Trials@uspto.gov
`571-272-7822
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`Paper 11
` Entered: August 21, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`CIPLA LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-00807
`Patent 8,168,620 B2
`____________
`
`
`
`Before BRIAN P. MURPHY, ZHENYU YANG, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`
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`571-272-7822
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`
`Paper 11
` Entered: August 21, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`CIPLA LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-00807
`Patent 8,168,620 B2
`____________
`
`
`
`Before BRIAN P. MURPHY, ZHENYU YANG, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`INTRODUCTION
`I.
`Argentum Pharmaceuticals LLC (“Petitioner”) filed a Petition for an
`inter partes review of claims 1, 4–6, 24–26, 29, and 42–44 of U.S. Patent
`No. 8,168,620 B2 (“the ’620 patent,” Ex. 1001). Paper 2 (“Pet.”). Cipla
`Ltd. (“Patent Owner”) timely filed a Preliminary Response. Paper 7
`(“Prelim. Resp.”).
`Institution of an inter partes review is authorized by statute when “the
`information presented in the petition . . . and any response . . . shows that
`there is a reasonable likelihood that the petitioner would prevail with respect
`to at least 1 of the claims challenged in the petition.” 35 U.S.C. § 314(a);
`see also 37 C.F.R. §§ 42.4, 42.108.
`For the reasons provided below, we determine that Petitioner has
`satisfied the threshold requirement set forth in 35 U.S.C. § 314(a) as to
`claims 1, 4–6, 24–26, 29, and 42–44 of the ’620 patent, and we institute an
`inter partes review of those claims.
`A. Related Proceedings
`The parties identify the following district court actions as related
`matters under 37 C.F.R. § 42.8(b)(2): Meda Pharms. Inc. v. Apotex Inc.,
`14-cv-01453 (D. Del.); Meda Pharms. Inc. v. Teva Pharms., 15-cv-00785
`(D. Del.); Meda Pharms. Inc. v. Perrigo UK Finco Ltd., 16-cv-00794
`(D. Del.). Pet. 1; Paper 9, 1. Patent Owner also identifies U.S. Patent
`Application Nos. 15/070,839 and 13/284,836 as claiming or potentially
`claiming priority to the ’620 patent. Paper 4, 1; Paper 9, 1.
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`B. Real Parties-in-Interest
`Petitioner identifies Argentum Pharmaceuticals LLC, Intelligent
`Pharma Research LLC, APS GP LLC, APS GP Investors LLC, and KVK-
`TECH, Inc. as real parties-in-interest under 37 C.F.R. § 42.8(b)(1). Pet. 1.
`Patent Owner identifies Cipla Limited, Meda Pharmaceuticals Inc., Meda
`AB, Mylan N.V., Mylan Inc., Mylan Pharmaceuticals, Inc., and Mylan
`Specialty L.P. as real parties-in-interest under 37 C.F.R. § 42.8(b)(1). Paper
`9, 1.
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`C. The ’620 Patent
`The ’620 patent discloses and claims pharmaceutical compositions
`comprising azelastine (or its pharmaceutically acceptable salt) and
`fluticasone (or its pharmaceutically acceptable ester) in a dosage form
`suitable for nasal administration. See generally Ex. 1001. The ’620 patent
`teaches that azelastine is an antihistamine useful for treating allergy-related
`conditions. “Thus, for example, it is known to use the antihistamine
`azelastine (usually as the hydrochloride salt) as a nasal spray against
`seasonal or perennial allergic rhinitis . . . .” Id. at 1:21–24. The ’620 patent
`also teaches that it was known in the art to treat allergic rhinitis with
`corticosteroids, “which will suppress nasal and ocular inflammatory
`conditions.” Id. at 1:26–28. The ’620 patent lists fluticasone as a
`corticosteroid “known for nasal use.” Id. at 1:28–30.
`“It would be highly desirable, however,” the ’620 patent continues,
`“to provide a treatment that combines the effects of anti-histamine
`treatments and steroid treatments, in a pharmaceutically acceptable
`formulation.” Id. at 1:34–36. The ’620 patent teaches that these
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`formulations should be “tolerated in situ, without significantly disrupting the
`potency of the constituent pharmaceuticals.” Id. at 1:37–38. The ’620
`patent then states that the inventors “found that, very surprisingly, azelastine
`. . . can advantageously be combined with a steroid . . . to provide a stable,
`very effective combination product or formulation” for nasal treatment. Id.
`at 1:39–48. The combination of azelastine and a steroid such as fluticasone,
`the ’620 patent explains, “can provide, in a single administration or dosing
`regime, the antihistaminic properties of azelastine and the anti-inflammatory
`(and/or other) properties of the steroid, without any significant interference
`between the two, or adverse reaction in situ.” Id. at 1:48–53.
`The ’620 patent teaches that the disclosed pharmaceutical
`compositions are preferably in the form of nasal drops, eye drops, nasal
`sprays, nasal inhalation solutions, aerosols, or insufflation powders. Id. at
`2:14–16. Of these, the ’620 patent states that a nasal spray is a particularly
`preferred form. Id. at 2:23–25. The ’620 patent also teaches that the
`formulations may contain pharmaceutically acceptable excipients, such as
`preservatives, stabilizers, auxiliary substances, isotonization agents,
`thickening agents, and buffers. Id. at 2:31–4:3.
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`D. Challenged Claims
`Petitioner challenges claims 1, 4–6, 24–26, 29, and 42–44 of the ’620
`patent. Pet. 2. Claims 1 and 25 are independent and illustrative of the
`claimed subject matter:
`A pharmaceutical formulation comprising:
`1.
`azelastine, or a pharmaceutically acceptable salt thereof,
`and
`a pharmaceutically acceptable ester of fluticasone,
`wherein said pharmaceutical formulation is in a dosage form suitable
`for nasal administration.
`
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`25. A nasal spray formulation comprising (i) azelastine, or a
`pharmaceutically acceptable salt thereof, (ii) a pharmaceutically
`acceptable ester of fluticasone, and (iii) a pharmaceutically acceptable
`carrier or excipient therefor.
`
`Ex. 1001, 11:46–51, 13:24–27.
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`E. The Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1, 4–6, 24–26, 29, and
`42–44 of the ’620 patent on the following grounds:
`Reference(s)
`Claims
`Basis
`1 and 25 Anticipation under 35 U.S.C. § 102(b) Segal1
`1, 4–6,
`Obviousness under 35 U.S.C. § 103
`Hettche,2 Phillipps,3
`24–26,
`and Segal
`and 29
`42–44
`
`Obviousness under 35 U.S.C. § 103
`
`Hettche, Phillipps,
`Segal, and Flonase
`Label4
`
`Pet. 2. Petitioner also relies on the Declarations of Robert P. Schleimer,
`Ph.D. (Ex. 1003), and of Maureen D. Donovan, Ph.D. (Ex. 1004). Patent
`Owner disputes Petitioner’s asserted grounds. See generally Prelim. Resp.
`Patent Owner relies on the Declarations of Warner Carr, M.D. (Ex. 2001),
`Alexander Dominic D’Addio, Ph.D. (Ex. 2003), John C. Jarosz (Ex. 2005),
`and Hugh David Charles Smyth, Ph.D. (Ex. 2007).
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`1 Catherine A. Segal, Int’l Publication No. WO 98/48839 (Nov. 5,
`1998) (“Segal”). Ex. 1012.
`2 Helmut Hettche, U.S. Patent No. 5,164,194 (Nov. 17, 1992)
`(“Hettche”). Ex. 1007.
`3 Gordon H. Phillipps, et al., U.S. Patent No. 4,335,121 (Jun. 15,
`1982) (“Phillipps”). Ex. 1009.
`4 FLONASE® (fluticasone propionate) Nasal Spray, 50 mcg Product
`Information (Dec. 1998) (“Flonase Label”). Ex. 1010.
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`II. ANALYSIS
`A. Broadest Reasonable Interpretation
`At this stage of the proceeding, and based on the record before us, we
`determine that no claim terms require express interpretation for purposes of
`this Decision. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`795, 803 (Fed. Cir. 1999) (only those claim terms that are in controversy
`need to be construed, and only to the extent necessary to resolve the
`controversy).
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`B. Priority Date of the ’620 Patent
`Before turning to the asserted grounds of unpatentability, we briefly
`dispose of Petitioner’s argument that the ’620 patent is not entitled to
`priority to foreign application GB 0213739.6 (“the GB application”). See
`Pet. 8–10 (citing Ex. 1006). Although Petitioner correctly notes that we do
`not presume the ’620 patent is entitled to the priority date of the GB
`application, Pet. 9, we find Petitioner’s priority challenge legally irrelevant
`to this proceeding.
`The ’620 patent claims priority pursuant to 35 U.S.C. § 119 to the GB
`application, which was filed on June 14, 2002. See Ex. 1001, [30].
`Petitioner argues that the ’620 patent is not entitled to that 2002 priority date
`because the GB application fails to provide adequate written description for
`a “pharmaceutically acceptable ester of fluticasone,” as recited in, e.g., claim
`1 of the ’620 patent. Pet. 9–10.
`We find it unnecessary to determine whether the ’620 patent is
`entitled to the foreign priority date of the GB application, because every
`reference Petitioner relies upon to allege unpatentability in the Petition—
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`Segal, Hettche, Phillipps, and the Flonase Label—has an undisputed
`publication date well before June 14, 2002. Pet. 8; see also Exs. 1007, 1009,
`1010,5 1012. Thus, regardless of whether the ’620 patent is entitled to the
`2002 foreign-priority date, Segal, Hettche, Phillipps, and the Flonase Label
`all qualify as prior art under 35 U.S.C. § 102(b) (pre-AIA). Pet. 8. Finally,
`because the priority date of the ’620 patent is not relevant to the grounds
`instituted herein, we do not consider this issue “preserved” for trial, as
`Petitioner contends. See Pet. 8.
`C. Alleged Anticipation by Segal
`Petitioner contends that claims 1 and 25 are unpatentable as
`anticipated by Segal. Pet. 2. Relying on Dr. Schleimer’s and Dr. Donovan’s
`Declarations, Petitioner asserts that Segal teaches each and every limitation
`of claims 1 and 25. See Pet. 16–21 (citing Ex. 1003; Ex. 1004).
`Patent Owner argues that we should invoke our discretion under
`35 U.S.C. § 325(d) and deny the anticipation challenge over Segal, because
`Petitioner presents “the same arguments on substantially the same prior art”
`raised during prosecution. Prelim. Resp. 12–15. We decline to exercise our
`discretion under § 325(d). But we find that, on the merits, Petitioner fails to
`show a reasonable likelihood that it would prevail in its anticipation
`challenge to claims 1 and 25 by Segal.
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`5 Page 9 of the Flonase Label is marked “December 1998.” Patent
`Owner does not dispute that the Flonase Label constitutes prior art under
`§ 102(b). See, e.g., Prelim. Resp. 42.
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`1. Overview of Segal
`Segal, titled “Topical Nasal Antiinflammatory Compositions,”
`“provides topically applicable nasal compositions comprising a
`therapeutically effective amount of an antiinflammatory agent and a
`therapeutically effective amount of at least one agent selected from the
`group consisting of a vasoconstrictor, a neuramidinase [sic] inhibitor, a
`leukotriene inhibitor, an antihistamine, an antiallergic agent, an
`anticholinergic agent, an anesthetic and a mucolytic agent.” Ex. 1012
`(Abstract). Segal teaches that the disclosed compositions are “useful as
`nasal sprays and nose drops for the treatment of nasal and sinus conditions,”
`such as allergic rhinitis and the common cold. Id.; see also id. at 2:20–21.
`Segal states that the anti-inflammatory agent is a corticosteroid that is
`known in the art to suppress inflammation. Id. at 2:22–23. Segal lists
`beclomethasone diproprionate [sic], budesonide, dexamethasone,
`mometasone furoate, fluticasone proprionate [sic], and triamcinolone
`acetonide as preferred anti-inflammatory agents. Id. at 2:23–26. As the “at
`least one additional therapeutic agent,” Segal lists eight preferred classes of
`compounds and examples of each: (1) vasoconstrictors (oxymetazoline,
`naphazoline, xylometazoline, and phenylephrine); (2) leukotriene inhibitors
`(zafirlukast, pranlukast, and zileuton); (3) neuramidinase [sic] inhibitor
`(zanamivir); (4) antihistamines (diphenhydramine, chlorpheniramine,
`cetirizine, terfenadine, fenofexadine, astemizole, norastemizole, azelastine,
`and azatidine); (5) antiallergic agents (cromolyn sodium, nedocromil, and
`levocabastine); (6) an anticholinergic agent (ipratropium bromide); (7) local
`topical anesthetics (dyclonine, pramoxine, and benzocaine); and (8)
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`mucolytic agents (acetylcysteine, guaifenisin [sic], and mucocysteine). Id. at
`3:3–25. Segal states that the use of the additional therapeutic agent with a
`corticosteroid “provides additive and synergistic effects in the treatment of
`nasal and sinus conditions.” Id. at 3:9–12.
`Segal teaches that the disclosed compositions “are formulated as
`aqueous solutions comprising an antiinflammatory agent and at least one
`additional therapeutic agent and further comprising a pharmaceutically
`acceptable nasal carrier.” Id. at 3:29–31. Segal states that nose drops and
`nasal sprays containing a water-buffered aqueous solution as a carrier are
`preferred formulations. Id. at 4:4–5. Segal also teaches that the
`formulations may contain pharmaceutically acceptable preservatives,
`stabilizers, flavoring agents, and pH adjusters, or may be preservative free.
`Id. at 4:12–19.
`
`2. Analysis
`Petitioner contends that Segal anticipates claims 1 and 25 of the ’620
`patent. Pet. 16–21. As to claim 1, Petitioner states that Segal “discloses a
`nasal formulation having both a topical anti-inflammatory and an
`antihistamine,” id. at 17 (citing Ex. 1012, 2:10–15, 5 (claim 1); Ex. 1003
`¶ 32), with “fluticasone propionate as a preferred embodiment of the topical
`anti-inflammatory agent, along with azelastine as a suitable antihistamine,”
`id. (citing Ex. 1012, 2:23–26, 3:19-20, 5 (claims 1, 2, 4); Ex. 1003 ¶¶ 33–34,
`37–38). As to claim 25, Petitioner states that Segal “teach[es] a formulation
`containing a ‘water buffered aqueous solution as a carrier,’ which is a
`pharmaceutically acceptable carrier or excipient.” Id. (citing Ex. 1012,
`4:4–5; Ex. 1004 [sic, 1003] ¶ 39).
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`A claim is anticipated and therefore unpatentable under 35 U.S.C.
`§ 102, if all its limitations are disclosed either explicitly or inherently in a
`single prior art reference. In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir.
`1997). That single prior art reference must disclose all of the limitations of
`the claim “arranged or combined in the same way as in the claim.” Net
`MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1370 (Fed. Cir. 2008).
`Moreover, “[a]n anticipating reference must be enabling; that is, the
`description must be such that a person of ordinary skill in the field of the
`invention can practice the subject matter based on the reference, without
`undue experimentation.” Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075,
`1082 (Fed. Cir. 2008).
`Having reviewed the record, we determine that Petitioner has not
`shown a reasonable likelihood of prevailing in its assertion that claims 1 and
`25 of the ’620 patent are anticipated by Segal. Specifically, we find that
`Petitioner has not shown sufficiently that an ordinarily skilled artisan would
`immediately envision from Segal’s disclosure the combination of fluticasone
`and azelastine as recited in claims 1 and 25 of the ’620 patent. When the
`allegedly anticipatory disclosure is found in separate lists, as here, “[t]he
`question for purposes of anticipation is . . . whether the number of categories
`and components in [the single prior-art reference is] so large that the
`combination of [one item from each list] would not be immediately apparent
`to one of ordinary skill in the art.” Wm. Wrigley Jr. Co. v. Cadbury Adams
`USA LLC, 683 F.3d 1356, 1361 (Fed. Cir. 2012).
`As the anti-inflammatory agent, Segal lists six preferred
`corticosteroids: beclomethasone dipropionate, budesonide, dexamethasone,
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`mometasone furoate, fluticasone propionate, and triamcinolone acetonide.
`Id. at 2:23–26, 5 (claim 2). Thus, fluticasone propionate, a pharmaceutically
`acceptable ester of fluticasone, is one of six possibilities for the anti-
`inflammatory agent. Id. As the “at least one additional therapeutic agent,”
`Segal lists eight preferred classes of compounds: a vasoconstrictor, a
`neuraminidase inhibitor, a leukotriene inhibitor, an antihistamine, an
`antiallergic agent, an anticholinergic agent, an anesthetic, and a mucolytic
`agent. Id. at 3:3–9, 5 (claim 1). And for each class of compounds, Segal
`lists 1 to 9 preferred examples: four vasoconstrictors, three leukotriene
`inhibitors, one neuraminidase inhibitor, nine antihistamines, three
`antiallergic agents, one anticholinergic agent, three anesthetics, and three
`mucolytic agents. Id. at 3:13–25, 5–6 (claims 2–10); see also Ex. 2001
`¶ 80.6 Thus, Segal lists 27 preferred therapeutic agents. Ex. 2001 ¶ 80. For
`antihistamines in particular, Segal lists: diphenhydramine, chlorpheniramine,
`cetirizine, terfenadine, fenofexadine, astemizole, norastemizole, azelastine,
`and azatidine. Id. at 3:19–20, 5 (claim 4).
`As to the number of categories and components disclosed in Segal,
`Petitioner argues that “Segal discloses at most 54 discrete compositions, of
`which the combination of fluticasone proprionate [sic] and azelastine is
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`6 Some compounds in Segal’s lists are not properly separated by
`commas. For example, in the listing of suitable vasoconstrictors, Segal lacks
`a comma between “oxymetazoline” and “naphazoline,” which implies that
`“oxymetazoline naphazoline” is a single compound. We credit Dr. Carr’s
`undisputed testimony that “oxymetazoline” and “naphazoline” are, in fact,
`two separate compounds. See Ex. 2001 ¶ 80. Our understanding is also
`supported by claim 3 of Segal, where “oxymetazoline” and “naphazoline”
`are separated by a comma. Ex. 1012, 5 (claim 4).
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`one.” Pet. 19. Petitioner arrives at this number by “taking claims 1, 2 and 4
`together.” Id. Specifically, Petitioner asserts that claim 1 of Segal limits the
`pharmaceutical composition to a topical anti-inflammatory agent and “one of
`seven types of therapeutic agents, of which an antihistamine is one.” Id. at
`18. Petitioner further asserts that claim 2 “limits the anti-inflammatory
`agent to six compounds, of which fluticasone proprionate [sic] is one” and
`that “claim 4 limits the antihistamine to one of nine compounds, of which
`azelastine is one.” Id. at 18–19. Petitioner then calculates “54 discrete
`components” by multiplying the number of anti-inflammatory agents in
`claim 2 by the number of antihistamines in claim 4 (i.e., 6 x 9 = 54).
`The fault in Petitioner’s analysis, however, is that claim 4 of Segal
`does not depend from claim 2. Put differently, Petitioner arrives at the “54
`discrete components” number by improperly reading claim 4 as dependent
`upon claim 2, when, in fact, claim 4 depends from claim 1. Ex. 1012, 5
`(claims 2, 4). Contrary to Petitioner’s arguments, therefore, Segal does not
`limit the number of possible combinations of an anti-inflammatory agent and
`at least one therapeutic agent to 54 possibilities. Instead, as Patent Owner
`explains, Segal teaches the combination of an anti-inflammatory agent and
`“at least one” additional therapeutic agent, Ex. 1012, 2:12, 2:19, 3:3, 3:5,
`3:30, 4:16, 5 (claim 1), and thus, literally discloses more than 800 million
`combinations within its broad genus, Prelim. Resp. 21 & n.4 (citing
`Ex. 2001 ¶¶ 79–81). We find that Petitioner has failed to show with
`persuasive evidence or reasoning that an ordinarily skilled artisan would
`immediately envision the combination of fluticasone and azelastine from the
`broad genus disclosed in Segal.
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`Thus, for the reasons explained above, we determine that the present
`record, including the information presented in the Petition and supporting
`evidence, does not establish a reasonable likelihood that Petitioner would
`prevail in showing that claims 1 and 25 of the ’620 are unpatentable under
`35 U.S.C. § 102(b) as anticipated by Segal.
`D. Obviousness over Hettche, Phillipps, and Segal
`Petitioner contends that claims 1, 4–6, 24–26, and 29 are unpatentable
`as obvious over Hettche, Phillipps, and Segal. Pet. 2. Relying on the
`Declarations of Drs. Schleimer and Donovan, Petitioner explains how the
`references teach or suggest the claim limitations and provides reasoning for
`combining the references. See Pet. 21–43 (citing Ex. 1003; Ex. 1004).
`1. Overview of Hettche
`Hettche, titled “Azelastine Containing Medicaments,” teaches a
`“medicament for nasal use . . . which contains as [an] active ingredient
`azelastine or a physiologically acceptable salt.” Ex. 1007 (Abstract).
`Hettche teaches that azelastine “is used in particular for prophylactic
`treatment of asthma” and has “anti-allergic and antihistamine properties.”
`Id. at 1:28–30.
`Hettche teaches that the disclosed pharmaceutical compositions are
`preferably formulated as solutions in water or mixtures of water with other
`physiologically acceptable solvents, and preferably in the form of a nasal
`spray. Id. at 2:12–17 & 41–43. Hettche states that the formulations contain
`0.0005 to 2% of azelastine. Id. at 3:26–31. Hettche also teaches that the
`formulations may contain preservatives, stabilizers, auxiliary substances,
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`isotonization agents, thickening agents, buffers, and carrier substances. Id.
`at 2:46–5:68.
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`2. Overview of Phillipps
`Phillipps, titled “Androstane Carbothioates,” discloses a genus of
`androstane compounds and claims S-fluoromethyl 6α, 9α-difluoro-11β-
`hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-
`carbothioate (i.e., fluticasone propionate).7 Ex. 1009, 36:7–10 (claim 13).
`Phillipps teaches that the disclosed androstane compounds are useful as
`pharmaceutical compositions for anti-inflammatory therapy, and may be
`formulated with one or more pharmaceutical carriers or excipients. Id. at
`32:46–50. Phillipps states that the pharmaceutical compositions may be
`formulated as topical sprays for the nose. Id. at 32:57–60. Such spray
`compositions, Phillipps teaches, “may for example be formulated as aqueous
`solutions or suspensions.” Id. at 33:12–14. Phillips also teaches that
`“formulations for administration by inhalation or insufflation are intended
`for administration on a prophylactic basis to humans suffering from allergic
`and/or inflammatory conditions of the nose, throat or lungs such as asthma
`and rhinitis, including hay fever.” Id. at 33:40–44.
`3. Analysis
`Petitioner has shown sufficiently for the purpose of institution that the
`combination of Hettche, Phillips, and Segal discloses each and every
`limitation of claims 1, 4–6, 24–26, and 29. See Pet. 26–33 (citing Exs. 1007,
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`7 S-fluoromethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-
`17α-propionyloxyandrosta-1,4-diene-17β-carbothioate is the chemical name
`for fluticasone propionate. Ex. 1010, 1.
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`Patent 8,168,620 B2
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`1009, 1012). Specifically, we have reviewed Petitioner’s claim chart and
`find that sufficient evidence supports Petitioner’s contention that the cited
`references collectively disclose the limitations of the challenged claims. Id.
`We also note that, in its Preliminary Response, Patent Owner does not
`identify any particular claim limitation as not disclosed in the prior art. See
`generally Prelim. Resp. 27–42 (Patent Owner’s response to obviousness
`ground over Hettche, Phillipps, and Segal).
`We also find that Petitioner has shown sufficiently for the purpose of
`institution that an ordinarily skilled artisan would have been motivated to
`combine the disclosures of Hettche, Phillips, and Segal to provide an
`improved treatment for allergic rhinitis (“AR”) using a nasal dosage
`formulation of azelastine and fluticasone. See Pet. 33–39 (discussing
`reasons to select azelastine and fluticasone and to combine these compounds
`into a single nasal product).
`For example, Petitioner contends that the ordinarily skilled artisan
`would have had a reason to attempt a combination drug formulation
`comprising a nasal corticosteroid and an antihistamine based upon the prior
`clinical use of these compounds together for treating AR. Pet. 35–36 (citing
`Ex. 1019, 505 (stating that intranasal antihistamines “are appropriate for use
`as first line treatment for the symptoms of allergic rhinitis, or as part of
`combination therapy with nasal corticosteroids or oral antihistamines”),
`Ex. 1021, 536 (stating that “for those patients whose symptoms [of AR] are
`not adequately controlled by either treatment often a combination of both an
`antihistamine with an intranasal corticosteroid is prescribed”); Ex. 1022, 125
`(stating that “a combination of nasal steroids and antihistamines (oral and/or
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`topical) is recommended” for treatment of patients with severe seasonal
`AR)).
`Petitioner also contends that an ordinarily skilled artisan would have
`had a reason to select azelastine as an antihistamine, due to its alleged
`superior qualities over other known antihistamines. See Pet. 33–34 (citing
`Ex. 1003 ¶¶ 63–67; Ex. 1015, 387, 391–92; Ex. 1016, Fig. 2, 99–100;
`Ex. 1007, 1:44–48 & 53–55, 1:63–2:2; Ex. 1050, 823–24). And Petitioner
`contends that an ordinarily skilled artisan would have had a reason to select
`fluticasone as the corticosteroid, in part because it was known as the “most
`potent FDA-approved corticosteroid available.” Id. at 34 (citing Ex. 1017,
`623; Ex. 1018, S434; Ex. 1003 ¶¶ 59, 61).
`Petitioner also asserts that a skilled artisan “would have wanted to
`take advantage of the known complementary mechanisms of action of
`azelastine and fluticasone” in creating a combined drug formulation. Id. at
`36–37 (citing Ex. 1011, 2:25–27; Ex. 1021, 535; Ex. 1023, S386–87;
`Ex. 1024, S226, S230–32; Ex. 1003 ¶¶ 53–55, 57–58, 70, 78–79). Petitioner
`contends that “[t]aking advantage of complementarity of mechanisms of
`action of two therapeutics was a known technique in the art,” and
`specifically points to the combination drug product Advair® (fluticasone
`propionate and salmeterol) as evincing this motivation. Id. at 37–38
`(Ex. 1020, 223; Ex. 1025, 1213; Ex. 1003 ¶¶ 52, 58, 73, 83–84). In addition,
`Petitioner points out that it was well known in the art to combine drugs into
`a single nasal spray to improve patient compliance. Id. at 38–39 (citing
`Ex. 1012, 1:15–20, 2:2–3, 3:3–9; Ex. 1020, 224; Ex. 1003 ¶¶ 80, 82).
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`Patent Owner disputes Petitioner’s assertion that an ordinarily skilled
`artisan would have been motivated to combine the teachings of Hettche,
`Phillipps, and Segal to create a combination drug formulation comprising
`azelastine and fluticasone. See Prelim. Resp. 27–42. First, Patent Owner
`contends that the clinical art, and the art as a whole, taught away from co-
`administration of an antihistamine and a steroid. Id. at 27–38. Second,
`Patent Owner contends that the ordinarily skilled artisan would not have had
`a reasonable expectation of success in formulating a combination drug for
`nasal administration. Id. at 38–42.
`As part of its teaching-away argument, Patent Owner points out that
`before the earliest-possible filing date of the ’620 patent, several clinical
`studies showed that antihistamines and corticosteroids had redundant
`mechanisms of action in vivo and, thus, several prior art references
`discouraged their combined use. Id. at 29–31 (citing Ex. 1039, 1 (study
`finding that the co-administration of the corticosteroid beclomethasone with
`the anti-histamine astemizole “provided no better control of rhinitis than
`beclomethasone alone”); Ex. 1036, 1, 3 (study finding that “budesonide
`[corticosteroid] and terfenadine [anti-histamine] combination treatment
`produced a similar effect to treatment with budesonide alone”); Ex. 1040, 1
`(study finding “no significant difference in efficacy between [fluticasone]
`alone . . . and [fluticasone] in combination with oral [antihistamine]
`cetirizine”); Ex. 1034, 1 (study finding that “adding [antihistamine]
`loratadine to [fluticasone] does not confer meaningful additional benefit”)).
`Patent Owner adds that, even if the prior art would have suggested to
`try antihistamines and corticosteroids, “clinical studies that actually tested
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`this theory demonstrated no . . . benefits.” Prelim. Resp. 31 (citing Ex. 2001
`¶ 52). Patent Owner points to Howarth8 and Nielsen9—two reviews
`published in 2000 and 2001, respectively—for concluding that “[c]ombining
`antihistamines and intranasal corticosteroids in the treatment of allergic
`rhinitis does not provide any additional effect to intranasal corticosteroids
`alone,” Ex. 2042, 2, and that “[t]he lack of additional clinical benefit when
`antihistamines are used in combination with corticosteroids” indicates that
`the action of antihistamines is “redundant,” Ex. 2041, 5.
`Patent Owner also disputes that an ordinarily skilled artisan would
`have had a reason to select azelastine as the antihistamine, and asserts that
`combining azelastine and a steroid would, in fact, decrease patient
`compliance. Prelim. Resp. 34–37. For example, Patent Owner shows
`through a graph that “azelastine exhibited greater side effects than three
`popular oral antihistamines combined.” Id. at 35 (citing Ex. 2001 ¶ 73;
`Ex. 1008, 3; Ex. 2034, 4, 6, 9). Patent Owner argues that an ordinarily
`skilled artisan would have understood that these side effects would have
`deterred patient compliance. Id. at 34.
`As part of its lack-of-reasonable-expectation-of-success argument,
`Patent Owner contends that “[t]here was no guidance in 2002 of how to
`combine a solution formulation—like azelastine—with a suspension
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`8 P.H. Howarth, “A comparison of the anti-inflammatory properties
`of intranasal corticosteroids and antihistamines in allergic rhinitis,” Allergy,
`62:6–11 (2000) (“Howarth”). Ex. 2041.
`9 Lars Peter Nielsen et al., “Intranasal Corticosteroids for Allergic
`Rhinitis Superior Relief?,” Drugs, 61(11):1563–79 (2001) (“Nielsen”).
`Ex. 2042.
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`formulation—like fluticasone.” Id.at 40 (citing Ex. 2007 ¶¶ 36–38). Patent
`Owner points to what is described as known formulation difficulties with
`combined drug formulations, see id. at 40–41 (citing Ex. 2007 ¶¶ 40–41;
`Ex. 2111, 1; Ex. 2044, 1–2), as well as to Example III of Cramer,10 a prior
`art disclosure of a combination drug formulation containing azelastine and a
`corticosteroid, that when formulated exhibited unacceptably high osmolality,
`poor spray quality, and unacceptable settling and caking, id. (Ex. 2007
`¶¶ 42–47; Ex. 1002, 268–87).
`Upon considering the record developed at this stage of the proceeding,
`we are of the opinion that Patent Owner’s arguments and expert testimony
`highlight disputed issues of fact about whether the skilled artisan would have
`been motivated to combine the teachings of Hettche, Phillipps, and Segal to
`arrive at the claimed subject matter, and would have had a reasonable
`expectation of success. We conclude that these issues are best resolved
`following trial with the benefit of a full record. Thus, based on the limited
`record before us and the application of the “reasonable likelihood” standard,
`we are persuaded that Petitioner has articulated sufficient reasoning with
`rational underpinning for combining the teachings of Hettche, Phillipps, and
`Segal for instituting trial.
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`10 Ronald Dean Cramer, European Patent (EP) Application No.
`0,780,127 A1 (published June 25, 1997) (“Cramer”). Ex. 1011. Cramer was
`thoroughly considered and relied upon by the Examiner during prosecution
`of the application leading to the ’620 patent. See generally Ex. 1002.
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`E. Obviousness over Hettche, Phillipps, Segal, and the Flon
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