Trials@uspto.gov
`Tel.: 571.272.7822
`
`
`
`
`
`
`
`
`
` Paper 58
`
` Entered: May 29. 2020
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMNEAL PHARMACEUTICALS LLC, AMNEAL
`PHARMACEUTICALS OF NEW YORK, LLC, and MYLAN
`PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`ALMIRALL, LLC,
`Patent Owner.
`____________
`
`IPR2019-002071
`Patent 9,517,219 B2
`____________
`
`Before SUSAN L. C. MITCHELL, CHRISTOPHER G. PAULRAJ,
`and RYAN H. FLAX, Administrative Patent Judges.
`
`FLAX, Administrative Patent Judge.
`
`
`JUDGMENT
`Final Written Decision
`Determining All Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`
`
`
`1 Mylan Pharmaceuticals Inc., the petitioner in IPR2019-01095, has been
`joined in this proceeding. When referring herein to “this case” or “this
`proceeding” or “this Inter Partes Review,” or variants of these, we refer to
`both IPR2019-00207 and IPR2019-01095.
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`INTRODUCTION
`I.
`Almirall, LLC (“Patent Owner”) is the owner of U.S. Patent
`9,517,219 B2 (Ex. 1001, “the ’219 patent”). Amneal Pharmaceuticals LLC,
`and Amneal Pharmaceuticals of New York, LLC (collectively, “Amneal” or
`“Petitioner”) filed a Petition requesting inter partes review of claims 1–8 of
`the ’219 patent. Paper 3 (“Pet.”). We instituted trial in this matter on May
`10, 2019. Paper 13 (“Institution Decision”). On November 27, 2019,
`IPR2019-01095 was instituted between Mylan Pharmaceuticals Inc.
`(“Mylan”) and Almirall, LLC over the ’219 patent and Mylan joined this
`proceeding. Paper 35 (“me-too” joinder). Unless otherwise stated, we
`include Mylan when referring to Petitioner herein.
`Following institution and joinder, Patent Owner filed a Response.
`Paper 20 (“PO Resp.”). Petitioner filed a Reply to Patent Owner’s Response
`and Patent Owner filed a Sur-Reply to Petitioner’s Reply. Paper 28 (“Pet.
`Reply”); Paper 37 (“PO Sur-Reply”). A hearing was conducted on February
`7, 2020, where the parties presented oral argument. Paper 55 (“Hr’g Tr.”).
`We have jurisdiction under 35 U.S.C. § 6. After considering the
`parties’ arguments and supporting evidence, we conclude that Petitioner has
`proven by a preponderance of the evidence that claims 1–8 of the ’219
`patent are unpatentable. 35 U.S.C. § 316(e) (2012).
`Petitioner and Patent Owner each separately filed Motions to Exclude
`regarding certain evidence of record. Paper 41 (“Pet. Mot. Exclude”); Paper
`43 (“PO Mot. Exclude”). We deny Patent Owner’s motion and deny-in-part
`and dismiss-in-part Petitioner’s motion.
`
`2
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`A.
`
`II. BACKGROUND
`REAL PARTIES-IN-INTEREST
`Amneal identifies the real parties-in-interest to be “Amneal
`Pharmaceuticals LLC; Amneal Pharmaceuticals of New York, LLC.”
`Pet. 64. Patent Owner identifies the real party-in-interest to be “Almirall,
`LLC (‘Almirall’)” and states that “Almirall is a wholly-owned subsidiary of
`Almirall, S.A.” Paper 5. Mylan identifies the real parties-in-interest to be
`“Mylan Pharmaceuticals Inc., DPT Laboratories, Ltd., Mylan Inc., and
`Mylan N.V.,” which “are subsidiaries of Mylan N.V.” Mylan Pharma. Inc.
`v. Almirall, LLC, IPR2019-01095, Paper 1, 68 (PTAB June 7, 2019).
`RELATED MATTERS
`B.
`Petitioner has disclosed:
`The following matters would affect, or be affected by, a
`decision in this proceeding: (1) IPR2018-00608, challenging
`claims of the related [U.S. Patent 9,161,926 (“the ’926 patent”)],
`which are directed to the same topical dapsone compositions as
`the ’219 patent; and (2) Almirall, LLC v. Taro Pharmaceutical
`Industries Ltd., C.A[.] 1-17-cv-00663 (consolidated) (D.Del.)
`. . . . Petitioners are not a party [to the district court case].
`Pet. 64–65. In IPR2018-00608, the Board determined that the challenged
`claims of the ’926 patent were not shown to be unpatentable. IPR2018-
`00608, Paper 50. Patent Owner identifies the same related matters. See
`Paper 5. In its petition, Mylan identifies these same related matters and
`added IPR2019-00207, the current proceeding, which it sought to join.
`Mylan Pharma. Inc. v Almirall, LLC, IPR2019-01095, Paper 1 at 68 (PTAB
`June 7, 2019).
`
`3
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`C.
`
`THE ’219 PATENT
`The ’219 patent issued December 13, 2016, from US Application
`14/855,805, which was filed October 16, 2015. Ex. 1001, codes (45), (21),
`(22). This application is identified as a divisional of US Application
`14/082,955, filed November 18, 2013 (now US 9,161,926 B2). Id. at code
`(62). The ’219 patent further asserts priority to provisional 61/728,403 filed
`November 20, 2012, and provisional 61/770,768 filed February 28, 2013.
`Id. at code (60). The parties each rely upon and do not dispute that the
`earliest priority date, November 20, 2012, is the applicable date for
`analyzing the patentability issues in this proceeding. See, e.g., Pet. 6, 7; PO
`Resp. 2, 3.
`The ’219 patent has eight claims, all of which are challenged and of
`which claims 1 and 6 are independent claims. Independent claim 1 is
`illustrative and is reproduced below:
`1. A method for treating a dermatological condition
`selected from the group consisting of acne vulgaris and rosacea
`comprising administering to a subject having the dermatological
`condition selected from the group consisting of acne vulgaris and
`rosacea a topical pharmaceutical composition comprising:
`about 7.5% w/w dapsone;
`about 30% w/w to about 40% w/w diethylene glycol
`monoethyl ether;
`about 2% w/w to about 6% w/w of a polymeric viscosity
`builder comprising acrylamide/sodium acryloyldimethyl taurate
`copolymer; and
`water;
`wherein the topical pharmaceutical composition does not
`comprise adapalene.
`
`4
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`Id. at 15:40–16:13. Claim 6 is very similar to claim 1. The only difference
`between claims 1 and 6 is that claim 6 more specifically claims “about 30%
`w/w diethylene glycol monoethyl ether” (“DGME”)2 and “about 4% w/w of
`the viscosity building acrylamide/sodium acryloyldimethyl taurate
`copolymer” (also identified by the commercial product name Sepineo and
`referred to in this proceeding as “A/SA”––see Hr’g Tr. 37:1–5). Id. at
`16:23–36. Claims 2–5 each depends directly from claim 1, and claims 7 and
`8 each depends directly from claim 6. Ex. 1001, 16:14–22, 16:37–40.3
`The ’219 patent’s abstract states:
`Dapsone and dapsone/adapalene compositions can be useful for
`treating a variety of dermatological conditions.
` The
`compositions of
`this disclosure
`include dapsone and/or
`adapalene
`in a polymeric viscosity builder.
` Subject
`compositions can be adjusted to optimize the dermal delivery
`profile of dapsone to effectively treat dermatological conditions
`and improve the efficiency of pharmaceutical products applied
`to the skin. Use of the polymeric viscosity builder provides
`compositions with increased concentrations of diethylene glycol
`monoethyl ether relative to compositions without the polymeric
`viscosity builder.
`Id. at Abstract. The Specification of the ’219 patent further states:
`
`
`2 DGME is also called ethoxydiglycol and is known by the commercial
`product name Transcutol. See Pet. 1; Ex. 1040, 17:23–21:20 (Dr. Osborne’s
`(Patent Owner’s expert) deposition testimony discussing his published
`patent application (Ex. 1007) and confirming that in 2006, a formulation of
`7.5% dapsone and 30% Transcutol/DGME was created).
`3 The claims that were considered in IPR2018-00608 recited a similar
`composition to that included as part of the method of treatment claims of the
`’219 patent, except that claim 1 of the ’926 patent recited about 2% w/w to
`about 6% w/w of a polymeric viscosity builder “consisting of” (instead of
`“comprising”) acrylamide/sodium acryloyldimethyl taurate copolymer. See
`IPR2018-00608, Paper 50, 4–5.
`
`5
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`Dapsone, (4,4′-diaminodiphenyl sulfone) is a medicament
`possessing several beneficial medicinal activities. Dapsone is
`typically administered as one of the medicinal agents used in the
`treatment of leprosy. Dapsone and its derivatives are also
`effective for
`treatment of bacterial
`infections, protozoal
`infections such as malaria, pneumocystis carinii, and plasmonic
`infections such as toxoplasmosis.
`Dapsone is also useful as an anti-inflammatory agent. It
`has been used to treat skin diseases characterized by the
`abnormal infiltration of neutrophils, such as Dermatitis herpetic-
`formis, linear IgA dermatosis, pustular psoriasis, pyoderma
`gangrenosum, acne vulgaris, and Sweet’s Syndrome.
`Id. at 2:12–24.
`Regarding the additional claimed components used in the claimed
`acne/rosacea-treating method, the ’219 patent states “[d]iethylene glycol
`monoethyl ether is a solubilizer for dapsone, thereby allowing compositions
`to be prepared with increased solubilized concentrations of dapsone.” Id. at
`2:48–50. The ’219 patent further states:
`[U]se of a polymeric viscosity builder minimizes the intensity of
`yellowing of the composition caused by the increased solubility
`of dapsone in diethylene glycol monoethyl ether. In addition, the
`polymeric viscosity builder influences dapsone crystallization.
`This, in turn, results in compositions with improved aesthetics
`(i.e., reduction in particle size which minimizes “gritty” feeling
`upon application).
`Id. at 2:54–61. Regarding this polymeric viscosity builder, the ’219 patent
`further states, “[i]n some embodiments, the polymeric viscosity builder is an
`acrylamide/sodium acryloyldimethyltaurate copolymer, and further includes
`isohexadecane, sorbitan oleate, water, and Polysorbate 80.” Id. at 5:47–50.
`The ’219 patent describes 62 different “embodiments” where various
`amounts of these, and other, components are provided for an acne/rosacea-
`treating composition. Id. at 6:58–12:40. The ’219 patent also describes
`
`6
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`eight different examples of formulations including these and other
`components. Id. at 12:42–15:33.
`PETITIONER’S ASSERTED GROUNDS FOR UNPATENTABILITY
`D.
`Petitioner asserts two grounds for unpatentability, each under
`35 U.S.C. § 103(a) for obviousness, as set forth below. Pet. 20–55.
`
`
`
`
`Ground 1
`Ground 2
`
`Claims
`Challenged
`1–8
`1–8
`
`35 U.S.C. §
`
`References/Basis
`
`103(a)
`103(a)
`
`Garrett,4 Nadau-Fourcade5
`Garrett, Bonacucina6
`
`
`In support of these grounds for unpatentability, Petitioner submits, inter alia,
`a Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.,7
`and a Declaration of Elaine S. Gilmore, M.D., Ph.D.8
`E. OVERVIEW OF THE PRIOR ART
`Garrett
`Garrett, entitled Topical Treatment with Dapsone in G6PD-Deficient
`Patients, is the May 14, 2009, published version of international application
`PCT/US/2007/023468, which was filed November 7, 2007. Ex. 1004, codes
`
`
`4 WO 2009/061298 Al (published May 14, 2009) (Ex. 1004, “Garrett”).
`5 WO 2010/072958 A2 (published July 1, 2010), English translation
`(Ex. 1005, “Nadau-Fourcade”).
`6 Giulia Bonacucina et al., Characterization and Stability of Emulsion Gels
`Based on Acrylamide/Sodium Acryloyldimethyl Taurate Copolymer, 10(2)
`AAPS PHARMSCITECH 368–75 (2009) (Ex. 1015, “Bonacucina”).
`7 Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Ex. 1002, “Michniak-Kohn Declaration”).
`8 Declaration of Elaine S. Gilmore, M.D., Ph.D. (Ex. 1018, “Gilmore
`Declaration”).
`
`7
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`(21), (22), (54). Garrett is prior art with respect to the claims of the ’219
`patent.
`Garrett states:
`The present invention provides a pharmaceutical carrier system
`comprising 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
`dapsone in a microparticulate state that does not readily cross the
`stratum corneum of the epidermis. The present invention also
`discloses the treatment of dermatological conditions in G6PD-
`deficient patients with the composition, while avoiding adverse
`hematologic effects.
`Id. at Abstract.
`In its Background section, Garrett states “[d]apsone is a sulfone with
`both anti-inflammatory and antimicrobial properties” that has been used in
`an oral formulation to treat a variety of disorders, including severe acne, but
`notes that oral dapsone use presents issues relating to hemolysis and
`hemolytic anemia, which causes oxidative damage to red blood cells in
`association with the dapsone hydroxylamine metabolite. Id. at 2:7–18.9
`Garrett identifies that individuals who are glucose-6-phosphate
`dehydrogenase (G6PD) enzyme deficient (G6PD-deficient) are more prone
`to such adverse reactions to dapsone, and that its invention seeks a method
`of treating dermatological conditions in patients without the adverse
`hematologic effects associated with oral dapsone administration. Id. at
`2:18–3:6.
`
`
`9 We note that, as submitted by Petitioner, Garrett (Ex. 1004) includes page
`numbering at both the top and bottoms of the pages. We use the pagination
`at the bottom of the exhibit’s pages, as has Petitioner.
`
`8
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`Furthermore, Garrett identifies that:
`Aczone™ gel, 5%,[10] a topical formulation of dapsone, was
`developed to deliver therapeutic concentrations of dapsone to the
`skin. The United States Food and Drug Administration (US
`FDA) approved Aczone™ gel, 5%, for the treatment of acne
`vulgaris, but required certain language in the package insert due
`to the US FDA’s concern that this drug carries a significant risk
`of serious hematological adverse effects, including hemolysis, in
`G6PD-deficient patients.
`The US FDA required that the Aczone™ gel, 5%, label
`state that all patients should be screened for G6PD deficiency
`prior
`to
`initiation of Aczone™
`treatment, with routine
`monitoring of complete blood counts and reticulocyte counts
`during treatment with Aczone™ in those patients identified as
`having a history of anemia and predisposition to increased
`hemolytic effect with dapsone (e.g., G6PD deficiency). While
`previous clinical studies did not demonstrate evidence of
`clinically significant anemia, an increased reticulocyte count and
`a decreased hemoglobin level were noted to be associated in a
`G6PD deficient patient treated with Aczone™ gel, 5% for acne
`vulgaris.
`Id. at 10:6–21. Garrett then noted that the results from its disclosed
`invention demonstrate “that treatment of G6PD-deficient patients with the
`Aczone gel, 5%, formulation does not result in adverse hematological
`effects.” Id. at 10:22–25. Garrett also notes that previous clinical studies
`showed that treatment with topical dapsone 5% gel (i.e., Aczone 5%) results
`in ≤ 1% systemic exposure. Id. at 12:1–4.
`
`
`10 Aczone (dapsone) Gel 5% (“Aczone 5%”) is Patent Owner’s first FDA-
`approved (in 2005) topical dapsone product for treating acne. Hr’g Tr.
`11:22–27; Ex. 2044; Ex. 2045; see also Ex. 1061 (Patent Owner’s second
`FDA-approved dapsone acne treatment is Aczone (dapsone) Gel 7.5%).
`
`9
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`Further, Garrett states:
`The present invention provides methods to treat glucose-
`6-phosphate dehydrogenase-deficient patients with dapsone. In
`one embodiment, the treatment is directed to dermatological
`conditions and the treatment is provided by a topical dapsone
`composition. The composition may include dissolved dapsone
`and microparticulate dapsone. In certain embodiments, the
`dermatological condition to be treated is inflammatory acne,
`non-inflammatory acne or rosacea.
`Id. at 3:9–15. Garrett states that “[i]n one preferred embodiment, the
`composition includes about 0.5% to 4.0% carbomer [i.e., Carbopol11]; about
`53.8% to 84.2% water; about 10% to 30% ethoxydiglycol [i.e., DGME];
`about 0.2% methylparaben; about 5% to 10% dapsone in a microparticulate
`and dissolved state; and about 0.1% to 2% sodium hydroxide solution.” Id.
`at 4:2–5, 15:3–14. Of note, neither this preferred embodiment nor any other
`formulation of Garrett is disclosed as including the pharmaceutical
`adapalene. See generally id. Garrett states that “[i]n each of these
`embodiments, the dapsone may exist as a microparticulate form, a dissolved
`form, or both.” Id. at 4:29–31.
`Further, Garret states that such compositions are used by
`applying topically a dermatological gel composition that
`includes a semisolid aqueous gel; dapsone dissolved in the gel,
`wherein the dapsone has the capacity to cross the stratum
`corneum
`layer of
`the epidermis and become available
`systemically; and a microparticulate dapsone dispersed in the
`gel, wherein the microparticulate dapsone does not cross the
`stratum corneum of the epidermis in its microparticulate state.
`
`
`11 Garrett identifies that the product Carbopol “is one of numerous cross-
`linked acrylic acid polymers that are given the general adopted name
`carbomer.” Ex. 1004, 13:17–18; see also Ex. 1005, 47:15–17 (Carbopol is a
`carbomer gelling agent).
`
`10
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`The dermatological condition can include inflammatory acne,
`non-inflammatory acne and/or rosacea.
`Id. at 4:18–24.12 Garrett states that, “[t]ypically, for most persons affected
`with acne, application [of its dapsone compositions] once or twice during a
`day is sufficient” for treatment. Id. at 23:8–12.
`Garrett’s formulations include a thickening agent. Garrett discloses
`
`that:
`
`Thickening agents include polymer thickeners. Polymer
`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.
`Preferably, the hydrophilic or hydroalcoholic gelling agent
`comprises “CARBOPOL®” (B. F. Goodrich, Cleveland, Ohio),
`“HYPAN®”
`(Kingston Technologies, Dayton, N.J.),
`“NATROSOL®” (Aqualon, Wilmington, Del.), “KLUCEL®”
`(Aqualon, Wilmington, Del.), or “STABILEZE®”
`(ISP
`Technologies, Wayne, N.J.). Preferably, the gelling agent
`comprises between about 0.2% to about 4% by weight of the
`composition. More particularly, the preferred compositional
`weight percent range for “CARBOPOL®” is between about
`0.5% to about 2%, while the preferred weight percent range for
`“NATROSOL®” and “KLUCEL®” is between about 0.5% to
`about 4%. The preferred compositional weight percent range for
`
`12 Garrett does not assert that topical dapsone formulations for treating acne
`were new as of its disclosure, and it identifies and incorporates by reference
`in its entirety, inter alia, U.S. Patent 5,863,560 to Osborne (Ex. 1016,
`“Osborne ’560”). Ex. 1004, 11:28–33. David W. Osborne, the named
`inventor of Osborne ’560, is Patent Owner’s expert witnesses in this
`proceeding (see Ex. 2057; Hr’g Tr. 9:15–16) and Osborne ’560, similar to
`Garrett, discloses a topical pharmaceutical for treating acne containing
`0.5–10% by weight dapsone in dissolved and microparticulate states, and
`also containing polymer thickeners (gelling agents) such as the carbomer
`product CARBOPOL, methylparaben, DGME, and water. Ex. 1016,
`Abstract, 4:7–6:6. Furthermore, like Garrett, no embodiment disclosed in
`Osborne ’560 contains adapalene. See generally id.
`
`11
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`both “HYPAN®” and “STABILEZE®” is between about 0.5%
`to about 4%.
`Id. at 13:3–16.
`Garrett indicates that its composition’s dapsone and DGME allow for
`an optimized ratio of microparticulate drug to dissolved drug, which
`determines the amount of drug delivered as compared to the amount of drug
`retained in the formulation. Id. at 14:29–32. Garrett further states that:
`The relative percentages for each of the reagents used in
`the present invention may vary depending upon the desired
`strength of the target formulation, gel viscosity, and the desired
`ratio of microparticulate to dissolved dapsone. Unless otherwise
`designated, all reagents listed [in Garrett] are commonly known
`by one of ordinary skill in the art and are commercially available
`from pharmaceutical or cosmetic excipient suppliers.
`Id. at 18:17–22; see also id. at 23:4–7 (the carrier system can be adjusted to
`optimize the delivery profile of the pharmacology of the active drug and the
`nature of the disease state).
`Garrett includes the following claim:
`5. The method of claim 4,[13] comprising:
`about 0.5% to 4.0% carbomer;
`about 53.8% to 84.2% water;
`about 10% to 30% ethoxydiglycol;
`about 0.2% methylparaben;
`
`
`13 Garrett’s independent claim 4, from which the quoted claim 5 depends, is
`directed to “[a] method to treat a dermatological condition in a glucose-6-
`phosphate dehydrogenase-deficient patient comprising applying topically a
`dermatological gel composition including microparticulate pharmaceutical
`and dissolved pharmaceutical.” Ex. 1004, 42:15–18. Garrett’s claim 8
`recites that the dermatological condition of claim 4 can be inflammatory or
`non-inflammatory acne or rosacea. Id. at 43:12–14.
`
`12
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`about 5% to 10% dapsone in a microparticulate and dissolved
`state;
`and about 0.1 to 2% sodium hydroxide solution.
`Id. at 42:26–33.
`Nadau-Fourcade
`Nadau-Fourcade is the July 1, 2020, published version of international
`application PCT/FR2009/052634, which was filed December 21, 2009, and
`asserts priority to US provisional 61/193,793, filed December 23, 2008.
`Ex. 1005, codes (43), (21), (22), (30). Nadau-Fourcade is prior art to the
`claims of the ’219 patent.
`Nadau-Fourcade states that that its
`invention relates to a topical pharmaceutical composition
`containing, as an active pharmaceutical ingredient, a water-
`sensitive compound[14] in a dissolved form in a physiologically
`acceptable medium, to a method for preparing same, and to the
`use thereof in dermatology.
`Id. at Abstract; see also id. at 40:21, 51:1–12 (a disclosed dermatological use
`is “for treating acne” and for treating “acne rosacea”).15
`
`
`14 Patent Owner identified dapsone as such a water-sensitive active
`ingredient. Hr’g Tr. 50:7–12; see also Ex. 2057 ¶ 160 (Osborne
`Declaration: “[W]hile dapsone is not mentioned in Nadau-Fourcade, a
`POSA would have recognized this compound to be ‘water-sensitive.’”
`(citing Ex. 1009, 3 (“Dapsone has negligible water solubility . . . .”))).
`15 Nadau-Fourcade was published in French; however, Exhibit 1005 includes
`both the French version and an English translation of the publication; the
`English translation begins at page 37 of the exhibit. Page numbering is
`provided at the bottom of each page of Exhibit 1005, which is how we cite
`to the reference herein. See Ex. 1006 (certification of Nadau-Fourcade’s
`translation from French to English).
`
`13
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`Nadau-Fourcade states:
`Many active ingredients are difficult to use because they do not
`dissolve
`easily
`in
`the
`commonly-used
`cosmetic or
`pharmaceutical solvents, particularly water, and/or they are
`sensitive to an aqueous, oxidizing environment. This water
`sensitivity may lead to chemical instability of the active
`ingredient and/or to crystallization of the initially-dissolved
`active ingredient. This water sensitivity thus limits their
`formulation in topically-applied cosmetic or dermatological
`compositions.
`Id. at 38:11–17. Nadau-Fourcade discloses that, to achieve a physically and
`chemically stable composition with a water-sensitive active ingredient, such
`a composition incudes:
`- at least one water-sensitive active ingredient,
`- a fatty phase containing at least one lipophilic phase that is a
`solvent for the active ingredient,
`- at least one polyol,
`- at least 5% water,
`characterized in that it is topical and that it includes at least one
`surfactant from the sucroester or polyglycerol ester family.
`Id. at 41:5–11; see also id. at 49:5–50:35 (describing topical composition of
`oil-in-water emulsion type preferably containing a gelling agent). In
`addition to these components, Nadau-Fourcade also teaches that “[i]n one
`particularly preferred embodiment, the composition according to the
`invention also contains one or more hydrophilic-phase gelling agents.” Id. at
`47:11–12.
`Nadau-Fourcade discloses several types and examples of gelling
`agents, as well as a range of preferred concentrations (overlapping with
`Garrett’s disclosure) that are suitable for its composition. Id. at 47:12–48:9.
`Nadau-Fourcade states that “[p]referred gelling agents include carbomers,
`
`14
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`for instance Carbopol 980® or 981®, polyacrylamides, for instance Sepineo
`P 600® or Simulgel 600 PHA®, and polysaccharides, for instance xanthan
`gum” and that “[t]he gelling agent as described above may be used . . . more
`preferentially ranging from 0.01% to 5%.” Id. at 48:5–9.
`Nadau-Fourcade discloses several examples of water-sensitive active
`composition formulations including gelling agents. Two such examples,
`Examples 6 and 13, utilize similar components (e.g., sucrose laurate, sucrose
`palmitate, demineralized water, glycerol, calcitriol, BHT, caprylic/capric
`triglycerides, mineral oil, methyl paraben), but different gelling agents. For
`comparison, we reproduce Nadau-Fourcade’s tables of components for these
`two examples below:
`
`
`
`Id. at 57, 62; see Hr’g Tr. 64:10–15 (Patent Owner directing the panel to
`compare these examples at oral argument); see also Ex. 1002 ¶ 61
`(Dr. Michniak-Kohn addressing Examples 5, 8, and 9). In the two examples
`above, one formulation includes 0.10 % carbomer and the other formulation
`
`15
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`uses 0.20 % Simulgel 600 (A/SA).16 See Hr’g Tr. 72:1–23 (when asked
`about these two examples from the reference and the similar amounts of
`gelling agents, Patent Owner stated that “[n]umerically it’s not” a huge
`difference and that in “evaluating[] [the examples,] does that difference
`matter for the function of stabilizing dapsone . . . I don’t think so.”).
`Bonacucina
`Bonacucina is an article discussing research about Sepineo P 600,
`published April 2, 2009. Ex. 1015, 368.17 Bonacucina is prior art with
`respect to the claims of the ’219 patent.
`Bonacucina states, “[i]n this work, the self-gelling properties of the
`acrylamide/sodium acryloyldimethyl taurate copolymer (Sepineo P 600),
`both alone and as dispersing phase for the preparation of o/w emulsion gels,
`have been investigated by oscillatory rheological measurements and acoustic
`spectroscopy.” Id. at 368–69.
`Bonacucina states that:
`Sepineo P 600, a concentrated dispersion of acrylamide/sodium
`acryloyldimethyl taurate copolymer in isohexadecane, has self-
`gelling and thickening properties and the ability to emulsify oily
`phases, which make it easy to use in the formulation of gels and
`o/w emulsion gels. In this paper, gels were prepared using a
`Sepineo P 600 concentration between the 0.5% and 5% (w/w).
`Id. at 368 (Abstract). Bonacucina further states that “the gel structure is
`characterized by weak polymer–polymer interactions, an advantageous
`characteristic for topical administration, as the sample is thus easier to rub
`
`
`16 Simulgel 600 is an A/SA gelling agent, which we understand is also
`referred to as Sepineo P 600. See Hr’g Tr. 65:17–66:2 (Patent Owner stating
`that Simulgel and Sepineo are the same).
`17 We use Bonacucina’s page numbering, original to the publication, herein.
`
`16
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`into the skin.” Id. Bonacucina’s Abstract concludes: “Sepineo P 600 gel
`and emulsion gel are very effective systems for use in topical and other types
`of applications.” Id.
`Bonacucina disclosed that it combined Sepineo gels with “Sepicide
`HB, an anti-microbial agent composed of a mixture of phenoxyethanol,
`methylparaben, ethylparaben, propylparaben, and butylparaben,” and also
`“almond oil . . . because it is widely used in pharmaceutical and cosmetic
`applications for its practically inexistent toxicity and its high tolerability.”
`Id. at 369.
`Bonacucina concludes “that Sepineo P 600 thickens and gels well, a
`property that depends strongly on polymer concentration. Concentration
`increases from 0.5% (w/w) to 5% (w/w) modified the viscoelastic properties
`of the Sepineo samples, changing the typical behavior of a concentrated non-
`entangled solution to that of a ‘gel-like’ sample.” Id. at 374. Bonacucina
`further concludes “Sepineo P 600 is a prime candidate for use in the
`formulation of gels and emulsion gels with rheological properties suitable
`for topical administration.” Id.
`III. DISCUSSION
`A. ORDINARY LEVEL OF SKILL IN THE ART
`Petitioner asserts that
`A POSA [(person of ordinary skill in the art)] relevant to
`the ’219 patent would have the knowledge of both a 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
`
`17
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`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).
`Pet. 6–7. Petitioner’s experts, Dr. Michniak-Kohn and Dr. Gilmore, echo
`these definitions in their declarations. Ex. 1002 ¶¶ 17–18; Ex. 1018 ¶ 20.
`Petitioner’s expert, Dr. Michniak-Kohn, adds:
`[T]he person of ordinary skill would have knowledge and skill
`relating to the use, function, and formulation of pharmaceutical
`actives and excipients; knowledge and training regarding the
`equipment, processes and techniques used to analyze and test
`formulation materials; and an understanding of pharmacokinetic
`principles and how they relate to drug development and use.
`Ex. 1002 ¶ 18.
`Patent Owner does not directly contest this combination, team-
`oriented definition of the relevant “skilled artisans,” but states:
`Patent [O]wner agrees with the examiner of what issued as the
`ʼ219 patent, that “the level of skill in the art is high and is at least
`that of a medical doctor with several years of experience in the
`art.” Ex. 1017 at 54; Ex. 2055 ¶ 20.
`To the extent that a skilled physician would have sought
`assistance, they would likely have consulted a skilled drug
`formulator. See Ex. 2055 ¶ [sic][.] The ordinary level of skill of
`that such formulator would possess (i) a bachelor- or master-
`level degree in chemistry, polymer science, pharmaceutics, or a
`related discipline, plus at least three years of experience in drug
`delivery, pharmaceutical formulations, or a related field; or (ii) a
`doctoral degree in chemistry, polymer science, pharmaceutics, or
`
`18
`
`

`

`IPR2019-00207
`Patent 9,517,219 B2
`
`
`a related discipline, plus some experience in drug delivery,
`pharmaceutical formulations, or a related field. Ex. 2057 ¶ 86.
`PO Resp. 27.
`We see very little difference between Petitioner’s and Patent Owner’s
`proposed definitions of the skilled artisan. Neither party argues that the
`other side’s definition is incorrect. See, e.g., Hr’g Tr. 5:10–16. Neither
`party asserts that selecting their definition over the other side’s definition is
`determinative of any issues in this matter. See generally Pet.; PO Resp.
`Each definition proposes a collaboration between a formulator and a
`clinician/medical doctor, each having either a very advanced degree or a
`le