Trials@uspto.gov
`571-272-7822
`
`Paper 18
`Entered: February 11, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGSVII LLC,
`Petitioner,
`
`Vv.
`
`POZENINC.,
`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
`
`Paper 18
`Entered: February 11, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGSVII LLC,
`Petitioner,
`
`Vv.
`
`POZENINC.,
`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
`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
`35 U.S.C. § 314, which providesthat an interpartes 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 challengedin the
`
`petition.”
`
`Upon consideration of the information presented in the Petition and
`
`the Preliminary Response, we are not persuadedthat Petitioner has
`established a reasonable likelihood that it would prevail in its challenges to
`claims 1-18 of the ’636 patent. Accordingly, we decline to institute an inter
`
`partes review ofthose claims.
`
`A. Related Proceedings
`
`Petitioner represents it is aware of a numberofjudicial matters
`involving the ’636 patent (c.g.,Horizon Pharma, Inc. v. Actavis Labs. Inc.,
`3:15-cv-03322 (D.N.J.)), as well as a numberofjudicial 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
`
`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.
`
`B. The Asserted Grounds of Unpatentability
`
`Petitioner asserts the challenged claims are unpatentable on the
`
`following grounds. Pet. 4-5, 12-60.'
`
`| Basis’— | ClaimsChallenged
`
`§ 103(a)|7-12 and 16-18
`
`References
`Goldman,” Remin ton: and
`
`Gimet,° Goldman and
`
`Ouali® and Lindberg
`
`' 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 etal.
`(“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 Lindbergetal.
`(“Lindberg”) (Ex. 1007).
`> U.S. Patent No. 5,698,225, issued December 16, 1997 to Gimetet al.
`(“Gimet’’) (Ex. 1006)
`© U.S. Patent No. 6,183,779 B1, issued February 6, 2001 to Ouali etal.
`(“Ouali’’) (Ex. 1008).
`.
`
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`C. The ’636 Patent (Ex. 1001)
`
`The 636 patent, titled “PHARMACEUTICAL COMPOSITIONS FOR THE
`
`COORDINATED DELIVERY OF NSAIDs”discloses pharmaceutical
`
`compositions“that provide for the coordinated release of an acid inhibitor
`
`and a non-steroidalanti-inflammatory drug (NSAID)”(id. at 1:22—24), such
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`that there is “a reduced likelihood of causing unwantedside effects,
`
`especially gastrointestinal side effects, when administered as a treatment for
`
`pain”(id. at 1:24—26).
`
`Specifically, the °636 patent discloses “a pharmaceutical composition
`
`in unit dosage form .
`
`.
`
`. contain[ing] an acid inhibitor present in an amount
`
`effective to raise the gastric pH ofa patientto at least 3.5” (id. at 3:27-31),
`
`and an NSAID “in an amounteffective to reduce or eliminate pain or
`
`inflammation”(id. at 3:67-4:1). “The term ‘unit dosage form’.. . refers to a
`
`single entity for drug administration. For example, a single tablet or capsule
`
`combining both an acid inhibitor and an NSAID would be a unit dosage
`
`form.” Id. at 4:42-45.
`
`A unit dosage form of the present invention preferably provides
`for coordinated drug release, in a way that elevates gastric pH
`and reduces the deleterious effects of the NSAID on the
`gastroduodenal mucosa,i.e., the acid inhibitor is released first
`and the release of NSAIDis 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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`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.
`
`The claims of the 636 patent are directed to unit dosage forms where
`the acid inhibitor is esomeprazole (id. at 3:46), and the NSAID is naproxen
`(id. at 4:6).
`
`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 amounteffective to raise
`the gastric pH ofsaid patient to at least 3.5 upon the
`administration of one or more ofsaid unit dosage forms;
`
`(b) naproxen present in an amounteffective 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
`naproxenis present in a core;
`ii) said tablet comprises a coating, wherein said
`coating surroundssaid core and doesnotrelease 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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`Patent 8,852,636 B2
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`B) are not surrounded byan enteric coating; and |
`C) upon ingestion ofsaid tablet by a patient,
`release said esomeprazoleinto said patient’s
`stomach.
`
`Ex. 1001, 21:22—-43.
`
`Independentclaim 7 is similar to claim 1, except that the unit dosage
`
`form is a capsule, instead of a tablet.
`
`/d. at 22:1-20.
`
`If. ANALYSIS
`
`A. Claim Construction
`
`Wedetermine that no claim term requires express construction for
`
`purposesof this Decision.
`
`B. Claims 1—18—Asserted Obviousness over Goldman,
`Remington, and Lindberg
`
`1. Goldman(Ex. 1004)
`
`Goldmanteachesthat “[t]he symptomsof overindulgence dueto
`
`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 ofthe symptoms ofoverindulgence often requires the co-
`administration of an analgesic to relieve the headache along with an agent to
`
`reducegastric acidity which is generally believed to cause the indigestion
`
`and heartburn.” Jd. at 2:52—-56.
`
`In order to “more effectively treat all the symptoms concurrently”(id.
`
`_at 2:67—-68), Goldman discloses “pharmaceutical compositionsfor treating
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`the symptomsof overindulgence. .
`
`. [comprising] a combination of non-
`
`steroidal anti-inflammatory drug or acetaminophenanda histamine receptor
`
`blocker and/or a proton pump inhibitor composition”(id. at 1:10—16).
`
`Goldman teaches that acceptable histamine receptor (Hz) blockers include
`
`famotidine(id. at 3:27), acceptable proton pumpinhibitors (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, acetaminophenor non-steroidal inflammatory agents with H;
`
`histamine and/or H> histaminereceptor blocking drugs are more efficacious”
`
`in treating the symptomsof overindulgence. Jd. at 5:61-65.
`
`Finally, Goldman discloses “chewable and liquid dosage forms”(id.
`
`at 6:4—5), and further teaches that “{v]arious conventional techniques for
`preparing medicamenttablets 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.” Ex. 1004, 6:26—-30.
`
`- 2. Remington (Ex. 1005)
`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. 1005, 1603-43.
`
`Among the many dosage forms mentioned, Remington discusses various
`
`7 This is the same publication submitted as Exhibit 1005.
`
`7
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`coated tablets, including enteric-coated tablets—“compressed tablets coated
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`with substancesthat resist solution in gastric fluid but disintegrate in the
`
`intestine.” Id. at 1604.
`
`Remington teachesthat “[e]nteric coatings can be used for tablets
`
`containing drug substances whichare inactivated or destroyed in the
`
`stomach, for those whichirritate the mucosa, or as a meansof delayed
`release ofthe medication.” Id. Remingtonalso teaches that tablets may be
`coated in orderto “[{r]educ[e] the risk of interaction between incompatible
`
`components .
`
`.
`
`. by using coated forms of one or moreofthe offending
`
`ingredients (particularly active compounds).” /d. at 1633. The reference
`
`further states that enteric coatings “can be usedto 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
`
`released further down the gastrointestinal tract.” Jd. at 1637.
`
`3. Lindberg (Ex. 1007)
`
`Lindberg discloses omeprazole andits optically pure crystalline
`
`enantiomeric salts, including a magnesium salt of S-omeprazole,
`esomeprazole,® 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 dayof active substance.” Ex. 1007, 6:24-25.
`
`Lindberg teaches that “[o]meprazole andits alkaline salts are effective
`
`8 See, e.g., Exhibit 1003 § 32 (citing Ex. 1023, 33) (“esomeprazole .
`enantiopure (S)-isomer of omeprazole).
`8
`
`.
`
`. is the
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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.” /d. at
`1:22—23. Lindbergstates 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 useofacid
`
`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 7 64). Petitioner also argues that an ordinary artisan would
`have knownthat “acid inhibitors are a well-known class of drugs that
`provide gastric acid inhibiting efficacy.” Jd. Thus, according to Petitioner,
`
`an ordinary artisan would have had a reason, with a reasonable expectation
`
`of success, for “substituting different acid inhibitor compoundsinto a given
`
`combination therapy formulation,” including substituting with “more
`
`effective compounds,such as PPIs, over previously known,less
`therapeutically effective compounds, such as prostaglandins and H2
`
`blockers.” Jd. at 11-12 (citing Ex. 1003 4 65). In addition, according to
`
`Petitioner, it would have been obviousto substitute Lindberg’s PPI,
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`9
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`;
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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.” Jd. 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 techniquesfor
`preparing medicamenttablets as set forth in Remington,” which Goldman
`
`incorporates by reference. /d. 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 overthe enteric coat is released in the
`
`stomach, while the remainder. .
`
`.
`
`, being protected by the coating, is
`
`released further down the gastrointestinaltract.” Jd. 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 nauseaor bleedingbyirritating the gastric. mucosa(eg, aspirin .
`
`. .),”
`
`and that manyenteric coatings “remain undissociated in the low pH
`
`environmentof the stomach, but readily ionize when the pHrises to about 4
`or 5” Id. at 15 (citing Ex. 1005, 1637; Ex. 1003 § 84), 22-23.
`Patent Ownerresponds 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 NSAIDis in any waydesirable.” Prelim. Resp. 15. Patent
`
`10
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`Ownerfurther argues that Remington and Lindberg,individually or
`
`collectively, “do[] not cure this deficiency”(id.).
`
`Patent Ownercontendsthat neither Lindberg nor Remington teaches
`
`or suggests non-enteric-coated esomeprazole, as required by the claims. Jd.
`
`at 16. In particular, Patent Owner contendsthat “Lindberg teaches enteric
`
`coated esomeprazole to protect it from the acidic environmentofthe
`
`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 Ownercontendsthat 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 theart to be acid
`
`labile” (id. at 17, 21 (citing Ex. 2008, 3; Ex. 2009, 2; 2010, 5)), and
`
`Remington teaches“that enteric coated tablet formulations are used with
`
`acid labile drug substances”(id. at 16 (citing Ex. 1005, 1604)).
`
`Weagreethat 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 haveprepared, for any reason, a
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`composition as claimed, whereat least some PPI(i.e., esomeprazole) 1S
`released regardless of pH andtherelease of at least some NSAID(i.e.,
`
`naproxen)is inhibited unless the pHis 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 manydisclosed by Remington. Goldman’s citation to Remington
`
`generally in relation to “[vJarious conventional techniques for preparing
`medicamenttablets or caplets” does not persuadeusthat an ordinary artisan
`
`would have madethe connection that Petitioner contends. /d.; Pet 11, 14—
`
`16, 21-27. Nor does Petitioner explain adequately how Lindberg remedies
`
`the deficiencies discussed abovein 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)
`
`Gimetteaches that NSAIDshave“high therapeutic value especially
`
`for the treatment of inflammatory conditions such as .
`
`.
`
`. osteoarthritis (OA)
`
`and rheumatoid arthritis,” but “also exhibit undesirable side effects.” Ex.
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`12
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`1006, 1:20-24). “An especially undesirable side effect of the administration
`
`of NSAIDsis 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.” Jd. at 1:29-
`
`33.
`
`According to Gimet, “[c]ertain prostaglandins have been shownto
`
`prevent NSAID inducedulcers.” Jd. at 1:39-40. Misoprostol, for example,
`
`“is a pharmaceutically acceptable prostaglandin which has been accepted for
`
`use in the treatment of NSAID inducedulcers.” Jd. at 1:45-47.
`
`Gimet discloses a pharmaceutical composition comprising a tablet
`
`having an inner core and an outer mantle coating surroundingthe innercore,
`
`designed to “[counter] (by inhibiting, reducing or preventing) the
`
`ulcerogenic side effects attendant to NSAID administration.” Jd. 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. Jd. at
`111-17, 39-47.
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`Figure 2 of Gimet, reproduced below, depicts tablet 16 in cross-
`
`section.
`
`Fis2
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`Figure 2 of Gimet depicts tablet 16. Tablet 16 includes an NSAID—
`
`diclofenac or piroxicam—ininner 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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`Theenteric coating “can be formulated from any suitable enteric
`coating material,” and “aids in segregating the NSAID from the
`prostaglandin andin directing the dissolution of the NSAID corein the
`
`lower G.I. tract as opposed to the stomach.” Jd. at 6:29-—30, 33-36.
`
`2. Analysis —
`
`Petitioner contends that an ordinary artisan would have knownthat
`
`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 Ff 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—.e., to
`
`replace diclofenac or piroxicam in Gimet’s composition, as shownin Figure
`
`2, with naproxen disclosed in Goldman—‘“because doing so would be a
`
`simple substitution of one known elementfor another to obtain predictable
`
`results.” Jd. at 35 (citing Ex. 1003 4 198).
`
`The only evidencethat 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 evidenceitself. Jd. 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 opinionis basedis 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—‘wherethe acid
`
`inhibitor compound contributesits 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.” /d. at 36
`
`(citing Ex. 1003 § 200).°
`
`Petitioner also argues that it would have been obviousto select
`
`“Lindberg’s disclosed PPI esomeprazole and substitute it for Gimet’s
`disclosed acid inhibitor (prostaglandin) because Goldmanspecifically
`teaches that ‘[p]roton pump inhibitors have been recently introduced as
`
`effective gastric acid inhibitors.’” /d. 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
`racemization.” Jd. at 36-37 (quoting Ex. 1007, 1:50-63, 3:48—55)(citing
`Ex. 1003 ¢ 200), 38 (citing Ex. 1007, 1:50-63; Ex. 1003 4 207).
`
`In response, Patent Ownerpoints to a numberof references indicating
`
`that an ordinary artisan would have understood that PPIs wereacid labile
`
`and should be protected from degradation in acidic environments, such as
`
`the stomach. Prelim. Resp. 20—24 (citing Ex. 2003, 15, 17; Ex. 2008, 3;
`
`Ex. 2009, 2; Ex. 2010, 5; Ex. 1041, 114, 115, 117). For example, a review
`
`article by Stedmanetal., published in 2000, comparing the
`
`“pharmacokinetics, acid suppression and efficacy of proton pump
`
`inhibitors,” indicates that PPIs “are all acid-labile, so when administered
`
`° In support of these contentions, Petitioner once again cites paragraphsin
`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 F¥ 199, 200).
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`Patent 8,852,636 B2
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`orally they must be formulated in an enteric coating to protect them from
`
`rapid degradation in the stomach. Theyare rapidly absorbedin the
`duodenum.” Ex. 2008, 1 (Title), 3. Similarly, in an article publishedin
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`1992, Bell et al. state in relation to the related parent compound of
`esomeprazole: “As omeprazole is acid-labile, it is formulated as enteric-
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`coated granules dispensedin 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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`“fo}]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.” Jd. at 114.
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`ASan 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
`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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`Patent 8,852,636 B2
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`Moreover, even if we assumethat 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
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`in the art indicating that PPIs were acid liable, nor explain adequately why
`
`one would have used any PPI (muchless 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
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`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 similarlines).
`
`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 J 232, 235). For example,
`
`immediately after the first quoted passage in Lindberg (Ex. 1007, 5:25-36),
`
`Lindberg teachesthat “[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 remainsin the stomach.” Ex. 1007, 5:36—-39.
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`Likewise, in Example 13, Lindberg teaches preparing an enteric-coated
`
`tablet and a capsule comprising pellets with a second coating(id. at
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`18
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`IPR2015-01680
`Patent 8,852,636 B2
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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
`persuadeus that Lindberg adequately suggests a composition whereatleast
`a portion of esomeprazole “is released regardless of the pH”(e.g., in the
`
`stomach where pH is low), muchless such a compositionthat also includes
`
`other elements recited in the challenged claims.
`
`Accordingly, we agree with Patent Ownerthat 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 argumentspresented in the
`Petition, we are not persuadedthat 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—
`18. Specifically, Quali discloses “a stabilized pharmaceutical composition
`
`19
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`IPR2015-01680
`Patent 8,852,636 B2
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`for [oral] administration of an NSAID anda prostaglandin, wherein the
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`NSAIDis enterically coated.” Jd. at 4:22—24. Suitable NSAIDsinclude
`
`naproxen, and the preferred prostaglandin is misoprostol.
`
`/d. at 4:36—50,
`
`6:35. “[T]he enteric coating . .. prevents NSAIDrelease in the low pH
`
`environmentof the stomachbut. .
`. ionizes at a slightly higher pH,typically
`apH of 4 or 5, and thus dissolves sufficiently in the small intestines to
`
`gradually release the active agent therein.” Jd. at 5:2—-7. Ouali also teaches
`that “prostaglandins are unstable compoundsand degradereadily in the
`presence of NSAIDs, thus requiring a stabilizing agent such as
`
`hydroxypropyl methylcellulose .
`
`.
`
`. which can, in turn, lessen the activity of
`
`an NSAID.” Id. at 1:65—2:3.
`
`Figures 1 and 2, reproduced below,are schematic representations of
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`certain embodiments of Ouali’s dosage forms.
`
`10
`
`—ad
`"1
`42
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`20
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`IPR2015-01680
`Patent 8,852,636 B2
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`Figure 1 of Ouali depicts bilayer tablet 10 with layers 11, 12, “wherein the
`enterically coated NSAIDis presentin a first region and the prostaglandin is
`
`present in a second region, along with a prostaglandin stabilizing agent.”
`
`Ex. 1008, 4:26—29. Figure 2 of Ouali depicts a tablet wherein the enterically
`
`coated NSAIDis present in first region 13, and the stabilized prostaglandin
`is present in adjacent second region 14.
`/d. at 4:34-35. “In an alternative
`embodiment[not depicted], the enterically coated NSAID andthe stabilized
`
`prostaglandin are mixed into a single granulation, and the admixtureis
`
`compressedinto a tablet or filled into a capsule.” Jd. at 7:65—8:1.
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`2. Analysis
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`Petitioner contends that an ordinary artisan “would have understood
`
`that Ouali discloses a combination therapy oral unit dosage form (e.g., a
`
`capsule) comprising an acid inhibitor(e.g., prostaglandin) in combination .
`
`with an NSAID(e.g., naproxen).” Pet. 47 (citing Ex. 1003 | 269). With
`respect to the acid inhibitor, Petitioner contendsthat the ordinary artisan
`would have had a reason, with a reasonable expectation of success, to
`
`substitute different acid inhibitor compounds—1.e., to replace the
`
`prostaglandin in Ouali’s composition with Lindberg’s esomepraxole—
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`“where the acid inhibitor compoundcontributes its individual therapeutic
`
`attributes (e.g., acid inhibition and gastric pH raising) to the combination.”
`
`Id. at 47-48 (citing Ex. 1003 § 270). Petitioner further contendsthat “doing
`
`so wouldbe a simple substitution of one known elementfor another to
`obtain improved pharmacokinetic, metabolic, and therapeutic properties as
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`21
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`IPR2015-01680
`Patent 8,852,636 B2
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`taught by Lindberg with predictable results.” Id. at 50 (citing Ex. 1007,
`1:50-63; Ex. 1003 § 278).
`
`The only evidence Petitioner cites for its assertion regarding
`
`“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. Jd. 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).
`
`Patent Ownerreiterates its arguments regarding priorart teachings
`that PPIs, such as Lindberg’s esomeprazole, must be enteric-coated, and
`contendsthat “[t]here is nothing in the combination of Ouali and Lindberg
`that negatesthat 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 comparedto prostaglandins in any formulation. Pet. 50 (citing Ex. 1007,
`
`1:50-63; Ex. 1003 4 278). 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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`IPR2015-01680
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`Moreover, even if we assume that one would have understood that
`
`prostaglandins and H2 blockers were“less therapeutically effective
`
`compounds”than PPIs (Pet. 48), Petitioner has not explained adequately
`why one would have hadreason to make a capsule, with a PPI rather than a
`
`prostaglandin, located on the outside of an enterically-coated NSAIDcore,
`
`as required by independent claim 7. Petitioner does not address the
`
`teachingsin the art indicating that PPIs were acid liable, nor explain
`
`adequately why one would have used any PPI (much less esomeprazole) in
`
`place of a prostaglandin in an non-enterically-coated form, 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).
`
`- Petitioner’s contention that Lindberg discloses “uncoated soft gelatin
`
`capsules containing a mixture of esomeprazole or hard gelatin capsules
`
`containing uncoated granules of esomeprazole” does not persuade us
`
`otherwise. Pet. 53 (citing Ex. 1007, 5:46—52; Ex. 1003 § 290). For
`
`example, as discussed above,just above the quoted passage in Lindberg (Ex.
`
`1007, 5:46—-52), Lindberg teachesthat “[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 remainsin the stomach.”
`
`Id. at 5:36-39. Likewise, in Example 13, Lindberg teaches preparing an
`
`enteric-coated tablet and a capsule
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