UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________
`
`
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.
`Petitioners
`
`v.
`
`POZEN, INC.
`Patent Owner
`
`___________
`
`CASE IPR: UNASSIGNED
`
`___________
`
`PETITION FOR INTER PARTES REVIEW OF
`
`U.S. PATENT NO. 8,852,636
`
`CLAIMS 1-6 AND 13-15
`
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`

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`
`
`Table of Contents
`
`I.
`II.
`III.
`
`INTRODUCTION .......................................................................................... 1
`RULE 42.8 MANDATORY NOTICES ......................................................... 3
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(A)) .......................................... 5
`IV. THE ’636 PATENT ........................................................................................ 5
`A.
`Priority Date ......................................................................................... 5
`B.
`Claims At Issue .................................................................................... 6
`C.
`The Technology .................................................................................... 8
`V. A PERSON OF ORDINARY SKILL IN THE ART (“POSA”) .................... 9
`VI. CLAIM CONSTRUCTION ........................................................................... 9
`VII.
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(B)) ................. 9
`A. Ground 1: Claims 1-6 And 13-15 Would Have Been Obvious
`Over The ’556 Patent Alone, Or In The Alternative, In View Of
`Chandramouli ..................................................................................... 10
`1.
`Claim 1 would have been obvious ........................................... 11
`2.
`Dependent pharmaceutical composition claims 2-4 and
`13-15 and method of treatment claims 5 and 6 would
`have been obvious .................................................................... 18
`Chandramouli further shows that claims 1-6 and 13-15
`would have been obvious ......................................................... 20
`Claim Chart .............................................................................. 21
`4.
`Ground 2: Claims 1-6 and 13-15 would have been obvious over
`the ’556 patent in view of the ’225 patent .......................................... 26
`1.
`Claim 1 is rendered obvious .................................................... 26
`2.
`The prior art renders obvious pharmaceutical
`composition claims 2-4 and 13-15 and method of
`treatment claims 5 and 6 .......................................................... 28
`Claim Chart .............................................................................. 29
`3.
`Ground 3: Claims 1-6 and 13-15 would have been obvious over
`the ’118 patent and ’225 patent .......................................................... 36
`
`3.
`
`B.
`
`C.
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`-i-
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`

`2.
`
`3.
`
`E.
`
`
`
`1.
`
`The ’118 patent discloses a combination tablet
`comprising naproxen and non-enteric coated
`esomeprazole ............................................................................ 36
`Claim 1 would have been obvious over the ’118 patent in
`view of the ’225 patent ............................................................ 37
`Dependent pharmaceutical composition claims 2-4 and
`13-15 and method of treatment claims 5 and 6 are
`rendered obvious ...................................................................... 37
`Claim Chart .............................................................................. 39
`4.
`D. Ground 4: Claims 1-6 and 13-15 would have been obvious over
`the ’118 patent in view of the ’225 patent and the ’192 patent .......... 44
`1.
`Claim Chart .............................................................................. 44
`Ground 5: Claims 1-6 and 13-15 would have been obvious over
`the ’225 patent in view of Chandramouli and WO ’185. ................... 50
`1.
`Claim 1 would have been obvious ........................................... 50
`2.
`Dependent pharmaceutical composition claims 2-4 and
`13-15 and method of treatment claims 5 and 6 are
`rendered obvious ...................................................................... 52
`Claim Chart .............................................................................. 53
`3.
`VIII. THERE ARE NO SECONDARY CONSIDERATIONS TO
`OVERCOME OBVIOUSNESS ................................................................... 58
`IX. CONCLUSION ............................................................................................. 60
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`-ii-
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`
`
`Exhibit Number
`1001
`1002
`1003
`
`1004
`1005
`1006
`
`1007
`1008
`
`1009
`
`1010
`1011
`
`1012
`1013
`1014
`
`1015
`
`PETITIONERS’ EXHIBIT LIST
`
`Exhibit
`U.S. Patent No. 8,852,636
`Declaration of Dr. Umesh V. Banakar
`U.S. Patent Application No. 14/045,156 (“the ’156
`application”)
`U.S. Patent No. 6,544,556 (“the ’ 556 patent”)
`U.S. Patent No. 5,877,192 (“the ’192 patent”)
`Howden et al., Effects of Single and Repeated Doses of
`Omeprazole in Gastric Acid and Pepsin Secretion in Man,
`Gut, Vol. 25, 707-710 (1984) (“Howden”)
`U.S. Patent No. 5,698,225 (“the ’225 patent”)
`Pilbrant et al., Development of an Oral Formulation of
`Omeprazole, Scand. J. Gastroenterol., 20(Suppl. 108):113-
`120 (1985) (“Pilbrant”)
`Preliminary Patent Owner Response to Petition for Inter
`Partes Review of U.S. Patent No. 8,557,285 submitted by
`Pozen Inc.
`U.S. Patent No. 5,204,118 (“the ’118 patent”)
`Chandramouli et al., Prevention and management of
`NSAID-Induced Gastropathy, Journal of Pharmaceutical
`Pain and Symptom Control, 8(4):27-40, 2000
`(“Chandramouli”)
`WO/2000/026185 (“WO’185”)
`U.S. Patent No. 5,840,737 (“the ’737 patent”)
`July 3, 2014 Citizen Petition Denial from FDA to Horizon
`Pharma (“Horizon Citizen Petition”)
`Horizon Pharma, Inc. 2014 Annual Report
`
`-iii-
`
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`

`

`
`
`I.
`
`INTRODUCTION
`this petition for Inter Partes Review, Lupin Ltd. and Lupin
`
`In
`
`Pharmaceuticals Inc. seek cancellation of claims 1-6 and 13-15 of U.S. Patent No.
`
`8,852,636 (“the ’636 patent”). The challenged claims are directed to a
`
`naproxen/esomeprazole combination tablet wherein the esomeprazole is not enteric
`
`coated and the naproxen is enteric coated so that esomeprazole is immediate
`
`release and naproxen is not released until a particular pH of the surrounding
`
`medium is reached. Lupin and the patent owner dispute only one aspect of the
`
`challenged claims because of the following incontrovertible facts.
`
`Naproxen and esomeprazole are drugs that, as of the time of the alleged
`
`invention, were well-known and widely described in the prior art. Naproxen is a
`
`well-known nonsteroidal anti-inflammatory drug (“NSAID”), a class of drugs
`
`known to treat pain. Esomeprazole was known to be in the class of drugs called
`
`proton pump inhibitors (“PPIs”), which raise the pH of the stomach to treat and
`
`protect against gastric injury caused by NSAIDs such as naproxen. The prior art
`
`disclosed their use in combination as it was a straightforward and obvious choice
`
`for a person of ordinary skill in the art (“POSA”) to combine these two drugs in a
`
`single tablet. Enteric coated naproxen was a standard treatment and well-known
`
`from the prior art. Likewise, as admitted by the ‘636 patent itself, the methods to
`
`make a tablet with an enteric coated drug combined with a non-enteric coated drug
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`
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`-1-
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`were standard knowledge and were described in the prior art. Thus, the only
`
`issue in this petition is whether a POSA would have found it obvious to use non-
`
`enteric coated esomeprazole in the combination tablet with naproxen.
`
`Simply put, the answer is yes.
`
`As explained below, a POSA would have known that non-enteric coated
`
`esomeprazole would be sufficiently available to effectively raise the pH of the
`
`gastric
`
`juices, particularly when a person
`
`takes repeated doses of
`
`the
`
`naproxen/esomeprazole tablet. So a POSA would have found the combination
`
`tablet obvious and would have reasonably expected it to effectively treat pain and
`
`protect from gastric injury related to the use of naproxen.
`
`Patentee may assert, as it has done in a response to an IPR petition involving
`
`a related patent, that the prior art taught away from using non-enteric coated
`
`esomeprazole because some prior art states that PPIs require an enteric coat to
`
`prevent degradation in the stomach. Although there are prior art references that
`
`make this statement, there are other prior art references that do not require the PPI
`
`to be enteric coated. Moreover, it was well within the knowledge of a POSA to
`
`simply adjust the amount of a non-enteric coated PPI to account for degradation
`
`and obtain a therapeutically effective dose.
`
`Patentee’s assertion relies on a POSA being an automaton that ignores the
`
`full disclosure
`
`in prior art references and
`
`lacks any understanding of
`
`
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`-2-
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`pharmaceutical formulations and the bioavailability of drugs. This is contrary to
`
`the educational background and experience of a POSA for the ’636 patent and is
`
`not consistent with the law of obviousness. See Syntex (U.S.A.) LLC v. Apotex,
`
`Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005) (“What a reference teaches or suggests
`
`must be examined in the context of the knowledge, skill and reasoning ability of a
`
`skilled artisan.” Thus, “[w]hat a reference teaches a person of ordinary skill in the
`
`art is not [...] limited to what a reference specifically ‘talks about’ or what is
`
`specifically ‘mentioned’ or ‘written’ in the reference.”)
`
`II. RULE 42.8 MANDATORY NOTICES
`Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)): The real party-in-interest
`
`
`is Lupin Ltd. and Lupin Pharmaceuticals Inc. (“Lupin” or “Petitioner”). Lupin is
`
`not barred by operation of estoppel to submit this petition for inter partes review.
`
`
`
`
`
`Related Matters (37 C.F.R. § 42.8(b)(2)):
`
`Petitioner is aware of two currently pending applications before the USPTO
`
`that claim priority to the application that resulted in the ’636 patent: Application
`
`Nos. 14/515,627 and 14/753,195.
`
`
`
`The ’636 patent is currently at issue in IPR2015-01680. Additionally, the
`
`’636 patent is related to U.S. Patent No. 6,626,907, which is at issue in IPR2015-
`
`01241; U.S. Patent No. 8,557,285, which is at issue in IPR2015-00802; U.S. Patent
`
`No. 8,858,996, which is at issue in IPR2015-01344; and U.S. Patent No.
`
`
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`-3-
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`8,945,621, which is at issue in IPR2015-01718. Petitioners are concurrently filing
`
`petitions for inter partes review against two additional patents in the same family:
`
`the ’996 patent and U.S. Patent No. 8,865,190.
`
`
`
`The ’636 patent, as well as the ’996 and ’190 patents, are being asserted in
`
`co-pending litigations captioned as: Horizon Pharma, Inc. v. Actavis Laboratories
`
`FL, Ltd., No. 3:15-cv-03322-MLC-DEA (D.N.J.); Horizon Pharma, Inc. v. Dr.
`
`Reddy’s Laboratories, Inc., No. 3:15-cv-03324-MLC-DEA (D.N.J.); Horizon
`
`Pharma, Inc. v. Lupin Ltd., No. 3:15-cv-03326-MLC-DEA (D.N.J.); and Horizon
`
`Pharma, Inc. v. Mylan Pharmaceuticals, Inc., No. 3:15-cv-03327-MLC-DEA
`
`D.N.J.). The ’907 and ’285 patents are being asserted in the following co-pending
`
`litigations: AstraZeneca AB v. Dr. Reddy’s Labs. Inc., 3:11-cv-02317 (D.N.J.);
`
`AstraZeneca AB v. Dr. Reddy’s Labs., Inc., 3:13-cv-00091(D.N.J.); AstraZeneca
`
`AB v. Watson Labs., Inc.- Florida, 3:13-cv-03038 (D.N.J.); and AstraZeneca AB v.
`
`Mylan Pharmas., 3:13-cv-04022 (D.N.J.).
`
`
`
`Designation of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)):
`
`Lead counsel is Sailesh K. Patel (Reg. No. 46,982) and back-up counsel is Dr. John
`
`K. Hsu (Reg. No. 45,563).
`
`
`
`Grounds for Standing (37 C.F.R. § 42.104(a)): Petitioner hereby certifies
`
`that the patent for which review is sought is available for inter partes review and
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`that Petitioner is not barred or estopped from requesting inter partes review
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`
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`-4-
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`challenging the patent claims on the grounds identified in the petition. Petitioner
`
`was served with a complaint asserting the ’636 patent no earlier than May 13,
`
`2015, and this petition is being filed on August 19, 2015.
`
`
`
`Service Information (37 C.F.R. § 42.8(b)(4)): Papers concerning this
`
`matter should be served on the following:
`
`Mail and hand-delivery address:
`
`Sailesh K. Patel
`
`
`
`Email:
`
`Telephone:
`
`Facsimile:
`
`Schiff Hardin LLP
`
`233 S. Wacker Dr., Suite 6600
`
`Chicago, Illinois 60606
`
`spatel@schiffhardin.com
`
`312-258-5698
`
`312-258-5600
`
`III. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a))
`Petitioner requests inter partes review and cancellation of independent claim
`
`1 and dependent claims 2-6 and 13-15 of the ’636 patent (Exh. 1001). Petitioner’s
`
`detailed statement of the reasons for relief requested is set for in §VII, below.
`
`IV. THE ’636 PATENT
`Priority Date
`A.
`The ’636 patent, titled “Pharmaceutical Compositions for the Coordinated
`
`Delivery of NSAIDs,” issued from U.S. Patent Application No. 14/045,156 (“the
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`-5-
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`’156 application”) (Exh. 1003), on October 7, 2014. The ’156 application was
`
`filed on October 3, 2013 as a continuation of Application No. 13/215,855 (“the
`
`’855 application”), which issued as U.S. Patent No. 8,557,285 (“the ’285 patent”).
`
`The ’855 application is a division of Application No. 12/553,804, filed Sept. 3,
`
`2009, which is a division of Application No. 11/129,320, filed May 16, 2005,
`
`which is a continuation-in-part of Application No. 10/158,216, filed May 31, 2002,
`
`which issued as U.S. Patent No. 6,926,907 and claims priority from Provisional
`
`Application No. 60/294,588, filed June 1, 2001. According to the face of the ’636
`
`patent, the record assignee is Pozen Inc. and the named inventor is John R.
`
`Plachetka.
`
`B. Claims At Issue
`The ’636 patent contains two independent claims (claims 1 and 7) and 16
`
`dependent claims.
`
` Independent claim 1 is directed to a pharmaceutical
`
`composition in a tablet unit dose form:
`
`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
`
`
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`-6-
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`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 [sic] naproxen;
`
`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.
`
`Claims 2-4 and 13-15 claim these pharmaceutical compositions with
`
`additional limitations. Claim 2 depends from claim 1 and specifies a single core
`
`comprising naproxen. Claim 3 depends from claim 2 and specifies esomeprazole
`
`is present in the amount of between 5-100 mg. Claim 4 depends from claim 2 and
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`specifies naproxen is present in the amount of 200-600mg.
`
`Claims 5-6 are directed to methods of use. Claim 5 depends from claim 1,
`
`and is directed to a method of treating a patient for pain or inflammation by
`
`administering the composition of claim 1. Claim 6 depends from claim 5 and
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`-7-
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`specifies the pain or inflammation is due to either osteoarthritis or rheumatoid
`
`arthritis.
`
`C. The Technology
`The ’636 patent claims a combination formulation containing naproxen and
`
`esomeprazole and methods of treating patients with the formulation. Naproxen is
`
`in the class of drugs known as nonsteroidal anti-inflammatory drugs (“NSAIDs”),
`
`and esomeprazole is in the class of drugs known as proton-pump inhibitors
`
`(“PPIs”). Both classes of drugs were widely described, used and understood as of
`
`the priority date of the ’636 patent (June 1, 2001). For example, naproxen was
`
`originally marketed as a prescription drug in 1976 and approved for use as an over-
`
`the-counter drug in 1994 under the trade name Aleve®. And the PPI omeprazole
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`was marketed in the United States in 1990 under the trade name Prilosec®.
`
`Omeprazole is a racemic compound consisting of two enantiomers, the S-
`
`enantiomer is esomeprazole. Esomeprazole was well-known as of the priority date
`
`and considered to be more efficacious than racemic omeprazole. Additionally,
`
`tablets and capsules withnon-enteric coated PPIs were known in the prior art. See
`
`Santarus, Inc. v. Par Pharmaceutical, 694 F.3d 1344 (Fed. Cir. 2012) (holding
`
`prior art taught solid dosage forms of omeprazole without enteric coating).
`
`As of the priority date of the ’636 patent, NSAIDs such as naproxen were
`
`known to cause gastrointestinal injury such as stomach ulcers. Also, PPIs such as
`
`
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`-8-
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`
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`esomeprazole were used to treat and protect against damage by NSAIDs because
`
`PPIs reduce acid production in the stomach, which causes an increase in stomach
`
`pH. Consequently, as of the priority date of the ’636 patent, formulations
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`combining a PPI with an NSAID to protect against gastrointestinal injury that
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`could arise from the use of the NSAID were described in the art.
`
`V. A PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
`As explained in the Declaration of Umesh V. Banakar, Ph.D., a POSA
`
`would be a pharmaceutical scientist having a Ph.D. degree in the field of
`
`pharmaceutical sciences or equivalent training or degree and at least two years of
`
`experience with pharmaceutical formulations. (Exh. 1002, ¶ 24)
`
`VI. CLAIM CONSTRUCTION
`Pursuant to 37 C.F.R. § 42.100(b), a challenged claim must be given its
`
`broadest reasonable construction in light of the specification of the ’636 patent.
`
`Under this standard, Petitioners submit that the terms of the challenged claims
`
`should be given their plain and ordinary meaning in light of the specification, and
`
`no terms or phrases require specific construction.
`
`
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`VII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`Inter partes review of claims 1-6 and 13-15 of the ’636 patent is requested
`
`based on the following grounds for unpatentability for obviousness under 35
`
`U.S.C. § 103. Pursuant to 37 C.F.R. § 42.6(d), copies of the references are filed
`
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`-9-
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`herewith. In support of the proposed grounds for unpatentability, this Petition is
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`accompanied by a declaration of technical expert Umesh Banakar, Ph.D. (Exh.
`
`1002) that explains what the art would have conveyed to a person of ordinary skill
`
`in the art.
`
`Ground 1: Claims 1-6, and 13-15 would have been obvious over the ’556
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`patent alone or, in the alternative, in view of Chandramouli.
`
`Ground 2: Claims 1-6 and 13-15 would have been obvious over the ’556
`
`patent in view of the ’225 patent.
`
`Ground 3: Claims 1-6 and 13-15 would have been obvious over the ’118
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`patent in view of the ’225 patent.
`
`Ground 4: Claims 1-6 and 13-15 would have been obvious over the ’118
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`patent in view of the ’225 patent and the ’192 patent.
`
`Ground 5: Claims 1-6 and 13-15 would have been obvious over the ’225
`
`patent in view of Chandramouli and WO’185.
`
`A. Ground 1: Claims 1-6 And 13-15 Would Have Been Obvious Over
`The ’556 Patent Alone, Or In The Alternative, In View Of
`Chandramouli
`
`As described below and further shown in the claim chart at the end of this
`
`section, each and every limitation in claims 1-6, and 13-15 of the ’636 patent is
`
`disclosed in the ’556 patent. The ’556 patent is directed to an oral solid
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`pharmaceutical tablet comprising both an NSAID such as naproxen and a proton
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`-10-
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`pump inhibitor such as esomeprazole. (Exh. 1003.) The ’556 patent issued on
`
`April 8, 2003 from an application filed on September 11, 2000 and therefore is
`
`prior art under 35 U.S.C. § 102(e). A POSA would have been motivated to make
`
`the invention claimed in the ’636 patent from the disclosure in the ’556 patent,
`
`with a reasonable expectation of success.
`
`1.
`
`Claim 1 would have been obvious
`a.
`
`The ’556 patent describes a therapeutically effective
`combination tablet of naproxen and esomeprazole
`
`The ’556 patent motivates and teaches the fundamental concept of the ’636
`
`patent: a combination tablet of naproxen and esomeprazole. The ’556 patent
`
`discloses “[a]n oral solid dosage form includ[ing] a therapeutically effective
`
`amount of an NSAID and a proton pump inhibitor in an amount effective to inhibit
`
`or prevent gastrointestinal side effects normally associated with the NSAID” and
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`teaches the “oral solid dosage form” can be a tablet. (Exh. 1004, [57]; 4:30-33.) It
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`expressly discloses the NSAID may be naproxen, (id., 5:60-63) and that the PPI
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`may be esomeprazole. (Id., 6:53-56.) The ’556 patent also discloses NSAIDs
`
`were well known in the art to treat pain and inflammation, and incorporates by
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`reference patents that are directed to naproxen.1 (Id., 5:58-60, 6:6-32.) The ’556
`
`
`1 The substance of materials incorporated by reference into an asserted prior art
`
`document may be considered as part of the asserted prior art for purposes of
`
`
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`-11-
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`patent further discloses that omeprazole and esomeprazole were known acid
`
`inhibitors and incorporates by reference patents describing this property and their
`
`use for reducing the risk of gastroduodenal injury associated with NSAID use. (Id.
`
`at 6:43-49, 53-58.) A POSA would have commonly understood omeprazole to be
`
`a racemic mixture comprised of approximately equal parts esomeprazole, its S-
`
`enantiomer, and its R-enantiomer. (Exh. 1002, ¶ 31, 40; Exh. 1005, 1:50-55.)
`
`b.
`
`The ’556 patent describes a naproxen/esomeprazole
`tablet with the formulation limitations required by
`the ’636 patent
`
`The ’556 patent teaches the structure of the combination tablet described in
`
`the ’636 patent, specifically a core with naproxen surrounded by a pH-dependent
`
`enteric coating and non-enteric coated esomeprazole. The ’556 patent describes
`
`formulations with pH-dependent and pH-independent coatings to permit the
`
`coordinated release of one drug before the other. (Exh. 1004, 12:17-18.)
`
`Specifically, the ’556 patent states it is “possible and preferable to formulate
`
`compositions which release a portion of the dose [. . .] in one desired area of the GI
`
`
`anticipation. See, e.g., Callaway Golf Co. v. Acushnet Co., 576 F.3d 1331, 1346
`
`(Fed. Cir. 2009) (“[m]aterial not explicitly contained in the single, prior art
`
`document may still be considered for purposes of anticipation if that material is
`
`incorporated by reference into the document.”.
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`tract, e.g., the stomach, and release the remainder of the dose [. . .] in another area
`
`of the GI tract, e.g., the small intestine.” (Id., 12:27-32.)
`
`While the ’556 patent discloses a preferred formulation that would release
`
`the NSAID in the stomach and omeprazole in the small intestine, (id., 12:27-32.), it
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`is not limited to such formulations, and a POSA would have understood that PPIs
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`are preferably released in the gastrointestinal tract prior to reaching the small
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`intestine. (Exh. 1002, ¶ 33, 38.) Accordingly, a POSA would have applied the
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`teachings of the ’556 patent to develop a naproxen/esomeprazole tablet with
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`esomeprazole released before naproxen. (Id., ¶ 55.)
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`In the alternative, claim 1 is invalid at least because the ’556 patent would
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`have rendered the alleged invention “obvious to try.” “When there is a design need
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`or market pressure to solve a problem and there are a finite number of identified,
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`predictable solutions, a person of ordinary skill has good reason to pursue the
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`known options within his or her technical grasp.” KSR Int’l Co. v. Teleflex Inc.,
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`550 U.S. 398, 421 (2007). Again, a POSA would have understood the ’556 patent
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`to disclose a naproxen and esomeprazole combination tablet that permits release of
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`one drug in the stomach and one in the intestine. At the very least, the ’556 patent
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`would motivate a POSA to try to create the invention claimed in the ’636 patent.
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`c.
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`A person of skill would have been motivated to create
`a combination tablet with immediate release, non-
`enteric coated esomeprazole with a reasonable
`expectation of success.
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`With the disclosures in the ’556 patent, a person of ordinary skill at the time
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`would have found it obvious to make a combination tablet with enteric-coated
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`naproxen and immediate-release esomeprazole to be therapeutically effective. A
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`POSA would have reasonably expected non-enteric coated esomeprazole to be
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`therapeutically effective because a POSA would have known that a significant
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`amount of non-enteric esomeprazole would not degrade in the stomach.
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`The ’556 patent teaches that a combination tablet is preferable to separate
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`administration and further teaches release of each drug in a different location of the
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`gastrointestinal tract with the aid of pH-sensitive barriers such as enteric coatings.
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`(Exh. 1004, 12:14-31; Exh. 1002, ¶ 37.) The ’556 patent describes enteric-coated
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`omeprazole as “preferred”. A POSA would have understood this statement to show
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`non-enteric coated esomeprazole would be effective. (Exh. 1002, ¶ 38.) The ’556
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`patent does not suggest that formulas with non-enteric coated PPIs would result in
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`no bioavailability of the PPI. (Exh. 1004, 8:8-10; 7:15-17; Exh. 1002, ¶ 37.) A
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`POSA would know partial degradation of the PPI would not prevent non-enteric
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`coated esomeprazole from being therapeutically effective, but instead, a sufficient
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`amount of PPI could exist and loss of the PPI could be overcome by adjusting the
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`dosage. (See Exh. 1002, ¶ 48.)
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`Additionally, a POSA would have known at least a portion of non-enteric
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`coated, unbuffered esomeprazole would be bioavailable upon oral administration.
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`(Id., ¶ 38,47,48). Pilbrant discloses a study comparing the bioavailability of non-
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`enteric coated omeprazole when administered with and without a buffer and
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`teaches a substantial portion of the uncoated omeprazole is bioavailable. Pilbrant
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`contemplates “two principle options for the formulation of an oral, solid dosage
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`form of omeprazole”: (1) a “conventional” non-enteric coated form in which
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`“omeprazole is released and absorbed rapidly enough to avoid degradation in the
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`stomach” and (2) an enteric coated form of esomeprazole. (Exh. 1008, 114.)
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`Recognizing that some amount of degradation would occur in the stomach,
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`the study disclosed in Pilbrant was designed to identify “the magnitude of the
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`degradation occurring prior to the absorption of an oral dose” and reports that 44%
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`of uncoated, unbuffered omeprazole was not lost to degradation in the acidic
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`stomach. (Exh. 1008, 116-117 (emphasis added)) As confirmed by Dr. Banakar,
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`a POSA would have understood a therapeutically significant amount of non-enteric
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`coated and non-buffered omeprazole and/or esomeprazole does not degrade upon
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`immediate release in the stomach. (Exh. 1002, ¶ 47.)
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`Dr. Banakar further confirms a POSA would have been able to use well-
`
`known and routine techniques to compensate for the degraded amount. (Exh.
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`1002, ¶48-51,59) For example, while a POSA would have understood that while a
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`-15-
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`portion of omeprazole would degrade in the stomach resulting in a lower initial
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`bioavailability than enteric-coated esomeprazole, he or she would have easily been
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`able to overcome any low bioavailability by simply increasing the dosage of
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`esomeprazole. (Id., ¶48.) Indeed, a POSA with a formulation background would
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`have known to adjust the amount of esomeprazole through routine experimentation
`
`to compensate for any degradation.
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`A POSA would have also known that esomeprazole is self-propagating, and
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`thus increases its bioavailability upon repeated dosing. (See id., ¶ 31,51; Exh.
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`1006, 709.) As initial administration of esomeprazole increases gastric pH, less
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`and less of the later dosages would degrade, resulting in greater bioavailability.
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`Thus, it would have been obvious to a POSA that a viable, therapeutically effective
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`formulation could be developed using non-enteric coated esomeprazole.
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`Alternatively, a POSA would have understood that an alkalizing agent or
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`buffer could be included in the esomeprazole/naproxen formulation to further
`
`improve bioavailability of non-enteric coated esomeprazole. As an initial matter,
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`the claims of the ’636 patent allow for alkalizing agents or buffers in the claimed
`
`formulations. In fact, the specification of the ’636 patent discloses embodiments
`
`of the alleged invention expressly using alkalizing agents such as sodium
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`bicarbonate, sodium carbonate, and sodium hydroxide to protect omeprazole from
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`degradation. (See Exh. 1001, 17:47-52 (“The alkalizing agent helps solubilize and
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`-16-
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`protect omeprazole from degradation before its absorption.”).) With that scope of
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`the claims, Pilbrant discloses dramatic improvement of omeprazole bioavailability
`
`when used with a buffer. (See Exh. 1008, 116-117.) A POSA would have a
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`reasonable expectation that even a small amount of buffer would have a positive
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`effect on bioavailability. (Exh. 1002, ¶ 50,60.)
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`Further, a POSA would have known numerous alternative compounds that
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`have greater pH-adjusting effect than the sodium bicarbonate buffer tested in
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`Pilbrant. (Id.) The ’556 patent, for example, lists a number of alternative alkaline
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`compounds suitable for this purpose. (Exh. 1004, 9:15-17, 27-40.) Thus, it would
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`have been obvious to a POSA to use commonly known techniques to use these
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`alkaline compounds in conjunction with esomeprazole with a reasonable
`
`expectation of success.
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`In its preliminary response to IPR petition for U.S. Patent No. 8,557,285; a
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`related patent to the ’636 patent, Patentee highlights a single sentence in Pilbrant
`
`stating that a formulation with non-enteric coated omeprazole was “ruled out” and
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`that Pilbrant “teaches away” from using non-enteric coated esomeprazole. (Exh.
`
`1009, 30.) However, as explained above, that statement would not make a non-
`
`enteric coated omeprazole formulation non-obvious when Pilbrant is properly
`
`viewed in context from the perspective of a POSA. A POSA is not an automaton
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`and would not simplistically conclude that non-enteric coated esomeprazole could
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`
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`not work based on this lone statement in Pilbrant. Instead, a POSA would read and
`
`evaluate the entire disclosure of a reference and their understanding would be
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`based on their experience in evaluating formulations and the bioavailability of a
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`drug in formulations. Further, the Federal Circuit has acknowledged that Pilbrant
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`teaches non-enteric solid dosage forms of PPIs as a “viable alternative to enteric
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`coating.” Santarus, 694 F.3d at 1355-56. Although the Federal Circuit did not find
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`Pilbrant expressly teaches tablets containing non-enteric formulations, a POSA
`
`would have understood Pilbrant to nevertheless teach such formulations were
`
`likely to be viable. (Exh. 1002, ¶ 46.) So hardly from teaching away from
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`formulations with non-enteric PPIs, Pilbrant describes non-enteric buffered
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`formulations as a “second best choice.” Santarus, 694 F.3d at 1355-56. Thus,
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`contrary to patentee’s assertions, a POSA would have understood that uncoated
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`esomeprazole, with or without an alkaline buffering compound, would be an
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`obvious choice and would have had a reasonable expectation of success.
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`2.
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`Dependent pharmaceutical composition claims 2-4 and 13-
`15 and method of treatment claims 5 and 6 would have been
`obvious
`
`The ’556 patent renders claim 2 of the ’636 patent obvious because it
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`describes a “tablet core containing the drugs within a normal release matrix, with
`
`t