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 No. IPR2015-01718
`Patent No. 8,945,621
`
`______________
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`

`
`Case No. IPR2015-01718
`Patent No. 8,945,621
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`BACKGROUND ............................................................................................ 1
`
`CLAIM INTERPRETATION ........................................................................ 5
`
`A.
`
`B.
`
`“Low Dose Aspirin” and “LDA” ......................................................... 5
`
`“Unit Dosage Form” ............................................................................. 5
`
`III. THE USPTO HAS ALREADY CONSIDERED THE PRIOR ART ............ 6
`
`IV. THE BOARD SHOULD DENY CFAD’S PETITION BECAUSE IT
`FAILS TO DEMONSTRATE A REASONABLE LIKELIHOOD OF
`PREVAILING .............................................................................................. 11
`
`A. Ground 1: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-16 are Obvious Over Plachetka in
`View of Graham and Goldstein .......................................................... 11
`
`B. Ground 2: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-16 are Obvious Over Plachetka ............... 18
`
`C.
`
`The Objective Indicia of Nonobviousness Support the
`Patentability of the Claims ................................................................. 22
`
`1.
`
`2.
`
`Surprising and Unexpected Results ......................................... 23
`
`The Petition’s Discussion of “Secondary Considerations”
`is Irrelevant and Should be Disregarded. ................................. 29
`
`V.
`
`CONCLUSION ............................................................................................. 30
`
`
`
`
`
`ii
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`Case No. IPR2015-01718
`Patent No. 8,945,621
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Anova Food, LLC. v. Sandau,
`IPR2013-00114, Paper No. 11 (P.T.A.B. June 25, 2014) ............................27
`
`Crocs, Inc. v. Int’l Trade Comm’n,
`598 F.3d 1294 (Fed. Cir. 2010) .....................................................................23
`
`Excelsior Med. Corp. v. Lake,
`IPR2013-00494, Paper No. 10 (P.T.A.B. Feb. 6, 2014) .................................. 6
`
`Hulu LLC v. Intertainer, Inc.,
`IPR2014-01456, Paper No. 8 (P.T.A.B. Mar. 6, 2015) ................................... 6
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .....................................................................23
`
`Numatics, Inc. v. Balluff, Inc.,
`66 F. Supp. 3d 934 (E.D. Mich. 2014) ..........................................................18
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .....................................................................23
`
`Par Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186, (Fed. Cir. 2014) ....................................................... 19, 20, 22
`
`Prism Pharma Co. v. Choongwae Pharma Corp.,
`IPR2014-00315, Paper No. 14 (P.T.A.B. July 8, 2014) .................................. 6
`
`Application of Shetty,
`566 F.2d 81 (C.C.P.A. 1977) .........................................................................20
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .....................................................................23
`
`
`
`
`
`iii
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`Case No. IPR2015-01718
`Patent No. 8,945,621
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`Statutes
`
`35 U.S.C. § 325(d) .......................................................................................... 6, 7, 11
`
`Rules
`
`37 C.F.R. § 132 ........................................................................................................27
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.107(c) ...............................................................................................27
`
`
`
`iv
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`Case No. IPR2015-01718
`Patent No. 8,945,621
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`TABLE OF EXHIBITS
`
`Ex. No. Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`License Agreement between Patent Owner Pozen Inc. and Exclusive
`Licensee Horizon Pharma, Inc.
`Bhatt, et al., ACCF/ACG/AHA 2008 Expert Consensus Document on
`Reducing the Gastrointestinal risks of Antiplatelet Therapy and NSAID
`Use: a Report of the American College of Cardiology Foundation Task
`Force on Clinical Expert Consensus Documents, J Am Coll Cardiol
`52:1502–17 (2008) (“Bhatt 2008”)
`PREVACID® (lansoprazole) Delayed-Release Capsules, Prescribing
`Information (May 1, 2001), downloaded from
`http://www.accessdata.fda.gov/scripts/cder/drugsatfda
`/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist on
`November 17, 2015 (“PREVACID 2001”)
`Laine et al., Assessment of Upper Gastrointestinal Safety of Etoricoxib
`and Diclofenac in Patients with Osteoarthritis and Rheumatoid
`Arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-
`term (MEDAL) Programme: a Randomised Comparison, Lancet
`369:465-473 (2007) (“Laine 2007”)
`Angiolillo et al., Impact of Concomitant Low-Dose Aspirin on the
`Safety and Tolerability of Naproxen and Esomeprazole Magnesium
`Delayed-Release Tablets in Patients Requiring Chronic Nonsteroidal
`Anti-Inflammatory Drug Therapy: an Analysis from 5 Phase III Studies,
`J Thromb Thrombolysis 38(1):11-23 (2014; first published 12/25/2013)
`(“Angiolillo 2013”)
`
`Declaration of Lee S. Simon, MD, FACP, FACR, submitted May 22,
`2015 from File History of U.S. Patent Application No. 14/593,212
`(“Simon Declaration 2015”)
`
`Goldstein, et al., PN400 Significantly Reduces the Incidence of Gastric
`Ulcers Compared With Enteric-Coated Naproxen in Patients Requiring
`Chronic NSAID Therapy Regardless of Low-Dose Aspirin Use: Results
`from Two Prospective, Randomized Controlled Trials, Arthritis Rheum
`60 Suppl. 10:842 (2009) (“Goldstein 2 2009”)
`
`v
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`

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`Case No. IPR2015-01718
`Patent No. 8,945,621
`
`Pursuant
`
`to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Horizon
`
`Pharmaceuticals, Inc. (“Horizon”) and Pozen Inc. (“Pozen”) (collectively, “Patent
`
`Owner”)1 submit this Patent Owner’s Preliminary Response (“Preliminary
`
`Response”) to the Petition for Inter Partes Review (“Petition”) of claims 1-18 of
`
`U.S. Patent No. 8,945,621 (“the ’621 patent”), filed by Coalition for Affordable
`
`Drugs VII LLC (“CFAD” or “Petitioner”). This Response is timely under 35
`
`U.S.C. § 313 and 37 C.F.R. § 42.107.
`
`I.
`
`BACKGROUND
`
`Non-steroidal anti-inflammatory drugs (“NSAIDs”) are valuable agents in
`
`the treatment of arthritis and other musculoskeletal disorders and are one of the
`
`most widely used classes of drugs in the United States. The use of NSAIDs,
`
`however, has been associated with mucosal injury to the upper gastrointestinal
`
`(“GI”)
`
`tract,
`
`including
`
`the development of peptic ulcer disease, upper
`
`gastrointestinal hemorrhage, and perforation. This injury is increased when the
`
`NSAID is taken in conjunction with low dose aspirin. VIMOVO® is a unique
`
`
` As explained in Patent Owner’s Mandatory Notices, Paper No. 7, Pozen is
`
` 1
`
`the assignee of the ’621 patent and Horizon is its exclusive licensee.
`
`1
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`

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`Case No. IPR2015-01718
`Patent No. 8,945,621
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`drug product specifically designed to reduce the potential for gastric mucosal tissue
`
`damage due to NSAID use. VIMOVO® consists of a delayed-release, enteric-
`
`coated NSAID core (naproxen) surrounded by an immediate-release acid inhibitor
`
`(esomeprazole magnesium). The acid inhibitor is released before the NSAID,
`
`allowing its gastroprotective effects to take hold before naproxen is released, thus
`
`reducing the potential for gastric damage.
`
`The ’621 patent is one of twelve patents listed in the FDA’s Approved Drug
`
`Products with Therapeutic Equivalence Evaluations (the “Orange Book”) that
`
`cover VIMOVO®.2 As described in more detail below, the ’621 patent claims
`
`
` VIMOVO® is also protected by U.S. Patent No. 8,557,285, at issue in
`
` 2
`
`IPR2015-00802 with institution denied; U.S. Patent No. 8,858,996, at issue in
`
`IPR2015-01344 (filed by Petitioner) and IPR2015-01773; U.S. Patent No.
`
`6,926,907, at issue in IPR2015-01241 (filed by Petitioner); U.S. Patent No.
`
`6,852,636, at issue in IPR2015-01680 (filed by Petitioner) and IPR2015-01774;
`
`U.S. Patent Nos. 5,714,504, 5,900,424, 6,369,085, 7,411,070, 7,745,466, and
`
`9,161,920. VIMOVO® is also covered by U.S. Patent No. 8,865,190, at issue in
`
`IPR2015-01775, which is not listed in the Orange Book.
`
`2
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`

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`Patent No. 8,945,621
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`certain methods of reducing the incidence of NSAID-associated gastric ulcers in
`
`patients who are also taking low dose aspirin (“LDA”). Those methods require
`
`that the patient receive a unit dosage form that, like VIMOVO®, comprises 20 mg
`
`of esomeprazole and 500 mg of naproxen and that provides for coordinated release
`
`of the esomeprazole and the naproxen. The claimed method also requires that the
`
`dosage form is more effective at reducing the incidence of NSAID-associated
`
`ulcers in patients taking LDA than in patients not taking LDA.
`
`Prior to the inventions claimed in the ’621 patent, it was widely accepted
`
`that a patient’s concomitant use of multiple NSAIDs increased the risk of upper
`
`gastrointestinal complications and ulcers. (Bhatt 2008, Ex. 2002 at 4 (p. 1505).)
`
`In particular, it was understood that the use of an NSAID in conjunction with LDA
`
`increased the risk of gastrointestinal injury as compared to the use of NSAID
`
`alone. (Id.) However, the ’621 patent unexpectedly demonstrates the opposite in
`
`the context of the formulations disclosed in the patent: the administration of a unit
`
`dose form of immediate-release esomeprazole and delayed-release naproxen is
`
`more effective at reducing the incidence of the NSAID-associated ulcers in patients
`
`taking LDA than in patients not taking LDA. Thus, rather than increasing the risk
`
`of occurrence of an NSAID-associated gastric ulcer, the concomitant usage of
`
`LDA with a unit dose form of immediate-release esomeprazole and delayed-
`
`release naproxen, surprisingly, reduces that risk.
`
`3
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`No prior art disclosed, taught, or even remotely suggested that such
`
`concomitant use of LDA could result in a reduced risk of NSAID-associated
`
`gastric ulcer. In the Notice of Allowance for the ’621 patent, the Examiner
`
`recognized the “unexpected results that patients taking low dose aspirin who were
`
`administered [immediate-release esomeprazole and delayed-release naproxen]
`
`showed a lower incidence of gastric ulcers than non-aspirin-using patients
`
`administered [the same].” (9/25/14 Notice of Allowance, Ex. 1002 Pt. A at 2.)
`
`Those results are discussed more fully below.
`
`The ’621 patent issued over U.S. Patent No. 6,926,907 (Ex. 1004,
`
`“Plachetka”), cited by the Petition as the primary reference of Ground 1 and the
`
`only reference of Ground 2. The Petition does not address why Plachetka, which
`
`was thoroughly considered by the Examiner, warrants reconsideration by the Board
`
`now. Although the Petition bluntly characterizes the data presented in the
`
`specification as “expected,” it fails to explain why it was expected or how the
`
`Examiner came to a different conclusion. As discussed below, the ’621 patent’s
`
`claimed inventions are not taught or suggested by the prior art. The Petition should
`
`be denied in its entirety.
`
`4
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`Case No. IPR2015-01718
`Patent No. 8,945,621
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`II. CLAIM INTERPRETATION
`“Low Dose Aspirin” and “LDA”
`A.
`The Patent Owner agrees with the Petition’s proposed definition of “low
`
`dose aspirin,” as found in claims 1, 8, 15, and 16, and the acronym “LDA,” as
`
`found in claims 15 and 16, as referring to “dosages of aspirin that are ≤ 325 mg.”
`
`That interpretation is consistent with the definition for that term found in the
`
`specification of the ’621 patent. (Ex. 1001 at 5:9-10.)
`
`“Unit Dosage Form”
`
`B.
`The Petition’s proposed definition of the term “unit dose form” and “unit
`
`dosage form” found in claims 1, 5-8, 12, and 14-16 is “a single entity for drug
`
`administration,” taken in isolation with no limitation on route of administration. It
`
`is clear from the specification and claims of the ’621 patent that “unit dosage
`
`form” and “unit dose form” should be interpreted as a “unit dosage form suitable
`
`for oral administration to a patient.”3 The specification states that “[u]nit dosage
`
`
`
`
`
`3 The specification also states that the terms “unit dosage form,” "unit dose form,”
`
`“fixed dosage form,” “fixed dose form,” “fixed dosage combination,” and “fixed
`
`dose combination” are interchangeable. (Ex. 1001 at 5:37-41.)
`
`
`
`5
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`forms of the present disclosure provide for sequential drug release in a way that
`
`elevates gastric pH and reduces the deleterious effects of naproxen on the
`
`gastroduodenal mucosa, e.g., the esomeprazole is released first and the release of
`
`naproxen is delayed until after the pH in the GI tract has risen to 3.5 or greater.”
`
`(Ex. 1001 at 5:29-37.) Accordingly, the term should be construed, consistent with
`
`the specification, as directed solely to oral delivery.
`
`III. THE USPTO HAS ALREADY CONSIDERED THE PRIOR ART
`Under 35 U.S.C. § 325(d), “the Director may take into account whether, and
`
`reject the petition or request because, the same or substantially the same prior art or
`
`arguments previously were presented to the Office.” The Board has exercised that
`
`authority to deny institution of an IPR based on art or arguments that were
`
`previously considered by an examiner during prosecution. See, e.g., Hulu LLC v.
`
`Intertainer, Inc., IPR2014-01456, Paper No. 8 at 7-8 (P.T.A.B. Mar. 6, 2015);
`
`Prism Pharma Co. v. Choongwae Pharma Corp., IPR2014-00315, Paper No. 14 at
`
`12-13 (P.T.A.B. July 8, 2014); Excelsior Med. Corp. v. Lake, IPR2013-00494,
`
`Paper No. 10 at 20 (P.T.A.B. Feb. 6, 2014) (“The Board exercises its authority
`
`
`
`6
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`

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`Case No. IPR2015-01718
`Patent No. 8,945,621
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`under 35 U.S.C. § 325(d) to deny this ground because the asserted prior art
`
`references and arguments were considered previously by the Office.”).
`
`In this case, Plachetka, i.e., the primary reference of Ground 1 and the only
`
`reference of Ground 2, was extensively considered during the examination of the
`
`ʼ621 patent. Significantly, the arguments made in the Petition are the same or
`
`substantially the same as the arguments presented during prosecution.
`
`The original application of the ʼ621 patent contained dependent claims
`
`drawn to the treatment of patients taking low dose aspirin. (See original claims 5
`
`and 28, Ex. 1002 Part E at 584.)4 Those claims were rejected as obvious over
`
`Plachetka. (See Office Action of 9/14/2012, Ex. 1002 Part A at 539-542.)
`
`Specifically, the examiner stated:
`
`
` 4
`
` Then-pending claims 5 and 28 recited:
`
`5.
`
`The method according to any one of claims 1-4, wherein said
`
`patient is taking low dose aspirin.
`
`28. The method of claim 25, wherein the risk is associated with
`
`chronic NSAID treatment and administration of low dose aspirin prior
`
`to or during NSAID treatment.
`
`7
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`Patent No. 8,945,621
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`[Plachetka] teaches a method for reducing the risk of
`gastrointestinal side effects for people taking NSAIDs
`during chronic treatment by administration of a single,
`coordinated, unit-dose product that combines an agent
`which actively raises gastric pH to levels associated with
`less risk of NSAID-induced ulcers and an NSAID that is
`specially formulated to be released in a coordinated way
`to minimize adverse effects (col.3, lines 1-17). . . .
`Accordingly, it would have been obvious to administer
`the tablets of [Plachetka] to subsets of these patients
`where the subsets are included in the group of patients
`needing prolonged NSAID treatment.
`
`(Id.)
`
`In response, the Patent Owner argued that the pending claims represented a
`
`selection invention over Plachetka.
`
`[T]o arrive at the presently claimed invention, the
`following selections from [Plachetka] are required:
`• select one NSAID among 24 of such agents; then
`• select one gastric acid inhibitor among 12 such
`agents; then
`• select one dosage for the gastric acid inhibitor
`and two for the NSAID; then
`• select a duration of treatment; and then
`• select patient subsets for treatment.
`(See Response filed 3/14/2013, Ex. 1002 Part A at 215.)
`
`8
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`Patent No. 8,945,621
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`The examiner maintained the rejection, asserting that “[c]laim 1 does not
`
`require a specific patient population. The specific populations recited in the
`
`dependent claims (e.g. claims 3 and 4) would have been obvious given [that
`
`Plachetka] teaches the use of the acid inhibitor coated NSAID on any patient who
`
`requires prolonged NSAID administration.” (See Final Office action of 7/18/2013,
`
`Ex. 1002 Part A at 114.)
`
`In response, the Patent Owner amended the claims to recite the specific
`
`population of patients taking low dose aspirin. (See Response of 01/17/14, Ex.
`
`1002 Part A at 95-101.) The response also presented data evidencing the
`
`unexpected results that patients taking both low dose aspirin and a unit dosage
`
`form of
`
`immediate-release esomeprazole and delayed-release naproxen
`
`experienced a lower incidence of gastric ulcers, compared to patients taking the
`
`unit dosage form of immediate-release esomeprazole and delayed-release naproxen
`
`but not low-dose aspirin. (Id. at 104-107.)
`
`The examiner acknowledged that the results were unexpected but questioned
`
`whether the specification supported such a result and whether the claims were
`
`commensurate in scope with the unexpected results. (Office action of 4/2/2014,
`
`Ex. 1002 Part A at 78.) The Applicant explained that the support for the data
`
`underlying the surprising result in the subset of patients taking low-dose aspirin
`
`was contained in the specification as-filed. After the Applicant amended the
`
`9
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`Patent No. 8,945,621
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`claims to focus on the embodiment having 500 mg naproxen, the examiner allowed
`
`the claims.
`
`The Office repeatedly acknowledged that the results from concomitant use
`
`of LDA and naproxen together with esomeprazole were surprising and unexpected.
`
`(See Examiner-Initiated Interview Summary of 9/25/14, Ex. 1002 Part A at 27;
`
`Examiner-Initiated Interview Summary of 4/28/14, Ex. 1002 Part A at 66; and
`
`Office action of 4/2/14, Ex. 1002 Part A at 78.) Ignoring this evidence, the Petition
`
`asserts that these results were expected, and relies on Plachetka as the primary
`
`reference in Ground 1 and the only reference in Ground 2.
`
`The Patent Owner does not dispute the Petition’s characterization of
`
`Plachetka as “recogniz[ing] that NSAID ‘administration can lead to the
`
`development of gastroduodenal lesions, e.g., ulcers and erosions, in susceptible
`
`individuals.’” (Pet. at 10 (citing Ex. 1004 at 1:23-25).) The Patent Owner also
`
`agrees that Plachetka disclosed that a person of ordinary skill in the art (“POSA”)
`
`would have “appreciated the problem of patients developing gastric ulcers when
`
`taking both LDA and another NSAID.” (Pet. at 11 (citing Ex. 1004 at 2:35-40).)
`
`Indeed, those exact points were raised by the examiner during prosecution and
`
`successfully overcome. (See, e.g., Non-final Office action of 9/14/2012, Ex. 1002
`
`Part A at 539-42.)
`
`10
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`Patent No. 8,945,621
`
`Although the Graham and Goldstein references relied upon in Ground 1
`
`were not submitted to the Office during prosecution of the ’621 patent, these
`
`references provide no information regarding the effects of low-dose aspirin on
`
`patients taking a dosage form providing coordinated release of 500 mg naproxen
`
`and 20 mg esomeprazole.
`
`The material prior art and arguments presented in the Petition were
`
`presented previously to the Office. The Petition has not presented any persuasive
`
`evidence to supplement the record that was in front of the Office or to counter the
`
`evidence showing unexpected results that was submitted during prosecution of the
`
`application. The Petition does not raise any issues that have not already been fully
`
`considered and decided and should be denied under 35 U.S.C. § 325(d).
`
`IV. THE BOARD SHOULD DENY CFAD’S PETITION BECAUSE IT
`FAILS TO DEMONSTRATE A REASONABLE LIKELIHOOD OF
`PREVAILING
`
`Grounds 1 and 2 each allege that the challenged claims are unpatentable as
`
`obvious. As discussed below, each ground is legally deficient and should be
`
`denied.
`
`A. Ground 1: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-16 are Obvious Over Plachetka in View
`of Graham and Goldstein
`
`In Ground 1, the Petition cites to Plachetka in view of Graham and
`
`Goldstein. The cited combination does not render any claim of the ’621 patent
`
`11
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`Case No. IPR2015-01718
`Patent No. 8,945,621
`
`invalid at
`
`least because no reference discloses or renders obvious
`
`the
`
`administration of a unit dose form “wherein administration of the unit dose form is
`
`more effective at reducing the incidence of the NSAID-associated ulcers in patients
`
`taking LDA than in patients not taking LDA who are administered the unit dose
`
`form” as required by each of the independent claims of the ’621 patent.
`
`That low-dose aspirin exacerbated the risk of ulcers in patients taking an
`
`NSAID was well known in the art. (See infra p. 3). Plachetka “recogniz[ed] that
`
`NSAID ‘administration can lead to the development of gastroduodenal lesions,
`
`e.g., ulcers and erosions, in susceptible individuals.’” (Pet. at 10 (citing Ex. 1004 at
`
`1:23-25).) Thus, a POSA would have appreciated the problem of patients
`
`developing gastric ulcers when taking both LDA and another NSAID. (Pet. at 11,
`
`citing Ex. 1004 at 2:35-40.) What was not recognized by Plachetka or any of the
`
`cited art is that the administration of a unit dose form providing coordinated release
`
`of 500 mg of naproxen and 20 mg of esomeprazole to patients also taking low dose
`
`aspirin provided an unexpected reduction in the incidence of NSAID-associated
`
`gastric ulcers in such patients.
`
`The Petition
`
`is
`
`incorrect
`
`in
`
`stating “the
`
`results disclosed by
`
`Graham/Goldstein would indicate the compositions disclosed in Plachetka could be
`
`used for treating patients on an LDA regimen and achieve the predictable result of
`
`12
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`

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`Case No. IPR2015-01718
`Patent No. 8,945,621
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`lower gastric ulcer incidence.” (Pet. at 12.) The Petition claims that Graham and
`
`Goldstein disclose that patients taking lansoprazole and an NSAID with LDA have
`
`fewer gastric ulcers than patients taking lansoprazole and an NSAID without LDA.
`
`(Id. at 17–18). But neither Graham nor Goldstein make such a comparison. In
`
`particular, neither reference provides data for a group of patients taking
`
`lansoprazole and an NSAID but not LDA.
`
`Graham summarizes a study of 537 patients who were long-term NSAID
`
`users, had a history gastric ulcer, and were H pylori negative. (Ex. 1005 at
`
`abstract.) The study participants continued to take NSAIDs and were randomly
`
`assigned to receive: a placebo, misoprostol, a 15 mg dose of lansoprazole, or 30
`
`mg dose of lansoprazole, daily for 12 weeks. (Id. at 170.) The participants were
`
`not separated based on the type of NSAID taken and included those taking low
`
`dose aspirin in addition to another NSAID. (Id.) Graham does not present data for
`
`a group of participants taking NSAID and lansoprazole but not LDA, and it does
`
`not provide any analysis comparing patients taking LDA with those not taking
`
`LDA.
`
`Goldstein describes a post hoc, non-randomized analysis of data from a
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`subgroup of only 70 patients taking LDA out of the over 500 patients studied in the
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`earlier Graham study and compared them by arm. Goldstein sought to determine
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`the effectiveness of misoprostol or lansoprazole in patients taking NSAIDs and
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`LDA. (Ex. 1006 at abstract.) The paper concludes that, for patients taking
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`NSAIDs with LDA, that administration of misoprostol or lansoprazole reduced the
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`risk of gastric ulcer compared to placebo. (Id.)
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`As explained above, neither Graham nor Goldstein reports data for a group
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`of study participants taking NSAID and lansoprazole but not LDA. Neither
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`reference makes any effort to compare patient populations taking LDA with those
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`not taking LDA, which is not surprising given the sample size. And certainly,
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`neither reference makes any conclusion regarding the risk of gastric ulcers for
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`patients taking NSAIDs and lansoprazole with LDA as compared to patients
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`NSAIDs and lansoprazole without LDA.
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`Further, even if the Petition’s description of Graham and Goldstein were
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`accurate—which it is not—its argument overreaches because a POSA could not
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`divine from the references anything regarding the effect of the use of naproxen and
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`esomeprazole, let alone the use of a unit dosage form providing the coordinated
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`release of 500 mg delayed-release naproxen and 20 mg immediate release
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`esomeprazole, as claimed in the ’621 patent, on patients on an LDA regimen.
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`As an initial matter, Goldstein’s analysis is based on data from just 70
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`patients, which were then further subdivided into four subgroups. The largest of
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`those subgroups was just 25 patients, with the smallest, i.e., patients taking 30 mg
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`lansoprazole, LDA and one or more NSAIDs, was only 7 patients. (Ex. 1003,
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`Appendix B at 30.) Goldstein’s post hoc, non-randomized analysis simply is not
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`large enough to draw any meaningful conclusions. Any statistical significance that
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`could be drawn from Graham’s study is lost due to Goldstein’s further division and
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`dissection of the data.
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`Furthermore, Graham and Goldstein only present data on NSAID use
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`generally. None of the data is specific to the use of naproxen. Rather, in the
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`patients taking 15 mg lansoprazole, only 37.5% were taking naproxen. The
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`majority of the patients were taking other NSAIDS. In the 30 mg lansoprazole
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`group, only 28.6% of the patients were on naproxen. (Ex. 1006 at 1640, Table II.)
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`Graham and Goldstein provide no data on ulcer rates specific to the naproxen
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`patients. A POSA would not be able to ascertain from Graham and Goldstein the
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`effect of lansoprazole on patients taking naproxen and LDA specifically.
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`Moreover, Graham and Goldstein do not specify what dosages of NSAIDs
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`were being taken for any of the patients. Indeed, the references alludes to the fact
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`that patients may be taking more than one NSAID, but again provides no details as
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`to which NSAIDs may have been used together, the dosages of those NSAIDS, or
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`the ulcer rate on those patients. (Id. at Footnote at Table II (noting that patients
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`may have taken more than one NSAID).)
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`With regard to the PPI lansoprazole, Graham and Goldstein indicate that
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`PREVACID was used. (Ex. 1005 at 171.) In January 2002, i.e., at the time of
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`publication of Graham, PREVACID was only available as enteric coated capsules
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`that delay the release of lansoprazole until the capsules have left the low pH
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`environment of the stomach. (PREVACID 2001, Ex. 2003.) In contrast, the
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`claims of the ’621 patent require esomeprazole rather than lansoprazole and
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`specify that at least a portion of the esomeprazole is immediate release, i.e.,
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`released independent of the pH of the surrounding medium. Given the difference
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`in release characteristics (as well as PPI), a POSA would not have been able to
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`extrapolate from the results in Graham and Goldstein to those described and
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`claimed in the ’621 patent.
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`Finally, the patients in Graham and Goldstein also received antacid tablets
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`for use as needed for symptom relief. (Ex. 1005 at 170 Abstract; Ex. 1006 at
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`1638.)
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` Specifically, additional antacid was used by the patients taking
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`lansoprazole during about 25% of the treatment period. (Id. at 173, Table 3.)
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`Neither Graham nor Goldstein provides any analysis of how such antacid use may
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`have confounded the data on ulcer rates.
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`The Petition fails to explain how the Graham and Goldstein references,
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`lacking such fundamental details, would overcome the express teachings of the
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`prior art describing the increased ulcer risk associated with the use of LDA in
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`combination with naproxen or other NSAIDs. There is no indication that a POSA
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`would have found obvious a reduction in the incidence of NSAID-associated
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`gastric ulcers in patients taking LDA compared to patients not taking LDA as a
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`result of the administration of a unit dose form providing coordinated release of
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`500 mg of naproxen, or a pharmaceutically acceptable salt thereof, and 20 mg of
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`esomeprazole, or a pharmaceutically acceptable salt thereof.
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`Not only does the Petition fail to provide an explanation, it fails to provide
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`any indication that a POSA would have given any weight whatsoever to the results
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`of a study with parameters so fundamentally different from those disclosed in the
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`ʼ621 patent. In particular, the Petition does not explain why results from a post
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`hoc, non-randomized study in which a very small number of patients are:
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`• taking one or more of a number of unspecified NSAIDs,
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`• may or may not be taking LDA,
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`• administered lansoprazole rather than esomeprazole,
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`• administered a PPI that is enteric coated rather than one of which at
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`least a portion is immediate release, and
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`• administered antacids as supplemental gastrointestinal protection
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`would render obvious the specific elements of the claims of the ’621 patent (that
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`do not include lansoprazole, are specific as to the use of naproxen and LDA, and
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`require that at least a portion of the esomeprazole is immediate release).
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`In addition, while the Petition cites to a declaration from Dr. Leon Shargel,
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`the declaration merely recites, word-for-word, the Petition and provides no
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`independent analysis. (Compare, e.g., Pet. at 17–19 with Ex. 1003, ¶¶ 82–85.)
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`Accordingly, the declaration should be disregarded. See, e.g., Numatics, Inc. v.
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`Balluff, Inc., 66 F. Supp. 3d 934, 941 (E.D. Mich. 2014) (“An expert witness who
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`is merely a party’s lawyer’s avatar contributes nothing useful to the decisional
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`process.”).
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`Plachetka, in view of Graham and Goldstein, does not teach the claimed
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`inventions. The Petition has not carried its burden of establishing a reasonable
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`likelihood that it will prevail on its proposed Ground 1. Accordingly, Ground 1
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`should be denied in its entirety.
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`B. Ground 2: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-16 are Obvious Over Plachetka
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`Ground 2 of the Petition states that claims 1-16 are obvious over Plachetka.
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`This ground fails because Plachetka does not disclose or render obvious the
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`administration of a unit dose form to patients taking LDA “wherein administration
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`of the unit dose form is more effective at reducing the incidence of the NSAID-
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`associated ulcers in patients taking LDA than in patients not taking LDA who are
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`administered