`Patent No. 8,852,636
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
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` LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`POZEN INC.
`Patent Owner
`______________
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`Case No. IPR2015-01774
`Patent No. 8,852,636
`______________
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`PATENT OWNER’s PRELIMINARY RESPONSE
`37 C.F.R. § 42.107
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`Case No. IPR2015-01774
`Patent No. 8,852,636
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`INTRODUCTION .......................................................................................... 1
`
`BACKGROUND ............................................................................................ 2
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`III. DENIAL OF INSTITUTION OF IPR2015-00802 ........................................ 6
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`IV. LEVEL OF ORDINARY SKILL IN THE ART ............................................ 8
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`V.
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`CLAIM INTERPRETATION ........................................................................ 8
`
`A.
`
`“Unit Dosage Form” ............................................................................. 8
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`VI. THE BOARD SHOULD DENY THE PETITION BECAUSE IT
`FAILS TO DEMONSTRATE A REASONABLE LIKELIHOOD OF
`PREVAILING ................................................................................................ 9
`
`A. Ground 1: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-6 and 13-15 Would Have Been
`Obvious Over the ’556 Patent Alone, or in the Alternative, in
`View of Chandramouli ......................................................................... 9
`
`1.
`
`Ground 1A: The Petition Has Not Established a
`Reasonable Likelihood That Claims 1-6 and 13-15
`Would Have Been Obvious Over the ’556 Patent Alone ........ 10
`
`a.
`
`b.
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`The ’556 Patent Does Not Describe a Combination
`Tablet of Naproxen and Esomeprazole ......................... 10
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`A POSA Would Not Have Been Motivated to
`Create a Combination Tablet With Immediate-
`Release Esomeprazole With a Reasonable
`Expectation of Success .................................................. 13
`
`2.
`
`Ground 1B: The Petition has Not Established a
`Reasonable Likelihood That Claims 1-6 and 13-15
`Would Have Been Obvious Over the ’556 Patent in View
`of Chandramouli ...................................................................... 17
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`B.
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`C.
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`Ground 2: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-6 and 13-15 Would Have Been
`Obvious Over the ’556 Patent or Alternatively, Over the ’556
`Patent in View of the ’225 Patent ...................................................... 18
`
`Ground 3: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-6 and 13-15 Would Have Been
`Obvious Over the ’118 Patent in View of the ’225 Patent................. 23
`
`D. Ground 4: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-6 and 13-15 Would Have Been
`Obvious Over the ’118 Patent in View of the ’225 Patent and
`the ’192 Patent .................................................................................... 28
`
`E.
`
`F.
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`Ground 5: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-6 and 13-15 Would Have Been
`Obvious Over the ’225 Patent in View of Chandramouli and
`WO ’185 ............................................................................................. 29
`
`The Petition Fails to Offer Evidence Refuting Objective Indicia
`of Nonobviousness ............................................................................. 31
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`1.
`
`2.
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`3.
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`4.
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`Surprising and Unexpected Results ......................................... 32
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`Long Felt But Unresolved Need .............................................. 36
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`Licensing .................................................................................. 37
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`Copying .................................................................................... 37
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`VII. CONCLUSION ............................................................................................. 38
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`Page iii
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`TABLE OF AUTHORITIES
`
`Cases
`Crocs, Inc. v. Int’l Trade Comm’n, 598 F.3d 1294 (Fed. Cir. 2010) ....................... 32
`
`Dr. Reddy’s Labs., Inc. v. Pozen, Inc., IPR2015-00802, Paper No. 28
`(P.T.A.B. Oct. 9, 2015) .................................................................................... 2
`
`In re Haruna, 249 F.3d 1327 (Fed. Cir. 2001) ........................................................ 22
`
`In re Huai-Hung Kao, 639 F.3d 1057 (Fed. Cir. 2011) ........................................... 32
`
`KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007) ............................................ 13
`
`McGinley v. Franklin Sports, Inc., 262 F.3d 1339 (Fed. Cir. 2001) ....................... 37
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`Micron Tech., Inc. v. Bd. of Trs. of the Univ. of Ill., IPR2013-00005,
`Paper No. 54 (P.T.A.B. Mar. 10, 2014) ......................................................... 33
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358 (Fed.
`Cir. 2008) ....................................................................................................... 32
`
`In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ......................................................... 37
`
`Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530 (Fed. Cir. 1983) ........................ 32
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`Tec Air, Inc. v. Denso Mfg. Mich. Inc., 192 F.3d 1353 (Fed. Cir. 1999) ................ 23
`
`
`
`Statutes
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`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 325(d). .................................................................................................... 7
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`
`
`Rules
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`37 C.F.R. § 42.107 ..................................................................................................... 1
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`TABLE OF EXHIBITS
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`EX. NO. DESCRIPTION
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`2001
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`2002
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`2003
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`2004
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`2005
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`2006
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`2007
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`2008
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`2009
`
`2010
`
`License Agreement between Patent Owner Pozen Inc. and exclusive
`licensee Horizon Pharma, Inc.
`
`Norman & Hawkey, What you need to know when you prescribe a
`proton pump inhibitor, Frontline Gastroenterology, 1-7 (2011)
`(“Norman 2011”)
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`Chiverton et al., Does misoprostol given as a single large dose improve
`its antisecretory effect?, Aliment Pharmacol Ther. 3(4):403-07 (1989)
`(“Chiverton 1989”)
`
`Cederberg et al., Omeprazole: Pharmacokinetics and Metabolism in
`Man, Scand. J. of Gastroenterology 24:33-40 (1989) (“Cederberg
`1989”)
`
`Prosecution History of U.S. Patent No. 6,926,907 (“the ’907 patent”)
`
`Excerpt from the Compact American Medical Dictionary, 138,
`“duodenum” (Houghton Mifflin Co., Boston/New York, 1998)
`
`Wolfe et al., Gastrointestinal Toxicity of Nonsteroidal
`Antiinflammatory Drugs, New England Journal of Medicine,
`340(24):1888-99 (1999) (“Wolfe 1999”)
`
`Stedman & Barclay, Review article: comparison of the
`pharmacokinetics, acid suppression and efficacy of proton pump
`inhibitors, Aliment Pharmacol. Ther. 14:963-78 (2000) (“Stedman
`2000”)
`
`Bell & Hunt, Progress with Proton Pump Inhibition, Yale J. Biology &
`Med., 65:649-57 (1992) (“Bell 1992”)
`
`Sachs et al., Review article: the control of gastric acid and Helicobacter
`pylori eradication, Aliment Pharmacol. Ther. 14:1383-401 (2000)
`(“Sachs 2000”)
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`2011
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`Prosecution History of U.S. Patent No. 8,858,636 (“the ’636 patent”)
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`2012
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`2013
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`Stollman et al., Pathophysiology and prophylaxis of stress ulcer in
`intensive care unit patients, Journal of Critical Care 20:35-45 (2005)
`(“Metz 2005”)
`Decl. of M. Mayersohn in Support of Def.'s Claim Const. Br., Par
`Pharms,, Inc. v. Takeda Pharm. Co., No. 5:13-cv-01927-LHK (N.D.
`Cal. Apr. 24, 2014) (“Mayersohn”)
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`Pursuant
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`to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Horizon
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`Pharmaceuticals, Inc. (“Horizon”) and Pozen Inc. (“Pozen”) (collectively, “Patent
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`Owner”)1 submit this Patent Owner’s Preliminary Response (“Preliminary
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`Response”) to the Petition for Inter Partes Review (“Petition”) of claims 1-18 of
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`U.S. Patent No. 8,852,636 (“the ’636 patent”), filed by Lupin Ltd. and Lupin
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`Pharmaceuticals Inc. (collectively, “Petitioner”). This Response is timely under 35
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`U.S.C. § 313 and 37 C.F.R. § 42.107.
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`I.
`
`INTRODUCTION
`The Petition seeking inter partes review of the ’636 patent should be denied.
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`The Petition asserts that Lupin and the Patent Owner dispute only one aspect of the
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`challenged claims: “whether a POSA would have found it obvious to use non-
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`enteric coated esomeprazole in the combination tablet with naproxen.” (Pet. at 1-
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`2.) At the outset, the Petition’s failure to show that the use of non-enteric coated
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`esomeprazole with coated naproxen in a coordinated release tablet is obvious is
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`cause for denial of the entire petition. Furthermore, as discussed below, the prior
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`art
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`teaches away from
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`the claimed combination of non-enteric coated
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` As explained in Patent Owner’s Mandatory Notices, Paper No. 8, Pozen is
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` 1
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`the assignee of the ’636 patent and Horizon is its exclusive licensee.
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`esomeprazole with naproxen. The Board agreed when it denied institution of inter
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`partes review of a parent patent to the ’636 patent in IPR2015-00802. “Motivation
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`to combine in the face of an express teaching away must be found in the prior art
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`itself and reliance on the teachings of the [] patent is impermissible hindsight.” Dr.
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`Reddy’s Labs., Inc. v. Pozen, Inc., IPR2015-00802, Paper No. 28 at 25 (P.T.A.B.
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`Oct. 9, 2015) (Decision of the Patent Trial and Appeal Board, hereinafter
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`“Decision”). For the reasons stated in the Patent Owner’s Preliminary Response
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`filed in IPR2015-00802, the Board’s decision denying institution of that
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`proceeding, and as set forth below, the Petition fails to demonstrate a reasonable
`
`likelihood that any of the challenged claims are obvious. The Petition should be
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`denied.
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`II. BACKGROUND
`Non-steroidal anti-inflammatory drugs (“NSAIDs”) are valuable agents in
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`the treatment of arthritis and other musculoskeletal disorders and are one of the
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`most widely used classes of drugs in the United States. The use of NSAIDs,
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`however, has been associated with mucosal injury to the upper gastrointestinal (GI)
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`tract, including the development of peptic ulcer disease, upper gastrointestinal
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`hemorrhage, and perforation. VIMOVO® is a unique drug product specifically
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`designed to reduce the potential for gastric mucosal tissue damage due to NSAID
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`use. VIMOVO® consists of a delayed-release, enteric-coated NSAID core
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`(naproxen) surrounded by an immediate-release acid inhibitor (esomeprazole
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`magnesium). The acid inhibitor is released before the NSAID, allowing its
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`gastroprotective effects to take hold before naproxen is released, thus reducing the
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`potential for gastric damage.
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`The ’636 patent is one of twelve patents listed in the FDA’s Approved Drug
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`Products with Therapeutic Equivalence Evaluations (the “Orange Book”) that
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`cover VIMOVO®.2 As described in more detail below, the ’636 patent claims
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`pharmaceutical compositions that provide for the coordinated release of an
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`immediate-release acid inhibitor and a delayed-release NSAID within a single oral
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`dosage form that reduces the risk of GI injury arising from NSAID therapy. (Ex.
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`
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` VIMOVO® is also protected by U.S. Patent No. 8,557,285, at issue in
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` 2
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`IPR2015-00802 with institution denied; U.S. Patent No. 8,858,996, at issue in
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`IPR2015-01344 and IPR2015-01773 (filed by Petitioner); U.S. Patent No.
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`6,926,907, at issue in IPR2015-01241; U.S. Patent No. 8,945,621, at issue in
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`IPR2015-01718; and U.S. Patent Nos. 5,714,504, 5,900,424, 6,369,085, 7,411,070,
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`7,745,466, and 9,161,920. The ’636 patent is also at issue in IPR2015-01680.
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`U.S. Patent No. 8,865,190, at issue in IPR2015-01775 (filed by Petitioner) also
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`covers VIMOVO® but is not listed in the Orange Book.
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`1001 at 1:21-27.) The ’636 patent also claims methods of treating a patient for
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`pain or inflammation with said pharmaceutical compositions.
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`The immediate-release acid inhibitor in VIMOVO®, esomeprazole, is a
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`proton pump inhibitor (“PPI”). In contrast to VIMOVO®’s immediate-release
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`PPI, it was—and remains—widely accepted that PPIs must be administered with a
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`delayed release, enteric coating to protect the drug from gastric acid degradation.
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`(Norman 2011, Ex. 2002 at 1.) Even experts retained by the Petitioner in the
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`related district court litigation (see Pet. at 4) have taught that proton pump
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`inhibitors, like esomeprazole, must be enteric coated to protect them from
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`degradation in stomach acid. For example, in 2005, David Metz, MD, a
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`gastroentereologist retained by Petitioner, wrote, “Proton pump inhibitors are
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`inactivated by gastric acid and thus must be given as enteric-coated granules in
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`gelatin capsules or enteric-coated tablets.” (Metz 2005, Ex. 2012 at 42 (emphasis
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`added).) Similarly, Michael Mayersohn, Ph.D., another expert retained by
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`Petitioner, provided a sworn declaration in 2014 in which he stated:
`
`Because 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 drug formulation that has an outer layer
`(referred to as the ‘enteric coat’) that protects the PPI
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`from stomach acid. The enteric coat allows the drug to
`pass through the stomach intact, ending up in the small
`intestine, where the PPI can be released and absorbed by
`the body.
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`(Mayersohn, Ex. 2013 at ¶ 25 (emphasis added).) While this enteric coating
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`protects acid-labile PPIs from acid degradation, it also delays the PPI’s absorption
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`into the systemic circulation. (Cederberg 1989, Ex. 2004 at 6-7.)
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`No prior art disclosed, taught, or suggested pharmaceutical compositions
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`providing coordinated release of a delayed-release NSAID and an immediate-
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`release acid inhibitor, as claimed in the ’636 patent. Indeed, the ’636 patent issued
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`over several references cited by the Petitioner, including Goldman. The Petition
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`does not address why Goldman or any of the other references thoroughly
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`considered by the Examiner warrants reconsideration by the Board now. As
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`discussed below, the ’636 patent’s claimed inventions are not taught or suggested
`
`by the prior art.
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`Although co-administrations of NSAIDs with acid inhibitors were attempted
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`in the prior art, none of those efforts utilized or suggested unit dosage forms with
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`the specific structural features and functional properties that provide for
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`coordinated delivery of an immediate-release acid inhibitor and a delayed-release
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`NSAID. (Ex. 1001 at 2:27-37.)
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`III. DENIAL OF INSTITUTION OF IPR2015-00802
`The ’636 patent is related in scope and priority to U.S. Patent No. 8,557,285,
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`(“the ’285 patent”) at issue in IPR2015-00802. Specifically, the ’636 patent is a
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`continuation of the ’285 patent and the claims of each patent have several common
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`elements, as shown in the table below.
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`Claim 1 of ’636 Patent
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`Claim 1 of ’285 Patent
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`A pharmaceutical composition in unit
`dose form
`
`A pharmaceutical composition in unit
`dosage form
`
`comprising: (a) esomeprazole [and] (b)
`naproxen
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`coating surrounds [the naproxen] and
`does not release said naproxen until
`the pH of the surrounding medium is
`3.5 or higher
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`comprising . . . (a) esomeprazole [and]
`(b) naproxen
`naproxen surrounded by a coating that
`inhibits its release from said unit dosage
`form unless said dosage form is in a
`medium with a pH of 3 .5 or higher
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`esomeprazole [is] not surrounded by
`an enteric coating
`
`at least a portion of said esomeprazole is
`not surrounded by an enteric coating;
`
`upon ingestion of said tablet by a
`patient, said esomeprazole is released
`into said patient's stomach.
`
`unit dosage form provides for release of
`said esomeprazole such that upon
`introduction of said unit dosage form
`into a medium, at least a portion of said
`esomeprazole is released regardless of
`the pH of the medium
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`The grounds for unpatentability set forth in IPR2015-00802 and the instant
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`Petition are similar in substance. For example, both the IPR2015-00802 and the
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`instant Petition rely on the Pilbrant reference to show why one of skill in the art
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`would combine the teachings of the cited references to arrive at the claimed
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`invention and more particularly, that omeprazole need not be enterically coated to
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`provide a therapeutic effect. See IPR2015-00802, Paper No. 1, 47–53 (P.T.A.B.
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`Feb. 24, 2015) (Petition for Inter Partes Review). (see also Pet. at 46-51.) In its
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`institution decision, however, the Board rejected that argument and concluded that
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`“Pilbrant teaches away from the claimed combination.” See Decision at 25.
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`Not only are the Petition’s grounds substantively meritless, as discussed
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`below, they are also duplicative of considerations already settled at the Patent
`
`Office and rejected by a prior panel of this Board. Institution was denied for
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`IPR2015-00802 and all the references included in this Petition, or similar
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`disclosures thereof, were cited to the Patent Office during prosecution of the ’636
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`patent. In determining whether to institute or order a proceeding, the Board “may
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`take into account whether, and reject the petition or request because, the same or
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`substantially the same prior art or arguments previously were presented to the
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`Office.” 35 U.S.C. § 325(d). The Board should deny the Petition not only because
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`the Petition fails to demonstrate a reasonable likelihood that it can prevail, but also
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`because revisiting these contentions is unnecessary and would be burdensome
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`upon both the Board and the Patent Owner, and ultimately wasteful of both time
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`and resources.
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
`The Patent Owner proposes the following definition of a person of ordinary
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`skill in the art (“POSA”): “A person with at least a graduate degree in pharmacy,
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`chemistry, chemical engineering, pharmaceutics, or a comparable field, and some
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`relevant pharmaceutical formulation work experience in industry.” While that
`
`definition is similar to the first definition provided by the Petitioner, i.e., “a
`
`pharmaceutical scientist having a Ph.D. degree in the field of pharmaceutical
`
`sciences or equivalent training or degree and at least two years of experience with
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`pharmaceutical formulations” (Pet. at 9), the Petition’s definition of a POSA does
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`not extend to a person having a graduate degree in chemistry or chemical
`
`engineering.
`
`V. CLAIM INTERPRETATION
`“Unit Dosage Form”
`A.
`It is clear from the specification and claims of the ’636 patent that “unit
`
`dosage form” should be interpreted as a “unit dosage form suitable for oral
`
`administration to a patient.” (Ex. 1001 at 3:27-29.) The specification states that
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`“[a]ll of the dosage forms are designed for oral delivery and provide for the
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`coordinated release of therapeutic agents, i.e., for the sequential release of acid
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`inhibitor followed by analgesic.” (Ex. 1001 at 6:20-23.) Accordingly, the term is
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`at the core of the “invention” and should be construed, consistent with the
`
`specification, as directed solely to oral delivery.
`
`The Board has construed that claim term previously in its decision denying
`
`institution in IPR2015-00802 as meaning “a single entity for drug administration
`
`that is suitable for oral administration.” 3 (Decision at 17.) The Patent Owner
`
`maintains that the phrase should be construed consistent with the Board’s prior
`
`decision, i.e., as meaning “a single entity for drug administration that is suitable for
`
`oral administration.”
`
`VI. THE BOARD SHOULD DENY THE PETITION BECAUSE IT FAILS
`TO DEMONSTRATE A REASONABLE LIKELIHOOD OF
`PREVAILING
`
`Each of the proposed grounds in the Petition alleges that the challenged
`
`claims are unpatentable as obvious. As discussed below, each ground is legally
`
`deficient and should be denied.
`
`A. Ground 1: The Petition has Not Established a Reasonable
`Likelihood That Claims 1-6 and 13-15 Would Have Been Obvious
`Over the ’556 Patent Alone, or in the Alternative, in View of
`Chandramouli
`
`Ground 1 is actually two grounds, though they are vertically redundant. The
`
`Petition alleges obviousness over the ’556 patent either alone or in view of
`
`
` 3
`
` The ’285 patent shares the same specification with the ’636 patent.
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`Chandramouli. For clarity, the Patent Owner addresses each of those sub-grounds
`
`separately, starting with a discussion of the ’556 patent alone.
`
`1. Ground 1A: The Petition Has Not Established a
`Reasonable Likelihood That Claims 1-6 and 13-15 Would
`Have Been Obvious Over the ’556 Patent Alone
`a.
`
`The ’556 Patent Does Not Describe a Combination
`Tablet of Naproxen and Esomeprazole
`
`The ’556 patent describes the combination of an NSAID and a proton pump
`
`inhibitor. (Ex. 1004, abstract.) The ’556 patent discloses “a preferred formulation
`
`that would release the NSAID in the stomach and omeprazole in the small
`
`intestine.” (Id. at 12:27-32.) The Petition, however, posits that the ʼ556 patent is
`
`not limited to such enteric-coated formulations. “The ’556 patent describes
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`enteric-coated omeprazole as ‘preferred’. A POSA would have understood this
`
`statement to show non-enteric coated esomeprazole would be effective.” (Pet. at
`
`14 (citing Ex. 1002, ¶ 38).)
`
`The Petition misconstrues the ‘556 patent. The ’556 patent describes that
`
`“[t]he invention is further directed to a solid oral dosage form comprising . . . an
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`enterically coated proton-pump inhibitor.” (Ex. 1004 at 3:55-61 (emphasis
`
`added).) “The invention” is later described as a “dosage form comprising . . . a
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`proton pump inhibitor . . . wherein the proton pump inhibitor is coated with a
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`material suitable to prevent contact of said proton pump inhibitor with acidic
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`gastric juice (e.g., an enteric coating.)” (Id. at 4:4-10 (emphasis added).) The
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`’556 patent further explains that “the half-life of degradation of omeprazole in
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`water solutions at pH-values less than three is shorter than ten minutes.” (Id. at
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`8:11-13.) The ’556 patent characterizes enteric-coated omeprazole formulations as
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`“preferred” embodiments, but fails to provide any alternative to enteric-coated
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`PPIs, or any other solution for solving this well-recognized problem of PPI
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`degradation in stomach acid. In fact, all twelve working examples explicitly
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`require the PPI to be enteric coated. (Id. at 15-20.) The ’556 patent must be read,
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`in keeping with the prevailing understanding as of the filing date, as teaching that
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`use of such an enteric coating is necessary due to the instability of PPIs in acidic
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`environments.
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`Next, the Petition attempts to argue that the mechanism of action of the PPI
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`would lead a POSA to conclude that an enteric coating is not necessary. The
`
`Petition asserts that “a POSA would have understood that PPIs are preferably
`
`released in the gastrointestinal tract prior to reaching the small intestine,” and cites
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`to the Banakar declaration for support. (Pet. at 13 (citing Ex. 1002, ¶¶ 33, 38).)
`
`The Banakar declaration, however, states that PPIs “function by inhibiting H2
`
`receptors in the parietal cells. Parietal cells are located in the duodenum.” (Ex.
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`1002, ¶38.) As an initial matter, this statement is incorrect. PPIs do not function by
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`inhibiting H2 receptors, instead, as their name suggests, they inhibit the H+,K+
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`ATPase, or “proton pump.” (See, e.g., Wolfe, Ex. 1019 at S13–14.) An entirely
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`different class of compounds, H2-receptor antagonists, function by inhibiting H2
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`receptors. (Id. at S12.)
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`But even if the Banakar declaration were correct, a POSA would understand
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`that the duodenum is located in the small intestine. (See Ex. 2006.) This
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`anatomical fact is shown in Figure 1 of the Banakar declaration. Thus, based on
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`the Banakar declaration, the PPI must be present in the small intestine, as would be
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`possible through the use of an enteric coating, not released in the gastrointestinal
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`tract and degraded prior to reaching the small intestine. The Petition provides no
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`explanation for this inconsistency.
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`Furthermore, based on the teachings of the ‘556 patent, a therapeutically
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`effective amount of immediate-release PPI would not be expected to survive transit
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`through the stomach to the small intestine. For example, the ’556 patent explains
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`that “the half-life of degradation of omeprazole in water solutions at pH-values less
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`than three is shorter than ten minutes.” (Ex. 1004 at 8:11-13.) Thus, contrary to
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`the conclusion set forth in the Petition, a POSA would not expect that an
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`immediate release PPI would be effective and this additional basis for challenging
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`the claims of the ’636 patent must fail.
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`In yet another alternative argument, the Petition alleges that the claims are
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`invalid as being “obvious to try” in view of the ’556 patent. The Petition does not
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`include any detailed reasoning in support of that allegation, simply stating that “a
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`POSA [would be motivated] to try to create the invention claimed in the ’636
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`patent.” (Pet. at 13.) But this is not a situation where “there are a finite number of
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`identified, predictable solutions to the recognized need or problem; and one of
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`ordinary skill in the art could have pursued these known potential solutions with a
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`reasonable expectation of success.” KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727,
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`1742 (2007). Rather, the evidence demonstrates the contrary, i.e., the prior art
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`unequivocally directed one of ordinary skill away from use of immediate-release
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`esomeprazole. As discussed below, the ’556 patent was not alone in its teaching
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`that there was no reasonable expectation of success for such a formulation.
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`b.
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`A POSA Would Not Have Been Motivated to Create a
`Combination Tablet With Immediate-Release
`Esomeprazole With a Reasonable Expectation of
`Success
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`The Petition offers another alternative challenge to the claims of the ’636
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`patent based on the teachings of the ’556 patent. Here, the Petition posits that even
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`if a POSA had known about the partial degradation of immediate-release PPI in the
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`stomach, the POSA would have known that “a sufficient amount of PPI could exist
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`and loss of the PPI could be overcome by adjusting the dosage.” (See Pet. at 14
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`(citing to Ex. 1002, ¶ 48.) Citing to Pilbrant and the Banakar declaration, the
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`Petition concludes that “a POSA would have been able to use well-known and
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`routine techniques to compensate for the degraded amount.”
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`But rather than suggesting the use of additional PPI to compensate for
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`degradation, the Pilbrant reference on which Dr. Banakar relies teaches away from
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`using an uncoated PPI. Pilbrant plainly states that an enteric coated solid dosage
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`form “offers the best possibilities.” (Pilbrant 1985, Ex. 1008 at 3.) Pilbrant
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`expressly “ruled out” the non-enteric coated solid dosage form for PPIs as an
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`option after a pilot bioavailability study showed that more than half of a nonenteric
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`coated dosage form was degraded in the stomach. (Id. at 2.) Pilbrant states that “a
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`conventional, non-buffered, oral dosage form of omeprazole will have a low
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`systemic bioavailability owing to preabsorption degradation of omeprazole in the
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`stomach.” (Id. at 5.)
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`As Pilbrant expressly “ruled out” oral unit dosage forms with non-enteric
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`coated PPIs as an option, it teaches away from using dosage forms containing non-
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`enteric coated PPIs. Thus, Pilbrant demonstrates that a POSA would not have had
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`a reasonable expectation of success with a dosage form utilizing a non-enteric
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`coated PPI. Indeed, as noted above, the Board has concluded that “Pilbrant teaches
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`away from the claimed combination [of immediate-release esomeprazole with
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`delayed-release naproxen].” Decision at 25.
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`In addition, the Federal Circuit has evaluated the Pilbrant reference in a prior
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`litigation involving PPI formulations and found that it “teaches away” from
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`“conventional oral dosage forms such as tablets, capsules, or granules with non-
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`enteric coated PPIs” and does not render them obvious. Santarus, Inc. v. Par
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`Pharm., Inc., 694 F.3d 1344, 1355 (Fed. Cir. 2012) (“Pilbrant explicitly ‘ruled out’
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`the third option—non-enteric coated conventional oral dosage forms such as
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`tablets, capsules, or granules—because they degrade too quickly in the stomach to
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`be absorbed in sufficient amounts to be effective. This disclosure would
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`discourage a person of ordinary skill in the art from pursuing conventional oral
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`dosage forms such as tablets, capsules, or granules with non-enteric coated PPIs,
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`and thus teaches away from such formulations. As a result, we hold that the
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`district court erred by concluding that claims directed to such conventional dosage
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`forms would have been obvious over Pilbrant . . . .”) (citation omitted).
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`The Petition states that “the Federal Circuit has acknowledged that Pilbrant
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`teaches non-enteric solid dosage forms of PPIs as a ‘viable alternative to enteric
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`coating.’ Santarus, 694 F.3d at 1355-56.” (Pet. at 18.) The Petition, however,
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`misquotes the Federal Circuit.
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` The Court plainly distinguished between
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`conventional dosage forms such as tablets, capsules, or granules of non-enteric
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`coated PPIs (which were not rendered obvious by Pilbrant), with buffered
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`suspensions using micronized, non-enteric coated omeprazole (which were
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`rendered obvious by Pilbrant). Santarus, 694 F.3d at 1355-1356. The Court stated
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`that “Pilbrant thus teaches that, although suspensions of buffered non-enteric
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`coated omeprazole may be the ‘second best choice,’ they are a viable alternative to
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`enteric coating.” Id. (emphasis added). Pilbrant does not teach that non-enteric
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`solid dosage forms of PPIs are a “viable alternative to enteric coating.” To the
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`contrary, as conclusively stated by the Federal Circuit in Santarus and discussed
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`above, “Pilbrant explicitly ‘ruled out’ the third option—non-enteric coated
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`conventional oral dosage forms such as tablets, capsules, or granules—because
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`they degrade too quickly in the stomach to be absorbed in sufficient amounts to be
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`effective.” Id. at 1355.
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`In a final attempt to challenge the claims of the ’636 patent in view of the
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`’556 patent, the Petition offers yet another possible solution to address PPI
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`degradation in an acidic environment. Here, the Petition suggests that an
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`alkalizing agent or buffer be included in the esomeprazole/naproxen formulation,
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`though such a formulation is neither taught not contemplated by the ’556 patent.
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`(Pet. at 16-17.) As noted by the Petition, the specification of the ’636 patent
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`discloses embodiments of the alleged invention that include an alkalizing agent
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`(see Ex. 1001, 17:47-52) as well as others that do not (see id. at 15:53-17:30).
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`That disclosure, however, does not negate the fact that the claims of the ’636
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`patent require that the esomeprazole not have an enteric coating, contrary to the
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`teachings of the prior art.
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`The ’556 patent does not teac