Trials@uspto.gov
`571-272-7822
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` Paper 18
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` Entered: February 11, 2016
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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 IPR2015-01680
`Patent 8,852,636 B2
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.
`
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`571-272-7822
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`
`
`
`
` Paper 18
`
`
`
` Entered: February 11, 2016
`
`
`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 IPR2015-01680
`Patent 8,852,636 B2
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.
`
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`IPR2015-01680
`Patent 8,852,636 B2
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`
`I. INTRODUCTION
`
`The Coalition for Affordable Drugs VII LLC (“Petitioner”) filed a
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`Petition (Paper 2, “Pet.”) on August 7, 2015, requesting an inter partes
`
`review of claims 1–18 of U.S. Patent No. 8,852,636 B2 (Ex. 1001, “the ’636
`
`patent”). Pozen Inc. (“Patent Owner”) filed a Preliminary Response (Paper
`
`15, “Prelim. Resp.”) on November 17, 2015. We have jurisdiction under
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`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.”
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`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
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`claims 1–18 of the ’636 patent. Accordingly, we decline to institute an inter
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`partes review of those claims.
`
`A. Related Proceedings
`
`
`
`Petitioner represents it is aware of a number of judicial matters
`
`involving the ’636 patent (e.g., Horizon Pharma, Inc. v. Actavis Labs. Inc.,
`
`3:15-cv-03322 (D.N.J.)), as well as a number of judicial and administrative
`
`matters involving patents related to the ’636 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, 8–9. Petitioner also filed other
`
`Petitions for inter partes review involving patents related to the ’636 patent
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`2
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`IPR2015-01680
`Patent 8,852,636 B2
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`or directed to similar subject matter, including Case Nos. IPR2105-01241
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`and IPR2015-01344.
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`B. The Asserted Grounds of Unpatentability
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`
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`Petitioner asserts the challenged claims are unpatentable on the
`
`following grounds. Pet. 4–5, 12–60.1
`
`References
`
`Basis
`
`Claims Challenged
`
`Goldman,2 Remington,3 and
`Lindberg4
`Gimet,5 Goldman, and
`Lindberg
`
`§ 103(a)
`
`1–18
`
`§ 103(a)
`
`1–6 and 13–15
`
`Ouali6 and Lindberg
`
`§ 103(a)
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`7–12 and 16–18
`
`
`1 Petitioner supports its challenges with the Declaration of Leon Shargel,
`Ph.D., R.Ph., executed August 7, 2015 (“Shargel Declaration”) (Ex. 1003).
`
`2 U.S. Patent No. 5,204,118, issued April 20, 1993 to Goldman et al.
`(“Goldman”) (Ex. 1004).
`
`3 Robert E. King & Joseph D. Schwartz, Oral Solid Dosage Forms, in
`REMINGTON’S PHARMACEUTICAL SCIENCES 1603–43 (Alfonso R. Gennaro et
`al., eds.) (17th ed. 1985) (“Remington”) (Ex. 1005).
`
`4 U.S. Patent No. 5,714,504, issued February 3, 1998 to Lindberg et al.
`(“Lindberg”) (Ex. 1007).
`
`5 U.S. Patent No. 5,698,225, issued December 16, 1997 to Gimet et al.
`(“Gimet”) (Ex. 1006)
`
`6 U.S. Patent No. 6,183,779 B1, issued February 6, 2001 to Ouali et al.
`(“Ouali”) (Ex. 1008).
`
`3
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`IPR2015-01680
`Patent 8,852,636 B2
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`C. The ’636 Patent (Ex. 1001)
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`The ’636 patent, titled “PHARMACEUTICAL COMPOSITIONS FOR THE
`
`COORDINATED DELIVERY OF NSAIDS” discloses pharmaceutical
`
`compositions “that provide for the coordinated release of an acid inhibitor
`
`and a non-steroidal anti-inflammatory drug (NSAID)” (id. at 1:22–24), such
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`that there is “a reduced likelihood of causing unwanted side effects,
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`especially gastrointestinal side effects, when administered as a treatment for
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`pain” (id. at 1:24–26).
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`Specifically, the ’636 patent discloses “a pharmaceutical composition
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`in unit dosage form . . . contain[ing] an acid inhibitor present in an amount
`
`effective to raise the gastric pH of a patient to at least 3.5” (id. at 3:27–31),
`
`and an NSAID “in an amount effective to reduce or eliminate pain or
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`inflammation” (id. at 3:67–4:1). “The term ‘unit dosage form’ . . . refers to a
`
`single entity for drug administration. For example, a single tablet or capsule
`
`combining both an acid inhibitor and an NSAID would be a unit dosage
`
`form.” Id. at 4:42–45.
`
`A unit dosage form of the present invention preferably provides
`for coordinated drug release, in a way that elevates gastric pH
`and reduces the deleterious effects of the NSAID on the
`gastroduodenal mucosa, i.e., the acid inhibitor is released first
`and the release of NSAID is delayed until after the pH in the GI
`tract has risen.
`
`In a preferred embodiment, the unit dosage form is a
`multilayer tablet, having an outer layer comprising the acid
`inhibitor and an inner core which comprises the NSAID. In the
`most preferred form, coordinated delivery is accomplished by
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`4
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`IPR2015-01680
`Patent 8,852,636 B2
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`having the inner core surrounded by a polymeric barrier coating
`that does not dissolve unless the surrounding medium is at a pH
`of at least 3.5[.]
`
`Id. at 4:45–58.
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`The claims of the ’636 patent are directed to unit dosage forms where
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`the acid inhibitor is esomeprazole (id. at 3:46), and the NSAID is naproxen
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`(id. at 4:6).
`
`D. Illustrative Claim
`
`Petitioner challenges claims 1–18 of the ’636 patent, of which claims
`
`1 and 7 are independent. Claim 1, reproduced below, is illustrative.
`
`1. A pharmaceutical composition in unit dose form suitable for
`oral administration to a patient, comprising:
`
`(a) esomeprazole present in an amount effective to raise
`the gastric pH of said patient to at least 3.5 upon the
`administration of one or more of said unit dosage forms;
`
`(b) naproxen present in an amount effective to reduce or
`eliminate pain or inflammation in said patient upon
`administration of one or more of said unit dosage forms;
`
`and wherein:
`
`i) said unit dosage form is a tablet in which said
`naproxen is present in a core;
`
`ii) said tablet comprises a coating, wherein said
`coating surrounds said core and does not release said
`naproxen until the pH of the surrounding medium is
`3.5 or higher; and
`
`iii) said esomeprazole is in one or more layers outside
`said core, wherein said one or more layers:
`
`A) do not include an naproxen;
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`5
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`Patent 8,852,636 B2
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`B) are not surrounded by an enteric coating; and
`C) upon ingestion of said tablet by a patient,
`release said esomeprazole into said patient’s
`stomach.
`
`Ex. 1001, 21:22–43.
`
`Independent claim 7 is similar to claim 1, except that the unit dosage
`
`form is a capsule, instead of a tablet. Id. at 22:1–20.
`
`II. ANALYSIS
`
`A. Claim Construction
`
`We determine that no claim term requires express construction for
`
`purposes of this Decision.
`
`B. Claims 1–18—Asserted Obviousness over Goldman,
`Remington, and Lindberg
`
`1. Goldman (Ex. 1004)
`
`
`
`Goldman teaches that “[t]he 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. 1004, 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 “pharmaceutical compositions for treating
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`IPR2015-01680
`Patent 8,852,636 B2
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`the symptoms of overindulgence . . . [comprising] a combination of non-
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`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”
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`in treating the symptoms of overindulgence. Id. at 5:61–65.
`
`Finally, Goldman discloses “chewable and liquid dosage forms” (id.
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`at 6:4–5), and further teaches that “[v]arious conventional techniques for
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`preparing medicament tablets or caplets can be employed as would be
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`known to those skilled in the art as is disclosed for example by Remington’s
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`Pharmaceutical Sciences.”7 Ex. 1004, 6:26–30.
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`2. Remington (Ex. 1005)
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`
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`Remington discusses generally the production of oral solid dosage
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`forms, such as tablets and capsules, and the many considerations that
`
`influence the choice of a particular dosage form. Ex. 1005, 1603–43.
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`Among the many dosage forms mentioned, Remington discusses various
`
`
`7 This is the same publication submitted as Exhibit 1005.
`
`7
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`IPR2015-01680
`Patent 8,852,636 B2
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`coated tablets, including enteric-coated tablets—“compressed tablets coated
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`with substances that resist solution in gastric fluid but disintegrate in the
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`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. The reference
`
`further states that enteric coatings “can be used to give a simple repeat-
`
`action effect where unprotected drug coated over the enteric coat is released
`
`in the stomach, while the remainder, being protected by the coating, is
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`released further down the gastrointestinal tract.” Id. at 1637.
`
`
`
`3. Lindberg (Ex. 1007)
`
`
`
`Lindberg discloses omeprazole and its optically pure crystalline
`
`enantiomeric salts, including a magnesium salt of S-omeprazole,
`
`esomeprazole,8 in the form of a “dosage unit.” Ex. 1007, 1:57–63, 5:25–27.
`
`Lindberg further discloses that “oral and parenteral dosages will be in the
`
`range of 5 to 500 mg per day of active substance.” Ex. 1007, 6:24–25.
`
`Lindberg teaches that “[o]meprazole and its alkaline salts are effective
`
`
`8 See, e.g., Exhibit 1003 ¶ 32 (citing Ex. 1023, 33) (“esomeprazole . . . is the
`enantiopure (S)-isomer of omeprazole).
`8
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`IPR2015-01680
`Patent 8,852,636 B2
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`gastric acid secretion inhibitors, and are useful as antiulcer agents.” Id. at
`
`1:22–23. Lindberg states that its “novel salts of single enantiomers of
`
`omeprazole” provide “improved pharmacokinetic and metabolic properties.”
`
`Id. at 1:50–55.
`
`In addition, Lindberg teaches that granules, tablets and capsules of
`
`“the optically pure compound” (i.e., esomeprazole) “may be coated with an
`
`enteric coating which protects the active compound from acid catalyzed
`
`degradation as long as the dosage form remains in the stomach.” Id. at
`
`5:26–27, 36–39; see also 48–49, 56–57.
`
`4. Analysis
`
`
`
`Petitioner contends that Goldman discloses the combined use of acid
`
`inhibitors with NSAIDs, such as naproxen, to prevent the incidence of
`
`gastric ulcers and bleeding resulting from the use of the NSAIDs. Pet. 11
`
`(citing Ex. 1003 ¶ 64). Petitioner also argues that an ordinary artisan would
`
`have known that “acid inhibitors are a well-known class of drugs that
`
`provide gastric acid inhibiting efficacy.” Id. Thus, according to Petitioner,
`
`an ordinary artisan would have had a reason, with a reasonable expectation
`
`of success, for “substituting different acid inhibitor compounds into a given
`
`combination therapy formulation,” including substituting with “more
`
`effective compounds, such as PPIs, over previously known, less
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`therapeutically effective compounds, such as prostaglandins and H2
`
`blockers.” Id. at 11–12 (citing Ex. 1003 ¶ 65). In addition, according to
`
`Petitioner, it would have been obvious to substitute Lindberg’s PPI,
`
`9
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`IPR2015-01680
`Patent 8,852,636 B2
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`esomeprazole, for Goldman’s PPI, omeprazole, because it was known that
`
`the “enantiomeric magnesium salt of omeprazole” would have provided
`
`“improved pharmacokinetic and metabolic properties.” Id. at 12 (citing Ex.
`
`1007, 1:50–63; Ex. 1003 ¶ 65).
`
`Petitioner also contends that Goldman would have provided an
`
`ordinary artisan with a reason “to look to conventional techniques for
`
`preparing medicament tablets as set forth in Remington,” which Goldman
`
`incorporates by reference. Id. at 11, 15, 23. Petitioner points to
`
`Remington’s teaching that an enteric coating can be used to give an effect
`
`“where unprotected drug . . . coated over the enteric coat is released in the
`
`stomach, while the remainder . . . , being protected by the coating, is
`
`released further down the gastrointestinal tract.” Id. at 16 (citing Ex. 1005,
`
`1637; Ex. 1003 ¶ 86), 25. Petitioner also contends that Remington teaches
`
`using enteric coatings to delay the release of drugs, such as those that “may
`
`cause nausea or bleeding by irritating the gastric mucosa (eg, aspirin . . .),”
`
`and that many enteric coatings “remain undissociated in the low pH
`
`environment of the stomach, but readily ionize when the pH rises to about 4
`
`or 5.” Id. at 15 (citing Ex. 1005, 1637; Ex. 1003 ¶ 84), 22–23.
`
`Patent Owner responds that Goldman “does not disclose formulations
`
`with an immediate release acid inhibitor and a delayed release NSAID that
`
`would provide coordinated release,” or that “coordinated release of an acid
`
`inhibitor with an NSAID is in any way desirable.” Prelim. Resp. 15. Patent
`
`10
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`Owner further argues that Remington and Lindberg, individually or
`
`collectively, “do[] not cure this deficiency” (id.).
`
`Patent Owner contends that neither Lindberg nor Remington teaches
`
`or suggests non-enteric-coated esomeprazole, as required by the claims. Id.
`
`at 16. In particular, Patent Owner contends that “Lindberg teaches enteric
`
`coated esomeprazole to protect it from the acidic environment of the
`
`stomach” (id.), in that it states that granules and tablets [and capsules] of
`
`esomeprazole “may be coated with an enteric coating which protects the
`
`active compound from acid catalyzed degradation as long as the dosage form
`
`remains in the stomach” (id. (citing Ex. 1007, 5:36–39, 48–50, 56–57)).
`
`Similarly, Patent Owner contends that an ordinary artisan would have coated
`
`a PPI like esomeprazole with an enteric coating, rather than use non-enteric
`
`coated esomeprazole, because “PPIs were well known in the art to be acid
`
`labile” (id. at 17, 21 (citing Ex. 2008, 3; Ex. 2009, 2; 2010, 5)), and
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`Remington teaches “that enteric coated tablet formulations are used with
`
`acid labile drug substances” (id. at 16 (citing Ex. 1005, 1604)).
`
`We agree that Petitioner has not established that the teachings of
`
`Goldman, Remington, and Lindberg would have given an ordinary artisan a
`
`reason to formulate a tablet or capsule with the structural and functional
`
`features required by the challenged claims. Although Goldman discloses a
`
`combination dosage form comprising a PPI and an NSAID (discussed
`
`above), Petitioner does not point to anything in Goldman that describes or
`
`suggests adequately why one would have prepared, for any reason, a
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`IPR2015-01680
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`composition as claimed, where at least some PPI (i.e., esomeprazole) is
`
`released regardless of pH and the release of at least some NSAID (i.e.,
`
`naproxen) is inhibited unless the pH is 3.5 or higher (e.g., via a coating).
`
`Moreover, although Goldman incorporates Remington’s discussion of
`
`oral solid dosage forms by reference (Ex. 1004, 6:26–33), Petitioner does
`
`not identify anything in Goldman that points to any particular dosage form
`
`among the many disclosed by Remington. Goldman’s citation to Remington
`
`generally in relation to “[v]arious conventional techniques for preparing
`
`medicament tablets or caplets” does not persuade us that an ordinary artisan
`
`would have made the connection that Petitioner contends. Id.; Pet 11, 14–
`
`16, 21–27. Nor does Petitioner explain adequately how Lindberg remedies
`
`the deficiencies discussed above in relation to Goldman and Remington.
`
`Having considered the evidence and arguments presented in the
`
`Petition, we are not persuaded that Petitioner has established a reasonable
`
`likelihood of prevailing in its challenge of independent claims 1 and 7, or
`
`their dependent claims, on the basis of obviousness over Goldman,
`
`Remington, and Lindberg.
`
`C. Claims 1–6 and 13–15—Asserted Obviousness over
`Gimet, Goldman, and Lindberg
`
`1. Gimet (Ex. 1006)
`
`
`
`Gimet teaches that NSAIDs have “high therapeutic value especially
`
`for the treatment of inflammatory conditions such as . . . osteoarthritis (OA)
`
`and rheumatoid arthritis,” but “also exhibit undesirable side effects.” Ex.
`
`12
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`1006, 1:20–24). “An especially undesirable side effect of the administration
`
`of NSAIDs is the ulcerogenic effects generally associated with chronic use.”
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`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 1:11–14,
`
`61–63. The inner core consists of an NSAID—disclofenac or piroxicam—
`
`and the outer mantel consists of a prostaglandin—e.g., misoprostol. Id. at
`
`1:11–17, 39–47.
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`13
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`Figure 2 of Gimet, reproduced below, depicts tablet 16 in cross-
`
`section.
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`
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`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. 1006, 6:24–44.
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`The enteric coating “can be formulated from any suitable enteric
`
`coating material,” and “aids in segregating the NSAID from the
`
`prostaglandin and in directing the dissolution of the NSAID core in the
`
`lower G.I. tract as opposed to the stomach.” Id. at 6:29–30, 33–36.
`
`2. Analysis
`
`
`
`Petitioner contends that an ordinary artisan would have known that
`
`both Gimet and Goldman disclose a combination therapy oral unit dosage
`
`form comprising an acid inhibitor (e.g., misoprostol, a prostaglandin, in
`
`Gimet) in combination with an NSAID (e.g., naproxen in Goldman). Pet. 34
`
`(citing Ex. 1003 ¶¶ 196, 197). In relation to naproxen, Petitioner also argues
`
`that an ordinary artisan would have had a reason, as well as a reasonable
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`expectation of success, to substitute different NSAID compounds—i.e., to
`
`replace diclofenac or piroxicam in Gimet’s composition, as shown in Figure
`
`2, with naproxen disclosed in Goldman—“because doing so would be a
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`simple substitution of one known element for another to obtain predictable
`
`results.” Id. at 35 (citing Ex. 1003 ¶ 198).
`
`The only evidence that Petitioner cites for its assertion regarding
`
`“predictable results” in relation to NSAIDs is Dr. Shargel’s Declaration at
`
`paragraph 198, which repeats the statements presented in the Petition on this
`
`point, without citing any evidence itself. Id. Conclusory assertions by
`
`Petitioner, merely repeated in conclusory and unsupported statements by an
`
`expert witness in support, are not persuasive here. See 37 C.F.R. § 42.65(a)
`
`(“Expert testimony that does not disclose the underlying facts or data on
`
`which the opinion is based is entitled to little or no weight.”).
`
`In relation to esomeprazole, Petitioner also argues an ordinary artisan
`
`would have had a reason, with a reasonable expectation of success, to
`
`substitute different acid inhibitors—i.e., to replace misoprostol in Gimet’s
`
`composition with the esomeprazole disclosed in Lindberg—“where the acid
`
`inhibitor compound contributes its individual therapeutic attributes (e.g.,
`
`acid inhibition and gastric pH raising) to the combination.” Pet. 35–36
`
`(citing Ex. 1003 ¶ 199). Petitioner further contends that an ordinary artisan
`
`would have had a reason, with a reasonable expectation of success, “in
`
`employing more recently obtained and therapeutically more effective
`
`compounds, such as PPIs, over previously known, less therapeutically
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`effective compounds, such as prostaglandins and H2 blockers.” Id. at 36
`
`(citing Ex. 1003 ¶ 200).9
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`Petitioner also argues that it would have been obvious to select
`
`“Lindberg’s disclosed PPI esomeprazole and substitute it for Gimet’s
`
`disclosed acid inhibitor (prostaglandin) because Goldman specifically
`
`teaches that ‘[p]roton pump inhibitors have been recently introduced as
`
`effective gastric acid inhibitors.’” Id. at 36 (citing Ex. 1004, 1:25–27;
`
`Ex. 1003 ¶ 200). Petitioner also points to teachings in Lindberg indicating
`
`that its “novel salts of single enantiomers of omeprazole” provide “improved
`
`pharmacokinetic and metabolic properties” and “high stability against
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`racemization.” Id. at 36–37 (quoting Ex. 1007, 1:50–63, 3:48–55) (citing
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`Ex. 1003 ¶ 200), 38 (citing Ex. 1007, 1:50–63; Ex. 1003 ¶ 207).
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`In response, Patent Owner points to a number of references indicating
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`that an ordinary artisan would have understood that PPIs were acid labile
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`and should be protected from degradation in acidic environments, such as
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`the stomach. Prelim. Resp. 20–24 (citing Ex. 2003, 15, 17; Ex. 2008, 3;
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`Ex. 2009, 2; Ex. 2010, 5; Ex. 1041, 114, 115, 117). For example, a review
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`article by Stedman et al., published in 2000, comparing the
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`“pharmacokinetics, acid suppression and efficacy of proton pump
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`inhibitors,” indicates that PPIs “are all acid-labile, so when administered
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`9 In support of these contentions, Petitioner once again cites paragraphs in
`Dr. Shargel’s Declaration that simply repeat statements presented in the
`Petition on these points, without citing supporting evidence themselves. Pet.
`35–36 (citing Ex. 1003 ¶¶ 199, 200).
`16
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`orally they must be formulated in an enteric coating to protect them from
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`rapid degradation in the stomach. They are rapidly absorbed in the
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`duodenum.” Ex. 2008, 1 (Title), 3. Similarly, in an article published in
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`1992, Bell et al. state in relation to the related parent compound of
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`esomeprazole: “As omeprazole is acid-labile, it is formulated as enteric-
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`coated granules dispensed in a gelatine capsule.” Ex. 2009, 2.
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`In addition, in an article published in 1985, Pilbrant et al. teach that
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`“[o]meprazole degrades very rapidly in water solutions at low pH-values.”
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`Ex. 1041, 113. In this context, Pilbrant et al. teach the use of an “enteric-
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`coated dosage form, which releases omeprazole for absorption in the small
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`intestine,” while stating that a conventional oral dosage “was ruled out”
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`because “more than half of the omeprazole in a rapidly dissolving dosage
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`form degrades in the stomach.” Id. at 114.
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`As an initial matter, we are not persuaded that Petitioner establishes
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`adequately that esomeprazole administered in a non-enteric-coated form
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`(thereby allowing it to be released regardless of pH) would have obtained
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`“improved pharmacokinetic, metabolic, and therapeutic properties” as
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`compared to misoprostol in any formulation. Pet. 37–38 (citing Ex. 1007,
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`1:50–63; Ex. 1003 ¶ 207). For example, we are not persuaded that Lindberg
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`indicates such an improvement. Rather, Lindberg suggests that
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`esomeprazole may have improved properties over omeprazole (a related
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`PPI). Ex. 1007, 1:17–63.
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`17
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`Moreover, even if we assume that one would have understood that
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`prostaglandins and H2 blockers were “less therapeutically effective
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`compounds” than PPIs (Pet. 36), Petitioner has not explained adequately
`
`why one would have had reason to make the composition taught in Gimet,
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`e.g., in Figure 2, with a PPI rather than a prostaglandin in “mantle 22”
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`located on the outside of “enteric coating 20” surrounding “inner core 18” of
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`an NSAID. Ex. 1006, 6:15–44, Fig. 2. Petitioner does not address teachings
`
`in the art indicating that PPIs were acid liable, nor explain adequately why
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`one would have used any PPI (much less esomeprazole) in place of a
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`prostaglandin in an uncoated form (as taught in Gimet), when other relevant
`
`references taught the use of PPIs with an enteric coating to avoid
`
`degradation of the drug. See, e.g., Ex. 2008, 3; Ex. 2009, 2; Ex. 1041, 114
`
`(discussed above); see also Prelim. Resp. 21–24 (discussing other references
`
`along similar lines).
`
`Petitioner’s contention that Lindberg discloses “uncoated dosage units
`
`of esomeprazole in the form of tablets” does not persuade us otherwise. Pet.
`
`42 (citing Ex. 1007, 5:25–36; Ex. 1003 ¶¶ 232, 235). For example,
`
`immediately after the first quoted passage in Lindberg (Ex. 1007, 5:25–36),
`
`Lindberg teaches that “[g]ranules and tablets may be coated with an enteric
`
`coating which protects the active compound from acid catalyzed degradation
`
`as long as the dosage form remains in the stomach.” Ex. 1007, 5:36–39.
`
`Likewise, in Example 13, Lindberg teaches preparing an enteric-coated
`
`tablet and a capsule comprising pellets with a second coating (id. at
`
`18
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`12:13–13:15). Thus, even Lindberg suggests using an enteric or some type
`
`of protective coating when administering esomeprazole. Petitioner does not
`
`persuade us that Lindberg adequately suggests a composition where at least
`
`a portion of esomeprazole “is released regardless of the pH” (e.g., in the
`
`stomach where pH is low), much less such a composition that also includes
`
`other elements recited in the challenged claims.
`
`Accordingly, we agree with Patent Owner that Petitioner has not
`
`established that the teachings of Gimet, Goldman, and Lindberg would have
`
`given an ordinary artisan a reason to formulate a composition with the
`
`structural and functional features required by the challenged claims. Prelim.
`
`Resp. 17–25.
`
`Having considered the evidence and arguments presented in the
`
`Petition, we are not persuaded that Petitioner has established a reasonable
`
`likelihood of prevailing in its challenge of claim 1, or its dependent claims
`
`2–6 and 13–15, on the basis of obviousness over Gimet, Goldman, and
`
`Lindberg.
`
`D. Claims 7–12 and 16–18—Asserted Obviousness over
`Ouali and Lindberg
`
`1. Ouali (Ex. 1008)
`
`Ouali discloses “a composition for administering an NSAID wherein
`
`the undesirable gastrointestinal side effects of the drug are minimized but
`
`wherein the drug’s therapeutic effectiveness is maintained.” Ex. 1008, 2:14–
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`18. Specifically, Ouali discloses “a stabilized pharmaceutical composition
`
`19
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`for [oral] administration of an NSAID and a prostaglandin, wherein the
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`NSAID is enterically coated.” Id. at 4:22–24. Suitable NSAIDs include
`
`naproxen, and the preferred prostaglandin is misoprostol. Id. at 4:36–50,
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`6:35. “[T]he enteric coating . . . prevents NSAID release in the low pH
`
`environment of the stomach but . . . ionizes at a slightly higher pH, typically
`
`a pH of 4 or 5, and thus dissolves sufficiently in the small intestines to
`
`gradually release the active agent therein.” Id. at 5:2–7. Ouali also teaches
`
`that “prostaglandins are unstable compounds and degrade readily in the
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`presence of NSAIDs, thus requiring a stabilizing agent such as
`
`hydroxypropyl methylcellulose . . . which can, in turn, lessen the activity of
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`an NSAID.” Id. at 1:65–2:3.
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`
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`Figures 1 and 2, reproduced below, are schematic representations of
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`certain embodiments of Ouali’s dosage forms.
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`20
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`Figure 1 of Ouali depicts bilayer tablet 10 with layers 11, 12, “wherein the
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`enterically coated NSAID is present in a first region and the prostaglandin is
`
`present in a second region, along with a prostaglandin stabilizing agent.”
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`Ex. 1008, 4:26–29. Figure 2 of Ouali depicts a tablet wherein the enterically
`
`coated NSAID is present in first region 13, and the stabilized prostaglandin
`
`is present in adjacent second region 14. Id. at 4:34–35. “In an alternative
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`embodiment [not depicted], the enterically coated NSAID and the stabilized
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`prostaglandin are mixed into a single granulation, and the admixture is
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`compressed into a tablet or filled into a capsule.” Id. at 7:65–8:1.
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`2. Analysis
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`
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`Petitioner contends that an ordinary artisan “would have understood
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`that Ouali discloses a combination therapy oral unit dosage form (e.g., a
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`capsule) comprising an acid inhibitor (e.g., prostaglandin) in combination
`
`with an NSAID (e.g., naproxen).” Pet. 47 (citing Ex. 1003 ¶ 269). With
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`respect to the acid inhibitor, Petitioner contends that the ordinary artisan
`
`would have had a reason, with a reasonable expectation of success, to
`
`substitute different acid inhibitor compounds—i.e., to replace the
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`prostaglandin in Ouali’s composition with Lindberg’s esomepraxole—
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`“where the acid inhibitor compound contributes its individual therapeutic
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`attributes (e.g., acid inhibition and gastric pH raising) to the combination.”
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`Id. at 47–48 (citing Ex. 1003 ¶ 270). Petitioner further contends that “doing
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`so would be a simple substitution of one known element for another to
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`obtain improved pharmacokinetic, metabolic, and therapeutic properties as
`
`21
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`taught by Lindberg with predictable results.” Id. at 50 (citing Ex. 1007,
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`1:50–63; Ex. 1003 ¶ 278).
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`
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`The only evidence Petitioner cites for its assertion regarding
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`“predictable results” in relation to acid inhibitors is Dr. Shargel’s
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`Declaration at paragraph 278, which repeats the statements presented in the
`
`Petition on this point, without citing any evidence itself. Id. Again,
`
`conclusory assertions by Petitioner, merely repeated in conclusory and
`
`unsupported statements by an expert witness in support, are not persuasive
`
`here. See 37 C.F.R. § 42.65(a).
`
`
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`Patent Owner reiterates its arguments regarding prior art teachings
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`that PPIs, such as Lindberg’s esomeprazole, must be enteric-coated, and
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`contends that “[t]here is nothing in the combination of Ouali and Lindberg
`
`that negates that teaching.” Prelim. Resp. 26.
`
`
`
`Again, as an initial matter, we are not persuaded that Petitioner
`
`establishes adequately that esomeprazole administered in a non-enteric-
`
`coated form (thereby allowing it to be released regardless of pH) would have
`
`obtained “improved pharmacokinetic, metabolic, and therapeutic properties”
`
`as compared to prostaglandins in any formulation. Pet. 50 (citing Ex. 1007,
`
`1:50–63; Ex. 1003 ¶ 278). We are not persuaded that Lindberg suggests
`
`such an improvement. Rather, Lindberg suggests that esomeprazole may
`
`have improved properties over omeprazole (a related PPI). Ex. 1007, 1:17–
`
`63.
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`22
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`Moreover, even if we assume that one would have unders
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