Trials@uspto.gov
`571-272-7822
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` Paper 22
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` Entered: December 8, 2015
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`COALITION FOR AFFORDABLE DRUGS VII LLC,
`Petitioner,
`
`v.
`
`POZEN INC.,
`Patent Owner.
`
`
`Case IPR2015-01241
`Patent 6,926,907 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
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` Paper 22
`
`
`
` Entered: December 8, 2015
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`COALITION FOR AFFORDABLE DRUGS VII LLC,
`Petitioner,
`
`v.
`
`POZEN INC.,
`Patent Owner.
`
`
`Case IPR2015-01241
`Patent 6,926,907 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
`
`
`
`
`
`
`
`IPR2015-01241
`Patent 6,926,907 B2
`
`
`I. INTRODUCTION
`
`The Coalition for Affordable Drugs VII LLC (“Petitioner”) filed a
`
`Petition (Paper 1, “Pet.”) on May 21, 2015, requesting an inter partes review
`
`of claims 1–23 of U.S. Patent No. 6,926,907 B2 (Ex. 1001, “the ’907
`
`patent”). Pozen Inc. (“Patent Owner”) filed a Preliminary Response (Paper
`
`15, “Prelim. Resp.”) on September 18, 2015.1, 2 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 1–23 of the ’907 patent. Accordingly, we decline to institute an inter
`
`partes review of those claims.
`
`
`
`
`
`
`1 Patent Owner filed an unopposed Motion for Extension of Time to File
`Preliminary Response. Paper 10. The motion was granted via an email from
`the Board dated September 4, 2015, and the due date for the Preliminary
`Response was extended until September 19, 2015.
`2 Patent Owner filed a Motion to File Under Seal its Preliminary Response
`and Exhibit 2011, an associated exhibit. Paper 16. Along with the Motion
`to Seal, Patent Owner filed a redacted version of the Preliminary Response
`to be available to the public. Paper 13.
`2
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`IPR2015-01241
`Patent 6,926,907 B2
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`A. Related Proceedings
`
`
`
`Petitioner represents it is aware of a number of judicial matters
`
`involving the ’907 patent (e.g., AstraZeneca AB v. Dr. Reddy’s Labs. Inc.,
`
`3:11-cv-02317 (D.N.J.)), as well as a number of judicial and administrative
`
`matters involving patents related to the ’907 patent (e.g., Dr. Reddy’s Labs.,
`
`Inc. v. Pozen Inc., Case IPR2015-00802 (PTAB)). Pet. 2–3. Patent Owner
`
`makes a similar representation. Paper 7, 8. After filing the current Petition,
`
`Petitioner also filed other Petitions for inter partes review involving patents
`
`related to the ’907 patent or directed to similar subject matter, including
`
`Case Nos. IPR2105-01344, IPR2015-01680, IPR2015-01718.
`
`B. The Asserted Grounds of Unpatentability
`
`
`
`Petitioner asserts the challenged claims are unpatentable on the
`
`following grounds. Pet. 12–60.3
`
`References
`
`Basis
`
`Claims Challenged
`
`Gimet4 and Chiverton5
`
`§ 103(a)
`
`1, 7, 8, 12, 13, 22,
`and 23
`
`
`3 Petitioner supports its challenge with the Declaration of Leon Shargel,
`Ph.D., R.Ph., executed May 25, 2015 (“Shargel Declaration”) (Ex. 1003).
`4 U.S. Patent No. 5,698,225, issued December 16, 1997 to Gimet et al.
`(“Gimet”) (Ex. 1004).
`5 S.G. Chiverton et al., Does misoprostol given as a single large dose
`improve its antisecretory effect?, 1 ALIMENT. PHARMACOL. 403–07 (1989)
`(“Chiverton”) (Ex. 1007).
`
`3
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`IPR2015-01241
`Patent 6,926,907 B2
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`
`References
`
`Basis
`
`Claims Challenged
`
`Gimet, Goldman,6 and
`Remington7
`Goldman, Remington, and
`Abe8
`Goldman, Remington, and
`Fitton9
`
`§ 103(a)
`
`1–5 and 7–23
`
`§ 103(a)
`
`1–5, 7–18, 21, and
`22
`
`§ 103(a)
`
`1, 5, and 6
`
`C. The ’907 Patent (Ex. 1001)
`
`The ’907 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)” (id. at 1:11–14), 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 1:14–18).
`
`
`6 U.S. Patent No. 5,204,118, issued April 20, 1993 to Goldman et al.
`(“Goldman”) (Ex. 1005).
`7 Robert E. King & Joseph D. Schwartz, Oral Solid Dosage Forms, in
`REMINGTON’S PHARMACEUTICAL SCIENCES 1603–32 (Alfonso R. Gennaro et
`al., eds.) (17th ed. 1985) (“Remington”) (Ex. 1006).
`8 Kazuo Abe et al., Effect of Oral and Intramuscular Famotidine on pH and
`Volume of Gastric Contents, 68 ANESTH. ANALG. 541–44 (1989) (“Abe”)
`(Ex. 1039).
`9 Andrew Fitton & Lynda Wiseman, Pantoprazole—A Review of its
`Pharmacological Properties and Therapeutic Use in Acid-Related
`Disorders, 51 DRUGS 460–82 (1996) (“Fitton”) (Ex. 1048).
`4
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`IPR2015-01241
`Patent 6,926,907 B2
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`
`Specifically, the ’907 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 3:18–22),
`
`and an NSAID “in an amount effective to reduce or eliminate pain or
`
`inflammation” (id. at 3: 40–41). “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 3:60–63.
`
`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, preferably at
`least 4 and more preferably, at least 5.
`
`Id. at 3:63–4:9.
`
`“The term ‘acid inhibitor’ refers to agents that inhibit gastric acid
`
`secretion and increase gastric pH.” Id. at 3:25–27. According to the ’907
`
`patent, preferred acid inhibiters are H2-blockers, such as famotidine (id. at
`
`3:28–30), and “[o]ther agents that may be effectively used include proton
`
`pump inhibitors such as . . . esomeprazole” (id. at 3:35–37).
`
`5
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`IPR2015-01241
`Patent 6,926,907 B2
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`
`D. Illustrative Claim
`
`Petitioner challenges claims 1–23 of the ’907 patent. Claim 1,
`
`reproduced below, is illustrative.
`
`1. A pharmaceutical composition in unit dosage[10] form
`suitable for oral administration to a patient, comprising:
`
`(a) an acid inhibitor 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) a non-steroidal anti-inflammatory drug (NSAID) 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 said unit dosage form provides for coordinated
`release such that:
`
`i) said NSAID is surrounded by a coating that, upon
`ingestion of said unit dosage form by said patient,
`prevents the release of essentially any NSAID from
`said dosage form unless the pH of the surrounding
`medium is 3.5 or higher;
`
`ii) at least a portion of said acid inhibitor is not
`surrounded by an enteric coating and, upon ingestion
`of said unit dosage form by said patient, is released
`regardless of whether the pH of the surrounding
`medium is below 3.5 or above 3.5.
`
`Ex. 1001, 20:8–31.
`
`
`10 As issued, claim 1 used the phrase “unit dose form,” but the phrase was
`corrected to read “unit dosage form” by Certificate of Correction entered
`December 25, 2007. Ex. 1028, 1.
`
`6
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`IPR2015-01241
`Patent 6,926,907 B2
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`
`II. ANALYSIS
`
`A. Claim Construction
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable construction in light of the
`
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`
`Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766 (Aug. 14,
`
`2012); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1275–79 (Fed. Cir.
`
`2015). Under that standard, claim terms are given their ordinary and
`
`customary meaning, as would be understood by one of ordinary skill in the
`
`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`
`F.3d 1249, 1257 (Fed. Cir. 2007).
`
`We determine that the only claim term requiring interpretation for
`
`purposes of this decision is “acid inhibitor.”
`
`Petitioner contends that the broadest reasonable interpretation of “acid
`
`inhibitor” in light of the specification includes prostaglandins, H2-blockers,
`
`and proton pump inhibitors (PPIs). Pet 10–11.
`
`
`
`Patent Owner contends that “the broadest reasonable interpretation of
`
`‘acid inhibitor’ excludes prostaglandins” because “the ’907 patent plainly
`
`distinguishes H2-blockers and PPIs, describing them as ‘acid inhibitors,’
`
`from synthetic prostaglandins, describing them as ‘cytoprotective agents.’”
`
`(Prelim. Resp. 8–9 (citing Ex. 1001, 1:40–44)). Patent Owner cites and
`
`compares passages of the specification in support of this proposition as
`
`follows:
`
`7
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`IPR2015-01241
`Patent 6,926,907 B2
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`
`(Compare Ex. 1001 at 1:40-44 (“In general, more potent and
`longer lasting acid inhibitors, such as proton pump inhibitors,
`are thought to be more protective during chronic administration
`of NSAIDs than shorter acting agents, e.g., histamine H2
`receptor antagonists . . . .”) with id. at 2:45-51 (“Other attempts
`to produce an NSAID therapy with less gastrointestinal toxicity
`have
`involved
`the
`concomitant
`administration of
`a
`cytoprotective agent” including ArthrotecTM which “contains
`misoprostol (a cytoprotective prostaglandin) and the NSAID
`diclofenac.”).)
`
`Prelim. Resp. 9.
`
`Nevertheless, the specification teaches that “[t]he term ‘acid inhibitor’
`
`refers to agents that inhibit gastric acid secretion and increase gastric pH”
`
`(Ex. 1001, 3:25–27), that preferred acid inhibiters are H2-blockers, such as
`
`famotidine (id. at 3:28–30), and “[o]ther agents that may be effectively used
`
`include proton pump inhibitors such as . . . esomeprazole” (id. at 3:35–37).
`
`Thus, the specification describes H2-blockers and PPIs as illustrative, rather
`
`than exclusive, acid inhibitors. Moreover, even if we assume arguendo that
`
`the specification distinguishes the claimed invention from ArthrotecTM (a
`
`composition comprising a combination of misoprostol and the NSAID
`
`diclofenac) (Prelim. Resp. 8–9), the distinction is not unambiguously based
`
`on the presence of misoprostol in the composition—it could just as well be
`
`that the amount of misoprostol in the composition is insufficient to raise
`
`gastric pH to 3.5 or more, as required by all the challenged claims.
`
`8
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`IPR2015-01241
`Patent 6,926,907 B2
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`Accordingly, we are not persuaded that the broadest reasonable
`
`interpretation of “acid inhibitor” excludes prostaglandins in general, or
`
`misoprostol in particular.
`
`B. Claims 1, 7, 8, 12, 13, 22, and 23—Asserted
`Obviousness over Gimet and Chiverton
`
`1. Gimet (Ex. 1004)
`
`
`
`Gimet teaches that NSAIDs have “high therapeutic value especially
`
`for the treatment of inflammatory conditions such as . . . osteoarthritis (OA)
`
`and rheumatoid arthritis” (id. at 1:20–22), but “also exhibit undesirable side
`
`effects” (id. at 1: 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,
`
`designed to “counter (by inhibiting, reducing or preventing) the ulcerogenic
`
`side effects attendant to NSAID administration.” Id. at 1:61–63. The inner
`
`9
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`IPR2015-01241
`Patent 6,926,907 B2
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`core consists of an NSAID—disclofenac or piroxicam—and the outer mantel
`
`consists of a prostaglandin—e.g., misoprostol. Ex. 1004, 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. 1004, 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.
`
`“When the prostaglandin is misoprostol . . . [it] is present in an
`
`amount from about 50 to about 500 mcg and preferably from about 100 to
`
`about 200 mcg.” Id. at 6:20–23.
`
`2. Chiverton (Ex. 1007)
`
`
`
`Chiverton teaches that “[m]isoprostol is a prostaglandin E1 analogue,
`
`currently prescribed as a q.d.s. dose regimen for the treatment of duodenal
`
`10
`
`
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`IPR2015-01241
`Patent 6,926,907 B2
`
`ulcer” (Ex. 1007, 404), and “is believed . . . [to] act[] primarily through its
`
`antisecretory activity rather than its cytoprotective effect” (id.). However,
`
`according to Chiverton, a study designed to determine whether the
`
`antisecretory effect of misoprostol could be improved by administering it as
`
`a single large dose “confirms that misoprostol is a weak, short-acting
`
`antisecretory drug” (id. at 405), and “raises the question of whether the
`
`positive effects on mucosal defense, induced by prostaglandins, might be
`
`more important for duodenal ulcer healing” (id. at 406–07).
`
`
`
`The results of Chiverton’s study are shown in Figures 1 and 2, and
`
`reproduced below.
`
`
`
`11
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`IPR2015-01241
`Patent 6,926,907 B2
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`Figures 1 and 2 of Chiverton are box whisker plots of total twenty-four hour
`
`gastric pH and night-time gastric pH, respectively, resulting from
`
`administration of misoprostol or placebo under various dosing regimens.11
`
`
`
`According to Chiverton, “only the 800 µg and 600 µg h.s. doses were
`
`significantly different from placebo” (id. at 406). Chiverton suggests that
`
`“the weak antisecretory action of misoprostol, seen here, raises the question
`
`of whether the positive effects on mucosal defense, induced by
`
`prostaglandins, might be more important for duodenal ulcer healing” (id. at
`
`406–07), for example, “an increase in thickness of the mucus gel layer could
`
`perhaps be of greater importance in the prophylaxis and treatment of
`
`NSAID-induced injury” (id. at 407).
`
`
`11 In Figures 1 and 2 of Chiverton, “q.d.s.” stands for quater die sumendus,
`i.e., four times a day; “h.s.” stands for hora somni, i.e., at bedtime.
`
`
`12
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`IPR2015-01241
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`3. Analysis
`
`
`
`With respect to claim 1, Petitioner contends that “Gimet teaches a unit
`
`dosage form suitable for administration that comprises an NSAID and an
`
`acid inhibitor (e.g. misoprostol), wherein the NSAID is present in an
`
`enterically-coated core and the acid inhibitor is present in a mantle coating
`
`surrounding the enterically-coated core.” Pet. 12 (citing Ex. 1003 ¶ 64).
`
`With respect to the claim’s requirement for “an acid inhibitor present
`
`in an amount effective to raise the gastric pH . . . to at least 3.5 upon the
`
`administration of one or more of said unit dosage forms,” Petitioner
`
`contends that “Gimet in view of Chiverton discloses this limitation.” Pet.
`
`13. That is, according to Petitioner, “[i]n considering the dosage and
`
`therapeutic effect upon administration of the acid inhibitor (e.g.,
`
`misoprostol) present in [Gimet’s] unit dosage form, a known method would
`
`be to look to related literature studying the therapeutic effect of the
`
`particular drug . . . to provide predictable results related to administering the
`
`drug.” Id. Petitioner contends a person of ordinary skill in the art, therefore,
`
`“would have been motivated to look to clinical studies showing results of
`
`misoprostol on gastric acid pH such as those shown in Chiverton to provide
`
`predictable results of an increase of gastric acid pH associated with the
`
`administration of . . . misoprostol.” Id. Petitioner contends that Chiverton
`
`discloses that misoprostol “‘acts primarily through its antisecretory
`
`activity[]’” (Pet. 14 (citing Ex. 1007, 404; Ex. 1003 ¶ 71)), and “further
`
`discloses that misoprostol can be dosed in an amount effective to raise
`
`13
`
`
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`IPR2015-01241
`Patent 6,926,907 B2
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`gastric pH to at least 3.5[]” (id. (citing Ex. 1007, 406, Fig. 2, Table 1; Ex.
`
`1003 ¶ 71)).
`
`
`
`Patent Owner contends that Gimet “does not disclose a dosage form
`
`comprising an acid inhibitor in an amount effective to raise the gastric pH of
`
`a patient to at least 3.5.” Prelim. Resp. 14. Patent Owner further contends
`
`that Chiverton “shows that the doses of prostaglandin taught by Gimet are
`
`insufficient to raise the gastric pH to 3.5” (id.), and “[e]ven [Chiverton’s]
`
`600 mcg and 800 mcg doses, doses greater than those taught by Gimet,
`
`failed to raise the mean pH to at least 3.5” (id.). Thus, Patent Owner argues
`
`that “neither Gimet nor Chiverton, either alone or in combination, provides
`
`any rationale for a dosage form comprising an acid inhibitor in an amount
`
`effective to raise the gastric pH of a patient to at least 3.5.” Id.
`
`First, we note that the challenged claims do not require raising the
`
`mean gastric pH to 3.5, and we agree with Petitioner that Chiverton suggests
`
`“that misoprostol can be dosed in an amount effective to raise gastric pH to
`
`at least 3.5.” Pet. 14. That is, we agree with Petitioner that Chiverton shows
`
`that it may be possible to raise gastric pH to 3.5 or higher, albeit unreliably,
`
`by administering a dose of misoprostol at the upper end or beyond the range
`
`disclosed by Gimet. For example, see the upper “whiskers” (i.e., vertical
`
`lines) for Chiverton’s 400 and 800 µg doses given h.s. on the box whisker
`
`plot shown in Figure 2 of Chiverton (Ex. 1007), and Gimet’s teaching of
`
`“about 50 to about 500 mcg” misoprostol (Ex. 1004, 6:20–23).
`
`14
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`
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`IPR2015-01241
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`Nevertheless, Petitioner has not explained adequately why one of
`
`ordinary skill in the art would have had a reason to formulate Gimet’s tablet
`
`to increase gastric (i.e., stomach12) and/or duodenal pH to at least 3.5 in the
`
`first place, when Gimet explicitly teaches that the enteric coating on its
`
`tablet “direct[s] the dissolution of the NSAID core in the lower G.I. tract as
`
`opposed to the stomach.” 13 Ex. 1004, 6:34–36 (emphasis added). We also
`
`note that Gimet states a preference for a lower dose of “about 100 to about
`
`200 mcg” misoprostol (id. at 6:20–23), a dose that Chiverton indicates
`
`would not raise gastric pH to 3.5 or higher (Ex. 1007, Figs. 1 and 2).
`
`Moreover, Petitioner does not point us to any discussion of gastric pH in
`
`
`12 “Gastric” is defined as “of or relating to the stomach” (see
`http://beta.merriam-webster.com/medical/gastric).
`13 We note Petitioner’s further assertion that
`
`[T]he POSA would know that a typical patient would have a pH
`in the small intestine after exiting the stomach of greater than
`about 3.5 . . . Thus, the POSA would have a rationale and a
`reasonable expectation of success in preparing a combination
`therapy, coordinated release, unit dosage form having a delayed
`release component, for example an enterically-coated drug
`(e.g., NSAID) to prevent the release of the drug from the
`dosage form unless the pH of the surrounding medium (e.g.,
`portions of the G.I. tract after exiting the stomach) is 3.5 or
`higher.
`
`Pet. 15 (citing Ex. 1033 ¶¶ 80–82).
`
`There is no dispute that Gimet discloses an enteric coating that
`prevents release of the NSAID before it reaches the lower G.I. tract—the
`claims, however, are directed to increasing gastric pH to at least 3.5.
`
`15
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`IPR2015-01241
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`Gimet (much less a discussion of pH as a factor in NSAID-associated
`
`ulcerogenesis).14 Nor does Petitioner point to anything in Chiverton which
`
`would suggest the desirability of increasing the dose of misoprostol in
`
`Gimet’s tablets in order to raise gastric pH to at least 3.5, especially as
`
`Chiverton suggests that “the weak antisecretory action of misoprostol . . .
`
`raises the question of whether the positive effects on mucosal defense,
`
`induced by prostaglandins, might be more important for duodenal ulcer
`
`healing than has been hitherto thought.” Ex. 1007, 406–07.
`
`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 to claim 1, or claims 7, 8, 12, 13, 22,
`
`and 23, which directly or indirectly depend from claim 1, on the basis of
`
`obviousness over Gimet and Chiverton.
`
`
`14 We note the statement in Petitioner’s background discussion of the state
`of the art that “since at least 1971, NSAIDs like aspirin and naproxen have
`been known to increase gastric acid production and, thus, increase the
`incidence of gastric ulcers.” Pet. 5 (citing Ex. 1003 ¶ 30). In support of this
`proposition, paragraph 30 of Exhibit 1003 (the Shargel Declaration) cites
`Exhibit 1011 (Valerie Vella, Drug-induced peptic ulcer disease, 10 JOURNAL
`OF THE MALTA COLLEGE OF PHARMACY PRACTICE 15–19 (2005) (“Vella”)).
`However, Vella discusses various deleterious effects of NSAIDs on gastric
`mucosa (attributed to, e.g., inhibition of prostaglandin synthesis, neutrophil-
`mediated injury, etc. (see Ex. 1011, 15–16)), but Dr. Shargel does not point
`to any discussion of gastric pH as a factor in the development of NSAID-
`induced gastric ulcers. Thus, Vella does not support adequately the link the
`link Petitioner and Dr. Shargel draw between gastric acid production and
`gastric ulcers.
`
`16
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`
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`IPR2015-01241
`Patent 6,926,907 B2
`
`
`C. Claims 1–5 and 7–23—Asserted Obviousness over
`Gimet, Goldman, and Remington
`
`1. Goldman (Ex. 1005)
`
`
`
`Goldman teaches that “the symptoms of overindulgence due to
`
`excessive or inappropriate intake of food and/or alcoholic beverage are well
`
`known and include headache as well as indigestion, upper abdominal
`
`discomfort, bloating, heartburn or pyrosis.” Ex. 1005, 1:28–32. “The
`
`treatment of the symptoms of overindulgence often requires the co-
`
`administration of an analgesic to relieve the headache along with an agent to
`
`reduce gastric acidity which is generally believed to cause the indigestion
`
`and heartburn.” Id. at 2:52–56.
`
`In order to “more effectively treat all the symptoms concurrently” (id.
`
`at 2:67–68), Goldman discloses “a pharmaceutical composition 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” (id. at 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).
`
`According to Goldman, “statistical methods are used to show that on
`
`the average, acetaminophen or non-steroidal inflammatory agents with H1
`
`histamine and/or H2 histamine receptor blocking drugs are more efficacious”
`
`in treating the symptoms of overindulgence. Id. at 5:51–65.
`17
`
`
`
`
`
`IPR2015-01241
`Patent 6,926,907 B2
`
`
`Finally, Goldman discloses “chewable and liquid dosage forms” (id.
`
`at 6:4–5), and further teaches that “[v]arious conventional techniques for
`
`preparing medicament tablets or caplets can be employed as would be
`
`known to those skilled in the art as is disclosed for example by Remington’s
`
`Pharmaceutical Sciences.”15 Ex. 1005, 6:26–30.
`
`2. Remington (Ex. 1006)
`
`
`
`Remington discusses generally the production of oral solid dosage
`
`forms, such as tablets and capsules, and the many considerations that
`
`influence the choice of a particular dosage form. Ex. 1006, 1603–33.
`
`Among the many dosage forms mentioned, Remington discusses various
`
`coated tablets, including enteric-coated tablets—“compressed tablets coated
`
`with substances that resist solution in gastric fluid but disintegrate in the
`
`intestine.” Id. at 1604. Remington teaches that “[e]nteric coatings can be
`
`used for tablets containing drug substances which are inactivated or
`
`destroyed in the stomach, for those which irritate the mucosa, or as a means
`
`of delayed release of the medication.” Id. Remington also teaches that
`
`tablets may be coated in order to “[r]educ[e] the risk of interaction between
`
`incompatible components . . . by using coated forms of one or more of the
`
`offending ingredients (particularly active compounds).” Id. at 1633.
`
`
`15 This is the same publication submitted as Exhibit 1006.
`
`18
`
`
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`
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`IPR2015-01241
`Patent 6,926,907 B2
`
`
`3. Analysis
`
`
`
`Petitioner contends that “[b]oth Gimet and Goldman are directed to
`
`pharmaceutical compositions comprising an NSAID and an acid inhibitor,
`
`and a POSA tasked with formulating an NSAID/acid inhibitor combination
`
`therapy would have considered their collective teachings on the subject.”
`
`Pet. 21 (citing Ex. 1003 ¶ 117). Petitioner contends:
`
`For example, the POSA would have substituted the NSAIDs
`and acid inhibitors in Gimet for other known NSAIDs and acid
`inhibitors
`in Goldman
`to obtain predictable
`results;
`alternatively, it would have been obvious to try Goldman’s
`NSAIDs and acid inhibitors with Gimet’s tablets; alternatively,
`Gimet has a teaching, suggestion, or motivation to be combined
`with Goldman. ([Ex. 1003 ¶ 117].) A POSA would have
`substituted Gimet’s prostaglandin with Goldman’s H2 blockers
`or PPIs to obtain predictable results of inhibiting gastric acid,
`particularly since Gimet discloses that “[w]hile prostaglandins
`are beneficial compounds and have found therapeutic usage,
`prostaglandins are generally considered highly unstable.” (Ex.
`1004, col. 1 ll. 51–53; Ex. 1003, ¶ 119.) Goldman discloses
`acid inhibitors other than the unstable prostaglandins, namely
`H2 blockers and PPIs, that are “more efficacious.” (Ex.1005,
`col. 5 ll. 64-65; Ex. 1003, ¶ 119.)
`
`Pet. 21.
`
`With respect to the challenged claims’ requirement for “an acid
`
`inhibitor present in an amount effective to raise the gastric pH . . . to at least
`
`3.5 upon the administration of one or more of said unit dosage forms,”
`
`Petitioner contends that “Gimet discloses this limitation.” Pet. 22.
`
`Petitioner contends that one of ordinary skill in the art “would know that a
`
`19
`
`
`
`
`
`IPR2015-01241
`Patent 6,926,907 B2
`
`typical patient would have a pH in the stomach in a range of from about 1.5
`
`to 3.5, and the POSA would know that the typical therapeutic effect of
`
`known acid inhibitors is to increase the gastric pH of the patient following
`
`the administration thereof.” Pet 23 (citing Ex. 1003 ¶ 130).
`
`Patent Owner contends, among other things, that “Gimet and
`
`Goldman seek solutions to two entirely different problems” in that “Gimet
`
`seeks a formulation that would reduce the gastric ulcers that are caused by
`
`chronic NSAID use . . . [while] Goldman discloses a formulation that can be
`
`used to alleviate the discomfort associated with overindulgence of food and
`
`alcohol.” Prelim Resp. 16–17 (citing Ex. 1004, 1:10–63; Ex. 1005 1:10–16).
`
`As in the challenge discussed above, Petitioner has not explained
`
`adequately why one of ordinary skill in the art would have had a reason to
`
`formulate Gimet’s tablet to increase gastric (i.e., stomach) and/or duodenal
`
`pH to at least 3.5 in the first place, when Gimet explicitly teaches that the
`
`enteric coating on its tablet “direct[s] the dissolution of the NSAID core in
`
`the lower G.I. tract as opposed to the stomach.” Ex. 1004, 6:34–36
`
`(emphasis added). Moreover, Petitioner does not point us to any discussion
`
`of gastric pH in Gimet (much less a discussion of pH as a factor in NSAID-
`
`associated ulcerogenesis). To the extent Petitioner contends that one of
`
`ordinary skill in the art “would know that a typical patient would have a pH
`
`in the stomach in a range of from about 1.5 [up] to 3.5” (Pet 23 (citing Ex.
`
`1003 ¶ 130)), we are not persuaded that Petitioner presents adequate support
`
`in the record for this point. For example, Chiverton (discussed above)
`
`20
`
`
`
`
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`IPR2015-01241
`Patent 6,926,907 B2
`
`shows total twenty-four hour gastric pH and night-time gastric pH values
`
`considerably below 3.5 in healthy volunteers in the absence of misoprostol
`
`administration. See Ex. 1007, Figures 1 and 2.
`
`Finally, to the extent Petitioner contends that Goldman provides “a
`
`specific teaching, suggestion, and motivation to look to conventional
`
`techniques for preparing medicament tablets as set forth in Remington . . .
`
`thereby providing a design incentive to prepare or improve tablets via known
`
`techniques including enteric and non-enteric coatings to yield predictable
`
`results” (Pet. 22 (citing Ex. 1005, 6:26–33; Ex. 1006, 1604, 1633; Ex. 1003
`
`¶ 122)), we are not persuaded. Remington’s generic discussion of enteric
`
`coatings adds little or nothing of relevance to Petitioner’s proposed
`
`combination of Gimet and Goldman. As discussed above, Gimet explicitly
`
`discloses an enteric coating which “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.” Ex. 1004, 6:29–30, 33–36.
`
`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 to claim 1, or claims 2–5 or 7–23,
`
`directly or indirectly dependent therefrom, on the basis of obviousness over
`
`Gimet, Goldman, and Remington.
`
`21
`
`
`
`
`
`IPR2015-01241
`Patent 6,926,907 B2
`
`
`D. Claims 1–5, 7–18, 21, and 22—Asserted Obviousness
`over Goldman, Remington, and Abe
`
`1. Abe (Ex. 1039)
`
`
`
`Abe teaches that famotidine “is a new, potent, highly selective H2-
`
`receptor antagonist.” Ex. 1039, 541. According to Abe, oral administration
`
`of famotidine “significantly increased the gastric pH and lowered the gastric
`
`volume” and “[t]he mean gastric pH in the famotidine-treated group[] was in
`
`the range of 5.7–7.2, which indicates that this drug effectively decreased
`
`gastric acid secretion.” Id. at 543.
`
`2. Analysis
`
`
`
`Claims 1–5, 7–18, 21, and 22 encompass dosage forms where the acid
`
`inhibitor is an H2-blocker, e.g., famotidine, or a PPI, e.g., omeprazole, and
`
`the NSAID is naproxen or piroxicam.
`
`Petitioner contends “[i]n considering the dosage and therapeutic effect
`
`upon administration of the acid inhibitor (e.g., famotidine) present in the unit
`
`dosage forms of Goldman, a known method would be to look to related
`
`literature studying the therapeutic effect of the particular drug . . . to provide
`
`predictable results related to selecting and administering the drug.” Pet. 39
`
`(citing Ex.
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