us to. 0V
`Trials
`571-272-7822
`
`Paper 37
`Entered: February 28, 2017
`
`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 IPR2015-01775
`
`Patent 8,865,190 B2
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`
`35 US. C. § 318(a) and 37 CFR. § 42. 73
`
`
`Trials
`571-272-7822
`
`Paper 37
`Entered: February 28, 2017
`
`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 IPR2015-01775
`
`Patent 8,865,190 B2
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`
`35 US. C. § 318(a) and 37 CFR. § 42. 73
`
`
`
`IPR2015-01775
`
`Patent 8,865,190 B2
`
`I.
`
`INTRODUCTION
`
`In this inter partes review, Lupin Ltd. and Lupin Pharmaceuticals Inc.
`
`(collectively, “Petitioner”) challenge the patentability of claims 1, 2, and 4—8
`
`ofU.S. Patent No. 8,865,190 B2 (Ex. 1001, “the ’190 patent”), assigned to
`
`Pozen Inc. (“Patent Owner”). We have jurisdiction under 35 U.S.C. § 6.
`
`For the reasons discussed below, we determine that Petitioner has not shown
`
`by a preponderance of the evidence that claims 1, 2, and 4—8 (“the
`
`challenged claims”) of the ’ 190 patent are unpatentable. This Final Written
`
`Decision is entered pursuant to 35 U.S.C. § 318(a) and 37 CPR. § 42.73.
`
`A. Procedural History
`
`Petitioner filed a Corrected Petition requesting an inter partes review
`
`of claims 1—8 of the ’190 patent. Paper 4 (“Pet”). Patent Owner filed a
`
`Preliminary Response. Paper 14 (“Prelim Resp”). On March 1, 2016, we
`
`instituted an inter partes review of claims 1, 2, and 4—8 of the ’190 patent on
`
`one asserted ground of unpatentability (i.e., Ground 4).1 Paper 15 (“Dec”).
`
`After institution, Patent Owner filed a Patent Owner Response to the Petition
`
`(Paper 22, “PO Resp”), and Petitioner filed a Reply (Paper 24, “Reply”).
`
`Following our decision to institute on some, but not all,- grounds
`1
`presented in the Petition, Petitioner filed a Request for Rehearing. Paper 17.
`We denied the Request. Paper 33. We do not reconsider the arguments set
`forth in the Request for Rehearing because those arguments are directed to
`claims and references not at issue in this inter partes review, and because
`Petitioner was required to make its obviousness case in the Petition—not the
`Request for Rehearing. See Ariosa Diagnostics v. Verinata Health, Inc, 805
`F.3d 1359, 1367 (Fed. Cir. 2015) (stating that the patent “challenger [is]
`obliged to make an adequate case in its Petition and the Reply [is] limited to
`a true rebuttal role.” (citing 37 CPR. §§ 42.104(b)(5), 42.23(b))).
`
`
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`IPR2015—01775 '
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`Patent 8,865,190 B2
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`An oral hearing was held on November 29, 2016. A transcript of the hearing
`
`has been entered into the record. Paper 36 (“Tr.”).
`
`B. Related Matters
`
`The parties identify the following district court proceedings in which
`
`the ’ 190 patent has been asserted: Horizon Pharma, Inc. v. Actavis
`Laboratories FL, Ltd, No. 3:15-cv—03322—MLC-DEA (D.N.J.); Horizon
`
`Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., No. 3:15-cv-03324-MLC-
`
`DEA (D.N.J.); Horizon Pharma, Inc. v. Lupin Ltd., No. 3:15-CV-03326-
`
`lVELC-DEA (D.N.J.); and Horizon Pharma, Inc. v. Mylan Pharmaceuticals,
`
`Inc., No. 3:15-cv-03327-MLC—DEA (D.N.J.). Pet. 3—4; Paper 8, 8. The
`
`parties also identify a number ofjudicial and administrative matters
`
`involving patents related to the ’190 patent or directed to similar subject
`
`matter. Pet. 3—4; Paper 8, 8—9; PO Resp. 2.
`
`C. The ’190 Patent
`
`Non-steroidal anti-inflammatory drugs (“NSAIDs”) are “widely
`
`accepted as effective agents for controlling pain.” Ex. 1001 (col. 1, 11. 35—
`
`36). But their administration “can lead to the development of
`
`gastroduodenal lesions, e.g., ulcers and erosions, in susceptible individuals.”
`
`Id. (col. 1, 11. 37—3 8). A “major factor contributing to the development of
`
`these lesions is the presence of acid in the stomach and upper small intestine
`
`of” those individuals. Id. (col. 1, 11. 39—41).
`
`The ’ 190 patent discloses pharmaceutical compositions, and processes
`
`for making those compositions, “that provide for the coordinated release of
`
`an acid inhibitor and a non-steroidal anti-inflammatory drug (NSAID),” such
`
`that there is “a reduced likelihood of causing unwanted side effects,
`
`especially gastrointestinal side effects, when administered as a treatment for
`
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`IPR2015-Ol775
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`Patent 8,865,190 B2
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`pain.” Ex. 1001 (col. 1, 11. 25—31); see also id. (col. 8, 1. 59—001. 9, l. 9).
`
`Specifically, the ’ 190 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. (col. 3, ll. 31—
`
`37), and an NSAID “in an amount effective to reduce or eliminate pain or
`
`inflammation,” id. (col. 4, 11. 3—5). “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. (col. 4, 1146—49).
`
`The ’ 190 patent teaches that the unit dosage form “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.” Id.
`
`(col. 4, 11. 49—53). Put differently, “the acid inhibitor is released first and the
`
`release of NSAID is delayed until after the pH in the GI tract has risen.” Id.
`
`(col. 4, 11. 53455). The ’190 patent continues:
`
`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,
`preferably at least 4 and more preferably, at least 5.
`
`Id. (col. 4, 11. 56—63).
`
`“The term ‘acid inhibitor’ refers to agents that inhibit gastric acid
`
`secretion and increase gastric pH.” Id. (col. 3, 11. 38—40). According to the
`
`’ 190 patent, preferred acid inhibiters are Hz-blockers, such as famotidine,
`
`but “[o]ther preferred agents that may be effectively used as acid inhibitors
`
`are the proton pump inhibitors such as .
`
`.
`
`. esomeprazole,” for example, in a
`
`
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`IPR2015-01775
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`Patent 8,865,190 B2
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`typical amount of 5—100 mg. Id. (col. 3, I]. 40—51, col. 8, 11. 17—18).
`
`The ’ 190 patent also discloses that the NSAID may be a number of
`
`different options, such as aspirin, acetaminophen, etc., where the “most
`
`preferred NSAID is naproxen in an amount of between 50 mg and 1500 mg,
`
`and more preferably, in an amount of between 200 mg and 600 mg.” Id.
`
`(col. 4, 11. 5—18).
`
`D. Illustrative Claim
`
`Claim 1, the only independent claim of the challenged claims, is
`
`illustrative of the claimed subject matter:
`
`1. A process for preparing a pharmaceutical composition in
`unit dosage form comprising therapeutically effective amounts
`of esomeprazole and naproxen, said process comprising the
`steps of:
`
`a) providing a first layer comprising said naproxen; and
`
`b) applying a second layer to said first layer, wherein said
`second layer comprises said esomeprazole,
`
`wherein said unit dosage form provides for release of said
`esomeprazole such that upon introduction of said unit
`dosage form into a medium, at least a portion of said
`esomeprazole is released regardless of the pH of the
`medium and release ofat least a portion ofsaid
`naproxen is inhibited unless the pH ofsaid medium is 3.5
`or higher.
`
`Id.
`
`(col. 21, l. 24—col. 22, l. 6) (emphasis added).
`
`E. Asserted Ground of Unpatentability
`
`We instituted an inter partes review of claims 1, 2, and 4—8 of the
`
`’190 patent for unpatentability, under 35 U.S.C. § 103(a), for obviousness
`
`
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`IPR2015-01775
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`Patent 8,865,190 B2
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`based on a combination of the ’225 patent,2 Chandramouli,3 and W0 ’185.4
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`Dec. 37.
`
`II.
`
`DISCUSSION
`
`A. Principles ofLaw
`
`To prevail in challenging claims 1, 2, and 4—8 of the ’190 patent,
`
`Petitioner must demonstrate by a preponderance of the evidence that the
`
`claims are unpatentable. 35 U.S.C. § 316(c); 37 C.F.R. § 42.1(d). “In an
`
`[inter partes review], the petitioner has the burden from the onset to show
`
`with particularity why the patent it challenges is unpatentable.” Harmonic
`
`Inc. v. Avid. Tech, Inc, 815 F.3d 1356, 1363 (Fed. Cir. 2016); see also 35
`
`U.S.C. § 312(a)(3) (requiring inter partes review petitions to identify “with
`
`particularity .
`
`.
`
`. the evidence that supports the grounds for the challenge to
`
`each claim”). That burden of persuasion never shifts to Patent Owner. See
`
`Dynamic Drinkware, LLC v. Nat ’1 Graphics, Inc, 800 F.3d 1375, 1378
`
`(Fed. Cir. 2015); see also In re Magnum Oil Tools Int’l, Ltd, 829 F.3d 1364,
`
`1375—78 (Fed. Cir. 2016) (discussing the burden of proof in inter partes
`
`review).
`
`US. Patent No. 5,698,225 (issued Dec. 16, 1997) (“the ’225 patent”)
`2
`(Ex. 1013).
`
`Chandramouli et al., Prevention and management ofNSAID-Ina’uced
`3
`Gastropathy, J. PHARM. PAIN AND SYMPTOM CONTROL, 8(4):27—40 (2000)
`(“Chandramouli”) (Ex. 1009).
`
`PCT Int’l Patent Appl. WO 00/26185 (published May 11, 2000)
`4
`(“WC ’185”) (Ex. 1015).
`
`
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`IPR2015-01775
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`Patent 8,865,190 B2
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`A claim is unpatentable for obviousness if, to one of ordinary skill in
`
`the pertinent art, “the differences between the subject matter sought to be
`
`patented and the prior art are such that the subject matter as a whole would
`
`have been obvious at the time the invention was made.” 35 U.S.C. § 103(a)
`
`(2006); see also KSR Int ’1 Co. v. Teleflex, Inc, 550 US. 398, 406 (2007).
`
`The question of obviousness is resolved on the basis of underlying factual
`
`determinations including: (1) the scope and content of the prior art; (2) any
`
`differences between the claimed subject matter and the prior art; (3) the level
`
`of ordinary skill in the art; and (4) objective evidence of nonobviousness.
`
`Graham v. John Deere C0,, 383 US. 1, 17—18 (1966). A petitioner cannot
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`satisfy its burden of proving obviousness by employing “mere conclusory
`
`statements.” Magnum Oil, 829 F.3d at 1380.
`
`B. Analysis
`
`Petitioner contends that the challenged claims are unpatentable under
`
`35 U.S.C. § 103(a) for obviousness over the combination of the ’225 patent,
`
`Chandramouli, and WO ’185. Pet. 39—45. Relying in part on the testimony
`
`of its declarant, Umesh V. Banakar, Ph.D., Petitioner asserts that the
`
`combination of the ’225 patent, Chandramouli, and W0 ’185 renders the
`
`challenged claims obvious. Id. at 39—47 (citing Ex. 1002). Patent Owner
`
`challenges Petitioner’s contentions. PO Resp. 9—19. In reply, Petitioner
`
`maintains its position. Reply 4—21.
`
`We have reviewed the Petition, Patent Owner’s Response, and
`
`Petitioner’s Reply, as well as the relevant evidence discussed in those
`
`papers. For the reasons that follow, we determine that Petitioner has not
`
`shown by a preponderance of the evidence that claims 1, 2, and 3—11 are
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`IPR201 5-01775
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`Patent 8,865,190 B2
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`unpatentable under 35 U.S.C. § 103(a) for obviousness over the ’225 patent,
`
`Chandramouli, and WO ’185.
`
`1. Level of Ordinary Skill
`
`The person of ordinary skill in the art is a hypothetical person who is
`
`presumed to have known the relevant art at the time of the invention. In re
`
`GPAC, Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995). Factors that may be
`
`considered in determining the level of ordinary skill in the art include, but
`
`are not limited to, the types of problems encountered in the art, the
`
`sophistication of the technology, and the educational level of active workers
`
`in the field. Id.
`
`Dr. Banakar, opines that a person of ordinary skill in the art “would
`
`include a pharmaceutical scientist having a Ph.D. degree in the field of
`
`pharmaceutical sciences or equivalent training or degree with at least two
`
`years of experience with pharmaceutical formulations.” Ex. 1002 11 26. Dr.
`
`Banakar explains that this definition is based on, inter alia, his evaluation of
`
`the ’ 190 patent and his “over 35 years of experience working in the field of
`
`formulating pharmaceutical compositions.” Id. Patent Owner does not
`
`directly challenge Dr. Banakar’s testimony as to the level of ordinary skill in
`
`the art, but claims that Petitioner’s definition should “extend to a person
`
`having a graduate degree in chemistry or chemical engineering.” PO Resp.
`
`5—6.
`
`We determine that the level of ordinary skill pr0posed by Petitioner is
`
`consistent with the challenged patent and the asserted prior art, which are
`
`directed to pharmaceutical compositions and methods for treating patients
`
`with those formulations. Nevertheless, we also agree with Patent Owner that
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`IPR2015-01775
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`Patent 8,865,190 B2
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`the ordinarily skilled artisan also may have a graduate degree in chemistry or
`
`chemical engineering, because as we discuss below, the interactions between
`‘ chemical compounds inform our obviousness analysis. See PO Resp. 5—6.
`
`We therefore adopt Dr. Banakar’s definition of a person having
`
`ordinary skill in the art, as modified by the Patent Owner’s addition, for the
`
`obvious analysis herein. Our analysis would be the same, however, if we
`
`did not include a person having a graduate degree in chemistry or chemical
`
`engineering within that definition.
`
`2. Prior Art and Knowledge of One of Ordinary Skill in the Art
`
`a. Background knowledge
`
`NSAIDs “cause gastrointestinal damage via topical injury of the
`
`mucosal barrier, systemic inhibition of prostaglandin synthesis or a
`
`combination of both.” Ex. 1009, 27 (Abstract). Because they are weak
`
`acids, NSAIDS “freely diffuse across the lipid membrane of the epithelial
`
`cell” at gastric pH of 1—2, become “trapped in .
`
`.
`
`. ionized form,” and
`
`promote the release of hydrogen ions. Id. at 32. “The bioconcentration of
`
`ionized NSAIDs and release of H+ causes epithelial cell necrosis and
`
`sloughing exposing mucosal structures to gastric acid, pepsin, and NSAID.”
`
`Id.
`
`Studies showed that patients taking concomitant doses of an agent that
`
`suppresses gastric acid secretion experienced improved NSAID tolerability.
`
`Id. at 36. Proton pump inhibitors (“PPIs”)——a particular class of acid
`
`inhibitors—were known in the art to “suppress acid secretion to a greater
`
`degree” than other known acid inhibitors. Id. The PPI omeprazole was
`
`known in the art as useful for the treatment of gastrointestinal disorders
`
`
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`IPR2015-01775
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`Patent 8,865,190 B2
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`associated with NSAID therapy. Ex. 1008 (col. 1, 11. 37—40). Omeprazole
`
`exists as “a racemic mixture of its two single enantiomers, the
`
`(+)-enantiomer of omeprazole and the (-)-enantiomer of omeprazole,” i.e.,
`
`esomeprazole. Id. (col. 1, 11. 61—64); see also Ex. 1007 (col. 6, 11. 53—58).
`
`No clinical difference exists between the two enantiomers. Ex. 1008 (col. 2,
`
`11. 4—10).
`
`PPIs inhibit the secretion of gastric acid by “blocking the final step of
`
`acid production.” Ex. 1007 (col. 2, 11. 57—60). Specifically, PPIs bind to the
`
`“proton pumps” (i.e., the H"/K+-ATPase enzyme) of parietal cells to “cause
`
`prolonged inhibition of gastric acid secretion.” Ex. 2009, 2. “The normal
`
`human stomach contains approximately 1 billion parietal cells that secrete
`
`hydrogen ions into the gastric lumen in response to various physiological
`
`stimuli.” Ex. 1022, S9. But PPIs do not affect resting parietal cells: “Acid
`
`catalysed activation of the drug is necessary, so only activated parietal cells
`
`will be inhibited, whereas resting parietal cells .
`
`.
`
`. will escape initial
`
`inhibition.” Ex. 2009, 3. The prior art also taught that PPIs were to be
`
`“given in association with food, so as to stimulate the parietal cell to make
`
`acid.” Ex. 2011, 6; see also Ex. 1022, S14 (stating that because PPIs “are
`
`most effective when the parietal cell is stimulated to secrete acid in response
`
`to a meal, these drugs should only be taken before or with a meal”).
`‘ As a consequence of the inability of PPIs to inhibit resting parietal
`
`cells, “[a]cid inhibition is not necessarily maximal after the first dose” of the
`
`PPI. Ex. 2009, 3; see also Ex. 1022, S14 (“Because all PPIs require
`
`accumulation and acid activation, their onset of inhibition is delayed .
`
`.
`
`. .”).
`
`Indeed, “[s]teady state [is] not achieved for several days” in clinical use. Ex.
`
`1022, 814; see also id. at S15 (stating that once-daily dosing of PPI “results
`
`10
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`IPR2015-01775
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`Patent 8,865,190 B2
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`in 66% steady-state inhibition of maximal acid output after 5 days”).
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`PPIs were well known in the art as “highly acid labile.” See, e. g.,
`
`Ex. 1007 (col. 4, 11. 47—50); see also id. (col. 8, 11. 9—16) (“For example, the
`
`half-life of omeprazole in water solutions at pH—values less than three is
`
`shorter than ten minutes”). Thus, the art generally taught that PPIs had to
`
`be protected from gastric acid by a protective coating (e.g., an enteric
`
`coating). See, e. g., Ex. 2019, 42 (“Proton pump inhibitors are inactivated by
`
`gastric acid and thus must be given as enteric-coated granules in gelatin
`
`capsules or enteric—coated tablets”); Ex. 2009, 3 (“The drugs are all acid-
`
`labile, so when administered orally they must be formulated in an enteric
`
`coating to protect them from rapid degradation in the stomach”).
`
`Enteric coatings were well known in the art as useful for preparing
`
`“delayed-release” formulations. Specifically, enteric coatings “provide acid
`
`resistance” to a substrate by inhibiting release of the substrate in the
`
`stomach, but then allow for the release of the substrate “in near neutral or
`
`alkaline media” found further down the gastrointestinal tract. Ex. 1007 (col.
`
`8, 11. 18—40; col. 12, 11. 33—40); see also Ex. 1013 (col. 6, 11. 33-36) (stating
`
`that the enteric coating aids in directing the dissolution of the core substrate
`
`“in the lower GI. tract as opposed to the stomach”). Conversely, non-
`
`enteric coated substrates comprise“immediate-release” formulations: the ‘
`
`unprotected substrates are released immediately in the stomach after
`
`ingestion. Ex. 1007 (col. 12, 11. 33—37). The prior art also taught that enteric
`
`coatings could be “formulated from any suitable enteric coating material,
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`many of which are known to those skilled in the art and many of which are
`
`employed for coating commercially available NSAIDs.” Ex. 1013 (col. 6, 11.
`
`29—33).
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`11
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`IPR2015—01775
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`Patent 8,865,190 B2
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`b. The ’225 patent
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`The ’225 patent 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. 1013 (col. 1, 11. 20—24). “An especially undesirable side
`
`effect of the administration of NSAIDs is the ulcerogenic effects generally
`
`associated with chronic use.” Id. (col. 1, 11. 24—27). The ’225 patent
`
`continues: “NSAID induced ulcers in the stomach .
`
`.
`
`. generally exhibit few
`
`or no symptoms and may cause dangerous bleeding when undetected. .
`
`.
`
`.
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`[and] [i]n some instances .
`
`.
`
`. can prove fatal.” 1d. (col. 1, 11. 29—33).
`
`According to the ’225 patent, “[c]ertain prostaglandins have been shown to
`
`prevent NSAID induced ulcers.” Id. (col. 1,11. 39—40). Misoprostol, for
`
`example, “is a pharmaceutically acceptable prostaglandin which has been
`
`accepted for use in the treatment of NSAID induced ulcers.” Id. (col. 1,
`
`11. 43—49).
`
`The ’225 patent discloses a pharmaceutical composition comprising a
`
`tablet having an inner core and an outer mantle surrounding the inner core,
`
`designed to “counter[] (by inhibiting, reducing or preventing) the
`
`ulcerogenic side effects attendant to NSAID administration.” Id. (col. 1, 11.
`
`61—63). The inner core consists of an NSAID (i.e., diclofenac or piroxicam
`
`or their salts) and the outer mantel consists of a prostaglandin (e.g.,
`
`misoprostol). Id. (col. 1,11. 11—17, 39—47).
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`12
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`Patent 8,865,190 B2
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`Figure 2 of the ’225 patent, reproduced below, depicts tablet 16 in
`
`cross-section.
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`
`
`Figure 2 depicts tablet 16 in cross-section.
`
`Tablet 16 contains diclofenac or piroxicam (or their salts) in the inner
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`core 18. Id. (col. 6, 11. 24—28). Enteric coating 20 surrounds core 18, and
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`mantle 22—consisting of a prostaglandin, e.g., misoprostol—surrounds the
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`coated inner core. Id. (col. 6, 11. 41—44). The ’225 patent teaches that the
`
`enteric coating “can be formulated from any suitable enteric coating
`
`material,” “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,” and also “aid[s] in the prevention of the
`
`degradation of the prostaglandin by the presence of the NSAID.” Id. (col. 6,
`
`ll. 7.9—3 8).
`
`c. Chandramouli
`
`Chandramouli is entitled “Prevention and Management of NSAID-
`
`Induced Gastropathy.” Ex. 1009, 27. Chandramouli states that
`
`“[g]astrointestinal complications from NSAID treatment are a major cause
`
`of morbidity and mortality,” and that “[p]roton pump inhibitors and
`
`misoprostol are the only agents proven beneficial in preventing GI adverse
`
`events from NSAIDs.” Id. at 27—28.
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`13
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`Chandramouli teaches that misoprostol works by replacing gastric
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`prostaglandins depleted by NSAID use. Id. at 37. “It prevents both gastric
`
`and duodenal ulceration.” Id. But, Chandramouli notes, “[s]ignificant dose-
`
`related diarrhea and abdominal pain limits its tolerability.” Id. Moreover,
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`misoprostol “is an abortifacient; therefore, its use in women of childbearing
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`potential is contraindicated.” Id.
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`Chandramouli continues that, because “NSAID-associated GI injury is
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`dependent on the presence of acid, the prophylactic use of an H2 blocker
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`seems reasonable.” Id. at 36. Chandramouli also states that PPIs “suppress
`
`acid secretion to a greater degree than Hz-receptor antagonists,” and that
`
`“[n]evertheless, omeprazole is more effective against duodenal than gastric
`
`ulceration.” Id. Chandramouli further states that a study called the
`
`“OMNIUM study (Omeprazole versus Misoprostol for NSAID-Induced
`
`Ulcer Management) concluded however that omeprazole may be as effective
`
`[as] or more effective than misoprostol for the prevention of NSAID-
`
`induced gastropathy.” Id.
`
`d. W0 ’185
`
`WO ’185 teaches that “[p]roton pump inhibitors such as omeprazole
`
`represent an advantageous alternative to the use of H2 antagonists, antacids,
`
`and sucralfate as a treatment for complications related to stress-related
`
`mucosal damage.” Ex. 1015, 8:12—15. But, WO ’185 explains, “in their
`
`current form (capsules containing an enteric-coated granule formulation of
`
`proton pump inhibitor), proton pump inhibitors can be difficult or
`
`impossible to administer to patients who are unable .
`
`.
`
`. to swallow tablets or
`
`capsules.” Id. at 8:15—22.
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`14
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`IPR2015-01775
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`Patent 8,865,190 B2
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`To solve this problem, W0 ’185 describes solutions and suspensions
`
`of PPIs, such as omeprazole, that “can be enterally delivered to a patient
`
`thereby providing the benefits of the proton pump inhibitor without the
`
`drawbacks of the current capsule dose form.” Id. at 8:22—26. Specifically,
`
`WO ’185 teaches “a pharmaceutical composition including a proton pump
`
`inhibitor in a pharmaceutically acceptable carrier including a bicarbonate
`
`salt of a Group IA metal.” Id. at 16:16—23. WO ’ 185 states that the
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`disclosed “omeprazole solution/suspension has significant pharmacokinetic
`
`advantages over standard time-release omeprazole capsules” including “a
`
`decreased drug absorbance time (~10 to 12 minutes) following
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`administration for the omeprazole solutions versus (~2—3 hours) following
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`administration for the enteric coated pellets.” Id. at 19:23—20: 1.
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`WO ’185 teaches that in a preferred embodiment, “enterically-coated
`
`omeprazole particles are obtained from delayed release capsules,” and those
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`“particles are mixed with a sodium bicarbonate (NaHCO3) solution which
`
`dissolves the enteric coating and forms an omeprazole solution/suspension.”
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`Id. at 19:16—23. Specifically, WO ’185 discloses that the enteric-coated
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`pellets of omeprazole “completely breakdown” within 30 minutes. Id. at
`
`35:8—10. WO ’185 explains that the sodium bicarbonate solution “protects
`
`the omeprazole from acid degradation prior to absorption” and “acts as an
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`antacid while the omeprazole is being absorbed.” Id. at 2021—4.
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`In addition to a solution or suspension, W0 ’185 discloses dry
`
`formulations, such as a powder, tablet, capsule, or granules, in which the
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`“dosage form is not enteric coated or time-released.” Id. at 57:17—24 (claim
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`8), 16:24—17:7, 25:19—2624, 26:26—-27:9. Those solid formulations “then
`
`create the present invention when acted upon by a suitable vehicle, for
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`15
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`IPR2015-01775
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`Patent 8,865,190 B2
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`example water.” Id. at 27:2—4. As stated in WO ’185, “[t]he water may be
`
`added either prior to ingestion or the dry formulation may be ingested first
`
`and then acted upon by the water utilized to swallow the solid formulation,”
`
`or a “third mechanism enables water in the stomach secretions to produce
`
`the present invention.” Id. at 27:4—9.
`
`3. Differences Between the Prior Art and the Claimed Invention
`
`a. The prior art discloses or suggests each and every
`element of the challenged claims
`
`Petitioner asserts that the prior art discloses or suggests each element
`
`of the challenged claims and presents a chart mapping the language of the
`
`claims to the disclosures of the ’225 patent, Chandramouli, and WO ’185.
`
`Pet. 41—45. We have reviewed Petitioner’s claim chart and find that a
`
`preponderance of the evidence supports Petitioner’s contention that the cited
`
`references collectively disclose or suggest each and every limitation of the
`
`challenged claims. We therefore adopt the claim chart as our own.
`
`Patent Owner challenges Petitioner’s argument only as to the claimed
`
`element “esomeprazole.” Specifically, Patent Owner points out that
`
`esomeprazole is not specifically disclosed in the ’225 patent, in
`
`Chandramouli, or in WO ’185. PO Resp. 10.
`
`Although Patent Owner is correct that none of the ’225 patent,
`
`Chandramouli, and WO ’185 explicitly recites esomeprazole, the case law is
`
`clear that “obviousness does not require the prior art to reach expressly each
`
`limitation exactly.” Beckson Marine, Inc. v. NFM Inc, 292 F.3d 718, 727
`
`(Fed. Cir. 2002). Both Chandramouli and WO ’ 185 disclose the PPI
`
`omeprazole and teach its use as an acid inhibitor. WO ’185 teaches that
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`16
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`IPR2015-01775
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`Patent 8,865,190 B2
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`omeprazole is a PPI that inhibits gastric acid secretion, and that omeprazole
`
`“is a logical choice for stress ulcer prophylaxis.” Ex. 1015, 4:8—15. And
`
`Chandramouli states that “omeprazole may be as effective [as] or more
`
`effective than misoprostol for the prevention of NSAID-induced
`
`gastropathy.” Ex. 1009, 36. Dr. Banakar states that the skilled artisan
`would have understood at the time of the invention that omeprazole existed
`
`as a racemic mixture of two enantiomers, with the S-enantiomer (or (—)-
`
`enantiomer) known as esomeprazole. Ex. 1002 11 34 (citing Ex. 1008 (col. 1,
`
`11. 50-55)). Dr. Banakar further states that the skilled artisan would have
`
`understood that esomeprazole had a similar therapeutic effect as omeprazole,
`
`less inter-individual variability, and was considered safe and effective for
`
`human administration. Ex. 1002 11 34 (citing Ex. 1008 (col. 2, 11. 4—12 &
`
`29—33), Ex. 1026 (621), Ex. 1029 (23)).
`
`We find that the evidence of record supports Dr. Banakar’s
`
`statements, and we credit his testimony that a skilled artisan would have
`
`understood the disclosure of omeprazole in Chandramouli and W0 ’185 to
`
`encompass the (-)-enantiomer, i.e., esomeprazole. 1d,; see also Ex. 1007
`
`(col. 6, 11. 53—5 8) (“In certain preferred embodiments, the proton pump
`
`inhibitor is omeprazole, either in racemic mixture or only the (-)—enantiomer
`
`of omeprazole (i.e., esomeprazole) .
`
`.
`
`.”). Thus, we find that the disclosure
`
`of omeprazole in Chandramouli and WO ’ 185, combined with the skilled
`
`artisan’s knowledge based on the prior art that esomeprazole is an active
`
`enantiomer form of the PPI, suffices to show that the prior art suggests the
`
`claim limitation “esomeprazole.”
`
`l7
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`b. Motivation to combine the prior art references and reasonable
`expectation ofsuccess
`
`Even “[i]f all elements of the claims are found in a combination of
`5, cc
`
`prior art references,
`
`the factfinder should further consider whether a
`
`person of ordinary skill in the art would [have been] motivated to combine
`
`those references, and whether in making that combination, a person of
`
`ordinary skill would have [had] a reasonable expectation of success.” Merck
`
`& Cie v. Gnosis S.P.A., 808 F.3d 829, 833 (Fed. Cir. 2015). The
`
`“motivation to combine” and “reasonable expectation of success” factors are
`
`subsidiary requirements for obviousness subsumed within the Graham
`
`factors. Pfizer, Inc. v. Apotex, Inc, 480 F.3d 1348, 1361 (Fed. Cir. 2007).
`
`As noted above, claim 1 recites a process for preparing a
`
`pharmaceutical composition in the unit dosage form of two layers: the first
`
`layer containing naproxen (the NSAID) and the second layer containing
`
`esomeprazole (the PPI). Ex. 1001 (col. 21, 11. 24—30). As claimed, “at least
`
`a portion of [the] esomeprazole is released regardless of the pH of the
`
`medium,” while “release of at least a portion of [the] naproxen is inhibited
`
`unless the pH of [the] medium is 3.5 or higher.” Id. (col. 22, 11. 1—6).
`
`According to Petitioner, claim 1 requires a process for preparing a
`
`composition that allows for the immediate release of non-enteric coated
`
`esomeprazole in the stomach and the delayed release of at least some portion
`
`of naproxen in the gastrointestinal tract. Specifically, Petitioner states that
`
`“[t]he ’190 patent claims the process of preparing a combination tablet
`
`containing an NSAID, naproxen, with an acid inhibitor, the PPI
`
`esomeprazole, in a single tablet,” and “[t]he tablet releases the drugs in two
`
`stages: the esomeprazole is immediately-released when the tablet is taken
`
`18
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`IPR2015-01775
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`Patent 8,865,190 B2
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`and at least some portion of naproxen is delayed from being released until
`
`the pH of the surrounding medium is 3.5 or greater.” Reply at 4—5 (citing
`
`claim 1); see also Pet. 1 (“The challenged claims are directed to a process
`
`for preparing a naproxen/esomeprazole combination tablet wherein at least a
`
`portion of the esomeprazole is not enteric coated and at least a portion of the
`
`naproxen is enteric coated so that esomeprazole is released immediately and
`
`naproxen is not released until a particular pH of the surrounding medium is
`
`reached.” (emphases added)).
`
`Petitioner presents its obviousness case as whether the ordinarily
`
`skilled artisan would have found obvious the claimed process for preparing a
`
`pharmaceutical composition containing an immediate-release esomeprazole
`
`and a delayed-release naproxen, based on a combination of the ’225 patent,
`
`Chandramouli, and W0 ’185. See Reply 2 (stating that the prior art
`
`references “clearly point to the approach claimed in the ’ 190 patent — a
`
`process for preparing a tablet combining a rapid release esomeprazole with a
`
`delayed-release naproxen”); see also Pet. 23 (stating that an ordinarily
`
`skilled artisan would have been motivated to create a combination tablet
`
`“with esomeprazole released first in the stomach followed by naproxen in
`
`the small intestine”).
`
`To aid its argument, Petitioner provides a schematic representation of
`
`the structure of the acid inhibitor-NSAID combination tablet disclosed in the
`
`’225 patent next to the acid inhibitor-NSAID combination tablet disclosed in
`
`the ’ 190 patent. Reply 5. We find the schematic useful for understanding
`
`Petitioner’s obviousness case and reproduce it here:
`
`19
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`IPR2015-01775
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`Patent 8,865,190 B2
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`Acid inhibitdr
`(misoprostol)
`
`
`
`_
`-
`ESE;
`
`,
`
`NSAID
`
`(NBPIOXEII)
`
`Add inhibimf
`(esomeprazole)
`
`Enteric
`Coating
`
`’225 patent
`
`”996 patent
`
`Id.
`
`As shown on the left side of Petitioner’s schematic, the dosage unit
`
`form disclosed in the ’225 patent is a tablet containing an NSAID core (i.e.,
`
`diclofenac or piroxicam) surrounded by an enteric coating. Id. The ’225
`
`patent teaches that the enteric coating protects the NSAID from the acidic
`
`environment of the stomach and delivers the NSAID into the lower G.I. tract
`
`for release. Ex. 1013 (col. 6, 11. 33—36). The outer layer, or mantle, is made
`
`up of a prostaglandin acid inhibitor (i.e., misoprostol). Id. (col. 2, 11. 1—2).
`
`The ’225 patent describes the prostaglandin as preferably “orally available.”
`
`Id. (col. 2, 11. 2—3). The right-hand schematic represents a tablet dosage
`
`form encompassed by claim 1 of the ’190 patent. Petitioner asserts that an
`
`ordinarily skilled artisan would have been motivated to prepare the claimed
`
`pharmaceutical composition by substituting the
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