Paper 36
`Trials@uspto.gov
`571-272-7822 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 IPR2015-01773
`Patent 8,858,996 B2
`____________
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`
`
`
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`Trials@uspto.gov
`571-272-7822 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 IPR2015-01773
`Patent 8,858,996 B2
`____________
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`
`
`
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`IPR2015-01773
`Patent 8,858,996 B2
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`I.
`
`INTRODUCTION
`
`In this inter partes review, Lupin Ltd. and Lupin Pharmaceuticals Inc.
`(collectively, “Petitioner”) challenge the patentability of claims 1 and 3–11
`of U.S. Patent No. 8,858,996 B2 (Ex. 1001, “the ’996 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 and 3–11 (“the challenged
`claims”) of the ’996 patent are unpatentable. This Final Written Decision is
`entered pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`A. Procedural History
`
`Petitioner filed a Corrected Petition requesting an inter partes review
`of claims 1–19 of the ’996 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 and 3–11 of the ’996 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”).
`
`
`1
`Following our decision to institute on some, but not all, grounds
`presented in the Petition, Petitioner filed a Request for Rehearing. Paper 17.
`We denied the Request. Paper 32. We do not reconsider the arguments set
`forth in the Request for Rehearing because they are directed to the non-
`instituted grounds and/or non-instituted claims. Moreover, 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 C.F.R. §§ 42.104(b)(5), 42.23(b))).
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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 35 (“Tr.”).
`B. Related Matters
`The parties identify the following district court proceedings in which
`the ’996 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-
`MLC-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 of judicial and administrative matters
`involving patents related to the ’996 patent or directed to similar subject
`matter. Pet. 3–4; Paper 8, 8–9; PO Resp. 2.
`C. The ’996 Patent
`Non-steroidal anti-inflammatory drugs (“NSAIDs”) are “widely
`accepted as effective agents for controlling pain.” Ex. 1001 (col. 1, ll. 35–
`36). But their administration “can lead to the development of
`gastroduodenal lesions, e.g., ulcers and erosions, in susceptible individuals.”
`Id. (col. 1, ll. 37–38). 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, ll. 39–41).
`The ’996 patent discloses pharmaceutical 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 pain.” Ex. 1001 (col. 1, ll. 25–31).
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`Specifically, the ’996 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, ll. 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, ll. 46–49).
`The ’996 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, ll. 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, ll. 53–55). The ’996 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, ll. 56–63).
`“The term ‘acid inhibitor’ refers to agents that inhibit gastric acid
`secretion and increase gastric pH.” Id. (col. 3, ll. 38–40). According to the
`’996 patent, preferred acid inhibiters are H2-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
`typical amount of 5–100 mg. Id. (col. 3, ll. 40–51, col. 8, ll. 17–18).
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`The ’996 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, ll. 5–18).
`
`D. Illustrative Claim
`Claim 1, the only independent claim of the challenged claims, is
`illustrative of the claimed subject matter:
`1. A pharmaceutical composition in unit dosage form in the
`form of a tablet, said composition comprising:
`naproxen in an amount of 200–600 mg per unit dosage form;
`and
`esomeprazole in an amount of from 5 to 100 mg per unit
`dosage form,
`wherein 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
`of at least a portion of said naproxen is inhibited unless
`the pH of said medium is 3.5 or higher.
`Id. (col. 21, ll. 24–35) (emphasis added).
`
`E. Asserted Ground of Unpatentability
`We instituted an inter partes review of claims 1 and 3–11 of the ’996
`patent for unpatentability, under 35 U.S.C. § 103(a), for obviousness based
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`on a combination of the ’225 patent,2 Chandramouli,3 and WO ’185.4 Dec.
`39.
`
`II. DISCUSSION
`
`A. Principles of Law
`To prevail in challenging claims 1 and 3–11 of the ’996 patent,
`Petitioner must demonstrate by a preponderance of the evidence that the
`claims are unpatentable. 35 U.S.C. § 316(e); 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’l 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).
`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
`
`2
`U.S. Patent No. 5,698,225 (issued Dec. 16, 1997) (“the ’225 patent”)
`(Ex. 1013).
`
`Chandramouli et al., Prevention and management of NSAID-Induced
`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
`(“WO ’185”) (Ex. 1015).
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`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’l Co. v. Teleflex, Inc., 550 U.S. 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 Co., 383 U.S. 1, 17–18 (1966). A petitioner cannot
`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. 48–58. 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 WO ’185 renders the
`challenged claims obvious. Id. at 29–53 (citing Ex. 1002). Patent Owner
`challenges Petitioner’s contentions. PO Resp. 9–20. 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 and 3–11 are
`unpatentable under 35 U.S.C. § 103(a) for obviousness over the ’225 patent,
`Chandramouli, and WO ’185.
`
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`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 ¶ 26. Dr.
`Banakar explains that this definition is based on, inter alia, his evaluation of
`the ’996 patent and his “over 35 years of experience working in the field of
`formulating pharmaceutical compositions.” Id. at ¶ 26. 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 proposed 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
`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.
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`We therefore adopt Dr. Banakar’s definition of a person of ordinary
`skill in the art, as modified by Patent Owner’s addition, for our 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
`associated with NSAID therapy. Ex. 1008 (col. 1, ll. 37–40). Omeprazole
`exists as “a racemic mixture of its two single enantiomers, the
`(+)-enantiomer of omeprazole and the (-)-enantiomer of omeprazole,” i.e.,
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`esomeprazole. Id. (col. 1, ll. 61–64); see also Ex. 1007 (col. 6, ll. 53–58).
`No clinical difference exists between the two enantiomers. Ex. 1008 (col. 2,
`ll. 4–10).
`PPIs inhibit the secretion of gastric acid by “blocking the final step of
`acid production.” Ex. 1007 (col. 2, ll. 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 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, S14; see also id. at S15 (stating that once-daily dosing of PPI “results
`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, ll. 47–50); see also id. (col. 8, ll. 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. 2017, 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, ll. 18–40; col. 12, ll. 33–40); see also Ex. 1013 (col. 6, ll. 33–36) (stating
`that the enteric coating aids in directing the dissolution of the core substrate
`“in the lower G.I. 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, ll. 33–37). The prior art also taught that enteric
`coatings could be “formulated from any suitable enteric coating material,
`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, ll.
`29–33).
`
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`b. The ’225 patent
`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, ll. 20–24). “An especially undesirable side
`effect of the administration of NSAIDs is the ulcerogenic effects generally
`associated with chronic use.” Id. (col. 1, ll. 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. . . .
`[and] [i]n some instances . . . can prove fatal.” Id. (col. 1, ll. 29–33).
`According to the ’225 patent, “[c]ertain prostaglandins have been shown to
`prevent NSAID induced ulcers.” Id. (col. 1, ll. 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, ll.
`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,
`ll. 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, ll. 11–17, 39–47).
`
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`Figure 2 of the ’225 patent, reproduced below, depicts tablet 16 in
`cross-section.
`
`Figure 2 depicts tablet 16 in cross-section.
`
`
`
`Tablet 16 contains diclofenac or piroxicam (or their salts) in the inner
`core 18. Id. (col. 6, ll. 24–28). Enteric coating 20 surrounds core 18, and
`mantle 22—consisting of a prostaglandin, e.g., misoprostol—surrounds the
`coated inner core. Id. (col. 6, ll. 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. 29–38).
`
`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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`Chandramouli teaches that misoprostol works by replacing gastric
`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,
`misoprostol “is an abortifacient; therefore, its use in women of childbearing
`potential is contraindicated.” Id.
`Chandramouli continues that, because “NSAID-associated GI injury is
`dependent on the presence of acid, the prophylactic use of an H2 blocker
`seems reasonable.” Id. at 36. Chandramouli also states that PPIs “suppress
`acid secretion to a greater degree than H2-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. WO ’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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`To solve this problem, WO ’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
`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
`administration for the omeprazole solutions versus (~2–3 hours) following
`administration for the enteric coated pellets.” Id. at 19:23–20:1.
`WO ’185 teaches that in a preferred embodiment, “enterically-coated
`omeprazole particles are obtained from delayed release capsules,” and those
`“particles are mixed with a sodium bicarbonate (NaHCO3) solution which
`dissolves the enteric coating and forms an omeprazole solution/suspension.”
`Id. at 19:16–23. Specifically, WO ’185 discloses that the enteric-coated
`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
`antacid while the omeprazole is being absorbed.” Id. at 20:1–4.
`In addition to a solution or suspension, WO ’185 discloses dry
`formulations, such as a powder, tablet, capsule, or granules, in which the
`“dosage form is not enteric coated or time-released.” Id. at 57:17–24 (claim
`8), 16:24–17:7, 25:19–26:4, 26:26–27:9. Those solid formulations “then
`create the present invention when acted upon by a suitable vehicle, for
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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. 51–56. 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
`
`16
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`IPR2015-01773
`Patent 8,858,996 B2
`
`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 ¶ 34 (citing Ex. 1008, col. 1,
`ll. 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 ¶ 34 (citing Ex. 1008 (col. 2, ll. 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 WO ’185 to
`encompass the (-)-enantiomer, i.e., esomeprazole. Id.; see also Ex. 1007
`(col. 6, ll. 53–58) (“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.”
`
`17
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`IPR2015-01773
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`
`b. Motivation to combine the prior art references and reasonable
`expectation of success
`
`Even “[i]f all elements of the claims are found in a combination of
`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 pharmaceutical composition in the
`unit dosage form of a tablet containing naproxen (the NSAID) and
`esomeprazole (the PPI). Ex. 1001 (col. 21, ll. 25–30). 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. 21, ll. 31–35).
`According to Petitioner, claim 1 requires a combination tablet 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 ’996 patent
`claims a combination of 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
`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 4 (citing claim
`
`18
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`IPR2015-01773
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`1); see also Pet. 1 (“The challenged claims are directed to 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 a pharmaceutical composition
`containing an immediate-release esomeprazole and a delayed-release
`naproxen, based on a combination of the ’225 patent, Chandramouli, and
`WO ’185. See Reply 2 (stating that the prior art references “clearly point to
`the approach claimed in the ’996 patent – a tablet combining a rapid release
`esomeprazole with a delayed-release naproxen”); see also Pet. 25 (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 ’996 patent. Reply 5. We find the schematic useful for understanding
`Petitioner’s obviousness case and reproduce it here:
`
`19
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`IPR2015-01773
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`
`
`
`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, ll. 33–36). The outer layer, or mantle, is made
`up of a prostaglandin acid inhibitor (i.e., misoprostol). Id. (col. 2, ll. 1–2).
`The ’225 patent describes the prostaglandin as preferably “orally available.”
`Id. (col. 2, ll. 2–3). The right-hand schematic represents a tablet dosage
`form encompassed by claim 1 of the ’996 patent. Petitioner asserts that an
`ordinarily skilled artisan would have been motivated to prepare the claimed
`pharmaceutical composition by substituting
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