-16; AMN1039, ¶¶33-37;
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`AMN1044, ¶¶33-37, 42; EX2013, 3; EX2016, 5; EX2019, 5; EX2020; EX2034;
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`EX2031, 3. Just as omission of adapalene is sufficient for §112 support, it is
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`sufficient for prior art purposes.
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`Almirall next alleges that Amneal “ignores the developments in the field
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`teaching away from treatments using dapsone as the sole API, without adapalene.”
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`POR, 46. Even assuming arguendo that dapsone monotherapy was disfavored by
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`some, and a second agent was typically used, that still does not demonstrate any
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`teaching away from eliminating adapalene, as claimed. BTG, 923 F.3d at 1076. In
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`fact, Morris and Ahluwalia—which Almirall cites to support its argument—
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`describe many agents: over 100 by Morris (AMN1008, ¶¶34-40), and ten second
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`agents and five specific formulations by Ahluwalia that do not include adapalene.
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`EX2008, 6:25-7:33; AMN1044, ¶¶38-39. Whether monotherapy or with a second
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`agent that is not adapalene, both types of dapsone disclosures meet the “no
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`adapalene” limitation.
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`Drs. Kircik and Harper admitted that they would use dapsone with many
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`drugs other than adapalene. AMN1039, 15:57:3-17:62:1; AMN1047, Abstract;
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`AMN1057, 24:92:15-25:97:24; see also AMN1044, ¶¶21, 37-38, 40-41; EX2038,
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`2; EX2009, 2; EX2034. Optional inclusion of adapalene, among many options,
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`establishes that adapalene may also be excluded. Upsher-Smith Labs., Inc. v.
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`Pamlab, LLC, 412 F.3d 1319, 1322 (Fed. Cir. 2005) (holding prior art taught
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`“essentially free of antioxidants” by disclosing “optional inclusion,” which would
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`disclose compositions that contain and exclude antioxidants).7
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`Moreover, multiple prior-art references teach dapsone without adapalene,
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`including Garrett’s dapsone-only compositions, Aczone 5% Gel monotherapy
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`(AMN1010, 1), and use of dapsone with other agents that are not adapalene.
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`AMN1044, ¶¶15-18, 38, 43-45; EX2040, 2; EX2034 (Dr. Kircik).
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`F. Garrett teaches using the claimed ethoxydiglycol amounts.
`Whereas the claims require “about 30% w/w to about 40% w/w” of
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`ethoxydiglycol, Almirall argues that a POSA would not have used amounts greater
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`than 25%. POR, 21, 41. Almirall’s arguments are belied by the record. AMN1043,
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`¶¶27-43.
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`A POSA would not avoid using amounts greater than 25% for fear of
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`decreasing other elements, like water, as Almirall states. POR, 38. First, the
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`challenged claims do not