Case No. IPR2015-01774
`Patent No. 8,852,636
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`
` LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`POZEN INC.
`Patent Owner
`______________
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`______________
`
`
`
`PATENT OWNER’s PRELIMINARY RESPONSE
`37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent No. 8,852,636
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`
` LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`POZEN INC.
`Patent Owner
`______________
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`______________
`
`
`
`PATENT OWNER’s PRELIMINARY RESPONSE
`37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION .......................................................................................... 1
`
`BACKGROUND ............................................................................................ 2
`
`III. DENIAL OF INSTITUTION OF IPR2015-00802 ........................................ 6
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART ............................................ 8
`
`V.
`
`CLAIM INTERPRETATION ........................................................................ 8
`
`A.
`
`“Unit Dosage Form” ............................................................................. 8
`
`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.
`
`The ’556 Patent Does Not Describe a Combination
`Tablet of Naproxen and Esomeprazole ......................... 10
`
`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
`
`Page ii
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`B.
`
`C.
`
`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.
`
`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
`
`1.
`
`2.
`
`3.
`
`4.
`
`Surprising and Unexpected Results ......................................... 32
`
`Long Felt But Unresolved Need .............................................. 36
`
`Licensing .................................................................................. 37
`
`Copying .................................................................................... 37
`
`VII. CONCLUSION ............................................................................................. 38
`
`
`
`
`
`Page iii
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`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
`
`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
`
`Tec Air, Inc. v. Denso Mfg. Mich. Inc., 192 F.3d 1353 (Fed. Cir. 1999) ................ 23
`
`
`
`Statutes
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 325(d). .................................................................................................... 7
`
`
`
`Rules
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`
`
`Page iv
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`TABLE OF EXHIBITS
`
`EX. NO. DESCRIPTION
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`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”)
`
`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”)
`
`2011
`
`Prosecution History of U.S. Patent No. 8,858,636 (“the ’636 patent”)
`
`Page v
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`2012
`
`2013
`
`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”)
`
`
`Page vi
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`Pursuant
`
`to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Horizon
`
`Pharmaceuticals, Inc. (“Horizon”) and Pozen Inc. (“Pozen”) (collectively, “Patent
`
`Owner”)1 submit this Patent Owner’s Preliminary Response (“Preliminary
`
`Response”) to the Petition for Inter Partes Review (“Petition”) of claims 1-18 of
`
`U.S. Patent No. 8,852,636 (“the ’636 patent”), filed by Lupin Ltd. and Lupin
`
`Pharmaceuticals Inc. (collectively, “Petitioner”). This Response is timely under 35
`
`U.S.C. § 313 and 37 C.F.R. § 42.107.
`
`I.
`
`INTRODUCTION
`The Petition seeking inter partes review of the ’636 patent should be denied.
`
`The Petition asserts that Lupin and the Patent Owner dispute only one aspect of the
`
`challenged claims: “whether a POSA would have found it obvious to use non-
`
`enteric coated esomeprazole in the combination tablet with naproxen.” (Pet. at 1-
`
`2.) At the outset, the Petition’s failure to show that the use of non-enteric coated
`
`esomeprazole with coated naproxen in a coordinated release tablet is obvious is
`
`cause for denial of the entire petition. Furthermore, as discussed below, the prior
`
`art
`
`teaches away from
`
`the claimed combination of non-enteric coated
`
`
`
` As explained in Patent Owner’s Mandatory Notices, Paper No. 8, Pozen is
`
` 1
`
`the assignee of the ’636 patent and Horizon is its exclusive licensee.
`
`Page 1 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`esomeprazole with naproxen. The Board agreed when it denied institution of inter
`
`partes review of a parent patent to the ’636 patent in IPR2015-00802. “Motivation
`
`to combine in the face of an express teaching away must be found in the prior art
`
`itself and reliance on the teachings of the [] patent is impermissible hindsight.” Dr.
`
`Reddy’s Labs., Inc. v. Pozen, Inc., IPR2015-00802, Paper No. 28 at 25 (P.T.A.B.
`
`Oct. 9, 2015) (Decision of the Patent Trial and Appeal Board, hereinafter
`
`“Decision”). For the reasons stated in the Patent Owner’s Preliminary Response
`
`filed in IPR2015-00802, the Board’s decision denying institution of that
`
`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
`
`denied.
`
`II. BACKGROUND
`Non-steroidal anti-inflammatory drugs (“NSAIDs”) are valuable agents in
`
`the treatment of arthritis and other musculoskeletal disorders and are one of the
`
`most widely used classes of drugs in the United States. The use of NSAIDs,
`
`however, has been associated with mucosal injury to the upper gastrointestinal (GI)
`
`tract, including the development of peptic ulcer disease, upper gastrointestinal
`
`hemorrhage, and perforation. VIMOVO® is a unique drug product specifically
`
`designed to reduce the potential for gastric mucosal tissue damage due to NSAID
`
`use. VIMOVO® consists of a delayed-release, enteric-coated NSAID core
`
`Page 2 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`(naproxen) surrounded by an immediate-release acid inhibitor (esomeprazole
`
`magnesium). The acid inhibitor is released before the NSAID, allowing its
`
`gastroprotective effects to take hold before naproxen is released, thus reducing the
`
`potential for gastric damage.
`
`The ’636 patent is one of twelve patents listed in the FDA’s Approved Drug
`
`Products with Therapeutic Equivalence Evaluations (the “Orange Book”) that
`
`cover VIMOVO®.2 As described in more detail below, the ’636 patent claims
`
`pharmaceutical compositions that provide for the coordinated release of an
`
`immediate-release acid inhibitor and a delayed-release NSAID within a single oral
`
`dosage form that reduces the risk of GI injury arising from NSAID therapy. (Ex.
`
`
`
` VIMOVO® is also protected by U.S. Patent No. 8,557,285, at issue in
`
` 2
`
`IPR2015-00802 with institution denied; U.S. Patent No. 8,858,996, at issue in
`
`IPR2015-01344 and IPR2015-01773 (filed by Petitioner); U.S. Patent No.
`
`6,926,907, at issue in IPR2015-01241; U.S. Patent No. 8,945,621, at issue in
`
`IPR2015-01718; and U.S. Patent Nos. 5,714,504, 5,900,424, 6,369,085, 7,411,070,
`
`7,745,466, and 9,161,920. The ’636 patent is also at issue in IPR2015-01680.
`
`U.S. Patent No. 8,865,190, at issue in IPR2015-01775 (filed by Petitioner) also
`
`covers VIMOVO® but is not listed in the Orange Book.
`
`Page 3 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`1001 at 1:21-27.) The ’636 patent also claims methods of treating a patient for
`
`pain or inflammation with said pharmaceutical compositions.
`
`The immediate-release acid inhibitor in VIMOVO®, esomeprazole, is a
`
`proton pump inhibitor (“PPI”). In contrast to VIMOVO®’s immediate-release
`
`PPI, it was—and remains—widely accepted that PPIs must be administered with a
`
`delayed release, enteric coating to protect the drug from gastric acid degradation.
`
`(Norman 2011, Ex. 2002 at 1.) Even experts retained by the Petitioner in the
`
`related district court litigation (see Pet. at 4) have taught that proton pump
`
`inhibitors, like esomeprazole, must be enteric coated to protect them from
`
`degradation in stomach acid. For example, in 2005, David Metz, MD, a
`
`gastroentereologist retained by Petitioner, wrote, “Proton pump inhibitors are
`
`inactivated by gastric acid and thus must be given as enteric-coated granules in
`
`gelatin capsules or enteric-coated tablets.” (Metz 2005, Ex. 2012 at 42 (emphasis
`
`added).) Similarly, Michael Mayersohn, Ph.D., another expert retained by
`
`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
`
`Page 4 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`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.
`
`(Mayersohn, Ex. 2013 at ¶ 25 (emphasis added).) While this enteric coating
`
`protects acid-labile PPIs from acid degradation, it also delays the PPI’s absorption
`
`into the systemic circulation. (Cederberg 1989, Ex. 2004 at 6-7.)
`
`No prior art disclosed, taught, or suggested pharmaceutical compositions
`
`providing coordinated release of a delayed-release NSAID and an immediate-
`
`release acid inhibitor, as claimed in the ’636 patent. Indeed, the ’636 patent issued
`
`over several references cited by the Petitioner, including Goldman. The Petition
`
`does not address why Goldman or any of the other references thoroughly
`
`considered by the Examiner warrants reconsideration by the Board now. As
`
`discussed below, the ’636 patent’s claimed inventions are not taught or suggested
`
`by the prior art.
`
`Although co-administrations of NSAIDs with acid inhibitors were attempted
`
`in the prior art, none of those efforts utilized or suggested unit dosage forms with
`
`the specific structural features and functional properties that provide for
`
`coordinated delivery of an immediate-release acid inhibitor and a delayed-release
`
`NSAID. (Ex. 1001 at 2:27-37.)
`
`Page 5 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`III. DENIAL OF INSTITUTION OF IPR2015-00802
`The ’636 patent is related in scope and priority to U.S. Patent No. 8,557,285,
`
`(“the ’285 patent”) at issue in IPR2015-00802. Specifically, the ’636 patent is a
`
`continuation of the ’285 patent and the claims of each patent have several common
`
`elements, as shown in the table below.
`
`Claim 1 of ’636 Patent
`
`Claim 1 of ’285 Patent
`
`A pharmaceutical composition in unit
`dose form
`
`A pharmaceutical composition in unit
`dosage form
`
`comprising: (a) esomeprazole [and] (b)
`naproxen
`
`coating surrounds [the naproxen] and
`does not release said naproxen until
`the pH of the surrounding medium is
`3.5 or higher
`
`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
`
`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
`
`The grounds for unpatentability set forth in IPR2015-00802 and the instant
`
`Petition are similar in substance. For example, both the IPR2015-00802 and the
`
`instant Petition rely on the Pilbrant reference to show why one of skill in the art
`
`Page 6 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`would combine the teachings of the cited references to arrive at the claimed
`
`invention and more particularly, that omeprazole need not be enterically coated to
`
`provide a therapeutic effect. See IPR2015-00802, Paper No. 1, 47–53 (P.T.A.B.
`
`Feb. 24, 2015) (Petition for Inter Partes Review). (see also Pet. at 46-51.) In its
`
`institution decision, however, the Board rejected that argument and concluded that
`
`“Pilbrant teaches away from the claimed combination.” See Decision at 25.
`
`Not only are the Petition’s grounds substantively meritless, as discussed
`
`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
`
`IPR2015-00802 and all the references included in this Petition, or similar
`
`disclosures thereof, were cited to the Patent Office during prosecution of the ’636
`
`patent. In determining whether to institute or order a proceeding, the Board “may
`
`take into account whether, and reject the petition or request because, the same or
`
`substantially the same prior art or arguments previously were presented to the
`
`Office.” 35 U.S.C. § 325(d). The Board should deny the Petition not only because
`
`the Petition fails to demonstrate a reasonable likelihood that it can prevail, but also
`
`because revisiting these contentions is unnecessary and would be burdensome
`
`upon both the Board and the Patent Owner, and ultimately wasteful of both time
`
`and resources.
`
`Page 7 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`The Patent Owner proposes the following definition of a person of ordinary
`
`skill in the art (“POSA”): “A person with at least a graduate degree in pharmacy,
`
`chemistry, chemical engineering, pharmaceutics, or a comparable field, and some
`
`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
`
`pharmaceutical formulations” (Pet. at 9), the Petition’s definition of a POSA does
`
`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
`
`“[a]ll of the dosage forms are designed for oral delivery and provide for the
`
`coordinated release of therapeutic agents, i.e., for the sequential release of acid
`
`inhibitor followed by analgesic.” (Ex. 1001 at 6:20-23.) Accordingly, the term is
`
`Page 8 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`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.
`
`Page 9 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`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
`
`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
`
`enterically coated proton-pump inhibitor.” (Ex. 1004 at 3:55-61 (emphasis
`
`added).) “The invention” is later described as a “dosage form comprising . . . a
`
`proton pump inhibitor . . . wherein the proton pump inhibitor is coated with a
`
`material suitable to prevent contact of said proton pump inhibitor with acidic
`
`gastric juice (e.g., an enteric coating.)” (Id. at 4:4-10 (emphasis added).) The
`
`Page 10 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`’556 patent further explains that “the half-life of degradation of omeprazole in
`
`water solutions at pH-values less than three is shorter than ten minutes.” (Id. at
`
`8:11-13.) The ’556 patent characterizes enteric-coated omeprazole formulations as
`
`“preferred” embodiments, but fails to provide any alternative to enteric-coated
`
`PPIs, or any other solution for solving this well-recognized problem of PPI
`
`degradation in stomach acid. In fact, all twelve working examples explicitly
`
`require the PPI to be enteric coated. (Id. at 15-20.) The ’556 patent must be read,
`
`in keeping with the prevailing understanding as of the filing date, as teaching that
`
`use of such an enteric coating is necessary due to the instability of PPIs in acidic
`
`environments.
`
`Next, the Petition attempts to argue that the mechanism of action of the PPI
`
`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
`
`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.
`
`1002, ¶38.) As an initial matter, this statement is incorrect. PPIs do not function by
`
`inhibiting H2 receptors, instead, as their name suggests, they inhibit the H+,K+
`
`ATPase, or “proton pump.” (See, e.g., Wolfe, Ex. 1019 at S13–14.) An entirely
`
`Page 11 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`different class of compounds, H2-receptor antagonists, function by inhibiting H2
`
`receptors. (Id. at S12.)
`
`But even if the Banakar declaration were correct, a POSA would understand
`
`that the duodenum is located in the small intestine. (See Ex. 2006.) This
`
`anatomical fact is shown in Figure 1 of the Banakar declaration. Thus, based on
`
`the Banakar declaration, the PPI must be present in the small intestine, as would be
`
`possible through the use of an enteric coating, not released in the gastrointestinal
`
`tract and degraded prior to reaching the small intestine. The Petition provides no
`
`explanation for this inconsistency.
`
`Furthermore, based on the teachings of the ‘556 patent, a therapeutically
`
`effective amount of immediate-release PPI would not be expected to survive transit
`
`through the stomach to the small intestine. For example, the ’556 patent explains
`
`that “the half-life of degradation of omeprazole in water solutions at pH-values less
`
`than three is shorter than ten minutes.” (Ex. 1004 at 8:11-13.) Thus, contrary to
`
`the conclusion set forth in the Petition, a POSA would not expect that an
`
`immediate release PPI would be effective and this additional basis for challenging
`
`the claims of the ’636 patent must fail.
`
`In yet another alternative argument, the Petition alleges that the claims are
`
`invalid as being “obvious to try” in view of the ’556 patent. The Petition does not
`
`include any detailed reasoning in support of that allegation, simply stating that “a
`
`Page 12 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`POSA [would be motivated] to try to create the invention claimed in the ’636
`
`patent.” (Pet. at 13.) But this is not a situation where “there are a finite number of
`
`identified, predictable solutions to the recognized need or problem; and one of
`
`ordinary skill in the art could have pursued these known potential solutions with a
`
`reasonable expectation of success.” KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727,
`
`1742 (2007). Rather, the evidence demonstrates the contrary, i.e., the prior art
`
`unequivocally directed one of ordinary skill away from use of immediate-release
`
`esomeprazole. As discussed below, the ’556 patent was not alone in its teaching
`
`that there was no reasonable expectation of success for such a formulation.
`
`b.
`
`A POSA Would Not Have Been Motivated to Create a
`Combination Tablet With Immediate-Release
`Esomeprazole With a Reasonable Expectation of
`Success
`
`The Petition offers another alternative challenge to the claims of the ’636
`
`patent based on the teachings of the ’556 patent. Here, the Petition posits that even
`
`if a POSA had known about the partial degradation of immediate-release PPI in the
`
`stomach, the POSA would have known that “a sufficient amount of PPI could exist
`
`and loss of the PPI could be overcome by adjusting the dosage.” (See Pet. at 14
`
`(citing to Ex. 1002, ¶ 48.) Citing to Pilbrant and the Banakar declaration, the
`
`Petition concludes that “a POSA would have been able to use well-known and
`
`routine techniques to compensate for the degraded amount.”
`
`Page 13 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`But rather than suggesting the use of additional PPI to compensate for
`
`degradation, the Pilbrant reference on which Dr. Banakar relies teaches away from
`
`using an uncoated PPI. Pilbrant plainly states that an enteric coated solid dosage
`
`form “offers the best possibilities.” (Pilbrant 1985, Ex. 1008 at 3.) Pilbrant
`
`expressly “ruled out” the non-enteric coated solid dosage form for PPIs as an
`
`option after a pilot bioavailability study showed that more than half of a nonenteric
`
`coated dosage form was degraded in the stomach. (Id. at 2.) Pilbrant states that “a
`
`conventional, non-buffered, oral dosage form of omeprazole will have a low
`
`systemic bioavailability owing to preabsorption degradation of omeprazole in the
`
`stomach.” (Id. at 5.)
`
`As Pilbrant expressly “ruled out” oral unit dosage forms with non-enteric
`
`coated PPIs as an option, it teaches away from using dosage forms containing non-
`
`enteric coated PPIs. Thus, Pilbrant demonstrates that a POSA would not have had
`
`a reasonable expectation of success with a dosage form utilizing a non-enteric
`
`coated PPI. Indeed, as noted above, the Board has concluded that “Pilbrant teaches
`
`away from the claimed combination [of immediate-release esomeprazole with
`
`delayed-release naproxen].” Decision at 25.
`
`In addition, the Federal Circuit has evaluated the Pilbrant reference in a prior
`
`litigation involving PPI formulations and found that it “teaches away” from
`
`“conventional oral dosage forms such as tablets, capsules, or granules with non-
`
`Page 14 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`enteric coated PPIs” and does not render them obvious. Santarus, Inc. v. Par
`
`Pharm., Inc., 694 F.3d 1344, 1355 (Fed. Cir. 2012) (“Pilbrant explicitly ‘ruled out’
`
`the third option—non-enteric coated conventional oral dosage forms such as
`
`tablets, capsules, or granules—because they degrade too quickly in the stomach to
`
`be absorbed in sufficient amounts to be effective. This disclosure would
`
`discourage a person of ordinary skill in the art from pursuing conventional oral
`
`dosage forms such as tablets, capsules, or granules with non-enteric coated PPIs,
`
`and thus teaches away from such formulations. As a result, we hold that the
`
`district court erred by concluding that claims directed to such conventional dosage
`
`forms would have been obvious over Pilbrant . . . .”) (citation omitted).
`
`The Petition states that “the Federal Circuit has acknowledged that Pilbrant
`
`teaches non-enteric solid dosage forms of PPIs as a ‘viable alternative to enteric
`
`coating.’ Santarus, 694 F.3d at 1355-56.” (Pet. at 18.) The Petition, however,
`
`misquotes the Federal Circuit.
`
` The Court plainly distinguished between
`
`conventional dosage forms such as tablets, capsules, or granules of non-enteric
`
`coated PPIs (which were not rendered obvious by Pilbrant), with buffered
`
`suspensions using micronized, non-enteric coated omeprazole (which were
`
`rendered obvious by Pilbrant). Santarus, 694 F.3d at 1355-1356. The Court stated
`
`that “Pilbrant thus teaches that, although suspensions of buffered non-enteric
`
`coated omeprazole may be the ‘second best choice,’ they are a viable alternative to
`
`Page 15 of 38
`
`
`
`Case No. IPR2015-01774
`Patent No. 8,852,636
`
`enteric coating.” Id. (emphasis added). Pilbrant does not teach that non-enteric
`
`solid dosage forms of PPIs are a “viable alternative to enteric coating.” To the
`
`contrary, as conclusively stated by the Federal Circuit in Santarus and discussed
`
`above, “Pilbrant explicitly ‘ruled out’ the third option—non-enteric coated
`
`conventional oral dosage forms such as tablets, capsules, or granules—because
`
`they degrade too quickly in the stomach to be absorbed in sufficient amounts to be
`
`effective.” Id. at 1355.
`
`In a final attempt to challenge the claims of the ’636 patent in view of the
`
`’556 patent, the Petition offers yet another possible solution to address PPI
`
`degradation in an acidic environment. Here, the Petition suggests that an
`
`alkalizing agent or buffer be included in the esomeprazole/naproxen formulation,
`
`though such a formulation is neither taught not contemplated by the ’556 patent.
`
`(Pet. at 16-17.) As noted by the Petition, the specification of the ’636 patent
`
`discloses embodiments of the alleged invention that include an alkalizing agent
`
`(see Ex. 1001, 17:47-52) as well as others that do not (see id. at 15:53-17:30).
`
`That disclosure, however, does not negate the fact that the claims of the ’636
`
`patent require that the esomeprazole not have an enteric coating, contrary to the
`
`teachings of the prior art.
`
`The ’556 patent does not teac
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
