Trials@uspto.gov
`571-272-7822
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` Paper 15
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` Entered: March 1, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`POZEN INC.,
`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
`Denying Institution 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.
`
`POZEN INC.,
`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
`Denying Institution 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 (Paper 4, “Pet.”)1 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 December 2, 2015.
`We have jurisdiction under 35 U.S.C. § 314, which provides that an inter
`partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.”
`Upon consideration of the information presented in the Petition and
`the Preliminary Response, we are not persuaded that 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 of those claims.
`
`A. Related Proceedings
`Petitioner represents it is aware of a number of judicial 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.,
`
`
`1 We note that the Exhibit List in Petitioner’s Corrected Petition (Paper 4) is
`incorrect. The Exhibit numbers on page iii of the Corrected Petition do not
`match the entries in PRPS, or the designations in the body of the Corrected
`Petition.
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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 number of judicial and administrative
`matters involving the ’636 patent (Coalition for Affordable Drugs VII LLC v.
`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 makes a 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. 10–58.2
`
`References
`
`Basis
`
`Claims Challenged
`
`Chen3 and Chandramouli4
`
`§ 103(a)
`
`1–6 and 13–15
`
`
`2 Petitioner supports its challenges with the Declaration of Umesh V.
`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 Chen et al. (“Chen”)
`(Ex. 1004).
`4 Jane C. Chandramouli & Keith G. Tolman, Prevention and Management
`of NSAID-Induced Gastropathy, 8 J. PHARM. CARE PAIN & SYMPTOM
`CONTROL 27–40 (2000) (“Chandramouli”) (Ex. 1011).
`3
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`References
`
`Basis
`
`Claims Challenged
`
`Chen and Gimet5
`Goldman6 and Gimet
`Goldman, Gimet, and
`Lindberg7
`Gimet, Chandramouli, and
`Phillips8
`
`§ 103(a)
`§ 103(a)
`
`1–6 and 13–15
`1–6 and 13–15
`
`§ 103(a)
`
`1–6 and 13–15
`
`§ 103(a)
`
`1–6 and 13–15
`
`C. The ’636 Patent (Ex. 1001)
`The ’636 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 unwanted side effects,
`especially gastrointestinal side effects, when administered as a treatment for
`pain” (id. at 1:24–26).
`
`
`5 U.S. Patent No. 5,698,225, issued December 16, 1997 to Gimet et al.
`(“Gimet”) (Ex. 1007).
`6 U.S. Patent No. 5,204,118, issued April 20, 1993 to Goldman et al.
`(“Goldman”) (Ex. 1010).
`7 U.S. Patent No. 5,877,192, issued March 2, 1999 to Lindberg et al.
`(“Lindberg”) (Ex. 1005).
`8 PCT Int’l Patent Appl. WO 00/26185, published May 11, 2000, by Phillips
`(“Phillips”) (Ex. 1012).
`
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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 patient to at least 3.5” (id. at 3:27–31),
`and an NSAID “in an amount effective 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 NSAID is delayed until after the pH in the GI
`tract has risen.
`In a preferred embodiment, the unit dosage form is a
`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
`of at least 3.5[.]
`Id. at 4:45–58.
`The claims of 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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`
`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 amount effective to raise
`the gastric pH of said patient to at least 3.5 upon the
`administration of one or more of said unit dosage forms;
`(b) naproxen present in an amount effective to reduce or
`eliminate pain or inflammation in said patient upon
`administration of one or more of said unit dosage forms;
`and wherein:
`i) said unit dosage form is a tablet in which said
`naproxen is present in a core;
`ii) said tablet comprises a coating, wherein said
`coating surrounds said core and does not release said
`naproxen until the pH of the surrounding medium is
`3.5 or higher; and
`iii) said esomeprazole is in one or more layers outside
`said core, wherein said one or more layers:
`A) do not include an naproxen;
`B) are not surrounded by 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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`II. ANALYSIS
`
`A. Claim Construction
`We determine that no claim term requires express construction for
`purposes of 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 NSAID and an amount of a proton pump inhibitor 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 number of suitable proton pump inhibitors (PPIs),
`and teaches “[i]n certain preferred embodiments, the proton pump inhibitor
`is omeprazole, either in racemic mixture or only the (-)enantiomer of
`omeprazole (i.e. esomeprazole).” Id. at 6:53–56. In addition, Chen lists
`naproxen among a large number of well-known examples of NSAIDs. Id. at
`5:58–6:31.
`According to Chen, “proton pump inhibitors are susceptible to
`degradation and/or transformation in acidic and neutral media,” and the half-
`life of “omeprazole in water solutions at pH-values less than three is shorter
`than ten minutes.” Id. at 8:9–17. Chen teaches “it is preferable that in an
`oral solid dosage form [proton pump inhibitors] be protected from contact
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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.” Id. at 8:19–23.
`Accordingly, Chen discloses an embodiment in 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.” Id. at
`12:4–7. Chen further discloses that:
`The dosage forms . . . may optionally be coated with one
`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-
`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-
`changes in the environmental fluid, 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 remainder of the
`dose, preferably the proton pump inhibitor, in another area of the
`GI tract, 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 gastrointestinal tract.
`Id. at 12:14–40.
`
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`2. Chandramouli (Ex. 1011)
`Chandramouli teaches that, “[d]ue to the asymptomatic nature of
`NSAID-induced GI toxicity . . . prevention is crucial.” Ex. 1011, 36. “Since
`NSAID-associated GI injury is dependent on the presence of acid,”
`Chandramouli suggests that “the prophylactic use of an H2 blocker seems
`reasonable.” Id. Chandramouli teaches that “[c]oncomitant use of these
`agents prevents duodenal ulcers, but not gastric ulcers, which are 3 to 4
`times more common . . . among NSAID users. Thus H2 blockade alone does
`not constitute an adequate preventive treatment.” Id. According to
`Chandramouli, proton pump inhibitors “suppress acid secretion to a greater
`degree than H2-receptor antagonists. Nevertheless, omeprazole is more
`effective against duodenal than gastric ulceration.” Id. Further according to
`Chandramouli, “[t]he OMNIUM study (Omeprazole versus Misoprostol for
`NSAID-Induced Ulcer Management) concluded however that omeprazole
`may be as effective or more effective than misoprostol for the prevention of
`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
`and duodenal ulceration,” “[s]ignificant dose-related diarrhea and abdominal
`pain limits its tolerability,” and “its use in women of childbearing potential
`is contraindicated.” Id. at 37. The reference also teaches that “[i]n an
`attempt to be more cost-effective, [misoprostol] . . . was combined with
`diclofenac (Arthrotec®),” and the “combination is as effective for arthritis
`
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`pain and symptoms as diclofenac alone with a decreased incidence of
`ulcers.” Id.
`
`3. Analysis
`Petitioner contends that 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 discloses an oral solid
`dosage form, e.g., a tablet, comprising a therapeutically effective amount of
`an NSAID and a proton pump inhibitor (PPI) in an amount effective 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 known in the art for reducing the risk of gastroduodenal injury
`associated with NSAID use. Id. 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.” Id.
`at 12 (citing Ex. 1004, 12:17–18), 13 (citing Ex. 1002 ¶¶ 33, 38, 55; Ex.
`
`10
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`1004, 12:27–32). Relying on Dr. Banakar’s testimony for support,
`Petitioner contends that it would have been obvious for one of ordinary skill
`in the art “to develop a . . . tablet with esomeprazole released before
`naproxen” (id. at 13 (citing Ex. 1002 ¶ 55)), specifically, “a core with
`naproxen surrounded by a pH-dependent enteric coating and non-enteric
`coated esomeprazole” (id. at 12 (citing Ex. 1004, 12:17–18)—essentially the
`reverse of Chen’s preferred formulation.
`Again relying on Dr. Banakar’s testimony, Petitioner contends that
`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.” Id. at 13 (citing Ex. 1002 ¶¶ 33, 38). Moreover, Petitioner
`contends that 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 exposed to gastric fluid. Id. at 14 (citing Ex.
`1002 ¶¶ 37, 38). That is, Petitioner, relying on Dr. Banakar’s testimony,
`contends that one of ordinary skill in the art “would know partial
`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 overcome by adjusting the dosage.”
`Id. at 14 (citing Ex. 1002 ¶ 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”
`
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`with a reasonable expectation that it would “be therapeutically effective.”
`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,9 which according to
`Petitioner, “compar[es] the bioavailability of non-enteric coated omeprazole
`when administered with and without a buffer and teaches a substantial
`portion of the uncoated omeprazole is bioavailable.” Pet. 15 (citing Ex.
`1002 ¶¶ 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 was not lost 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 ¶¶ 48–51, 59). Additionally, Petitioner contends that the Court of
`
`
`9 Å. Pilbrant & C. Cederberg, Development of an Oral Formulation of
`Omeprazole, 20 SCAND. J. GASTROENTEROL. 113–120 (1985) (“Pilbrant”)
`(Ex. 1008).
`
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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.’” Id. at 18 (citing Santarus, Inc. v. PAR Pharm., Inc., 694 F.3d
`1344, 1355–56 (Fed. Cir. 2012).
`We are not persuaded that 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 which is 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-independent coatings are as broad
`and generic as Petitioner contends. As discussed above in Section II.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-changes in the environmental fluid, e.g., the GI
` It is also possible and preferable to formulate
`tract.
`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 remainder of the dose, preferably the proton
`pump inhibitor, in another area of the GI tract, e.g., the small
`intestine.
`
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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 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 gastrointestinal tract.
`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 so that it is released the stomach. Id. 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 so that it is
`released further down the GI tract (where the pH is 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
`away from the reverse of its preferred embodiments, it does not follow that it
`provides a suggestion to do so, or a reasonable expectation of success.
`
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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. Banakar cites Exhibits 1006, 1020, 1021, and 1022—none of
`which were cited 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 ¶ 31. To the extent Exhibit 100610 is cited by
`Dr. Banakar and by Petitioner on page 16 of the Petition, its relevance to
`Petitioner’s position is unclear as the reference discloses repeated
`administration of “capsules of enteric-coated omeprazole granules.” Ex.
`1006, 707. In addition, Dr. Banakar cites Exhibit 1021 and 1016 (neither of
`which were cited in the Petition) in support of the contentions that it was
`known that PPIs “function by inhibiting H2 receptors in the parietal cells”
`which “are located in the duodenum, which is located immediately after the
`stomach within the GI tract,” and “NSAIDs, on the other hand, are absorbed
`later in the GI tract.” Ex. 1002 ¶ 33. 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 may be released simultaneously, or
`preferably later than the release of esomeprazole, in order to reduce the risk
`of NSAID-associated gastroduodenal injury,” without citing additional
`
`
`10 C.W. Howden et al., Effects of single and repeated doses of omeprazole
`on gastric acid and pepsin secretion in man, 25 GUT 707–10 (1984) (Ex.
`1006).
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`evidence in support thereof. Id. at ¶¶ 33, 38. Such conclusory statements by
`Petitioner and Dr. Banakar do not explain sufficiently, nor provide adequate
`support as to why one of ordinary skill in the art would have done the
`opposite of what Chen teaches in 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
`“obvious to try” are likewise inadequate to address this point. Pet. 13, 19.
`Nor are we persuaded that Pilbrant’s teachings, relied on by Petitioner
`and Dr. Banakar, would have led 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 degrades in the stomach.” Id. at 114. In addition, Pilbrant
`states that a “rapidly dissolving suspension of micronised omeprazole is the
`second best choice” to the enteric-coated dosage form. Id. 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.” Id. at 117.
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`Petitioner’s arguments regarding Pilbrant and Santarus do not
`acknowledge the distinction between a 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) suspensions of 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. As further stated by the court, “Pilbrant
`explicitly ‘ruled out’ the third option—non-enteric coated conventional oral
`dosage forms such as tablets, capsules, or granules—because they degrade
`too quickly in the stomach to be absorbed in sufficient amounts to be
`effective.” Id. In contrast, regarding the second option, Pilbrant “teaches
`that, although suspensions of 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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`Asserted Obviousness over Chen and Chandramouli
`Nor are we persuaded that 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 NSAIDs results
`in significant deleterious effects on the upper gastrointestinal tract,”
`including the small intestine, and that “PPIs such as omeprazole can be used
`to reduce the 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 naproxen in 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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`IPR2015-01774
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`4. Conclusion
`Having considered the arguments and evidence presented in the
`Petition, we are not persuaded that 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 rheumatoid arthritis,” but “also exhibit undesirable side effects.” Ex.
`1007, 1:20–24). “An especially undesirable side effect of the administration
`of NSAIDs is the ulcerogenic effects generally associated with chronic use.”
`Id. at 1:24–27. “NSAID induced ulcers in the stomach . . . generally exhibit
`few or no symptoms and may cause dangerous bleeding when undetected
`. . . [and] [i]n some instances . . . can prove fatal.” Id. at 1:29–33.
`According to Gimet, “[c]ertain prostaglandins have been shown to
`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.” Id. at 1:45–47.
`Gimet discloses a pharmaceutical composition comprising a tablet
`having an inner core and an outer mantle coating surrounding the inner core,
`
`19
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`IPR2015-01774
`Patent 8,852,636 B2
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`designed to “[counter] (by inhibiting, reducing or preventing) the
`ulcerogenic side effects attendant to NSAID administration.” Id. 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.
`
`
`Figure 2 of Gimet depicts tablet 16. Tablet 16 includes an NSAID—
`diclofenac or piroxicam—in inner 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.
`The enteric coating “can be formulated from any suitable enteric
`coating material,” and “aids in segregating the NSAID from the
`prostaglandin and in directing the dissolution of the NSAID core in the
`lower G.I. tract as opposed to the stomach.” Id. 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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`Petitioner relies on the arguments and evidence discussed above as 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.” Id. at 28.
`Petitioner acknowledges that the acid inhibitor disclosed in Gimet is a
`prostaglandin, but argues that person of ordinary skill in the art “would have
`known that like misoprostol, esomeprazole is an acid inhibitor that reduces
`the risk of NSAID-associated gastrointestinal injury by increasing the pH of
`the gastrointestinal environment to at least 3.5.” Id. at 27–28 (citing
`Ex. 1002 ¶ 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 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. 1007, 8:17–40, 12:4–40; Ex. 1008,
`114, 116–117.
`
`21
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`3. Conclusion
`Having considered the evidence and arguments presented in the
`Petition, we are not persuaded that 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 and Gimet.
`
`D. Claims 1–6 and 13–15—Asserted Obviousness over
`Goldman and Gimet
`1. Goldman (Ex. 1010)
`Goldman discloses “pharmaceutical compositions for treating the
`symptoms of 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.
`Goldman teaches that acceptable histamine receptor (H2) blockers include
`famotidine (id. at 3:27), acceptable proton pump inhibitors (PPIs) include
`omeprazole (id.), and acceptable NSAIDs include 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 acetaminophen or 200 mg ibuprofen, 60 mg of omeprazole, “and
`other auxiliary agents and colori
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