`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`Filed: December 4, 2017
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`POZEN INC. and HORIZON PHARMA USA, INC.,
`
`Patent Owners
`
`
`
`U.S. Patent No. 9,393,208 to Ault et al.
`
`
`Inter Partes Review IPR2018-00272
`
`
`Petition for Inter Partes Review of U.S. Patent No. 9,393,208
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION .......................................................................................... 1
`I.
`II. MANDATORY NOTICES ............................................................................ 1
`A.
`Real Parties-In-Interest Under 37 C.F.R. § 42.8(b)(1) ......................... 1
`B.
`Related Matters Under 37 C.F.R. § 42.8(b)(2) .................................... 1
`C.
`Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) ................. 2
`D.
`Service Information Under 37 C.F.R. § 42.8(b)(4) .............................. 2
`III. GROUNDS FOR STANDING (37 C.F.R. §§ 42.101 AND 42.104) ............ 3
`IV.
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED (37 C.F.R. § 42.22(a) AND 37
`C.F.R. § 42.104(b)) ......................................................................................... 3
`THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW .............. 4
`V.
`VI. STATEMENT OF REASONS FOR THE RELIEF REQUESTED .............. 4
`A.
`Summary of the Argument ................................................................... 4
`B.
`Level of Ordinary Skill in the Art ........................................................ 7
`C.
`The ’208 Patent and Its Prosecution ..................................................... 8
`1.
`NSAID Gastropathy ................................................................... 8
`2.
`Specification of the ’208 Patent ................................................. 8
`3.
`The ’208 Patent Prosecution .................................................... 13
`Claim Construction (37 C.F.R. §§ 42.100(b), 42.104(b)(3)) ............. 13
`1.
`“Target” Means “With The Goal of Obtaining” ...................... 14
`Scope and Content of the Prior Art .................................................... 17
`1.
`PK/PD Overview...................................................................... 17
`2.
`References Disclosing Combined Naproxen-
`Esomeprazole Formulations ..................................................... 20
`a.
`’285 Patent ..................................................................... 20
`b.
`’907 Patent ..................................................................... 22
`c.
`Hochberg 2008 ............................................................... 23
`
`D.
`
`E.
`
`i
`
`

`

`
`
`3.
`
`4.
`
`F.
`
`d.
`Goldstein 2008 ............................................................... 25
`Hassan-Alin 2005 .......................................................... 25
`e.
`References Disclosing the PK/PD of Immediate-Release
`PPIs .......................................................................................... 27
`a.
`Howden 2005 ................................................................. 27
`Zegerid® Label ............................................................... 28
`b.
`References Disclosing the Pharmacokinetics of Naproxen ..... 29
`EC-Naprosyn® Label ..................................................... 29
`a.
`b.
`Khosravan 2006 ............................................................. 30
`c.
`Jung 1994 ....................................................................... 31
`d.
`Davies 1997 ................................................................... 32
`Ground 1: All Claims of the ’208 Patent Are Anticipated by the
`’285 Patent .......................................................................................... 32
`1.
`The Method of Claim 1 Is Anticipated by the ’285 Patent ...... 32
`a.
`The ’285 patent disclosed the drug formulation in
`claim 1 ........................................................................... 32
`The PK/PD elements in claim 1 are inherent in the
`formulation .................................................................... 35
`The dependent claims are anticipated by the ’285 patent ........ 39
`a.
`Dependent claim 2 is anticipated ................................... 39
`b.
`Dependent claims 3 and 4 are anticipated ..................... 40
`c.
`Dependent claims 5-7 are anticipated ............................ 41
`G. Ground 2: All Claims of the ’208 Patent Are Obvious Over the
`’285 Patent .......................................................................................... 43
`H. Ground 3: All Claims of the ’208 Patent Are Obvious Over the
`’285 patent in View of the EC-Naprosyn® Label and Howden
`2005 .................................................................................................... 48
`1.
`The Method of Claim 1 Is Obvious Over the ’285 patent
`in View of the EC-Naprosyn® Label and Howden 2005 ......... 48
`The EC-Naprosyn® label disclosed the PK
`a.
`elements for naproxen ................................................... 50
`
`b.
`
`2.
`
`ii
`
`

`

`
`
`b.
`
`2.
`
`Howden 2005 disclosed the PK elements for
`esomeprazole ................................................................. 53
`Howden 2005 disclosed the PD element ....................... 57
`c.
`The dependent claims are obvious over the ’285 patent in
`view of the EC-Naprosyn® label and Howden 2005 ............... 59
`a.
`Dependent claim 2 is obvious ........................................ 59
`b.
`Dependent claims 3 and 4 are obvious .......................... 59
`c.
`Dependent claims 5-7 are obvious ................................ 60
`No Secondary Considerations Support Nonobviousness ................... 60
`1.
`There Are No Unexpected Results .......................................... 60
`2.
`The ’208 Patent Satisfied No Long-Felt But Unmet Need ...... 63
`3.
`There Was No Industry Skepticism ......................................... 63
`4.
`Copying by Generic Drug Makers Is Irrelevant ...................... 64
`VII. CONCLUSION ............................................................................................. 64
`
`I.
`
`iii
`
`

`

`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page
`
`Abbvie Inc. v. Mathilda and Terence Kennedy Institute of
`Rheumatology Trust,
`764 F.3d 1366 (Fed. Cir. 2014) .......................................................................... 34
`
`Atlas Powder Co. v. Ireco, Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .......................................................................... 37
`
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 64
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ...................................................................... 4, 36
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 62
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .................................................................... 34, 35
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 13
`
`Eli Lilly & Co. v. Barr Labs., Inc.,
`251 F.3d 955 (Fed. Cir. 2001) ............................................................................ 36
`
`Ex parte DesOrmeaux,
`25 U.S.P.Q. 2d 2040 (Bd. Pat. App. & Inter. 1992) ........................................... 20
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .......................................................................... 14
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................... 45, 46
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 43
`
`iv
`
`

`

`
`
`King Pharmaceuticals, Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .......................................................................... 46
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 48
`
`Millennium Pharm., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 47
`
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ........................................................ 44, 45, 46, 47
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 43, 60
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 15
`
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................... 6, 38, 39, 45
`
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 36
`
`SmithKline Beecham Corp. v. Apotex Corp.,
`403 F.3d 1331 (Fed. Cir. 2005) ...................................................................... 6, 36
`
`Sun Studs, Inc. v. ATA Equip. Leasing, Inc.,
`872 F.2d 978 (Fed. Cir. 1989) ............................................................................ 20
`
`Taurus IP, LLC v. DaimlerChrysler Corp.,
`726 F.3d 1306 (Fed. Cir. 2013) .......................................................................... 21
`
`STATUTES
`
`35 U.S.C. § 102 .............................................................................................. 3, 44, 47
`
`35 U.S.C. § 102(e) ................................................................................................... 20
`
`35 U.S.C. § 102(e)(2) ............................................................................................... 20
`
`35 U.S.C. § 103 .............................................................................................. 3, 45, 47
`
`35 U.S.C. §§ 311-319 ................................................................................................ 1
`
`v
`
`

`

`
`
`35 U.S.C. § 314(a) ..................................................................................................... 4
`
`REGULATIONS
`
`37 C.F.R. § 42 ............................................................................................................ 1
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 1
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 1
`
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 2
`
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 2
`
`37 C.F.R. § 42.10(b) .................................................................................................. 1
`
`37 C.F.R. § 42.15(a) ................................................................................................... 1
`
`37 C.F.R. § 42.22(a) ................................................................................................... 3
`
`37 C.F.R. § 42.63(e) ................................................................................................... 1
`
`37 C.F.R. § 42.100(b) .............................................................................................. 13
`
`37 C.F.R. § 42.103 ..................................................................................................... 1
`
`37 C.F.R. § 42.104(a) ................................................................................................. 3
`
`37 C.F.R. § 42.104(b) ................................................................................................ 3
`
`37 C.F.R. § 42.106(a) ................................................................................................. 1
`
`OTHER AUTHORITIES
`
`MPEP § 2136.03 ...................................................................................................... 21
`
`
`
`vi
`
`

`

`
`
`Exhibit
`1001
`
`1002
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`LISTING OF EXHIBITS
`
`Description
`U.S. Patent No. 9,393,208, Method for Delivering a
`Pharmaceutical Composition to Patient in need thereof (filed
`Dec. 28, 2015) (issued Jul. 19, 2016) (“the ’208 patent”)
`Declaration of David C. Metz, M.D. (“Metz Decl.”)
`Declaration of Michael Mayersohn, Ph.D. (“Mayersohn Decl.”)
`U.S. Patent No. 6,926,907, Pharmaceutical Compositions for the
`Coordinated Delivery of NSAIDS (filed May 31, 2002) (issued
`Aug. 9, 2005)
`U.S. Patent No. 8,557,285, Pharmaceutical Compositions for the
`Coordinated Delivery of NSAIDS (filed Aug. 23, 2011) (issued
`Oct. 15, 2013)
`
`Howden, Review Article: Immediate-Release Proton-Pump
`Inhibitor Therapy – Potential Advantages, 22 (Suppl. 3)
`ALIMENT. PHARMACOL. THER. 25 (2005)
`U.S. Patent No. 5,877,192, Method for the Treatment of Gastric
`Acid-Related Diseases and Production of Medication using (-)
`Enantiomer of Omeprazole (filed Apr. 11, 1997) (issued Mar. 2,
`1999)
`Products on NDA 020067 (EC-Naprosyn), FDA.GOV,
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=
`overview.process&ApplNo=020067 (last visited Aug. 23, 2017)
`EC-Naprosyn prescribing information (Jan. 2007)
`
`Zegerid approval letter and prescribing information (2004)
`
`Goldstein et al., 116 A Single Tablet Multilayer Formulation of
`Enteric-Coated Naproxen Coupled with Non-Enteric Coated
`OMEPRAZOLE is Associated with a Significantly Reduced
`Incidence of Gastric Ulcers vs. Enteric-Coated Naproxen: A
`Prospective, Randomized, Double-Blind Study, 134(4)
`GASTROENTEROLOGY A19 (2008)
`
`vii
`
`

`

`
`
`Exhibit
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Description
`Hochberg et al., A Novel, Single-Tablet Formulation that Delivers
`Immediate-Release Omeprazole Followed by Enteric-Coated
`(EC) Naproxen Significantly Reduces the Incidence of Gastric
`Ulcers Compared with EC Naproxen Alone: Results of a
`Prospective, Randomised, Double-Blind, 6-Month Study including
`Patients with OA and RA, EULAR (2008)
`
`U.S. Patent No. 9,220,698 Prosecution History Excerpt:
`Amendment C and Response to Final Office Action (Jan. 30,
`2013)
`
`Wolfe et al., Acid Suppression: Optimizing Therapy for
`Gastroduodenal Ulcer Healing, Gastroesophageal Reflux
`Disease, and Stress-Related Erosive Syndrome, 118
`GASTROENTEROLOGY S9 (2000)
`
`Bell et al., Appropriate Acid Suppression for the Management of
`Gastro-Oesophageal Reflux Disease, 51(suppl. 1) DIGESTION 59
`(1992)
`
`Hassan-Alin et al., Lack of Pharmacokinetic Interaction between
`Esomeprazole and the Nonsteroidal Anti-Inflammatory Drugs
`Naproxen and Rofecoxib in Healthy Subjects, 25(11) CLIN. DRUG
`INVEST. 731 (2006)
`
`Khosravan et al., Pharmacokinetic Interactions of Concomitant
`Administration of Febuxostat and NSAIDs, 46 J. CLIN. PHARMA.
`855 (2006)
`
`Jung et al., Steady-State Pharmacokinetics of Enteric-Coated
`Naproxen Tablets Compared with Standard Naproxen Tablets,
`16(6) CLIN. THER. 923 (1994)
`
`Davies et al., Clinical Pharmacokinetics of Naproxen, 32(4) CLIN.
`PHARMACOKINET. 268 (1997)
`Naprosyn/EC-Naprosyn/Anaprox DS Prescribing Information
`(Mar. 2017)
`
`viii
`
`

`

`
`
`Exhibit
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`1031
`
`1032
`
`1033
`
`1034
`
`Description
`Dan M. Roden, Principles of Clinical Pharmacology, in
`HARRISON’S PRINCIPLES OF INTERNAL MEDICINE 13 (Dennis L.
`Kasper et al. eds., 16th ed. 2005)
`Malcolm Rowland & Thomas N. Tozer, CLINICAL
`PHARMACOKINETICS (3d ed. 1995)
`Clissold et al., Omeprazole A Preliminary Review of its
`Pharmacodynamic and Pharmacokinetic Properties, and
`Therapeutic Potential in Peptic Ulcer Disease and Zollinger-
`Ellison Syndrome, 32 DRUGS 15 (1986)
`U.S. Patent No. 7,411,070, Form of S-Omeprazole (filed Sept. 25,
`2003) (issued Aug. 12, 2008)
`U.S. Patent No. 5,714,504, Compositions (filed Jan. 23, 1995)
`(issued Feb. 3, 1998)
`Michael Mayersohn, Principles of Drug Absorption, in MODERN
`PHARMACEUTICS 21 (3d ed. 1996)
`Howden, Clinical Pharmacology of Omeprazole, 20(1) CLIN.
`PHARMACOKINET. 38 (1991)
`Lind et al., Esomeprazole Provides Improved Acid Control vs.
`Omeprazole in Patients with Symptoms of Gastro-Oesophageal
`Reflux Disease, 14 ALIMENT. PHARMACOL. THER. 861 (2000)
`Regårdh et al., Pharmacokinetics and Metabolism of Omeprazole
`in Animals and Man – An Overview, 20(suppl. 108) SCAND. J.
`GASTROENTEROL 79 (1985)
`Vimovo prescribing information (Dec. 2014)
`Target, WEBSTER’S NEW WORLD COLLEGE DICTIONARY (4th ed.
`2005)
`Target, THE AMERICAN HERITAGE DICTIONARY OF THE ENGLISH
`LANGUAGE (4th ed. 2006)
`Target, MERRIAM-WEBSTER’S CONCISE DICTIONARY (Large print
`ed. 2006)
`Intentionally Left Blank
`
`ix
`
`

`

`
`
`
`
`Exhibit
`1035
`1036
`1037
`1038
`1039
`1040
`1041
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`Description
`
`Intentionally Left Blank
`Intentionally Left Blank
`Intentionally Left Blank
`Intentionally Left Blank
`Intentionally Left Blank
`Intentionally Left Blank
`Intentionally Left Blank
`Goldlust et al., Nighttime Dosing of Omeprazole Immediate-
`Release Oral Suspension Rapidly Decreases Nocturnal Gastric
`Acidity, 99(10) AM. J. GASTROENTEROLOGY S39 (2004)
`Nexium Prescribing Information (Feb. 2001), available at
`https://www.accessdata.fda.gov/
`drugsatfda_docs/label/2001/21153lbl.pdf (last visited Nov. 22,
`2017)
`Prilosec Prescribing Information (June 2002), available at
`https://www.accessdata.fda.gov/
`drugsatfda_docs/label/2002/19810s074lbl.pdf (last visited Nov.
`22, 2017)
`Opinion & Order, Horizon Pharma, Inc. v. Dr. Reddy’s Labs.,
`Inc., No. 15-cv-3324-SRC-CLW (consolidated) (D.N.J. Nov. 14,
`2017), ECF No. 82
`U.S. Patent No. 9,393,208 Prosecution History Excerpts
`
`x
`
`

`

`
`
`I.
`
`INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Petitioner”) petitions for Inter Partes Review
`
`of claims 1-7 of U.S. Patent No. 9,393,208 (“the ’208 patent”) (Ex. 1001), which is
`
`assigned to Pozen Inc. (“Pozen”) and Horizon Pharma USA, Inc. (“Horizon”)
`
`(collectively, “Patent Owners”), under 35 U.S.C. §§ 311-319 and 37 C.F.R. Part 42
`
`and seeks a determination that all claims (1-7) of the ’208 patent be canceled as
`
`unpatentable.
`
`This Petition is filed in accordance with 37 C.F.R. § 42.106(a). Filed
`
`herewith is a power of attorney and exhibit list per § 42.10(b) and § 42.63(e).
`
`Pursuant to 37 C.F.R. § 42.103, the fee set forth in § 42.15(a) accompanies this
`
`Petition.
`
`II. MANDATORY NOTICES
`Petitioner provides the following mandatory notices.
`
`A. Real Parties-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`The real parties-in-interest for Petitioner are Mylan Pharmaceuticals Inc.,
`
`Mylan Laboratories Ltd., Mylan Inc., and Mylan N.V.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`The following litigations or instituted inter partes reviews related to the ’208
`
`patent are pending:
`
`• Horizon Pharma, Inc. v. Mylan Pharms. Inc., No. 16-4921 (D.N.J.);
`
`• Horizon Pharma, Inc. v. Actavis Labs. FL, Inc., No. 16-4916 (D.N.J.);
`
`1
`
`

`

`
`
`• Horizon Pharma, Inc. v. Dr. Reddy’s Labs., Inc., No. 16-9035
`
`(D.N.J.); and
`
`• Horizon Pharma, Inc. v. Lupin Ltd., No. 16-4920 (D.N.J.).
`
`In addition, Mylan previously filed a petition for inter partes review of
`
`related U.S. Patent No. 9,220,698 on August 24, 2017. Mylan Pharms. Inc. v.
`
`Pozen Inc., IPR2017-01995. That petition is currently pending.
`
`C. Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`Lead Counsel
`Back-Up Counsel
`Brandon M. White (Reg. No. 52,354)
`Emily J. Greb (Reg. No. 68,244)
`Perkins Coie LLP
`Perkins Coie LLP
`1 East Main Street, Suite 201
`700 Thirteenth Street, N.W.
`Madison, WI 53703
`Suite 600
`Telephone: (608) 663-7494
`Washington, D.C. 20005
`Facsimile: (608) 283-4494
`Telephone: (202) 654-6206
`egreb@perkinscoie.com
`Facsimile: (202) 654-9681
`bmwhite@perkinscoie.com
`
`D.
`Service Information Under 37 C.F.R. § 42.8(b)(4)
`Please direct all correspondence to lead counsel and back-up counsel at the
`
`contact information above. Petitioner consents to electronic service by e-mail at
`
`the following email addresses:
`
`bmwhite@perkinscoie.com;
`
`egreb@perkinscoie.com; and
`
`EsoNaproxen@perkinscoie.com.
`
`2
`
`

`

`
`
`III. GROUNDS FOR STANDING (37 C.F.R. §§ 42.101 and 42.104)
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ’208 patent is
`
`available for inter partes review and that the Petitioner is not barred or estopped
`
`from requesting inter partes review on the grounds identified herein.
`
`IV.
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED (37 C.F.R. § 42.22(a) and 37 C.F.R.
`§ 42.104(b))
`Petitioner respectfully requests inter partes review and cancellation of
`
`claims 1-7 on the grounds set forth below.
`
`Ground 1: Claims 1-7 are unpatentable as anticipated under 35 U.S.C.
`
`§ 102 by U.S. Patent No. 8,557,285 (“’285 patent”).
`
`Ground 2: Claims 1-7 are unpatentable as obvious under 35 U.S.C. § 103
`
`over the ’285 patent.
`
`Ground 3: Claims 1-7 are unpatentable as obvious under 35 U.S.C. § 103
`
`over the ’285 patent in view of the EC-Naprosyn® label and
`
`Howden 2005.
`
`Petitioner’s full statement of the reasons for the relief requested is set forth
`
`below. In support of these grounds for unpatentability, Petitioner submits the
`
`expert declarations of Dr. David Metz (Ex. 1002 (“Metz Decl.”)) and Dr. Michael
`
`Mayersohn (Ex. 1003 (“Mayersohn Decl.”)) and relies on other Exhibits set forth
`
`in the concurrently-filed Listing of Exhibits.
`
`3
`
`

`

`
`
`V. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`A petition for inter partes review must demonstrate “a reasonable likelihood
`
`that the petitioner would prevail with respect to at least 1 of the claims challenged
`
`in the petition.” 35 U.S.C. § 314(a). This Petition clears that threshold. There is a
`
`reasonable likelihood that Petitioner will prevail with respect to at least one of the
`
`challenged claims.
`
`VI. STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`Summary of the Argument
`A.
`The claims of the ’208 patent recite a method of administering a drug
`
`formulation to target certain pharmacokinetic (PK) and pharmacodynamic (PD)
`
`parameters. But the drug formulation and method of administration were both
`
`known—Patent Owners previously disclosed them in two prior art patents: U.S.
`
`Patent Nos. 6,926,907 (Ex. 1004) and 8,557,285 (Ex. 1005). And there is nothing
`
`novel about the PK/PD elements—they are the natural result of administering the
`
`known formulation according to the known method. To extend patent protection
`
`eight years beyond the ’907 patent’s expiration, the inventors of the ’208 patent
`
`simply ran a routine clinical trial using a known drug and known method to
`
`document an inherent property of the drug. They then claimed the expected and
`
`unsurprising results. “Newly discovered results of known processes directed to the
`
`same purpose are not patentable because such results are inherent.” Bristol-Myers
`
`Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001). The
`
`4
`
`

`

`
`
`’208 patent’s claims are unpatentable as anticipated by, or obvious over, the ’285
`
`patent.
`
`Specifically, the ’208 patent claims a method of treating arthritis by
`
`administering a combination tablet of naproxen 500mg (EC-Naprosyn®) and
`
`esomeprazole 20mg (Nexium®) twice daily. Naproxen relieves arthritis pain and
`
`inflammation, but long-term administration was known to cause gastric injury. To
`
`solve this problem, proton pump inhibitors (PPIs)—esomeprazole for example—
`
`were prescribed to raise gastric pH, preventing naproxen-induced injury.
`
`As a result, skilled artisans designed tablets combining naproxen and PPIs.
`
`In 2001, the ’285 and ’907 patents disclosed and claimed the “PN formulation,” a
`
`specific tablet structure combining naproxen and esomeprazole. The PN
`
`formulation purportedly features “coordinated release,” whereby esomeprazole is
`
`immediately released and the naproxen releases only once the esomeprazole has
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`raised gastric pH. Dr. John Plachetka, one of the four inventors of the ’208 patent,
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`is the named inventor of the ’285 and ’907 patents.
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`The ’208 patent claims the precise formulation and method of administration
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`disclosed in Dr. Plachetka’s ’285 and ’907 patents seven years prior. The only
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`other elements it recites are certain PK/PD values for naproxen and esomeprazole.
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`But these PK/PD values result from administering the prior art PN formulation per
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`the prior art method. The ’208 patent concedes this point, referring to the ’907
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`5
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`patent as a formulation that “can be effective in improving NSAID tolerability
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`through dosages of esomeprazole and naproxen that produce the desired
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`pharmacodynamic response and pharmacokinetic values.” Ex. 1001, 1:30-37.
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`The law does not permit Patent Owners to extend their monopoly nearly a
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`decade by simply claiming an inherent characteristic of their previously-disclosed
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`formulation and method of administration. Indeed, the ’208 patent is exactly why
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`the inherency doctrine exists: “one of the principles underlying the doctrine of
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`inherent anticipation is to ensure that the public remains free to make, use or sell
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`prior art compositions or processes, regardless of whether or not they understand
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`their complete makeup or the underlying scientific principles which allow them to
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`operate.” SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1345-46
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`(Fed. Cir. 2005) (quotation and alteration omitted).
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`The Federal Circuit previously held that “an obvious formulation cannot
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`become nonobvious simply by administering it to a patient and claiming the
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`resulting serum concentrations.” Santarus, Inc. v. Par Pharm., Inc., 694 F.3d
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`1344, 1354 (Fed. Cir. 2012). Yet, that is exactly what Patent Owners did here—
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`they gave a known formulation to patients and claimed the resulting serum
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`concentrations.
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` “The
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`initial blood serum concentration
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`resulting
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`from
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`administering a PPI dosage is an inherent property of the formulation.” Id. All
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`claims of the ’208 patent are anticipated by or obvious over at least the ’285 patent.
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`6
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`Alternatively, all claims of the ’208 patent are obvious over the ’285 patent
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`in view of the EC-Naprosyn® label (Ex. 1009) and Howden 2005 (Ex. 1006). Even
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`if not inherent, a skilled artisan would have known to target the claimed PK/PD
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`values because they were known to be produced by effective drugs already on the
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`market: EC-Naprosyn® for naproxen and Zegerid® for esomeprazole. Skilled
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`artisans would understand from the EC-Naprosyn® label and Howden 2005 that
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`EC-Naprosyn® and Zegerid® produced PK/PD values at which delayed-release
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`naproxen and immediate-release esomeprazole were effective. When developing
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`the claimed PN formulation, skilled artisans would target PK/PD values known to
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`provide efficacy. As the ’208 patent’s claims require only that the prior art teach a
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`skilled artisan to “target” the claimed PK/PD values, all claims are obvious over
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`the ’285 patent in view of the EC-Naprosyn® label and Howden 2005.
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`Level of Ordinary Skill in the Art
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`B.
`A person of ordinary skill in the art (“POSA”) is presumed to be aware of all
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`pertinent art, thinks along conventional wisdom in the art, and is a person of
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`ordinary creativity. The field of art involves the knowledge of a medical doctor
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`and that of a pharmacologist or pharmacokineticist with experience in dosage form
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`design and evaluation. Thus, the hypothetical POSA is a collaboration between a
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`pharmacologist or pharmacokineticist having a Ph.D. degree or equivalent training,
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`or a M.S. degree with at least 2 years of some experience in dosage form design
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`7
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`and in in vitro and in vivo evaluation of dosage form performance, and a medical
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`doctor having at least 2 years of practical experience treating patients in the
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`gastroenterology field. Ex. 1002 ¶¶23-24; Ex. 1003 ¶¶19-20.
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`C. The ’208 Patent and Its Prosecution
`NSAID Gastropathy
`1.
`The ’208 patent relates to formulations and methods of treatment to prevent
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`injury caused by chronic use of non-steroidal anti-inflammatory drugs
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`(“NSAIDs”). NSAIDs are a class of drugs used to treat pain and inflammation.
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`Ex. 1002 ¶25. The class includes, e.g., aspirin, naproxen, ibuprofen, and
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`diclofenac. Id. NSAIDs are among the most commonly prescribed medications in
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`the world and have been used for decades. Id. The NSAID naproxen was first
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`approved by the FDA in 1976 under the trade name Naprosyn. Ex 1020, 1.
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`NSAIDs can cause a variety of side effects over chronic administration. Ex.
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`1002 ¶26. These NSAID-induced side effects are commonly called “NSAID-
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`related injury” or “gastropathy.” Id. This injury, however, can be reduced by
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`controlling acid in the stomach through concomitant administration of an acid
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`inhibitor with the NSAID. Id., ¶27.
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`Specification of the ’208 Patent
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`2.
`The ’208 patent claims priority to a provisional application filed on
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`September 9, 2008. It relates to methods of administering to a patient delayed-
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`release naproxen 500mg and immediate-release esomeprazole 20mg in a single
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`tablet. Ex. 1001, 24:7-11; Ex. 1002 ¶¶29, 33-36; Ex. 1003 ¶¶40-45, 48-62. The
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`specification calls this formulation “PN400/E20.” Ex. 1001, 26:1-2; Ex. 1002
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`¶¶34-35; Ex. 1003 ¶43. The ’208 patent recites in its claims certain PK/PD results
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`for patients administered PN400/E20. See, e.g., Ex. 1001, col. 35, Tbls. 6, 11; Ex.
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`1003 ¶¶43-44. As explained in more detail infra, Section VI.E.1, when a patient
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`intakes a drug, it has a particular effect, i.e., it reduces pain and/or increases
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`stomach pH. Ex. 1003 ¶¶25-28. Scientists measure these effects by determining
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`PK/PD values. Ex. 1003 ¶27-29. PK measures the body’s absorption of the drug;
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`PD describes the drug’s effect on the body. Ex. 1003 ¶¶25-28.
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`The ’208 patent describes certain PK parameters: “Cmax,” “Tmax,” and “area
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`under the curve” or “AUC.” Id. ¶44. To a skilled artisan, Cmax is the maximum
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`concentration the drug achieves in the patient’s blood plasma. Id. ¶31. Tmax refers
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`to the time after administration at which the patient’s Cmax is reached. Id. Finally,
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`“area under the curve” or AUC measures the total amount of drug delivered over a
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`certain period after administration, for example after ten hours (AUC0-10) or after
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`twenty-four hours (AUC0-24). Ex. 1003 ¶¶31, 37-38. Because there is natural
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`intra- and inter-patient variation, pharmacokinetic parameters are generally recited
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`as average (mean) values plus or minus a variation, as in the ’208 patent. Ex. 1003
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`¶32, 44.
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`9
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`The background of the ’208 patent notes that NSAIDs were understood to
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`induce gastrointestinal injury, such as ulcers, when used frequently. Ex. 1001,
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`1:19-24; Ex. 1002 ¶30; Ex. 1003 ¶45. Skilled artisans knew that stomach acid was
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`“[a] major factor contributing to the development of gastrointestinal lesions.” Ex.
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`1001, 1:24-25; Ex. 1003 ¶45. The specification next refers to several strategies
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`previously taken “to reduce the gastrointestinal risk associated with taking
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`NSAIDs by administering agents that inhibit stomach acid secretion, such as, for
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`example, proton pump inhibitors with the NSAID.” Ex. 1001, 1:27-30; Ex. 1002
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`¶¶31-32; Ex. 1003 ¶45. The specification identifies the ’907 patent as an example
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`of a formulation that is “effective in improving NSAID tolerability through
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`dosages of esomeprazole and naproxen that produce the desired pharmacodynamic
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`response and pharmacokinetic values.” Ex. 1001, 1:34-37; Ex. 1003 ¶46. Notably,
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`the specification of the ’907 patent made similar statements and then also
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`disclosed, among others, the same formulation claimed in the ’208 patent: a unit
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`dose form containing 500mg of delayed-release naproxen and 20mg of immediate-
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`release esomeprazole. Ex. 1004, 1:11-44, 5:1-19, claims 1, 5, 51-52; Ex. 1002
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`¶¶51-54; Ex. 1003 ¶¶46-47; see Ex. 1001, 1:19-41. The prior art ’285 patent, which
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`shares a specification with the ’907 patent, again claims the same immediate-
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`release esomeprazole with coated naproxen formulation with the added specificity
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`10
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`of disclosing naproxen doses from 200-600mg and eso