Trials@uspto.gov
`571-272-7822
`
`Paper 15
`Entered: March 1, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`Petitioner,
`
`V.
`
`POZENINC.,
`Patent Owner.
`
`Case IPR2015-01774
`Patent 8,852,636 B2
`
`Before TONI R. SCHEINER, LORA M. GREEN,and
`JACQUELINE WRIGHT BONILLA,Administrative Patent Judges.
`
`SCHEINER,Administrative Patent Judge.
`
`DECISION.
`DenyingInstitution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`571-272-7822
`
`Paper 15
`Entered: March 1, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`Petitioner,
`
`V.
`
`POZENINC.,
`Patent Owner.
`
`Case IPR2015-01774
`Patent 8,852,636 B2
`
`Before TONI R. SCHEINER, LORA M. GREEN,and
`JACQUELINE WRIGHT BONILLA,Administrative Patent Judges.
`
`SCHEINER,Administrative Patent Judge.
`
`DECISION.
`DenyingInstitution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`IPR2015-01774
`Patent 8,852,636 B2
`
`I. INTRODUCTION
`
`Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively “Petitioner”)
`filed a Corrected Petition (Paper4, “Pet.”)! on August 31, 2015, requesting
`
`an inter partes review of claims 1-6 and 13-15 of U.S. Patent No. 8,852,636
`
`B2 (Ex. 1001, “the ’636 patent”). Pozen Inc. (“Patent Owner”)filed a
`
`Preliminary Response (Paper 14, “Prelim. Resp.”) on December2, 2015.
`
`Wehavejurisdiction under 35 U.S.C. § 314, which providesthat an inter
`
`partes review maynotbeinstituted “unless .
`
`.
`
`. there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the
`
`claims challengedin the petition.”
`Uponconsideration of the information presented in the Petition and
`
`the Preliminary Response, we are not persuadedthat Petitioner has
`
`established a reasonable likelihood that it would prevail in its challenges to
`
`claims 1-6 and 13-15 of the ’636 patent. Accordingly, we decline to
`
`institute an inter partes review ofthose claims.
`
`A. Related Proceedings
`
`Petitioner represents it is aware of a numberofjudicial matters
`
`involving the ’636 patent (e.g., Horizon Pharma, Inc. v. Actavis Labs. FL,
`
`Inc., 3:15-cv-03322 (D.N.J.); Horizon Pharma, Inc. v. Dr. Reddy’s Labs.,
`
`' Wenote that the Exhibit List in Petitioner’s Corrected Petition (Paper4)is
`incorrect. The Exhibit numbers on pageiii of the Corrected Petition do not
`match the entries in PRPS,or the designations in the body of the Corrected
`Petition.
`
`2
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`
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`IPR2015-01774
`Patent 8,852,636 B2
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`Inc., No. 3:15-cv-03324 (D.N.J.); Horizon Pharma, Inc. v. Lupin Ltd., 3:15-
`
`cv-03326 (D.N.J.)), as well as a numberofjudicial and administrative
`
`matters involving the ’636 patent (Coalition for Affordable Drugs VII LLCv.
`Pozen, Inc., Case IPR2015-01680), and patents related to the °636 patent
`(e.g., Dr. Reddy’s Labs., Inc. v. Pozen Inc., Case IPR2015-00802 (PTAB)).
`
`Pet. 3-4. Patent Owner makesa similar representation. Paper 8, 8—9.
`
`Petitioner also filed other Petitions for inter partes review involving related
`
`patents directed to similar subject matter—IPR2015-01773, IPR2015-01775.
`
`B. The Asserted Grounds of Unpatentability
`
`Petitioner asserts the challenged claims are unpatentable on the
`
`following grounds. Pet. 10-58.
`
`Bass“ClaimsChallenged Chen? and Chandramouli*|§ 103(a)|1-6 and 13-15
`References
`
`? Petitioner supports its challenges withthe Declaration of UmeshV.
`Banakar, Ph.D., executed August 18, 2015 (“Banakar Declaration”)
`.
`(Ex. 1002).
`3 U.S. Patent No. 6,544,556 B1, issued April 8, 2003 to Chenetal. (“Chen”)
`(Ex. 1004).
`4 Jane C. Chandramouli & Keith G. Tolman, Prevention and Management
`ofNSAID-Induced Gastropathy, 8 J. PHARM. CARE PAIN & SYMPTOM
`CONTROL 27-40 (2000) (“Chandramoul?’”) (Ex. 1011).
`
`3
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`IPR2015-01774
`Patent 8,852,636 B2
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`
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`Chen and Gimet? § 103(a)|1-6 and 13-15
`
`
`
`
`Goldman® and Gimet § 103(a)|1-6 and 13-15
`
`pormnan, Gimet and § 103(a)_|1-6 and 13-15
`
`
`
`Cimet,Chandramoull and § 103(a)|1-6 and 13-15
`
`C. The ’636 Patent (Ex. 1001)
`
`The 7636 patent, titled “PHARMACEUTICAL COMPOSITIONS FOR THE
`
`COORDINATED DELIVERY OF NSAIDs,” discloses pharmaceutical
`
`compositions “that provide for the coordinated release of an acid inhibitor
`
`and a non-steroidal anti-inflammatory drug (NSAID)” (Ex. 1001, 1:22-24),
`
`such that there is “a reduced likelihood of causing unwantedside effects,
`
`especially gastrointestinal side effects, when administered as a treatment for
`
`pain”(id. at 1:24-26).
`
`> U.S. Patent No. 5,698,225, issued December 16, 1997 to Gimetetal.
`(“Gimet”) (Ex. 1007).
`6 U.S. Patent No. 5,204,118, issued April 20, 1993 to Goldmanetal.
`(“Goldman”) (Ex. 1010).
`7 US. Patent No. 5,877,192, issued March 2, 1999 to Lindberg et al.
`(“Lindberg’’) (Ex. 1005).
`8 PCT Int’] Patent Appl. WO 00/26185, published May 11, 2000, by Phillips
`(“Phillips”) (Ex. 1012).
`
`
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`IPR2015-01774
`Patent 8,852,636 B2
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`Specifically, the ’636 patent discloses “a pharmaceutical composition
`in unit dosage form... contain[ing] an acid inhibitor present in an amount
`effective to raise the gastric pH of a patientto at least 3.5”(id. at 3:27-31),
`
`and an NSAID “in an amounteffective to reduce or eliminate pain or
`
`inflammation”(id. at 3:67-4:1). “The term ‘unit dosage form’ .
`
`.
`
`. refers to a
`
`single entity for drug administration. For example, a single tablet or capsule
`
`combining both an acid inhibitor and an NSAID would be a unit dosage
`
`form.” Id. at 4:42-45.
`
`A unit dosage form of the present invention preferably provides
`for coordinated drug release, in a way that elevates gastric pH
`and reduces the deleterious effects of the NSAID on the
`gastroduodenal mucosa, i.e., the acid inhibitor is released first
`and the release of NSAIDis delayed until after the pH in the GI
`tract has risen.
`
`the unit dosage form is a
`In a preferred embodiment,
`multilayer tablet, having an outer layer comprising the acid
`inhibitor and an inner core which comprises the NSAID. In the
`most preferred form, coordinated delivery is accomplished by
`having the inner core surrounded by a polymeric barrier coating
`that does not dissolve unless the surrounding medium is at a pH
`ofat least 3.5[.]
`
`Id. at 4:45-58.
`
`The claimsof the ’636 patent are directed to unit dosage forms where
`
`the acid inhibitor is esomeprazole (id. at 3:46), and the NSAID is naproxen
`
`(id. at 4:6).
`
`
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`IPR2015-01774
`Patent 8,852,636 B2
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`D. Illustrative Claim
`
`Petitioner challenges claims 1-6 and 13-15 of the 636 patent, of
`
`which claim 1 is the only independent claim. Claim 1, reproduced below,is
`
`illustrative.
`
`1. A pharmaceutical composition in unit dose form suitable for
`oral administration to a patient, comprising:
`(a) esomeprazole present in an amounteffective to raise
`the gastric pH ofsaid patient to at least 3.5 upon the
`administration of one or more ofsaid unit dosage forms;
`
`(b) naproxen present in an amounteffective to reduce or
`eliminate pain or inflammation in said patient upon
`administration of one or more ofsaid unit dosage forms;
`
`and wherein:
`
`i) said unit dosage form is a tablet in which said
`naproxenis present in a core;
`ii) said tablet comprises a coating, wherein said
`coating surroundssaid core and doesnotrelease said
`naproxen until the pH of the surrounding mediumis
`3.5 or higher; and
`iii) said esomeprazole is in one or morelayers outside
`said core, wherein said one or morelayers:
`
`A) do not include an naproxen;
`B) are not surroundedby an enteric coating; and
`C) upon ingestion of said tablet by a patient,
`release said esomeprazole into said patient’s
`stomach.
`
`Ex. 1001, 21:22—43.
`
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`IPR2015-01774
`Patent 8,852,636 B2
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`IJ. ANALYSIS
`
`A. Claim Construction
`
`Wedeterminethat no claim term requires express construction for
`
`purposesof this Decision.
`
`B. Claims 1—16 and 13—18—Asserted Obviousness over
`Chen and Chandramouli
`
`1. Chen (Ex. 1004)
`Chen discloses an oral dosage form comprising “an orally
`administrable dosage form comprising a therapeutically effective amount of
`
`an NSAIDand an amountof a proton pumpinhibitor effective to
`substantially inhibit gastrointestinal side effects of the NSAID,together with
`one or more pharmaceutically acceptable excipients.” Ex. 1004, 3:65—-4:3.
`
`Chen discloses a numberof suitable proton pumpinhibitors (PPIs),
`
`and teaches “[i]n certain preferred embodiments, the proton pumpinhibitor
`is omeprazole, either in racemic mixture or only the (-)enantiomer of
`
`omeprazole (i.e. esomeprazole).” Jd. at 6:53-56. In addition, Chen lists
`
`naproxen amonga large numberof well-known examples of NSAIDs. Jd. at
`5:58-6:31.
`|
`According to Chen, “proton pumpinhibitors are susceptible to
`
`degradation and/or transformation in acidic and neutral media,” andthe half-
`
`life of “omeprazole in water solutions at pH-valuesless than three is shorter
`
`than ten minutes.” Jd. at 8:9-17. Chen teaches “‘it is preferable that in an
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`oral solid dosage form [proton pumpinhibitors] be protected from contact
`
`7
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`IPR2015-01774
`Patent 8,852,636 B2
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`with the acidic gastric juice and the active substance must be transferred in
`
`intact form to that part of the gastrointestinal tract where the pH is near
`
`neutral.” Jd. at 8:19-23.
`
`Accordingly, Chen discloses an embodimentin which a “tablet
`
`contains the NSAID within a sustained release matrix and the proton pump
`inhibitor [is] coated into [sic] the tablet in an enteric coated layer.” Jd. at
`12:4-7. Chen further disclosesthat:
`
`. may optionally be coated with one
`.
`The dosage forms .
`or more materials suitable for the regulation of release or for the
`protection of the formulation. In one embodiment, coatings are
`provided to permit either pH-dependent or pH-independent
`release, e.g., when exposed to gastrointestinal fluid. A pH-
`dependentcoating serves to release the proton pump inhibitor in
`desired areas of the gastro-intestinal (GI) tract, e.g., the small
`intestine ... . When a pH-independent coating is desired, the
`coating is designed to achieve optimal release regardless of pH-
`changesin the environmentalfluid, e.g., the GI tract.
`It is also
`possible and preferable to formulate compositions which release
`a portion of the dose, preferably the NSAID,in one desired area
`of the GI tract, e.g., the stomach, and release the remainderof the
`dose, preferably the proton pumpinhibitor, in another area of the
`GItract, e.g., the small intestine.
`Formulations .
`.
`. that utilize pH-dependent coatings to
`obtain formulations may also impart a repeat-action effect
`whereby unprotected drug, preferably the NSAID,is coated over
`the enteric coat and is released in the stomach, while the
`remainder, preferably containing the proton pump inhibitor,
`being protected by the enteric coating, is released further down
`the gastrointestinaltract.
`
`Id. at 12:14-40.,
`
`
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`IPR2015-01774
`Patent 8,852,636 B2
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`2. Chandramouli (Ex. 1011)
`
`Chandramouli teachesthat, “[dJue to the asymptomatic nature of
`
`NSAID-induced GItoxicity .
`
`.
`
`. preventionis crucial.” Ex. 1011, 36. “Since
`
`NSAID-associated GI injury is dependent on the presenceofacid,”
`
`Chandramouli suggests that “the prophylactic use of an H2 blocker seems
`
`reasonable.” /d. Chandramouli teachesthat “[c]oncomitant use of these
`
`agents prevents duodenalulcers, but not gastric ulcers, which are 3 to 4
`times morecommon... among NSAID users. Thus H) blockade alone does
`not constitute an adequate preventive treatment.” Jd. According to
`
`Chandramouli, proton pumpinhibitors “suppress acid secretion to a greater
`
`degree than H2-receptor antagonists. Nevertheless, omeprazole is more
`
`effective against duodenal than gastric ulceration.” Jd. Further according to
`
`Chandramouli, “[t]he OMNIUM study (Omeprazole versus Misoprostol for
`
`NSAID-Induced Ulcer Management) concluded however that omeprazole
`
`maybeas effective or more effective than misoprostol for the prevention of
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`NSAID-induced gastropathy.” Id.
`
`In addition, Chandramouli discloses that although misoprostol“is the
`
`only agent labeled for co-therapy with NSAIDs,” and “prevents both gastric
`99 ce
`
`and duodenal ulceration,”
`
`“[s]ignificant dose-related diarrhea and abdominal
`
`pain limits its tolerability,” and “its use in womenofchildbearing potential
`
`is contraindicated.” Jd. at 37. The reference also teachesthat “[i]n an
`
`attempt to be more cost-effective, [misoprostol] . .. was combined with
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`diclofenac (Arthrotec®),” and the “combinationis as effective for arthritis
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`
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`IPR2015-01774
`Patent 8,852,636 B2
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`pain and symptomsas diclofenac alone with a decreased incidence of
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`ulcers.” Id.
`
`3. Analysis
`
`Petitioner contendsthat the subject matter of claims 1-6 and 13-15 of
`
`the ’636 patent would have been obvious over Chen alone, or Chen in view
`
`of Chandramouli. Pet. 10-26.
`
`Asserted Obviousness over Chen
`
`Specifically, Petitioner contends that Chen disclosesan oralsolid
`dosage form,e.g., a tablet, comprising a therapeutically effectiveamountof
`an NSAID and a proton pumpinhibitor (PPI) in an amounteffective to
`
`inhibit or prevent gastrointestinal side effects normally associated with the
`
`NSAID.Pet. 11 (citing Ex. 1004, Abstract, 4:30-33). Petitioner contends
`
`that Chen expressly discloses that the NSAID may be naproxen and the PPI
`may be omeprazole or omeprazole’s S-enantiomer, esomeprazole, both of
`which were knownin the art for reducing the risk of gastroduodenal injury
`
`associated with NSAID use. Jd. at 11-12 (citing Ex. 1002 {§ 31, 40; Ex.
`
`1004, 5:53-58, 60-63, 6:43-49, 53-56; Ex. 1005, 1:50—-55).
`
`Petitioner acknowledges that Chen “discloses a preferred formulation
`
`that would release the NSAID in the stomach and omeprazole in the small
`
`intestine,” but argues that Chen “is not limited to such formulations,” and
`
`discloses generally “formulations with pH-dependent and pH-independent
`
`coatings to permit the coordinated release of one drug before the other.” Jd.
`
`at 12 (citing Ex. 1004, 12:17-18), 13 (citing Ex. 1002 {{ 33, 38, 55; Ex.
`
`10
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`IPR2015-01774
`Patent 8,852,636 B2
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`1004, 12:27-32). Relying on Dr. Banakar’s testimony for support,
`
`Petitioner contends that it would have been obviousfor one of ordinary skill
`in the art “to develop a. .
`. tablet with esomeprazole released before
`|
`naproxen”(id. at 13 (citing Ex. 1002 4 55)), specifically, “a core with
`
`naproxen surrounded by a pH-dependententeric coating and non-enteric
`
`coated esomeprazole”(id. at 12 (citing Ex. 1004,:12:17-18)—ssentially the
`
`reverse of Chen’s preferred formulation.
`
`Again relying on Dr. Banakar’s testimony, Petitioner contendsthat
`
`one of ordinary skill in the art “would have understood that PPIs are
`
`preferably released in the gastrointestinal tract prior to reaching the small
`
`intestine.” Jd. at 13 (citing Ex. 1002 {{ 33, 38). Moreover, Petitioner
`contendsthat one of ordinary skill in the art would have understood Chen’s
`
`description of “enteric-coated omeprazole as ‘preferred’” to mean that “non-
`
`enteric coated esomeprazole would be effective” even though it would be
`
`released in the stomach and exposedto gastric fluid. Jd. at 14 (citing Ex.
`
`1002 J§ 37, 38). That is, Petitioner, relying on Dr. Banakar’s testimony,
`
`contendsthat one of ordinary skill in the art “would knowpartial
`
`degradation of the PPI would not prevent non-enteric coated esomeprazole
`
`from being therapeutically effective, but instead, a sufficient amount of PPI
`
`could exist and loss of the PPI could be overcomeby adjusting the dosage.”
`
`Id. at 14 (citing Ex. 1002 7 48). Petitioner contends, therefore, that one of
`ordinary skill in the art “would have found it obvious to make a combination
`tablet with enteric-coated naproxen and immediate-release esomeprazole”
`
`11
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`IPR2015-01774
`Patent 8,852,636 B2
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`with a reasonable expectation that it would “be therapeutically effective.”
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`Id. at 14.
`
`Additionally, in support of the assertion that one of ordinary skill in
`
`the art “would have known at least a portion of non-enteric coated,
`
`unbuffered esomeprazole would be bioavailable upon oral administration,”
`Petitioner and Dr. Banakar cite a study by Pilbrant,? which according to
`
`Petitioner, “compar[es] the bioavailability of non-enteric coated omeprazole
`
`when administered with and without a buffer and teaches a substantial
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`portion of the uncoated omeprazoleis bioavailable.” Pet. 15 (citing Ex.
`
`1002 Ff 38, 47, 48; Ex. 1008). Petitioner characterizes Pilbrant as
`
`contemplating “‘two principle options for the formulation of an oral, solid
`
`dosage form of omeprazole’: (1) a ‘conventional’ non-enteric coated form in
`
`which ‘omeprazole is released an absorbed rapidly enough to avoid
`
`degradation in the stomach’ and (2) and enteric coated form of
`esomeprazole.” Id. (citing Ex. 1008, 114). Petitioner contends that Pilbrant
`“reports that 44% of uncoated, unbuffered omeprazole wasnotlost to
`
`degradation in the acidic stomach”(id. (citing Ex. 1008, 116-117), and one
`
`of ordinary skill in the art “would have been able to use well-known and
`
`routine techniques to compensate for the degraded amount”(id. (citing Ex.
`
`1002 {J 48-51, 59). Additionally, Petitioner contends that the Court of
`
`° A. Pilbrant & C. Cederberg, Development ofan Oral Formulation of
`Omeprazole, 20 SCAND. J. GASTROENTEROL. 113-120 (1985) (“Pilbrant’”)
`(Ex. 1008).
`
`12
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`IPR2015-01774
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`Appeals for the Federal Circuit “has acknowledged that Pilbrant teaches
`
`non-enteric solid dosage forms of PPIs as a ‘viable alternative to enteric
`
`coating.’” Jd. at 18 (citing Santarus, Inc. v. PAR Pharm., Inc., 694 F.3d
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`1344, 1355-56 (Fed.Cir. 2012).
`
`Weare not persuadedthat Petitioner has established that a unit dosage
`
`form comprising a naproxen core with a protective coating that does not
`release the naproxen unless the pH of the surrounding medium is 3.5 or
`higher, surrounded by a layer of esomeprazole whichis released into the
`stomach upon ingestion, would have been obvious over Chen—which
`
`teaches essentially the opposite.
`
`First, Petitioner relies on selective portions of Chen, without adequate
`
`consideration of the surrounding context. We do not agree that Chen’s
`
`teachings regarding pH-dependent and pH-independentcoatings are as broad
`
`and generic as Petitioner contends. As discussed abovein Section JI.B.1,
`
`Chen actually states:
`
`A pH-dependent coating serves to release the proton pump
`inhibitor in desired areas of the gastro-intestinal (GI) tract, e.g.,
`the small
`intestine ... When a pH-independent coating is
`desired,
`the coating is designed to achieve optimal release
`regardless of pH-changesin the environmentalfluid,e.g., the GI
`tract.
`It
`is also possible and preferable to formulate
`compositions which release a portion ofthe dose, preferably the
`NSAID,in one desired area of theGItract, e.g., the stomach, '
`and release the remainderof the dose, preferably the proton
`pump inhibitor, in another area of the GItract, e.g., the small
`intestine.
`
`13
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`IPR2015-01774 ©
`Patent 8,852,636 B2
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`Formulations according to the invention that utilize pH-
`dependent coatings to obtain formulations may also impart a
`repeat-action effect whereby unprotected drug, preferably the
`NSAID,is coated over the enteric coat andis released in the
`stomach, while the remainder, preferably containing theproton
`pump inhibitor, being protected by the enteric coating,
`is
`releasedfurther down the gastrointestinaltract.
`
`Ex. 1004, 12:19-40 (emphases added). Elsewhere, e.g., in columns 8 and
`12, Chen repeatedly refers to using a pH dependent coating (e.g., an enteric
`coating) to facilitate release of the PPI in the small intestine, while not
`
`coating the NSAID sothatit is released the stomach. Jd. at 12:4—7, see also
`
`id. at 8:17—-40 (disclosing protecting PPIs so they are released “where the pH
`
`is near neutral”). Petitioner has not pointed to where Chen discloses or
`
`suggests doing the reverse, i.e., enterically coating NSAID sothatit is
`
`released further down the GI tract (where the pHis higher), and releasing
`
`“unprotected” PPI at any pH, such as in the stomach (where the pH is
`
`lower).
`Second,to the extent Petitioner argues that Chen “does not suggest
`that formulas with non-enteric coated PPIs would result in no-bioavailability
`
`of the PPI,” we are not persuaded. Pet. 14. If we understand Petitioner’s
`
`position,it is that Chen fails to teach away from non-enteric coated PPIs.
`
`Nevertheless, even if we were to agree that Chen does not explicitly teach
`
`awayfrom thereverseofits preferred embodiments,it does not follow thatit
`
`provides a suggestion to do so, or a reasonable expectation of success.
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`14
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`IPR2015-01774
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`Nor are we persuaded by Dr. Banakar’s testimony that one of ordinary
`
`skill in the art would have had a reason to do the opposite of what Chen
`
`teaches. Dr. Banakarcites Exhibits 1006, 1020, 1021, and 1022—noneof
`
`which werecited in the Petition, with the exception of Ex. 1006—in support
`
`of the contention that “repeated administration of PPIs results in a self-
`propagating effect.” Ex. 1002 931. To the extent Exhibit 1006!” is cited by
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`Dr. BanakarandbyPetitioner on page 16 ofthe Petition, its relevance to
`
`Petitioner’s position is unclear as the reference discloses repeated
`
`administration of “capsules of enteric-coated omeprazole granules.” Ex.
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`1006, 707. In addition, Dr. Banakarcites Exhibit 1021 and 1016 (neither of
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`which werecited in the Petition) in support of the contentions that it was
`
`knownthat PPIs “function by inhibiting H2 receptorsin the parietal cells”
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`which “are located in the duodenum,whichis located immediately after the
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`stomach within the GI tract,” and “NSAIDs, on the other hand, are absorbed
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`later in the GI tract.” Ex. 1002 933. Dr. Banakar thereafter summarily
`
`concludes that one of ordinary skill in the art “would have understood that
`
`esomeprazole should be released early in the GI tract to reduce the acidity
`
`(inhibit proton pumps) while naproxen maybe released simultaneously, or
`
`preferably later than the release of esomeprazole, in order to reducethe risk
`
`of NSAID-associated gastroduodenalinjury,” without citing additional
`
`10 C.W. Howdenetal., Effects ofsingle and repeated doses ofomeprazole
`on gastric acid andpepsin secretion in man, 25 GUT 707-10 (1984) (Ex.
`1006).
`
`15
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`IPR2015-01774
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`evidence in support thereof. Jd. at J] 33, 38. Such conclusory statements by
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`Petitioner and Dr. Banakar do not explain sufficiently, nor provide adequate
`
`support as to why oneof ordinary skill in the art would have donethe
`
`opposite of what Chen teachesin order to address the issue of PPI stability at
`
`lower pHs. See Ex. 1004, 8:17-40, 12:4~32. Petitioner’s conclusory
`
`assertions that the subject matter of the challenged claims would have been
`
`“obviousto try” are likewise inadequate to address this point. Pet. 13, 19.
`Norare we persuaded that Pilbrant’s teachings, relied on by Petitioner
`and Dr. Banakar, would haveled one of ordinary skill in the art to do
`
`essentially the opposite of what Chen teaches. Pilbrant, like Chen, teaches
`
`that “[o]meprazole degrades very rapidly in water solutions at low pH-
`values.” Ex. 1008, 113. In this context, Pilbrant describes the use of an
`“enteric-coated dosage form, which releases omeprazole for absorption in
`
`the small intestine,” while stating that a conventional oral dosage “was ruled
`
`out” because “more than half of the omeprazole in a rapidly dissolving
`
`dosage form degradesin the stomach.” Jd. at 114. In addition, Pilbrant
`
`states that a “rapidly dissolving suspension of micronised omeprazoleis the
`
`second best choice”to the enteric-coated dosage form. Jd. at 116 (emphasis
`
`added). Pilbrant describes administering that suspension “together with
`
`sodium bicarbonate buffer,” and states that “results clearly show that a
`
`conventional, non-buffered, oral dosage form of omeprazole will have a low
`
`systemic bioavailability owing to preabsorption degradation of omeprazole
`in the stomach.” Jd. at 117.
`
`16
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`IPR2015-01774
`Patent 8,852,636 B2
`
`Petitioner’s arguments regarding Pilbrant and Santarus do not
`
`acknowledgethe distinction betweena solid oral formulation (such as a
`
`tablet) and a solution/suspension comprising omeprazole. As stated by the
`
`court in Santarus, “Pilbrant discusses four options: 1) solutions;
`
`2) suspensionsof buffered non-enteric coated omeprazole; 3) conventional
`
`oral dosage forms—tablets, capsules or granules—with nonenteric coated
`
`PPIs; and 4) conventional oral dosage forms with enteric-coated PPIs.”
`Santarus, 694 F.3d at 1355. Asfurther stated by the court, “Pilbrant
`
`explicitly ‘ruled out’ the third option—non-enteric coated conventionaloral
`
`dosage forms suchastablets, capsules, or granules—because they degrade
`
`too quickly in the stomachto be absorbedin sufficient amounts to be
`
`effective.” Jd. In contrast, regarding the second option, Pilbrant“teaches
`
`that, although suspensionsof buffered non-enteric coated omeprazole may
`
`be the ‘second best choice,’ they are a viable alternative to enteric coating.”
`
`Id. at 1355-56.
`
`In other words, Pilbrant teaches preparing buffered suspensions of
`
`non-enteric coated omeprazole, but teaches away from preparing non-enteric
`
`coated tablets of the drug. Ex. 1008, 114, 116-117. Petitioner does not
`
`explain sufficiently why an ordinary artisan would have had a reasonable
`
`expectation of success in making a tablet comprising esomeprazole with no
`
`coating or a non-enteric coating, that releases the PPI regardless of the pH,
`
`i.e., in the stomach, as required by the claims of the ’636 patent.
`
`17
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`IPR2015-01774
`Patent 8,852,636 B2
`
`Asserted Obviousness over Chen and Chandramouli
`
`Norare we persuadedthat the subject matter of claims 1-6 and 13-15
`
`of the ’636 patent would have been obvious over Chen in view of
`
`Chandramouli.
`
`Petitioner contends Chandramouli teaches that “use of NSAIDsresults
`
`in significant deleterious effects on the upper gastrointestinal tract,”
`
`including the small intestine, and that “PPIs such as omeprazole can be used
`
`to reducethe risk of NSAID-associated gastrointestinal injury.” Pet. 20
`
`(citing Ex. 1011, 31-32, 36). Petitioner further contends “[g]iven the
`
`structure and function of the dosage form taught in [Chen], a [person of
`
`ordinary skill in the art] would have been strongly motivated by
`
`Chandramouli to make a combination tablet described in [Chen] with
`
`esomeprazole released in the stomach and naproxenin the small intestine.”
`
`Id. at 20-21.
`
`Petitioner’s contentions here, once again, do not explain sufficiently,
`
`nor provide adequate support as to why an ordinary artisan would have done
`
`the opposite of what Chen teaches in order to address the issue of PPI
`
`stability at lower pHs, especially in view of Pilbrant’s teachings regarding
`
`tablets comprising omeprazole, as discussed above. Ex. 1004, 8:17—40,
`
`12:4-40; Ex. 1008, 114, 116-117.
`
`18
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`
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`IPR2015-01774
`Patent 8,852,636 B2
`
`4, Conclusion
`
`Having considered the arguments and evidence presented in the
`
`Petition, we are not persuadedthat Petitioner has established a reasonable
`
`likelihood of prevailing in its challenge of claims 1-6 and 13-15, on the
`
`basis of obviousness over Chen alone, or Chen in combination with
`
`Chandramouli.
`
`C. Claims 1-6 and 13—15—Asserted Obviousness over
`Chen and Gimet
`
`1. Gimet (Ex. 1007)
`
`Gimet teaches that NSAIDs have“high therapeutic value especially
`
`for the treatment of inflammatory conditions such as .
`
`.
`
`. osteoarthritis (OA)
`
`and rheumatoidarthritis,” but “also exhibit undesirable side effects.” Ex.
`
`1007, 1:20—24). “An especially undesirable side effect of the administration
`
`of NSAIDsis the ulcerogenic effects generally associated with chronic use.”
`
`Id. at 1:24-27. “NSAID inducedulcers in the stomach .
`
`.
`
`. generally exhibit
`
`few or no symptomsand may cause dangerous bleeding when undetected
`... [and] [i]n someinstances .
`.
`. can provefatal.” Jd. at 1:29-33.
`
`According to Gimet, “[c]ertain prostaglandins have been shownto
`prevent NSAID induced ulcers.” Id. at 1:39-40. Misoprostol, for example,
`“is a pharmaceutically acceptable prostaglandin which has been accepted for
`
`|
`use in the treatment of NSAID induced ulcers.” Jd. at 1:45-47.
`Gimet discloses a pharmaceutical composition comprising a tablet
`
`having an inner core and an outer mantle coating surroundingthe innercore,
`
`19
`
`
`
`IPR2015-01774
`Patent 8,852,636 B2
`
`designed to “[counter] (by inhibiting, reducing or preventing) the
`
`ulcerogenicside effects attendant to NSAID administration.” /d. at 1:11—-14,
`
`61-63. The inner core consists of an NSAID—disclofenac or piroxicam—
`
`and the outer mantel consists of a prostaglandin—e.g., misoprostol. Id. at
`
`1:11-17, 39-47.
`
`Figure 2 of Gimet, reproduced below,depicts tablet 16 in cross-
`
`section.
`
`
`
`FIG2
`
`Figure 2 of Gimet depicts tablet 16. Tablet 16 includes an NSAID—
`diclofenac or piroxicam—ininner core 18. Enteric coating 20 surrounds
`
`core 18, and mantle 22—consisting of a prostaglandin, e.g., misoprostol—
`
`surrounds the coated inner core. Ex. 1007, 6:24—-44.
`
`Theenteric coating “can be formulated from any suitable enteric
`
`coating material,” and “aids in segregating the NSAID from the
`prostaglandin andin directing the dissolution ofthe NSAID core in the
`lower G.I. tract as opposed to the stomach.” Jd. at 6:29-30, 33-36.
`
`2. Analysis
`
`Petitioner contends that claims 1-6 and 13-15 of the ’636 patent
`
`would have been obvious over Chen in view of Gimet. Pet. 26-36.
`
`20
`
`
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`IPR2015-01774
`Patent 8,852,636 B2
`
`Petitioner relies on the arguments and evidence discussed aboveas to
`
`why “a person of ordinary skill . .. would have found it obvious to make a
`
`combination tablet with enteric-coated naproxen and immediate-release
`
`esomeprazole” and “would have reasonably expected non-enteric coated
`
`esomeprazole to be therapeutically effective.” Jd. at 28.
`
`Petitioner acknowledgesthat the acid inhibitor disclosed in Gimetis a
`
`prostaglandin, but argues that person ofordinary skill in the art “would have
`knownthat like misoprostol, esomeprazole is an acid inhibitor that reduces
`
`the risk of NSAID-associated gastrointestinal injury by increasing the pH of
`
`the gastrointestinal environmentto at least 3.5.” Id. at 27—28(citing
`
`Ex. 1002 9 50). Accordingly, Petitioner contends that one of ordinary skill
`
`in the art “would have been motivated to select the naproxen and
`
`esomeprazole combination from [Chen] to create a tablet with the structure
`
`disclosed in [Gimet] from the disclosures of [Chen] and a [person of
`
`ordinary skill in the art’s] understanding that the absorption and therapeutic
`
`active site for esomeprazole is located before the typical site of absorption of
`
`naproxen within the GI tract.” Pet. 28.
`
`Again, Petitioner does not explain sufficiently, nor provide adequate
`
`support as to why an ordinary artisan would have done the opposite of what
`
`Chen teachesin order to address the issue of PPI stability at lower pHs,
`
`especially in view of Pilbrant’s teachings regarding tablets comprising
`
`omeprazole, as discussed above. Ex. 1007, 8:17—40, 12:4—-40; Ex. 1008,
`
`114, 116-117.
`
`21
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`IPR2015-01774
`Patent 8,852,636 B2
`
`3. Conclusion
`
`Having considered the evidence and arguments presentedin the
`Petition, we are not persuadedthatPetitioner has established a reasonable
`likelihood of prevailing in its challenge of claims 1-6 and 13-15 on the basis
`
`of obviousness over Chen and Gimet.
`
`D. Claims 1-6 and 13—15—-Asserted Obviousness over
`Goldman and Gimet
`
`1. Goldman (Ex. 1010)
`
`Goldman discloses “pharmaceutical compositions fortreating the
`
`symptomsof overindulgence .
`
`.
`
`. [comprising] a combination of non-
`
`steroidal anti-inflammatory drug or acetaminophen and a histamine receptor
`
`blocker and/or a proton pump inhibitor composition.” Ex. 1010, 1:10-16.
`
`Goldmanteachesthat acceptable histamine receptor (H2) blockers include
`
`famotidine(id. at 3:27), acceptable proton pumpinhibitors (PPIs) include
`
`omeprazole (id.), and acceptable NSAIDsinclude naproxen and piroxicam
`
`(id. at 3:17-22). Goldman discloses using “naproxen from 200 to 500 mg
`" per dose”(id. at 5:18-19), and “omeprazole from 60 to 500 mg per dose”
`(id. at 9:25-27), while Examples 11 and 12 disclose tablets consisting of 500
`
`mg of acetaminophenor 200 mgibuprofen, 60 mg of omeprazole, “and
`
`other auxiliary agents and coloring agents”(id. at 7:24—42).
`
`Finally, Goldman discloses “chewable and liquid dosage forms”(id.
`
`at 6:45), and further teachesthat “[v]arious conventional techniques for
`
`22
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`IPR2015-01774
`Patent 8,852,636 B2
`
`preparing medicamenttablets or caplets can be employed as would be
`
`knownto those skilled in the art.” Jd. at 6:26—30.
`
`2. Analysis
`
`Petitioner contends that claims 1-6 and 13-15 of the ’636 patent
`
`would have been obvious over Goldman in view of Gimet. Pet. 36-43.
`
`Petitioner contends that Goldman “describes combinationtablets
`
`comprising therapeutic amounts of an NSAID and a PPI, where the PPIis
`
`not enteric coated,” as well as 200-500 mg dosages of naproxen and 60—500
`
`mg dosages of omeprazole. Pet. 36 (citing Ex. 1010, 5:18-19, 9:26—27).
`
`Petitioner further contends that although an ordinary artisan would have
`
`knownthat omeprazole and esomeprazole are acid labile, Goldman “makes
`
`no indication the PPI must be enteric coated in orderto be effective,” nor
`
`does it make “reference to enteric coating or use the term coatingatall,”
`
`referring to Examples 11 and 12, for example. Jd. at
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