IPR2015-01718
`Patent 8,945,621
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________
`
`
`
`COALITION FOR AFFORDABLE DRUGS VII, LLC,
`Petitioner,
`
`v.
`
`
`
`
`
`POZEN INC.,
`Patent Owner.
`
`___________
`
`
`
`Case IPR2015-01718
`Patent 8,945,621
`
`___________
`
`
`
`PATENT OWNER POZEN INC.’S PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`
`
`

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`IPR2015-01718
`Patent 8,945,621
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION .......................................................................................... 1
`A.
`Background .......................................................................................... 1
`B.
`Relief Requested ................................................................................... 1
`C.
`Related Proceedings ............................................................................. 1
`D.
`Summary of Argument ......................................................................... 2
`RELEVANT LAW ......................................................................................... 6
`II.
`III. RELEVANT TECHNICAL BACKGROUND .............................................. 9
`A. NSAID-Induced Gastric Ulcers ........................................................... 9
`B. NSAIDs Taken Concurrently With LDA Pose an Increased
`Risk of Gastric Ulcer Compared to NSAIDs Taken Alone ............... 13
`The Inventors of the ’621 Patent Surprisingly Found that a Unit
`Dose Form of Immediate-Release Esomeprazole and Delayed-
`Release Naproxen is More Effective at Reducing NSAID-
`Associated Ulcers in Patients Taking LDA than in Patients Not
`Taking LDA ....................................................................................... 15
`The Prosecution History of the ’621 Patent ....................................... 18
`D.
`IV. LEVEL OF SKILL IN THE ART ................................................................ 21
`V.
`INTERPRETATIONS OF THE ’621 PATENT CLAIMS .......................... 22
`A.
`“Low Dose Aspirin” and “LDA” ....................................................... 22
`B.
`“Unit Dosage Form” ........................................................................... 22
`VI. THE SCOPE AND CONTENT OF THE CITED ART ............................... 23
`A.
`Plachetka ............................................................................................ 23
`B. Graham ............................................................................................... 25
`C. Goldstein ............................................................................................ 26
`VII. ARGUMENT ................................................................................................ 28
`A.
`The “Wherein” Clause is Entitled to Patentable Weight Because
`it was Added by the Examiner as a Condition for Allowance ........... 29
`Claims 1-16 of the ’621 Patent are Not Obvious Over Plachetka
`in View of Graham and Goldstein...................................................... 33
`
`C.
`
`B.
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`1.
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`2.
`
`3.
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`IPR2015-01718
`Patent 8,945,621
`The Data from Graham and Goldstein Does Not Support
`a Conclusion as to the Effect of Taking Concomitant
`LDA with an Acid Inhibitor and an NSAID ............................ 36
`Dr. Shargel Uses Flawed Data from Goldstein that
`Render His Calculations Meaningless ..................................... 40
`A POSA Would Not Have Expected that Administering a
`Unit Dose Form of Immediate-Release Esomeprazole
`and Delayed-Release Naproxen is More Effective at
`Reducing NSAID-Associated Ulcers in Patients Taking
`LDA than in Patients Not Taking LDA ................................... 43
`Claims 1-16 of the ’621 Patent are Not Obvious Over Plachetka ..... 46
`1.
`Plachetka Does Not Inherently Teach that
`“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” ..... 47
`A POSA Would Have Had No Expectation of Success in
`Administering a Unit Dose Form of Immediate-Release
`Esomeprazole and Delayed-Release Naproxen that is
`More Effective at Reducing NSAID-Associated Ulcers in
`Patients Taking LDA than in Patients Not Taking LDA ......... 50
`Even if the Final “Wherein” Clause is Not Afforded Patentable
`Weight, the Challenged Claims are Not Obvious Due to
`Surprising and Unexpected Results ................................................... 51
`VIII. CONCLUSION ............................................................................................. 55
`
`C.
`
`D.
`
`2.
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`
`TABLE OF AUTHORITIES
`
`IPR2015-01718
`Patent 8,945,621
`
` Page(s)
`
`Cases
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) .......................................................................... 49
`
`Biosig Instruments, Inc. v. Nautilus, Inc.,
`783 F.3d 1374 (Fed. Cir. 2015) .......................................................................... 31
`
`Biosig Instruments, Inc. v. Nautilus, Inc.,
`715 F.3d 891 (Fed. Cir. 2013), vacated and remanded on other
`grounds, 134, S. Ct. 2120 (2014) ........................................................................ 32
`
`Crocs, Inc. v. Int’l Trade Comm’n,
`598 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 52
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ............................................................................ 6
`
`Eltech Sys. Corp. v. PPG Indus., Inc.,
`710 F. Supp. 622 (W.D. La. 1988) aff’d, 903 F.2d 805 (Fed. Cir.
`1990) ................................................................................................................... 32
`
`Graham v. John Deere Co. of Kansas City,
`383 U.S. 1 (1966) .................................................................................................. 7
`
`Hoffer v. Microsoft Corp.,
`405 F.3d 1326 (Fed. Cir. 2005) (per curiam) ..................................................... 31
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 52
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`No. 2015-1693, 2016 WL 2620512 (Fed. Cir. May 9, 2016) ............................... 7
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................................. 6
`
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`iii
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`IPR2015-01718
`Patent 8,945,621
`
`Minton v. Nat’l Ass’n of Sec. Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) .................................................................... 30, 31
`
`Nike, Inc. v. Adidas AG,
`812 F.3d 1326 (Fed. Cir. 2016) ............................................................................ 7
`
`Numatics, Inc. v. Balluff, Inc.,
`66 F. Supp. 3d 934, 941 (E.D. Mich. 2014) ....................................................... 43
`
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) .................................................................. 8, 48, 49
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 52
`
`Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) ............................................................................ 7
`
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ............................................................ 6, 8, 48, 49
`
`Research Found. of State Univ. of New York v. Mylan Pharm. Inc.,
`723 F. Supp. 2d 638 (D. Del. 2010) .................................................................... 31
`
`Ricoh Co., Ltd. v. Quanta Computer Inc.,
`550 F.3d 1325 (Fed. Cir. 2008) ............................................................................ 8
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 52
`
`Texas Instruments Inc. v. U.S. Int’l Trade Comm’n,
`988 F.2d 1165 (Fed. Cir. 1993) .......................................................................... 30
`
`Thermalloy Inc. v. Aavid Eng'g, Inc.,
`935 F. Supp. 55 (D.N.H. 1996), amended by, 935 F. Supp. 63
`(D.N.H. 1996), aff’d, 121 F.3d 691 (Fed. Cir. 1997) ......................................... 32
`
`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling
`USA, Inc.,
`699 F.3d 1340 (Fed. Cir. 2012) ............................................................................ 7
`
`Unigene Labs, Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ............................................................................ 7
`
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`IPR2015-01718
`Patent 8,945,621
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ............................................................................ 6
`
`Statutes
`
`35 U.S.C. § 102 ........................................................................................................ 19
`
`35 U.S.C. § 103 ........................................................................................................ 19
`
`35 U.S.C. § 103(a) ..................................................................................................... 6
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`IPR2015-01718
`Patent 8,945,621
`
`I.
`
`INTRODUCTION
`A. Background
`The Board has ordered an investigation into the patentability of claims 1-16
`
`(collectively, “the challenged claims”) of U.S. Patent No. 8,945,621 (“the ’621
`
`patent”). The present inter partes review has been instituted for the challenged
`
`claims solely on two related obviousness grounds. The first ground asserted by the
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`Petitioner and instituted by the Board requires combining three publications,
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`Plachetka (Ex. 1004), Graham (Ex. 1005), and Goldstein (Ex. 1006). The second
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`ground asserted by the Petitioner and instituted by the Board is based only on a
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`single publication, Plachetka (Ex. 1004).
`
`B. Relief Requested
`The Patent Owner respectfully requests that the Board determine that the
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`Petitioner has failed to meet its burden of demonstrating that claims 1-16 of the
`
`’621 patent are unpatentable in view of the asserted references.
`
`C. Related Proceedings
`The ’621 patent is involved in Horizon Pharma, Inc. v. Actavis Laboratories
`
`FL, Ltd. 3:15-cv-08524 (consolidated with 3:15-cv-03322 (D.N.J.)). There are no
`
`other administrative or judicial proceedings involving the ’621 patent.
`
`Related matters involving other patents include: Horizon Pharma, Inc. v.
`
`Actavis Labs. FL, Inc., 3:15-cv-03322 (D.N.J.); Horizon Pharma, Inc. v. Dr.
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`IPR2015-01718
`Patent 8,945,621
`Reddy’s Labs., Inc., 3:15-cv-03324 (D.N.J.); Horizon Pharma, Inc. v. Lupin Ltd.,
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`3:15-cv-03326 (D.N.J.); Horizon Pharma, Inc., v. Mylan Pharmas., Inc. 3:15-cv-
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`03327 (D.N.J.); AstraZeneca AB v. Dr. Reddy’s Labs. Inc., 3:11-cv-02317
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`(D.N.J.); Astrazeneca AB v. Lupin Ltd., 3-11-cv-04275 (D.N.J.); AstraZeneca AB
`
`v. Dr. Reddy’s Labs., Inc., 3:13-cv-00091 (D.N.J.); AstraZeneca AB v. Watson
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`Labs., Inc. Florida, 3:13-cv-03038 (D.N.J.); AstraZeneca AB v. Mylan Pharmas.,
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`3:13-cv-04022 (D.N.J.); Lupin Ltd. and Lupin Pharmaceuticals Inc. v. Pozen, Inc.,
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`IPR2015-01773 (P.T.A.B.); and Lupin Ltd. and Lupin Pharmaceuticals Inc. v.
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`Pozen, Inc., IPR2015-01775 (P.T.A.B.).
`
`U.S. Patent Appl. Nos. 14/593,212 and 15/050,527 claim, or may claim, the
`
`benefit of priority to U.S. Provisional Application Nos. 61/310,525, filed on March
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`4, 2010; 61/225,970, filed July 16, 2009; and 61/220,420, filed June 25, 2009, the
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`same applications to which the ’621 patent may claim priority.
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`Patent Owner does not concede that any of these applications would affect,
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`or be affected by, a decision in the present inter partes review of the ’621 patent.
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`Summary of Argument
`
`D.
`Prior to the inventions of the claimed subject matter of the ’621 patent in
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`2009, it was widely known and accepted that non-steroidal anti-inflammatory
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`drugs, or NSAIDs, caused gastrointestinal toxicity, including gastrointestinal ulcer
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`and hemorrhage. Moreover, prior to 2009, it was also widely known and accepted
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`IPR2015-01718
`Patent 8,945,621
`that taking low dose aspirin (“LDA”) in addition to a non-aspirin NSAID further
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`increased one’s risk for such gastrointestinal complications. However, in 2009, the
`
`inventors of the ’621 patent unexpectedly and surprisingly found that the unit dose
`
`form claimed in the ’621 patent results in a greater reduction in incidence of gastric
`
`ulcer in patients also taking LDA than in patients not taking LDA.
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`Prior to this finding, there was no teaching or suggestion in the prior art
`
`(including Plachetka, Graham, and Goldstein) that a unit dose form of immediate-
`
`release esomeprazole and delayed-release naproxen (an NSAID) is more effective
`
`at reducing gastric ulcers in patients taking LDA than in patients not taking LDA,
`
`as specifically recited in the final “wherein” clause of the challenged claims of the
`
`’621 patent. The Board correctly recognized this state of the art in its decision to
`
`institute the instant inter partes revew, when the Board stated: “Petitioner has not
`
`established that Plachetka, Graham, and Goldstein teach or suggest that
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`‘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
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`LDA who are administered the unit dose form,’ as required by each of independent
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`claims 1, 8, 15, and 16.” (Paper No. 17 at 14.) Thus, upon the Board’s
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`determination that this final “wherein” clause is entitled to patentable weight
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`because it was added by the Examiner via an Examiner’s Amendment as a
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`IPR2015-01718
`Patent 8,945,621
`condition for allowance, the Board should hold that the Petitioner has failed to
`
`meet its burden to show unpatentability of the challenged claims.
`
`The Petitioner’s first challenge to the claims of the ’621 patent rests on the
`
`combination of three references—Plachetka, Graham, and Goldstein—as the
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`Petitioner argues that the combination of these three references teaches the final
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`“wherein” clause of the challenged claims. However, Plachetka never once
`
`mentions that LDA could or should be administered with the unit dose forms
`
`taught therein, and Plachetka includes no teachings of LDA concurrently being
`
`administered along with the unit dose forms taught therein. Similarly, neither
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`Graham nor Goldstein discloses the naproxen and esomeprazole dosage form
`
`claimed in the ’621 patent, nor do they teach or suggest that the combination of an
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`acid inhibitor and an NSAID is more effective at reducing the incidence of
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`NSAID-associated gastric ulcers in patients taking LDA than in patients not taking
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`LDA.
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`Faced with an overwhelming lack of support in the prior art for its position,
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`the Petitioner resorts to taking a sub-set of data from Goldstein, who has, in turn,
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`taken a sub-set of data from Graham, and performing further calculations on these
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`data to arrive at the conclusory and incorrect allegation that Graham and Goldstein
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`teach that the combination of an acid inhibitor and an NSAID is more effective at
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`reducing the incidence of NSAID-associated ulcers in patients taking LDA than in
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`IPR2015-01718
`Patent 8,945,621
`patients not taking LDA. The Petitioner’s use of the data from Graham and
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`Goldstein in these calculations, however, is deeply flawed for a number of
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`scientific reasons, including that the Graham study did not track patients’ LDA
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`usage nor balance such usage across the treatment arms. In addition, Graham did
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`not identify LDA usage as an issue to be studied or a variable that could affect the
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`outcome of the study, and there were differential early patient withdrawals that
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`likely introduced bias into the study. The data sub-set used by the Petitioner from
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`Graham also includes far too few patients from which to draw any meaningful
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`conclusions because the data are not sufficiently robust and suffer from extremely
`
`high error rates. Thus, for at least these reasons, a person of ordinary skill in the
`
`art (“POSA”) would not rely on the data from Graham and Goldstein to draw any
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`conclusions regarding LDA usage, and the Petitioner’s first challenged to the
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`claims of the ’621 patent must fail.
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`The Petitioner’s second challenge to the claims of the ’621 patent rests on
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`the Plachetka reference alone and is based on the utilization of an incorrect
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`standard for the inherency doctrine in an obviousness analysis. Because the correct
`
`standard requires the Petitioner to show that the final “wherein” clause of the
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`challenged claims of the ’621 patent “necessarily must be present, or the natural
`
`result of the combination of elements explicitly disclosed by the prior art,” and
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`because Plachetka does not disclose that LDA could or should be administered
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`IPR2015-01718
`Patent 8,945,621
`with the unit dose forms taught therein and includes no teachings of LDA
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`concurrently being administered along with the unit dose forms taught therein, the
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`Petitioner’s second ground for challenging the claims of the ’621 patent must also
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`fail. See PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1196 (Fed. Cir.
`
`2014).
`
`As such, Petitioner presents no ground to successfully challenge Claims 1-16
`
`of the ’621 patent.
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`II. RELEVANT LAW
`Under pre-AIA 35 U.S.C. § 103(a), a claim is obvious when “the subject
`
`matter sought to be patented and the prior art are such that the subject matter as a
`
`whole would have been obvious at the time the invention was made to a person
`
`having ordinary skill in the art to which said subject matter pertains.” See also
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`Wyers v. Master Lock Co., 616 F.3d 1231, 1237 (Fed. Cir. 2010). “[A] patent
`
`composed of several elements is not proved obvious merely by demonstrating that
`
`each of its elements was, independently, known in the prior art.” KSR Int’l Co. v.
`
`Teleflex Inc., 550 U.S. 398, 418 (2007). Where a party seeks to invalidate a patent
`
`based on obviousness, it must demonstrate by a preponderance of the evidence that
`
`a “skilled artisan would have had reason to combine the teaching of the prior art
`
`references to achieve the claimed invention, and that the skilled artisan would have
`
`had a reasonable expectation of success from doing so.” In re Cyclobenzaprine
`
`
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`6
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`IPR2015-01718
`Patent 8,945,621
`Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1068-69
`
`(Fed. Cir. 2012). See also Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., No.
`
`2015-1693, 2016 WL 2620512, at *6 (Fed. Cir. May 9, 2016).
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`Obviousness is a question of law based on underlying findings of fact.
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`Unigene Labs, Inc. v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir. 2011). In
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`determining whether a claim is obvious, the Supreme Court has held that the
`
`following four factors must be examined: (1) the scope and content of the prior art;
`
`(2) the differences between the prior art and the claimed invention; (3) the level of
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`skill in the pertinent art; and (4) any objective indicia of nonobviousness. Graham
`
`v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966). All four factors must
`
`be considered in an obviousness analysis. Transocean Offshore Deepwater
`
`Drilling, Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1349 (Fed. Cir. 2012).
`
`See also Nike, Inc. v. Adidas AG, 812 F.3d 1326, 1335 (Fed. Cir. 2016).
`
`“A prior art reference must be considered in its entirety, i.e., as a whole,
`
`including portions
`
`that would
`
`lead away from
`
`the claimed
`
`invention.”
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`MPEP § 2141.02 (9th ed. Rev. 7, Nov. 2015); see also, Panduit Corp. v. Dennison
`
`Mfg. Co., 810 F.2d 1561, 1568 (Fed. Cir. 1987) (citing W.L. Gore & Assocs., Inc.
`
`v. Garlock, Inc., 721 F.2d 1540, 1550 (Fed. Cir. 1983)). “A reference may be said
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`to teach away when a person of ordinary skill, upon reading the reference, would
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`be discouraged from following the path set out in the reference, or would be led in
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`IPR2015-01718
`Patent 8,945,621
`a direction divergent from the path that was taken by the applicant.” Ricoh Co.,
`
`Ltd. v. Quanta Computer Inc., 550 F.3d 1325, 1332 (Fed. Cir. 2008) (quoting
`
`Optivus Tech., Inc. v. Ion Beam Applications S.A., 469 F.3d 978, 989 (Fed. Cir.
`
`2006)).
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`The Federal Circuit has consistently cautioned against finding obviousness
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`based on inherency. While the Federal Circuit has acknowledged that “inherency
`
`may supply a missing claim limitation in an obviousness analysis,” the Court has
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`also explained that “the use of inherency, a doctrine originally rooted in
`
`anticipation, must be carefully circumscribed in the context of obviousness.” Par
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`Pharm., Inc., 773 F.3d at 1194-95. “A party must, therefore, meet a high standard
`
`in order to rely on inherency to establish the existence of a claim limitation in the
`
`prior art in an obviousness analysis—the limitation at issue necessarily must be
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`present, or the natural result of the combination of elements explicitly disclosed by
`
`the prior art.” Id. at 1195-96 (emphasis added). “Inherency, however, may not be
`
`established by probabilities or possibilities. The mere fact that a certain thing may
`
`result from a given set of circumstances is not sufficient.” In re Oelrich, 666 F.2d
`
`578, 581 (C.C.P.A. 1981) (quoting Hansgirg v. Kemmer, 26 C.C.P.A. 937, 940
`
`(1939)). Thus, a patent challenger “must show that the natural result flowing from
`
`the operation as taught would result in the performance of the questioned
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`function.” Id. (emphasis added).
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`IPR2015-01718
`Patent 8,945,621
`
`III. RELEVANT TECHNICAL BACKGROUND
`A. NSAID-Induced Gastric Ulcers
`Non-steroidal anti-inflammatory drugs, or NSAIDs, have long been used for
`
`the management of inflammatory conditions including osteoarthritis, rheumatoid
`
`arthritis, and other musculoskeletal conditions. (Gabriel, S.E., et al., “Risk for
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`Serious Gastrointestinal Complications Related to Use of Nonsteroidal Anti-
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`inflammatory Drugs,” Annals of Internal Medicine, Vol. 115, No. 10, pp. 787-796
`
`at 787 (1991) (“Ex. 2008”); see also Declaration of David A. Johnson, M.D., in
`
`Support of Patent Owner’s Response (“Ex. 2022”) ¶ 30.) Chronic use of NSAIDs,
`
`however, has been associated with an increased risk of adverse gastrointestinal
`
`effects, including endoscopic gastric ulcers, and upper gastrointestinal hemorrhage
`
`and perforation. (Ex. 2008 at 787; Ex. 2022, ¶ 30.) This is believed to be the case
`
`because NSAIDs inhibit prostaglandin synthesis, which in turn, leads to
`
`gastrointestinal toxic effects. (Cryer, B. and Feldman, M., “Effects of Nonsteroidal
`
`Anti-inflammatory Drugs on Endogenous Gastrointestinal Prostaglandins and
`
`Therapeutic Strategies for Prevention and Treatment of Nonsteroidal Anti-
`
`inflammatory Drug-Induced Damage,” Archives of Internal Medicine, Vol. 152,
`
`No. 6, 1145-1155 at 1145 (1992) (“Ex. 2009”); Ex. 2022, ¶¶ 30, 32-33.) Thus, the
`
`use of NSAIDs has become increasingly recognized as causing the most prevalent
`
`serious drug toxicity in the United States, resulting in an estimated 2,600 deaths
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`IPR2015-01718
`Patent 8,945,621
`and 24,000 hospitalizations annually in rheumatoid arthritis patients alone. (Fries,
`
`J.F., et al., “Nonsteroidal Anti-inflammatory Drug-Associated Gastropathy:
`
`Incidence and Risk Factor Models,” The American Journal of Medicine, Vol. 91,
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`pp. 213-222 at 213 (1991) (“Ex. 2010”).) Indeed, it has been determined that
`
`NSAID users have an increased risk of experiencing gastrointestinal clinical
`
`events, such as bleeding ulcers, that is two to five times greater than the risk of
`
`such events in individuals who do not use NSAIDs. (Ex. 2004 at 465; see also Ex.
`
`2008 at 787 (stating that users of NSAIDs have an approximately three times
`
`greater risk for developing serious adverse gastrointestinal events than non-users of
`
`NSAIDs); Ex. 2022 at ¶ 31.)
`
`Even LDA, at doses of ≤ 325 mg per day, has been associated with an
`
`increased risk of adverse gastrointestinal effects. (See, e.g. Sørensen, H.T., et al.,
`
`“Risk of Upper Gastrointestinal Bleeding Associated With Use of Low-Dose
`
`Aspirin,” The American Journal of Gastroenterology, Vol. 95, No. 9, pp. 2218-
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`2224 at 2218 (2000) (“Ex. 2011”); Ex. 2022 at ¶ 31.) This is because aspirin, like
`
`other NSAIDs, decreases the production of prostaglandins that have protective
`
`effects on the stomach. (Tamura, A., et al., “Prevalence and independent factors
`
`for gastroduodenal ulcers/erosions in asymptomatic patients taking low-dose
`
`aspirin and gastroprotective agents: the OITA-GF study,” The Quarterly Journal of
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`Medicine, Vol. 104, pp. 133-139 at 137 (2010) (“Ex. 2012”); Ex. 2022 at ¶ 33.)
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`This decreased production of prostaglandins results in a gastric environment that is
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`more susceptible to topical attacks by acid, pepsin, and bile salts. (Ex. 2012 at
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`137) Additionally, LDA promotes gastrointestinal bleeding through its anti-
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`platelet effect. (Id.)
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`For example, Derry conducted a meta-analysis of 24 randomized controlled
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`trials
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`involving almost 66,000 participants
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`to assess
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`the
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`incidence of
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`gastrointestinal bleeding associated with long-term use of aspirin, including LDA.
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`(Derry, S. and Loke, Y.K., “Risk of gastrointestinal haemorrhage with long term
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`use of aspirin: meta-analysis,” British Medical Journal, Vol. 321, pp. 1183-1187 at
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`1183 (2000) (“Ex. 2013”).) Of these 24 trials, Derry separately analyzed eight
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`trials that used low doses of aspirin in the range of 50-162.5 mg/day. (Id. at 1186.)
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`Derry concluded that “[e]ven at these lower doses, aspirin was associated with a
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`significantly increased rate of gastrointestinal haemorrhage compared with
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`placebo.” (Id.)
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`Additionally, Rodriguez reviewed 17 original epidemiologic studies
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`published between 1990 and 2001 to determine the serious gastrointestinal
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`complications associated with aspirin use and to evaluate, inter alia, the influence
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`of dose on such serious complications. (Rodriguez, L.A.G., et al., “Association
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`between aspirin and upper gastrointestinal complications: Systematic review of
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`epidemiologic studies,” British Journal of Clinical Pharmacology, Vol. 52, pp.
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`563-571 at 563 (2001) (“Ex. 2014”).) As a result of this review, Rodriguez
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`determined that low doses of aspirin of up to 300 mg per day still produced an
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`elevated risk for gastrointestinal complications. (Id. at 567.) Rodriguez concluded
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`that “users of low dose of aspirin present a twofold increased risk with no clear
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`dose-response observed under 300 mg daily,” and that such findings were
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`consistent with the meta-analysis conducted by Derry (Ex. 2013). (Id. at 568.)
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`Indeed, the toxic gastrointestinal effects of LDA are even worse in aging
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`populations, such as individuals over the age of 70, as shown in a study by Bellary.
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`(See also Ex. 2022 at ¶ 31.)
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` Bellary studied the occurrence of upper
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`gastrointestinal disease in 511 patients over 70 years old and determined that
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`“[h]emorrhage was as common in aspirin takers as in standard-dose [non-aspirin
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`NSAID] takers, even though 86% were taking 300 mg of aspirin per day or less.”
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`(Bellary, S.V., et al., “Upper Gastrointestinal Lesions in Elderly Patients
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`Presenting for Endoscopy: Relevance of NSAID Usage,” The American Journal of
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`Gastroenterology, Vol. 86, No. 8, pp. 961-964 at 961 (1991) (“Ex. 2015”).)
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`Accordingly, Bellary concluded that “[d]espite the widely held belief that [LDA] is
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`safe, in this study the risk of peptic ulcer appears as great for those on [LDA] as for
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`[non-aspirin NSAID] takers.” (Id. at 963.)
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`In an effort to reduce the gastrointestinal complications associated with
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`NSAID use, the selective NSAIDs referred to as cyclooxygenase-2, or COX-2,
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`inhibitors were developed as an alternative to non-selective NSAIDs, such as
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`aspirin and naproxen. (See Ex. 2022 at ¶ 34.) However, while the use of COX-2
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`inhibitors results in fewer gastric ulcers than the use of non-selective NSAIDs,
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`COX-2 inhibitors are often co-prescribed with LDA, due to LDA’s cardiovascular
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`protective effects, and patients thus remain at risk for developing gastrointestinal
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`complications. (Id. at ¶ 35-36.)
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`B. NSAIDs Taken Concurrently With LDA Pose an Increased Risk
`of Gastric Ulcer Compared to NSAIDs Taken Alone
`
`In 2009, at the time of the inventions claimed in the ’621 patent, not only
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`was it widely known and accepted that NSAIDs, including LDA, cause
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`gastrointestinal toxicity including gastrointestinal ulcer and hemorrhage, as set
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`forth in Section III.A, supra, it was also widely known and accepted that taking
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`LDA in addition to a non-aspirin NSAID further increased one’s risk for such
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`gastrointestinal complications. (Id. at ¶ 37.) For example, in 1995, Weil
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`conducted a study of 1,121 subjects to determine the risks of hospitalization for
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`bleeding peptic ulcer on a LDA regimen of 300 mg per day or less. (Weil, J., et
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`al., “Prophylactic aspirin and risk of peptic ulcer bleeding,” British Medical
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`Journal, Vol. 310, pp. 827-830 at 827 (1995) (“Ex. 2016”).) Weil concluded that
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`“[n]o conventionally used prophylactic aspirin regimen seems free of the risk of
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`peptic ulcer complications,” and noted that “[r]isks seemed particularly high in
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`patients who
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`took non-aspirin non-steroidal
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`anti-inflammatory drugs
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`concurrently.” (Id.) Weil further concluded that “concurrent non-aspirin non-
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`steroidal anti-inflammatory drug use roughly doubled [the] risk” of gastric
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`bleeding. (Id. at 829.)
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`Rahme conducted a study, comparing patients receiving one of four
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`treatment regimens: Non-selective NSAID only, non-selective NSAID plus LDA,
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`COX-2 inhibitor only, or COX-2 inhibitor plus LDA. (Rahme, E., et al.,
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`“Gastrointestinal Effects of Rofecoxib and Celecoxib Versus NSAIDs Among
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`Patients on Low Dose Aspirin,” Gastroenterology, 126 (suppl. 2) (2004) (“Ex.
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`2018”); Ex. 2022 at ¶ 38.) Rahme determined that the patients who received the
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`non-selective NSAIDs alone, without LDA, had a lower hazard ratio than the
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`patients who received the NSAIDs with LDA. (Ex. 2018 at p. A-2; Ex. 2022 at
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`¶ 38.) Specifically, Rahme determined that a patient receiving a non-selective
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`NSAID alone had a hazard ratio of 1, while a patient receiving a non-selective
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`NSAID plus LDA had a significantly higher hazard ratio of 1.61. (Ex. 2018 at p.
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`A-2; see also Silverstein, F.E., et al., “Gastrointestinal Toxicity With Celecoxib vs
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`Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid
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`Arthritis,” The Journal of the American Medical Association, Vol. 284, No. 10, pp.
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`1247-1255 (2000) (“Ex. 2019”); Ex. 2022 at ¶ 38.)
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`Thus, at the time of the invention claimed in the ’621 patent, it was well-
`
`known and understood that LDA taken concurrently with NSAIDs would result in
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`a greater risk of gastric ulcer than an NSAID taken alone. (See Ex. 2022 at ¶ 39.)
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`C. The Inventors of the ’621 Patent Surprisingly Found that a Unit
`Dose Form of Immediate-Release Esomeprazole and Delayed-
`Release Naproxen
`is More Effective at Reducing NSAID-
`Associated Ulcers in Patients Taking LDA than in Patients Not
`Taking LDA
`
`The ’621 patent is directed to methods of reducing the incidence of gastric
`
`ulcers associated with the use of NSAIDs in patients who are also taking LDA.
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`(See, e.g., Ex. 1001 at claim 1.) These methods require the administration of a unit
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`dosage form that is comprised of 20 mg of the acid inhibitor esomeprazole and 500
`
`mg of the non-selective NSAID naproxen. (See id.) This unit dosage form
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`provides for the coordinated release of the esomeprazole and naproxen such that at
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`least a portion of the esomeprazole is released independent of the pH of the
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`surrounding medium, and such that less than 10% of the naproxen is released after
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`2 hours when tested using the USP Paddle Method in 1000 mL of 0.1 N HCl at 75
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`rpm at 37° C. +/- 0.5° C. (See id.) The claims of the ’621 patent further require
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`that the unit dosage form is more effective at reducing the