UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`
`v.
`
`
`POZEN INC. and HORIZON PHARMA USA, INC.,
`Patent Owners.
`
`___________
`
`
`Case IPR2017-01995
`Patent 9,220,698
`
`___________
`
`
`PATENT OWNERS POZEN INC. AND HORIZON PHARMA USA, INC.’S
`RESPONSE
`
`37 C.F.R. § 42.10
`
`
`
`

`

` 
`
`I.
`
`TABLE OF CONTENTS
`
`BACKGROUND ............................................................................................ 2
`A.
`The ’698 Patent and Vimovo® ............................................................ 2
`1.
`Technical Background ............................................................... 2
`2.
`The ’698 Patent .......................................................................... 8
`a.
`Dr. Plachetka and His Team Conceived Of and
`Reduced To Practice The Invention Claimed In
`The ’698 Patent By June 25, 2007 ................................... 9
`Illustrative Claim ........................................................... 13
`b.
`B. District Court Litigations Regarding The Vimovo® Patents ............. 15
`SUMMARY OF ARGUMENT .................................................................... 17
`II.
`III. MYLAN’S PETITION IS TIME BARRED ................................................ 19
`IV. THE OPINIONS OF MYLAN’S EXPERT DECLARANTS
`SHOULD BE AFFORDED LITTLE WEIGHT .......................................... 20
`V. MYLAN HAS FAILED TO ESTABLISH THAT THE ’285 PATENT
`OR THE EC-NAPROSYN LABEL ARE PRIOR ART .............................. 22
`A.
`The ’285 Patent Is Not § 102(e) Prior Art .......................................... 22
`B.
`The EC-NAPROSYN® Label Does Not Qualify As Prior Art ......... 26
`1.
`Petitioner Failed To Establish That Exhibit 1009 Is A
`Publicly Available Printed Publication .................................... 26
`Petitioner Failed To Establish That Exhibit 1009 Predates
`The Invention Date................................................................... 30
`VI. MYLAN HAS FAILED TO PROVE CLAIMS 1-7 ARE
`INHERENTLY ANTICIPATED BY THE ’285 PATENT ......................... 30
`VII. MYLAN HAS FAILED TO PROVE CLAIMS 1-7 ARE OBVIOUS
`IN LIGHT OF THE ’285 PATENT ............................................................. 34
`A.
`The ’285 Patent Cannot Not Be Used To Render the ’698
`Patent Obvious ................................................................................... 35
`The ’285 Patent Does Not Render The ’698 Patent Inherently
`Obvious .............................................................................................. 37
`
`2.
`
`B.
`
` 
`
` 
`
` 
`
`-i-
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
` 
`VIII. MYLAN HAS FAILED TO PROVE CLAIMS 1-7 ARE OBVIOUS
`IN LIGHT OF THE ’285 PATENT, EC-NAPROSYN LABEL, AND
`HOWDEN 2005 ............................................................................................ 40
`1.
`’285 patent (Exhibit 1005) ....................................................... 40
`2.
`EC-Naprosyn® Label (Exhibit 1009) ...................................... 40
`3.
`Howden 2005 (Exhibit 1006)................................................... 41
`4. Mylan’s Ground III Fails ......................................................... 45
`IX. OBJECTIVE INDICIA OF NONOBVIOUSNESS DEMONSTRATE
`THE PATENTABILITY OF THE CLAIMED INVENTIONS .................. 47
`A.
`Long-Felt Need ................................................................................... 47
`B.
`Teaching Away and Surprising and Unexpected Results .................. 49
`C.
`Skepticism .......................................................................................... 51
`CONCLUSION ............................................................................................. 52
`
`X.
`
` 
`
` 
`
` 
`
`-ii-
`
`

`

` 
`
`TABLE OF AUTHORITIES 
`
` Page(s)
`
`Cases
`Ariosa Diagnostics, Inc. v. Illumina, Inc.,
`IPR2014-01093, Paper 69 (P.T.A.B. Jan. 7, 2016) ............................................ 22
`Bruckelmyer v. Ground Heaters, Inc.,
`445 F.3d 1374 (Fed. Cir. 2006) .......................................................................... 28
`Burroughs Wellcome Co. v. Barr Labs., Inc.,
`40 F.3d 1223 (Fed. Cir. 1994) .............................................................................. 9
`Celltrion, Inc. v. Biogen, Inc.,
`IPR2016-01614, Paper 65 (P.T.A.B. Feb. 21, 2018) .................................... 29, 30
`Cohesive Techs., Inc. v. Waters Corp.,
`543 F.3d 1351 (Fed. Cir. 2008) .......................................................................... 37
`Cooper v. Goldfarb,
`154 F.3d 1321 (Fed. Cir. 1998) ............................................................................ 9
`In re Costello,
`717 F.2d 1346 (Fed. Cir. 1983) .......................................................................... 23
`In re DeBaun,
`687 F.2d 459 (C.C.P.A. 1982) ............................................................................ 23
`Dow Chem. Co. v. Astro-Valcour, Inc.,
`267 F.3d 1334 (Fed. Cir. 2001) .......................................................................... 10
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) .......................................................................... 22
`Fox Grp., Inc. v. Cree, Inc.,
`700 F.3d 1300 (Fed. Cir. 2012) ...................................................................... 9, 10
`
`Frontier Therapeutics, LLC v. Medac Gesellschaft Fur Klinische
`Spezialpraparate MBH,
`IPR2016-00649, Paper 10 (P.T.A.B. Sept. 1, 2016) ........................................... 29
`
`
`
`- iii -
`
`
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Page
`
` 
`Harmonic Inc. v. Avid Tech., Inc.,
`815 F.3d 1356 (Fed. Cir. 2016) .......................................................................... 26
`In re Haruna,
`249 F.3d 1327 (Fed. Cir. 2001) .......................................................................... 49
`
`Honeywell International Inc. v. Mexichem Amanco Holding S.A. DE
`C.V.,
`865 F.3d 1348 (Fed. Cir. 2017) .................................................................... 38, 39
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 47
`Kyocera Wireless Corp. v. ITC,
`545 F.3d 1340 (Fed. Cir. 2008) .......................................................................... 27
`In re Lister,
`583 F.3d 1307 (Fed. Cir 2009) ........................................................................... 27
`Microsoft Corp. v. Corel Software, LLC,
`IPR2016-01300, Paper 13 (P.T.A.B. Jan. 4, 2017) ............................................ 28
`Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`878 F.3d 1336 (Fed. Cir. 2018) .......................................................................... 37
`Mylan Pharm. Inc. v. Boehringer Ingelheim Intl. GMBH,
`IPR2016-01566, Paper 15 (P.T.A.B. Feb. 3, 2017) ............................................ 28
`Netgear, Inc. v. Ruckus Wireless, Inc.,
`5 F. Supp. 3d 592 (D. Del. 2013) ........................................................................ 36
`In re Omeprazole Patent Litig.
`483 F.3d 1364 (Fed. Cir. 2007) .......................................................................... 31
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 47
`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) ............................................................................ 38
`
`
`
`- iv -
`
`
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Page
`
` 
`Par Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................... 37, 38
`Pfizer, Inc. v. Biogen, Inc.,
`IPR2017-01166, Paper 9 (P.T.A.B. Nov. 13, 2017) ........................................... 29
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) .............................................................................. 38
`Riverwood Int’l Corp. v. R.A. Jones & Co.,
`324 F.3d 1346 (Fed. Cir. 2003) .................................................................... 22, 23
`Tec Air, Inc. v. Denso Mfg. Mich. Inc.,
`192 F.3d 1353 (Fed. Cir. 1999) .......................................................................... 49
`Teva Pharm. USA, Inc. v. Indivior UK Ltd.,
`IPR2016-00280, Paper 23 (P.T.A.B. June 10, 2016) ......................................... 29
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002) .......................................................................... 31
`Statutes
`35 U.S.C. § 103 ...................................................................................... 19, 34, 35, 37
`35 U.S.C. § 311 ........................................................................................................ 27
`35 U.S.C. § 315 ............................................................................................ 17, 19, 20
`35 U.S.C. § 316 .................................................................................................... 1, 26
`Other Authorities
`37 C.F.R. § 42.120 ..................................................................................................... 1
`
`
`
`
`- v -
`
`
`
`

`

`Exhibit
`No.
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`2010
`
`2011
`2012
`
` 
`
`
`
`EXHIBIT LIST
`
`Description of Document
`
`Gabriel, S.E., et al., “Risk for Serious Gastrointestinal Complications
`Related to Use of Nonsteroidal Antiinflammatory Drugs,” Annals of
`Internal Medicine, Vol. 115, No. 10, pp. 787-796 (1991)
`Cryer, B. and Feldman, M., “Effects of Nonsteroidal
`Antiinflammatory 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, pp. 1145-1155
`(1992)
`Fries, J.F., et al., “Nonsteroidal Anti-Inflammatory Drug-Associated
`Gastropathy: Incidence and Risk Factor Models,” The American
`Journal of Medicine, Vol. 91, pp. 213-222 (1991)
`Second Amended Complaint for Patent Infringement, Horizon
`Pharma, Inc. v. Mylan Pharmaceuticals Inc., Civil Action No. 2:15-
`cv-03327 (D.N.J. Feb. 10, 2016)
`Answer to Second Amended Complaint, Separate Defenses, And
`Counterclaims by Defendants Mylan Pharmaceuticals Inc., Mylan
`Laboratories Limited and Mylan Inc. , Horizon Pharma, Inc. v. Mylan
`Pharmaceuticals Inc., Civil Action No. 2:15-cv-03327 (D.N.J. Feb.
`19, 2016)
`Plaintiffs’ Answer to Defendants’ Counterclaims to Second Amended
`Complaint, Horizon Pharma, Inc. v. Mylan Pharmaceuticals Inc.,
`Civil Action No. 2:15-cv-03327 (D.N.J. Mar. 7, 2016)
`157 Cong. Rec. S5429 (daily ed. Sept. 8, 2011) (statement of Sen.
`Kyl)
`Declaration of Jonathan G. Graves in Support of Pro Hac Vice
`Motion
`Declaration of Susan Krumplitsch in Support of Pro Hac Vice Motion
`Email string from Mylan’s counsel Robert D. Swanson from February
`6, 2017 to February 15, 2017
`Declaration of Ellen Scordino in Support of Pro Hac Vice Motion
`Gabriel, S.E., et al., Risk for Serious Gastrointestinal Complications
`Related to Use of Nonsteroidal Anti-inflammatory Drugs, Annals of
`Internal Medicine, Vol. 115, No. 10, pp. 787-796 (1991) (with
`publication information)
`
`- vi -
`
` 
`
`

`

` 
`
` 
`
`Exhibit
`No.
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`Description of Document
`
`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, pp. 1145-1155 (1992) (with publication
`information)
`Fries, J.F., et al., Nonsteroidal Anti-Inflammatory Drug-Associated
`Gastropathy: Incidence and Risk Factor Models, The American
`Journal of Medicine, Vol. 91, pp. 213-222 (1991) (with publication
`information)
`Jan. 12, 2017 Trial Testimony of John R. Plachetka in the Horizon
`Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., Case No. 3:11-cv-
`02317 (D.N.J.)
`Jan. 24, 2018 Deposition Testimony of Dr. John R. Plachetka in the
`Horizon Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., Case No.
`3:15-cv-03324 (D.N.J.) PROTECTIVE ORDER MATERIAL
`PN400-104 Clinical Study Report
`PROTECTIVE ORDER MATERIAL
`Oct. 12, 2017 Deposition Testimony of Everardus Orlemans, Ph.D. in
`the Horizon Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., Case No.
`3:15-cv-03324 (D.N.J.)
`Oct. 27, 2017 Deposition Testimony of Mark Sostek, MD in the
`Horizon Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., Case No.
`3:15-cv-03324 (D.N.J.)
`PROTECTIVE ORDER MATERIAL
`Oct. 25, 2017 Deposition Testimony of Brian Ault, Ph.D. in the
`Horizon Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., Case No.
`3:15-cv-03324 (D.N.J.)
`PROTECTIVE ORDER MATERIAL
`Norman, A. and Hawkey, C.J., What you need to know when you
`prescribe a proton pump inhibitor, Frontline Gastroenterology, Vol.
`2, pp. 199-205 (2011)
`Stollman, N. and Metz, D.C., Pathophysiology and prophylaxis of
`stress ulcer in intensive care unit patients, J. Critical Care, Vol. 20,
`pp. 35-45 (2005)
`
`- vii -
`
` 
`
`

`

` 
`
` 
`
`Exhibit
`No.
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`Description of Document
`
`Declaration of Michael Mayersohn, Ph.D. in Support of Defendants’
`Claim Construction Brief filed on April 24, 2014 in Par Pharm., Inc.
`v. Takeda Pharm. Co., Case No. 5:13-CV-1927 LHK (PSG)
`January 30, 2013 Amendment C and Response to Final Office Action,
`Application No. 12/553,107
`Declaration of David R. Taft PH.D. In Support of Patent Owner
`Response to Petition for Inter Partes Review of U.S. Patent No.
`9,220,698
`Declaration of David A. Johnson. M.D. In Support of Patent Owner
`Response to Petition for Inter Partes Review of U.S. Patent No.
`9,220,698
`IPR2017-01995, May 25, 2018 Deposition Transcript of David C.
`Metz
`Redacted Amended Memorandum Opinion (D.I. 498), Case 3:11-cv-
`02317-MLC-DEA (D.N.J. July 12, 2017)
`IPR2017-01995, May 24, 2018 Deposition Transcript of Dr. Michael
`Mayersohn
`Oct. 16, 2014 Deposition Testimony of Brian Ault, Ph.D. in the
`Horizon Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., Case No.
`3:11-cv-02317 (D.N.J.)
`PROTECTIVE ORDER MATERIAL
`Oct. 10, 2014 Deposition Testimony of Dr. Mark Sostek in the
`Horizon Pharma, Inc. v. Dr. Reddy’s Laboratories, Inc., Case No.
`3:11-cv-02317 (D.N.J.)
`PROTECTIVE ORDER MATERIAL
`Email string from Tore Lind to Richard Leff, Doug Levine, David
`Magner, and Mark Sostek, dated May 27, 2006 to May 31, 2006
`Andersson et al., Pharmacokinetic Studies with Esomeprazole, the
`(S)-Isomer of Omeprazole, CLIN. PHARMACOKINET., 40(6):411-426
`(2001)
`Tolman et al., The Effects of Oral Doses of Lansoprazole and
`Omeprazole on Gastric pH, J. CLIN. GASTROENTEROL., 24(2):65-70
`(1997)
`Hartmann et al., Twenty-four-hour intragastric pH profiles and
`pharmacokinetics following single and repeated oral administration
`of the proton pump inhibitor pantoprazole in comparison to
`omeprazole, ALIMENT PHARMACOL. THER., 10:359-366 (1996)
`- viii -
`
` 
`
`

`

` 
`
` 
`
`Description of Document
`
`Exhibit
`No.
`2036
`
`2038
`2039
`
`2040
`
`Leucuta et al., Pharmcokinetics and Metabolic Drug Interactions,
`CURRENT CLINICAL PHARMACOLOGY, 1:5-20 (2006)
`2037 Meyer, Interaction of Proton Pump Inhibitors with Cytochromes
`P450: Consequences for Drug Interactions, YALE J. BIOL. MED.,
`69:203-209 (1996)
`Prilosec Label
`Vanderhoff et al., Proton Pump Inhibitors: An Update, AMERICAN
`FAMILY PHYSICIAN, 66:273-280 (2002)
`Arnold, Safety of proton pump inhibitors-an overview, Aliment
`Pharmacol. Ther., 8(Suppl. 1):65-70 (1994)
`VIMOVO Prescribing Information
`2041
`2042 M.M. Wolfe et al., Gastrointestinal toxicity of nonsteroidal
`antiinflammatory drugs, N. Engl. J. Med., 340(24):1888-1899 (1999)
`L. Laine, Nonsteroidal anti-inflammatory drug gastropathy,
`Gastrointest. Endosc. Clin. North Am., 6(3):489–504 (1996)
`F.E. Silverstein et al., Gastrointestinal toxicity with celecoxib vs.
`nonsteroidal anti-inflammatory drugs for osteoarthritis and
`rheumatoid arthritis: the CLASS study: A randomized controlled
`trial, JAMA, 284(10):1247–1255 (2000)
`C. Bombardier et al., Comparison of upper gastrointestinal toxicity of
`rofecoxib and naproxen in patients with rheumatoid arthritis, N.
`Engl. J. Med., 343(21):1520–1528 (2000)
`G. Singh, Gastrointestinal complications of prescription and over-
`the-counter nonsteroidal anti-inflammatory drugs: a view from the
`ARAMIS database, Am. J. Ther., 7:115–121 (2000)
`NIH, National Institute of Diabetes and Digestive and Kidney
`Diseases, Bleeding in the Digestive Tract, available at
`http://www.niddk.nih.gov/health-information/health-topics/digestive-
`diseases/bleeding-in-the-digestive-tract/Pages/facts.aspx (last
`accessed March 23, 2015)
`K.S. Jain, et al., Recent advances in proton pump inhibitors and
`management of acid-peptic disorders, Bioorganic & Medicinal
`Chemistry 15:1181-1205 (2007)
`N. Hudson et al., Famotidine for healing and maintenance in
`nonsteroidal anti-inflammatory drug-associated gastroduodenal
`ulceration, Gastroenterology, 112:1817-1822 (1997)
`
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`- ix -
`
` 
`
`

`

` 
`
` 
`
`Exhibit
`No.
`2050
`2051
`
`Description of Document
`
`Exhibit Not Used
`L. Olbe et al., Reviews: A Proton-pump inhibitor expedition: The case
`histories of omeprazole and esomeprazole, Nature 2:132-139 (2003)
`C.W. Howden, Clinical pharmacology of omeprazole, Clin.
`Pharmacokinet 20(1):38-49 (1991)).
`J.Q. Huang & R.H. Hunt, Pharmacological and pharmacodynamic
`essentials of H2-receptor antagonists and proton pump inhibitors for
`the practising physician, Best Prac. & Res. Clin. Gastroenterol.
`15(3):355-370 (2001)
`H. Koop, Review article: metabolic consequences of long-term
`inhibition of acid secretion by omeprazole, Aliment. Pharmacol. Ther.
`6:399–406 (1992)
`Donnellan C., Preston C., Moayyedi P., Sharma N., Medical
`treatments for the maintenance therapy of reflux oesophagitis and
`endoscopic negative reflux disease (Review), The Cochrane Library,
`Issue 4, at 14 (2004)
`D.A. Johnson, Review of esomeprazole in the treatment of acid
`disorders, Expert Opin. Pharmacother. 4(2):253-264 (2003)
`Nexium label
`S.H. Roth, NSAID gastropathy: A new understanding, Arch. Intern.
`Med. 156:1623–1628 (1996)
`2059 W. Bensen & A. Zizzo, Newer, safer nonsteroidal anti-inflammatory
`drugs. Rational NSAID selection for arthritis, Can. Fam. Physician
`44:101-102, 105-107 (1998)
`R.J. Flower, Reviews: The development of COX2 inhibitors, Nature
`2:179-191 (2003)
`2061 Wolfe et al., Gastroprotective therapy and risk of gastrointestinal
`ulcers: risk reduction by COX-2 therapy, J. Rheumatol. 29(3):467-
`473 (2002)
`FDA Public Health Advisory, April 7, 2005, available at
`http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformatio
`nforpatientsandproviders/ucm150314.htm (last accessed March 23,
`2015)).
`J.L. Wallace et al., Gastrointestinal-sparing anti-inflammatory drugs:
`the development of nitric oxide-releasing NSAIDs, Drug Dev Res
`42:144-149 (1997)
`
`2052
`
`2053
`
`2054
`
`2055
`
`2056
`
`2057
`2058
`
`2060
`
`2062
`
`2063
`
`- x -
`
` 
`
`

`

` 
`
` 
`
`Description of Document
`
`Exhibit
`No.
`2064
`
`2065
`
`F.L. Lanza, A guideline for the treatment and prevention of NSAID-
`induced Ulcers, Am. J. Gastroenterol., 93(11):2037–2046 (1998)
`J.L. Goldstein et al., Impact of adherence to concomitant
`gastroprotective therapy on nonsteroidal-related gastroduodenal
`ulcer complications, Clin. Gastroenterol. & Hepatology, 4:1337-1345
`(2006)
`J.L. Goldstein et al., Clinical trial: the incidence of NSAID-associated
`endoscopic gastric ulcers in patients treated with PN 400 (naproxen
`plus esomeprazole magnesium) vs. enteric-coated naproxen alone,
`Aliment Pharmacol. Ther., 32:401-413 (2010)
`AstraZeneca/Pozen Collaboration and License Agreement (August 1,
`2006)
`PROTECTIVE ORDER MATERIAL
`IPR2017-01995 Corrected Declaration of Bryan D. Beel in Support of
`Petitioner’s Evidence, June 1, 2018
`2069 M. Hassan-Alin et al., Pharmacokinetics of esomeprazole after oral
`and intravenous administration of single and repeated doses to
`healthy subjects, Eur. J. Clin. Pharmacol., 56:665-670 (2000)
`
`
`2066
`
`2067
`
`2068
`
`- xi -
`
` 
`
`

`

` 
`
`Pursuant to 35 U.S.C. § 316(a)(8) and 37 C.F.R. § 42.120, Patent Owners
`
`Pozen Inc. (“Pozen”) and Horizon Pharma USA, Inc. (“Horizon”) (collectively,
`
`“Patent Owner”) responds to the Petition filed by Mylan Pharmaceuticals Inc.
`
`(“Mylan”) regarding claims 1-7 of U.S. Patent No. 9,220,698 (“the ’698 patent”).
`
`The Board instituted inter partes review on the three grounds presented in Mylan’s
`
`Petition: (1) anticipation by the U.S. Patent No. 8,557,285 (“the ’285 patent”); (2)
`
`obviousness over the ’285 patent; and (3) obviousness over the combination of the
`
`’285 patent, Prescription Drug Label for EC-Naprosyn® and other Naprosyn®
`
`formulations (“EC-Naprosyn label”), and C.W. Howden, “Review Article:
`
`immediate-release proton pump inhibitor therapy-potential advantages,” 22
`
`ALIMENT PHARMACOL. THER. 25-30 (2005) (“Howden 2005”).
`
`For the reasons set forth herein, Mylan’s Petition is time barred and should be
`
`denied for that reason alone. Further, Mylan bears “the burden of proving a
`
`proposition of unpatentability by a preponderance of the evidence.” 35 U.S.C.
`
`§ 316(e). Mylan has failed to meet its burden to demonstrate, by a preponderance
`
`of the evidence, that any of the claims of the ’698 patent are inherently anticipated
`
`or obvious in view of the cited prior art.
`
`
`
`
`
`
`
`
`
`- 1 -
`
` 
`
`

`

` 
`
`I.
`
`BACKGROUND
`
`A. The ’698 Patent and Vimovo®
`
`1.
`
`Technical Background
`
`Nonsteroidal anti-inflammatory drugs, or NSAIDs, have long been used for
`
`the management of pain and inflammation. (Ex. 2012 at 6.) Although NSAIDs are
`
`one of the most widely used medicines in the world, NSAID use has long been
`
`known to increase the risk of serious damage to the gastrointestinal track, such as
`
`ulcers and bleeding. (Id.) This is believed to be the case because NSAIDs inhibit
`
`prostaglandin synthesis, which in turn, leads to toxic gastrointestinal effects. (Ex.
`
`2013 at 6.) The use of NSAIDs is recognized as causing the most prevalent serious
`
`drug toxicity in the United States, resulting in an estimated 2,600 deaths and 24,000
`
`hospitalizations annually in rheumatoid arthritis patients alone. (Ex. 2014 at 9.)
`
`Over the years, pharmaceutical companies tried various approaches to develop safer
`
`NSAIDs, but were unsuccessful in reducing the risk of NSAID-associated GI
`
`injuries.
`
`In the early 2000s, Dr. John Plachetka—the inventor of U.S. Patent Nos.
`
`6,926,907 (“the ’907 patent,” Ex. 1004) and 8,557,285 (“the ’285 patent,” Ex. 1005)
`
`(collectively, “the Plachetka patents”) and co-inventor of the ’698 patent—set out to
`
`create a better arthritis medicine with a lower risk of GI toxicity. While others in
`
`the field had tried to solve the GI toxicity problem by administering separate
`- 2 -
` 
`
` 
`
`

`

` 
`
`medicines to reduce gastric acidity or to replace gastroprotective prostaglandins, Dr.
`
`Plachetka approached the problem with an unorthodox solution: he combined
`
`proton pump inhibitor (“PPI”) to inhibit the production of gastric acid with an
`
`NSAID to relieve pain and inflammation into a single dosage form. (Ex. 1005 at
`
`3:14-20.)
`
`Significantly, Dr. Plachetka designed the dosage form to exhibit coordinated
`
`release of the active ingredients: the PPI would be released immediately into the
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`stomach to elevate the gastric pH (i.e., lower the acidity) to reduce the toxic effects
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`of the NSAID. (Ex. 2015 at 63:18-64:24.) The release of the NSAID would be
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`delayed until the pH of the environment was higher, such as in the small intestine.
`
`(Id.) Prior to Dr. Plachetka’s invention, no one had combined an immediate-release,
`
`unprotected PPI with a delayed-release NSAID in a single dosage form. (Ex. 2015
`
`at 46:25-48:2.) This dosage form reduces the side effects previously associated with
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`long-term, daily use of NSAIDs.
`
`In 2001 when Dr. Plachetka filed the provisional patent application that
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`eventually resulted in the ’907 and ’285 patents, the art taught away from the use of
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`an immediate-release, unprotected PPI. PPIs were, and continue to be, known to be
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`acid labile and subject to degradation in the low pH environment of the stomach.
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`Conventional wisdom taught, and continues to teach, that PPIs must therefore be
`
`protected from the acidic environment of the stomach. This could be accomplished
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`by using an enteric coating that does not dissolve until it reaches the higher pH of
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`the small intestine, or by administering the PPI with a sodium bicarbonate buffer
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`that raises the pH of the stomach. Petitioner’s own exhibits teach that PPIs must be
`
`protected. (Ex. 1042 at 2 (“A new omeprazole immediate-release suspension (OME-
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`IR[SUSP]) has been developed, using sodium bicarbonate to protect the acid-labile
`
`PPI . . . .”).)
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`After inventing the coordinated release dosage form claimed in the ’285 and
`
`’907 patents, Dr. Plachetka and his company, Pozen Inc., (“Pozen”) undertook
`
`efforts to refine the invention and initiate early clinical trials, including the PN100-
`
`103 study in 2004.1 (Ex. 2015 at 47:4-48:11.) With positive Phase I clinical trial
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`results, Dr. Plachetka thought about replacing lansoprazole with a different PPI,
`
`including omeprazole and esomeprazole. (Ex. 2016 at 148:25-149:12.)
`
`Dr. Plachetka reached out to a number of pharmaceutical companies,
`
`including AstraZeneca, to help bring the drug to market. (Ex. 2015 at 62:6-63:17,
`
`65:5-22.) Dr. Plachetka selected AstraZeneca as a potential partner because of its
`
`experience with proton pump inhibitors, including enteric-coated omeprazole
`
`                                                            
`1 The PN100 formulation was an early prototype that contained immediate-release
`
`lansoprazole and enteric-coated Naproxen®. PN100 was a precursor to Vimovo.
`
`(Ex. 2015 at 50:2-21.)
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`(Prilosec®) and enteric-coated esomeprazole (Nexium®). (Ex. 2015 at 68:15-
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`70:19.) AstraZeneca also held the patent rights to esomeprazole. (Ex. 2016 at 149:3-
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`150:12.) Thus, prior to approaching AstraZeneca, Dr. Plachetka had considered
`
`using esomeprazole in his coordinated-release dosage form. (Id.)
`
`Pozen and AstraZeneca eventually entered into a collaboration and license
`
`agreement. (Ex. 2015 at 70:21-25, 71:11-12; Ex. 2067.) In partnership with its
`
`licensee AstraZeneca, Pozen initiated Phase III clinical trials, including the PN400-
`
`104 study.2 (Ex. 2015 at 74:5-75:6.) The PN400-104 study began in April 2007 and
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`was completed on June 25, 2007. (Ex. 2017 at 1.) Dr. Plachetka delegated the
`
`responsibility of designing and running the PN400-104 clinical trial to his employee,
`
`Dr. Orlemans. (Ex. 2016 at 169:8-21; Ex. 2018 at 88:5-16.) AstraZeneca scientists
`
`Drs. Ault and Sostek were also involved in the PN400-104 clinical trial. (Ex. 2018
`
`at 27:24-29:10; Ex. 2019 at 60:3-4, 61:8-62:7; Ex. 2020 at 36:20-37:15, 39:3-
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`40:12.)
`
`The use of an immediate-release, unprotected PPI remained controversial in
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`2007 when Dr. Plachetka and his co-inventors conceived and reduced to practice the
`
`                                                            
`2 The PN400 formulation contained immediate-release esomeprazole and enteric
`
`coated Naproxen and was brought to market as Vimovo®. (Ex. 2016 at 148:4-
`
`149:4.)
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`invention claimed in the ’698 patent, and in 2008 when they filed the provisional
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`patent application that resulted in the ’698 patent. As of 2007 and 2008, all PPIs on
`
`the market were formulated with an enteric coat or were administered with a sodium
`
`bicarbonate buffer. Further, the art continued to teach that PPIs must be protected
`
`from the acidic environment of the stomach. For example, a 2011 article stated:
`
`“PPIs are easily protonated and therefore unstable at acid pH. In gastric juice, this
`
`would result in inactivation before absorption. This is why PPIs are enteric coated.”
`
`(Ex. 2021 at 1.)
`
`Even Mylan’s own experts taught that PPIs must be enteric coated. For
`
`example, in 2005, Dr. Metz wrote that “[p]roton pump inhibitors are inactivated by
`
`gastric acid and thus must be given as enteric coated granules in gelatin capsules or
`
`enteric coated tablets.” (Ex. 2022 at 8.) Likewise, in 2014, Dr. Mayersohn testified
`
`in a sworn expert declaration in a district court case that “[b]ecause PPIs are
`
`chemically unstable in the acidic environment of the stomach, they must be protected
`
`from stomach acid. Drug manufacturers accomplish this by combining the PPI with
`
`various stabilizers and coatings, resulting in a drug formulation that has an outer
`
`layer (referred to as the ‘enteric coat’) that protects the PPI from stomach acid.” (Ex.
`
`2023 at 6.)
`
`The results of the PN400-104 study demonstrated that the administration of
`
`the claimed dosage form twice per day resulted in a surprising and unexpected
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`extended period elevated gastric pH of 4.0 or greater. (Ex. 2024 at 7.) During
`
`prosecution, Applicants stated:
`
`Applicants further point out that they have unexpectedly discovered
`and demonstrated that, by practicing the recited method, they can
`achieve a pharmacodynamic profile in which the mean % of time for
`which a patient’s intragastric pH remains at about 4.0 or greater for
`about 24 hours after reaching steady state is at least about 60%. More
`specifically,
`in a 9-day clinical
`study,
`they achieved a
`pharmacodynamic profile in which the mean% time of intragastric pH
`at above 4.0 over 24 hours was about 71.35%. See, e.g., Specification,
`page 41, Table 4. By contrast, among the tested formulations in
`Plachetka , the combination of 40 mg of famotidine with 550 mg of
`naproxen maintained the intragastric pH at greater than 4.0 for only
`49% of the time during the 8-10 hours following naproxen sodium
`dosing. . . . Applicants submit that a skilled artisan would readily
`correlate the extended pH>4.0 period produced by Applicants’ method
`with desired reduced gastrointestinal risk associated with stomach acid
`secretion.
`
`(Id.)
`
`The surprising and unexpected results of the PN400-104 clinical study were
`
`incorporated into the patent application that issued as the ’698 patent.
`
`
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`2.
`
`The ’698 Patent
`
`The ’698 patent, entitled “Method for delivering a pharmaceutical
`
`composition to patient in need thereof” describes methods of treating osteoarthritis,
`
`rheumatoid arthritis, or ankylosing spondylitis using pharmaceutical compositions
`
`comprising naproxen and esomeprazole in a unit dosage form. (Ex. 1001 at 1:13-
`
`18.) The claims require administering AM and PM unit dose forms that provide 500
`
`mg of naproxen and 20 mg of esomeprazole. The claims further require that the
`
`esomeprazole is released from the unit dosage forms at a pH of 0 or greater and that
`
`the unit dosage forms particular pharmacokinetic (PK) profiles for naproxen and
`
`esomeprazole.
`
`The claimed unit dosage form is a multilayer tablet, with a core of naproxen
`
`surrounded by a coating that begins to release the naproxen at a pH of 3.5 or greater.
`
`Surrounding the enteric coated naproxen is a second layer comprised of
`
`esomeprazole that is released at a pH of about 0 or greater. (Ex. 1001 at 2:47-61.)
`
`The esomeprazole is not enteric coated, as the unit dosage form is designed to release
`
`the esomeprazole in the very low pH of the stomach. As stated in the specification:
`
`The term ‘unit dosage form’ ( or ‘unit dose form’) as used herein refers
`to a single entity for drug administration. For example, a single tablet
`or capsule containing both esomeprazole and naproxen is a unit dosage
`form. Unit dosage forms of the present disclosure provide for sequential
`drug release in a way that elevates gastric pH and reduces the
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`deleterious effects of naproxen on the gastroduodenal mucosa, i.e., 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 5:37-46.)
`
`a.
`
`Dr. Plachetka and His Team Conceived Of and
`Reduced To Practice The Invention Claimed In The
`’698 Patent By June 25, 2007
`On its face, the ’698 patent claims priority to U.S. Provisional A