UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________
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`
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioners
`
`v.
`
`POZEN, INC.
`Patent Owner
`
`___________
`
`CASE IPR2015-01773
`Patent No. 8,858,996
`___________
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`
`
`REPLY IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,858,996
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`
`
`
`
`
`
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________
`
`
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`Petitioners
`
`v.
`
`POZEN, INC.
`Patent Owner
`
`___________
`
`CASE IPR2015-01773
`Patent No. 8,858,996
`___________
`
`
`
`REPLY IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,858,996
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
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`TABLE OF CONTENTS
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`IPR2015-01773
`Patent 8,858,996
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`I.
`
`II.
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`INTRODUCTION .......................................................................................... 1
`
`SUMMARY OF ISSUES IN DISPUTE ........................................................ 2
`
`III. CLAIMS 1 AND 3-11 OF THE ’996 PATENT WOULD HAVE
`BEEN OBVIOUS ........................................................................................... 4
`
`A.
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`B.
`
`C.
`
`The Prior Art Discloses Each Element of the Claims of the ’996
`Patent .................................................................................................... 4
`
`A POSA Would Have Been Motivated to Replace Misoprostol
`Disclosed in the ’225 Patent with Esomeprazole ................................. 8
`
`The Prior Art Provides Ample Motivation to Combine an
`Immediate Release PPI with an NSAID .............................................. 9
`
`1. WO’185 Provides Explicit Motivation to Use an
`Immediate Release PPI Without an Enteric Coating ............... 10
`
`2.
`
`The Use of Bicarbonate Buffer in WO’185 is Entirely
`Compatible with the Teachings of the ’225 Patent .................. 11
`
`D. A POSA Would Have Been Motivated to Replace the NSAID
`in the ’225 Patent with Naproxen ....................................................... 15
`
`E.
`
`F.
`
`A POSA Would Have Known How to Formulate a
`Combination Tablet with a Reasonable Expectation of Success ....... 17
`
`There Are No Secondary Considerations to Overcome
`Obviousness ........................................................................................ 21
`
`IV. CONCLUSION ............................................................................................. 21
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`-ii-
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`IPR2015-01773
`Patent 8,858,996
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`I.
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`INTRODUCTION
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`Petitioners Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively, “Lupin”
`
`or “Petitioners”) submit this reply in support of their Petition for Inter Partes
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`Review of U.S. Patent No. 8,858,996 (“the ’996 patent” (Ex. 1001)).1 As
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`explained in Lupin’s Petition, the ’996 patent combines in a straightforward way
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`two well-known drugs, the nonsteroidal anti-inflammatory drug (“NSAID”)
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`naproxen and the proton-pump inhibitor (“PPI”) esomeprazole. Indeed, it cannot
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`be novel to merely combine the two drugs in a single tablet because the prior art
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`disclosed the very combination of naproxen and esomeprazole. The issue boils
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`down to whether it would have been obvious to use a rapid release PPI in the
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`context of the combination.
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`As the prior art and the ’996 patent itself acknowledge, the methods to make
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`a tablet with an enteric coated drug combined with a non-enteric coated drug were
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`1 The Board instituted inter partes review on claims 1 and 3-11. (Decision, Paper
`
`15, Decision Granting Institution(“Decision”).) The Board has not yet ruled on
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`Petitioners Request for Rehearing seeking inter partes review on the basis of
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`additional grounds and review of additional challenged claims 2 and 12-19. (Paper
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`17.) While this Reply is limited to the presently instituted claims and grounds,
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`Petitioners reserve the right to further address claims 1-19 in light of any future
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`ruling by the Board.
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`IPR2015-01773
`Patent No. 8,858,996
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`standard knowledge. (’996 patent, Ex. 1001 at 6:51-57.) Recognizing that each of
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`the claimed limitations was disclosed in the prior art, the Patent Owner argues that
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`one of ordinary skill in the art would have no reason to combine the teachings of
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`the prior art. But the Patent Owner’s arguments improperly reduce one of ordinary
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`skill to an automaton and ignore the teachings of the prior art themselves.
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`The Petitioner respectfully requests that the Board determine that claims 1
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`and 3-11 are obvious in view of U.S. Patent No. 5,698,225 (“the ’225 patent”) (Ex.
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`1013), Chandramouli et al., Prevention and management of NSAID-Induced
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`Gastropathy, J. PHARM. PAIN & SYMPTOM CONTROL, 8(4):27-40 (2000)
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`(“Chandramouli”) (Ex. 1009) and PCT Int’l Patent Appl. WO 00/26185
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`(“WO’185”) (Ex. 1015).
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`II.
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`SUMMARY OF ISSUES IN DISPUTE
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`As explained in Lupin’s Petition, a person of ordinary skill in the art
`
`(“POSA”) would have found the claimed formulation obvious in view of the ’225
`
`patent, Chandramouli, and WO’185 because those prior art references disclose all
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`of the elements claimed. The references clearly point to the approach claimed in
`
`the ’996 patent – a tablet combining a rapid release esomeprazole with a delayed-
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`release naproxen.
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`In its Decision to Institute Inter Partes Review, this Board has already
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`acknowledged that the ’225 patent teaches the same overall structure as the ’996
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`IPR2015-01773
`Patent No. 8,858,996
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`patent and that a POSA would be motivated to generally replace the drug disclosed
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`in the ’225 patent, misoprostol, with esomeprazole to treat NSAID-related gastric
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`injury. (Decision, Paper 15 at 34-35.) Naproxen was a well-known NSAID used
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`to pain treatment and, as being an NSAID, was associated with the risk of NSAID-
`
`related gastric injury. Thus, the claims of the ’996 patent would have been obvious
`
`because they merely combine well known elements of the prior art and employ
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`them in a predictable manner in order to address a widely recognized problem. In
`
`re Kerkhoven, 626 F.2d 846, 850 (C.C.P.A 1980) (“It is prima facie obvious to
`
`combine two compositions each of which is taught by the prior art to be useful for
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`the same purpose, in order to form a third composition to be used for the very same
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`purpose. . . . [T]he idea of combining them flows logically from their having been
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`individually taught in the prior art.”).
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`Although each of the claimed elements of the ’996 patent was described in
`
`the prior art, the Patent Owner now argues that the prior art did not establish: (1) a
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`rationale to substitute esomeprazole for misoprostol; (2) a rationale to substitute
`
`naproxen for other known NSAIDs, such as piroxicam or diclofenac; and (3) how
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`to prepare a therapeutically effective tablet. In making these last-ditch arguments
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`to save its claims, the Patent Owner fundamentally mischaracterizes the prior art
`
`and improperly ignores the general knowledge available to a POSA regarding these
`
`commonly used drugs. See Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371,
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`-3-
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`Patent No. 8,858,996
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`1380 (Fed. Cir. 2005) (“What a reference teaches or suggests must be examined in
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`the context of the knowledge, skill and reasoning ability of a skilled artisan.”).
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`III. CLAIMS 1 AND 3-11 OF THE ’996 PATENT WOULD HAVE BEEN
`OBVIOUS
`
`The Board instituted inter partes review for claims 1 and 3-11 of the ’996
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`patent as obvious over the ’225 patent in view of Chandramouli and WO’185
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`under 35 U.S.C. § 103. As shown in the Petition and this Reply, claims 1 and 3-11
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`of the ’996 patent would have been obvious and should be cancelled because:
`
` the prior art discloses each element of the challenged claims;
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` a POSA would have been motivated to replace misoprostol in the ’225
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`patent with esomeprazole;
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` the prior art provides motivation to combine an immediate-release
`
`esomeprazole with an NSAID;
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` a POSA would have been motivated to use naproxen as an enteric-
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`coated NSAID; and
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` there are no secondary considerations of obviousness that overcome
`
`the strong prima facie case of obviousness.
`
`A. The Prior Art Discloses Each Element of the Claims of the ’996
`Patent
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`The ’996 patent claims a combination of an NSAID, naproxen, with an acid
`
`inhibitor, the PPI esomeprazole, in a single tablet. The tablet releases the drugs in
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`IPR2015-01773
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`two stages: the esomeprazole is immediately-released when the tablet is taken and
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`at least some portion of naproxen is delayed from being released until the pH of the
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`surrounding medium is 3.5 or greater. (’996 Patent, Ex. 1001 at 21:24-35, 21:42-
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`22:16.) By April 2001, the prior art described the combination of an NSAID with
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`an acid inhibitor having this type of release profile. As acknowledged by the
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`Board, the ’225 patent teaches an NSAID/acid inhibitor combination tablet having
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`an enteric coated NSAID core surrounded by a non-enteric coated acid inhibitor.
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`(’225 patent, Ex. 1013 at 1:11-17.)
`
`Acid inhibitor
`
`(esomeprazole)
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`
`
`Enteric
`Coating
`
`NSAID
`(Diclofenac or
`Piroxicam)
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`
`
`NSAID
`(Naproxen)
`
`’225 patent
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`’996 patent
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`
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`Acid inhibitor
`(misoprostol)
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`
`
`Enteric
`Coating
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`
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`Like the ’996 patent, the ’225 patent discloses a combination tablet with an
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`enteric-coated NSAID in the core and further surrounded by an uncoated acid
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`inhibitor. The only difference between the alleged invention in the ’996 patent and
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`the ’225 patent is that the acid inhibitor is esomeprazole instead of misoprostol and
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`the NSAID is naproxen instead of diclofenac or piroxicam. This difference is
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`insignificant because the prior art, specifically Chandramouli and WO’185,
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`addresses these obvious substitutions. By the time of the invention, naproxen and
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`esomeprazole were known as the leading NSAIDs and PPIs, and would have been
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`the most obvious choice.
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`Naproxen was a well-known NSAID. The prior art explains that NSAIDs
`
`are considered “similar with respect to therapeutic efficacy,” and the selection of
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`one NSAID over another often came down to effectiveness for individual patients.
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`(Chandramouli, Ex. 1009 at 35.) Chandramouli expressly teaches naproxen was
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`known as of June 1, 2001 and teaches doses of naproxen that are the same as the
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`250-500 mg doses claimed in the ’996 patent. (Id. at 34.) Naproxen is a generic
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`NSAID available at low cost. (Id. at 37-38.) A POSA desiring to use an NSAID
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`would immediately consider naproxen in a variety of situations.
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`A POSA would also understand that esomeprazole was a superior acid
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`inhibitor to misoprostol. Chandramouli and WO’185 disclose the use of
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`omeprazole as an acid inhibitor. WO’185 discloses pharmaceutical preparations of
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`immediate release PPIs suitable for oral administration without enteric coating.
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`This includes tablets comprising omeprazole and a bicarbonate salt as a pH-
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`adjusting solution. (WO’185, Ex. 1015 at 18:1-23.) Chandramouli further
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`explains the mechanism of NSAID-induced gastric injury, the use of acid
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`inhibitors to prevent such injury, and teaches that omeprazole, which inherently
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`IPR2015-01773
`Patent No. 8,858,996
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`contains esomeprazole, may be as effective or more effective than the acid
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`inhibitor used in the ’225 patent, with reduced risk of side effects. (Chandramouli,
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`Ex. 1009 at 36.)
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`The Patent Owner does not dispute any of the above. Instead, the Patent
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`Owner nitpicks that the ’225 patent, Chandramouli, or WO’185 do not specifically
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`reference esomeprazole, even though WO’185 and Chandramouli disclose the use
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`of omeprazole. (Paper 22, Patent Owner Response (“PO Response”) at 10.)
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`Indeed, Chandramouli discusses omeprazole as preferable over misoprostol.
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`Importantly, esomeprazole is contained in omeprazole because omeprazole is a
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`racemic compound comprised of two enantiomers, one being esomeprazole, and
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`esomeprazole was widely known in the art to be more efficacious than racemic
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`omeprazole.
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`As the Board recognized, a POSA would have had reason to use
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`“omeprazole (or the related PPI, esomeprazole) based on the teachings of
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`Chandramouli.” (Decision at 33.) As further evidenced by the declaration of Dr.
`
`Banakar and the prior art, esomeprazole was already understood to be an
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`equivalent, if not better, substitution for its racemate omeprazole. (See, e.g.,
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`Declaration of Dr. Umesh V. Banakar, Ex. 1002, at ¶ 34 (citing U.S. Patent No.
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`5,877,192, Ex. 1008, at 2:4-12, 2:29-36).) Thus, a POSA would easily understand
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`IPR2015-01773
`Patent No. 8,858,996
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`that teachings directed to omeprazole would also apply to its known and preferred
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`enantiomer, esomeprazole.
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`B. A POSA Would Have Been Motivated to Replace Misoprostol
`Disclosed in the ’225 Patent with Esomeprazole
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`As the Board correctly recognized, a POSA “would have had reason to use
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`omeprazole (or the related PPI, esomeprazole) instead of misoprostol to prevent
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`NSAID-associated GI injury, as a general matter, based on teachings in
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`Chandramouli.” (Decision, Paper 15 at 33 (citing Chandramouli, Ex. 1009 at 36-
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`37).) In the face of this recognition, the Patent Owner inexplicably argues that a
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`POSA would not have been motivated to replace misoprostol with esomeprazole
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`within the tablet disclosed in the ’225 patent.
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`To the contrary, a POSA would have had ample motivation. A POSA would
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`have known that misoprostol had significant disadvantages in comparison to PPIs
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`such as esomeprazole including that misoprostol was a known abortifacient,
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`contraindicated in women of childbearing potential, and was linked to significant
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`diarrhea and abdominal pain. (Chandramouli, Ex. 1009, at 37). In addition,
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`misoprostol was “generally considered highly unstable.” (’225 patent, Ex. 1013, at
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`1:51-53.) In contrast to misoprostol, a POSA would know that esomeprazole and
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`omeprazole have a very good safety profile. (See, e.g., WO’185, Ex. 1015 at 4:08-
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`15.) Moreover, Chandramouli discloses a study that concluded “omeprazole may
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`IPR2015-01773
`Patent No. 8,858,996
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`be as effective as or more effective than misoprostol for the prevention of NSAID-
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`induced gastropathy.” (Ex. 1009 at 36.)
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`This same reasoning would motivate a POSA to replace misoprostol with
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`esomeprazole within the structure of the ’225 patent. The invention described
`
`within the ’225 patent is a single dosage form designed to provide NSAIDs for the
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`treatment of inflammatory conditions while reducing the risk of gastric injury
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`associated with NSAID use. (’225 patent, Ex. 1013 at 1:58-63.) In order to
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`develop a safer combination tablet and avoid the significant disadvantages of
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`misoprostol, a POSA would have been motivated to replace the abortifacient
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`misoprostol with the safer and more efficacious compound esomeprazole.
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`The inherent disadvantages associated with misoprostol would motivate a
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`POSA to substitute the use of a PPI such as esomeprazole in the context of the
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`’225 patent. When searching for an alternative to misoprostol a POSA would thus
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`recognize esomeprazole as a “logical choice.” (WO’185, Ex. 1015 at 4:8-15.)
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`C. The Prior Art Provides Ample Motivation to Combine an
`Immediate Release PPI with an NSAID
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`As shown above, a POSA would have found it obvious to substitute
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`esomeprazole for misoprostol and would have been motivated to do so. In turn,
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`the issue comes down to whether a POSA would have been motivated to use
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`esomeprazole in an immediate release formulation or, in other words, without an
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`enteric coating, in the same way that misoprostol is used in the ’225 patent, with a
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`IPR2015-01773
`Patent No. 8,858,996
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`reasonable expectation of success. (Banakar Declaration, Ex. 1002 at ¶ 82.) Based
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`on the prior art and the knowledge of a POSA, the answer is a resounding yes.
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`1. WO’185 Provides Explicit Motivation to Use an Immediate
`Release PPI Without an Enteric Coating
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`A POSA would have readily understood that esomeprazole could be
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`substituted for misoprostol within the context of the ’225 patent. To try to escape
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`this result, the Patent Owner incorrectly argues that the cited art would instead
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`motivate a POSA to replace the rapid release, non-enteric coated misoprostol, with
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`a delayed onset, enteric coated PPI. (PO Response, Paper 22 at 11.) But the
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`argument entirely ignores the stated motivation of WO’185. As WO’185 explains,
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`a POSA would find it “desirable to have an [sic] proton pump inhibitor formulation
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`. . . which is rapidly absorbed . . . And which acts as an antacid immediately upon
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`delivery.” (WO’185, Ex. 1015 at 15:25-16:11 (emphasis added).) WO’185 also
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`characterized the “immediate anti-acid effect” of its immediate-release omeprazole
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`as an improvement over prior art omeprazole formulations. (Id. at 9:16-17.) With
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`this motivation in mind, WO’185 discloses that non-enteric coated PPIs have the
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`benefit of immediate anti-acid effects. (Id. at 16:4-14.) Thus, WO’185 provides
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`explicit motivation to replace the non-enteric coated misoprostol of the ’225 patent
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`with a rapid release non-enteric coated esomeprazole.
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`In order to achieve its stated aim of delivering an immediate anti-acid effect,
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`WO’185 provides a method to administer a rapid onset PPI even considering that
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`IPR2015-01773
`Patent No. 8,858,996
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`some of the PPI could degrade from the acid in the stomach. WO’185 teaches that
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`bicarbonate salt can prevent degradation of omeprazole prior to absorption.
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`(WO’185, Ex. 1015 at 20:1-4; see also id. at 10:14-20 (describing prior art
`
`references employing sodium bicarbonate to protect omeprazole from acid
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`lability).) More specifically, WO’185 teaches that sodium bicarbonate salt can be
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`used as a pH-adjusting excipient in solid oral compositions, including tablets,
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`comprising non-enteric coated omeprazole. (Id. at 18:1-12). Thus, WO’185
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`formulation teaches the use of rapid release PPIs without an enteric coating. (Id. at
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`9:16-17, 15:25-16:11, 57:17-24 (claim 8), 16:24-17:7, 25:19-26:4, 26:26-27:9.)
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`2.
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`The Use of Bicarbonate Buffer in WO’185 is Entirely
`Compatible with the Teachings of the ’225 Patent
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`Relying entirely on one sentence taken from an isolated example, the Patent
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`Owner mischaracterizes WO’185 by stating that it teaches that omeprazole and
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`sodium bicarbonate “should not be administered with acidic substances.” (PO
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`Response, Paper 22 at 12 (emphasis in original).) WO’185 does not teach this
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`prohibition. In fact, the Patent Owner’s characterization of WO’185 conflates
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`“was not” and “should not.” (Compare WO’185, Ex. 1015 at 35:13-15 (“The
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`solution/suspension was not administered with acidic substances.”) with PO
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`Response, Paper 22 at 12 (“WO’185 teaches that a solution/suspension containing .
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`. . bicarbonate should not be administered with acidic substances.” (emphasis in
`
`original).)
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`Contrary to Patent Owner’s unsupported allegation, the cited example in no
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`way suggests a bicarbonate solution could or should not be administered with
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`acidic substances. Indeed, WO’185 expressly teaches administration of a sodium
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`bicarbonate buffer into acidic solutions (the stomach) for its antacid properties.
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`(See, e.g., WO’185, Ex. 1015 at 20:1-4 (explaining that sodium bicarbonate
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`protects the omeprazole from acid degradation and acts as an antacid while the
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`omeprazole is absorbed into the stomach).)
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`Moreover, a POSA would understand
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`that
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`the non-enteric coated
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`esomeprazole with solid bicarbonate salt from WO’185 could be incorporated into
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`a tablet such as the ’225 patent structure. As Dr. Banakar has explained, there is
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`no reason to expect a solid excipient would cause deterioration of an enteric
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`coating or other coating. (Banakar May 20, 2016 Deposition Transcript, Ex. 2021,
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`at 111:20-112:1 (“Enteric coats are typically acidic in nature. Sodium bicarbonate
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`is basic in nature. So they will interact to form a salt which is -- which is soluble
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`in water. But for that, it has -- there has to be a solvent or a medium. In a dry state
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`they would not do that.”).)
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`The Patent Owner further incorrectly asserts that WO’185 teaches that “a
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`skilled artisan would reasonably expect that the sodium bicarbonate would have an
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`adverse effect on an enteric coated core.” (PO Response, Paper 22 at 12.)
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`Specifically, Patent Owner cites the following text to suggest that the mere
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`inclusion of a bicarbonate salt dissolves an enteric coating: “The coated
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`omeprazole particles are mixed with a sodium bicarbonate (NaHCO3) solution
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`which dissolves the enteric coating . . . .” (WO’185, Ex. 1015 at 19:19-23.) But
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`the Patent Owner ignores a fundamental characteristic of enteric coatings. As
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`explained by Dr. Banakar, enteric coatings, by definition, dissolve above a
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`particular pH. (See Decision, Paper 15 at 15; PO Response, Paper 22 at 12-14;
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`Petition, Paper 2 at 21.) It is axiomatic that bicarbonate salt solutions are basic as
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`opposed to acidic — meaning the pH is well above 3.5. A POSA would read the
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`statement only to indicate enteric coatings are dissolved by basic solutions — not
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`that bicarbonate salt itself would dissolve the coating.
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`Moreover, the prior art confirms that formulations containing bicarbonates
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`are compatible with enteric coatings. For example, U.S. Patent No. 6,365,184
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`(“the ’184 patent”), which is referenced in the “Background of the Invention”
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`section on the face of the ’996 patent (’996 patent, Ex. 1001 at 2:38-41), discloses
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`a layered tablet in which a separating layer surrounds a core layer with an enteric
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`coating. The ’184 patent teaches that:
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`“The separating layer . . . may act as a pH-buffering zone. The pH-
`buffering properties of the separating layer(s) can be further
`strengthened by introducing into the layer(s) substances chosen from a
`group of compounds usually used in antacid formulations such as, for
`instance, magnesium oxide, hydroxide or carbonate, aluminium [sic]
`or calcium hydroxide, carbonate, or silicate; . . . Aluminium [sic]
`hydroxide/sodium bicarbonate coprecipitate . . . .
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`(’184 patent, Exhibit 1036 at 10:17:31; see also id. at 10:44-47 (“Alternatively,
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`the separating layer may be formed in situ by a reaction between an enteric coating
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`polymer layer applied on the core material and an alkaline reacting compound in
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`the core material.”) Thus, the prior art cited by the ’996 patent itself provides a
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`reasonable expectation that a POSA could successfully combine the use of
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`bicarbonates taught in WO’185 with the enteric coating used in the structure of the
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`’225 patent.
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`The ’996 patent itself discloses formulations containing both enteric coatings
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`and sodium bicarbonate or other alkaline compounds. Examples 7 and 8 of the
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`’996 patent disclose omeprazole granules containing sodium bicarbonate. (’996
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`Patent, Ex. 1001, 17:51-54; 18:24-25; 19:35-45.) Examples 5 and 6 also use
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`alkaline compounds, e.g., ammonium hydroxide, in the outer film coating to
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`increase pH. (Id. at 14:58-64, 16:31-39.) In each example, the alkaline buffer acts
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`to solubilize and protect the PPI from degradation by raising stomach pH. (Id. at
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`16:31-39; 17:47-49.) There is neither a suggestion that the buffer affects the
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`enteric coating, nor that the combination of enteric coatings and alkaline excipients
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`is in any way novel. Although admittedly not prior art, the ’190 patent’s examples
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`further demonstrate that a POSA would have known that the disclosure of sodium
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`bicarbonate buffer in the WO’185 is compatible with the use of enteric coatings.
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`IPR2015-01773
`Patent No. 8,858,996
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`Patent Owner even confirms the obviousness of the claims of the ’996 patent
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`when it argues that there is a “complete[] breakdown” of the enteric coating in the
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`presence of sodium bicarbonate. (PO Response, Paper 22 at 12.) Notably, Patent
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`Owner claims that, in the presence of sodium bicarbonate, enteric coatings will
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`breakdown within 30 minutes and that a fasted stomach will empty in 25 minutes.
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`(Id.) Thus, even accepting the arguments of the Patent Owner, some of the enteric
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`coating will remain intact until the stomach is emptied. As such, at least a portion
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`of the NSAID will be inhibited from release until after it has been emptied from
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`the stomach into the small intestine, where the pH is greater than 3.5. This is
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`precisely what is claimed in the challenged claims of the ’996 patent.
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`D. A POSA Would Have Been Motivated to Replace the NSAID in
`the ’225 Patent with Naproxen
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`The Patent Owner further asserts that a POSA would not have been
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`motivated to use naproxen within a combination NSAID-acid inhibitor tablet
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`described within the ’225 patent. This argument ignores the general knowledge
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`and common sense of a POSA that is critical to the obviousness analysis. See KSR
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`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
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`Based on the prior art including Chandramouli, a POSA would have been
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`motivated to use the pharmaceutical structure of the ’225 patent to develop a safer
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`composition for delivery of the commonly used NSAID naproxen. Chandramouli
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`generally teaches the risk of gastric injury associated with NSAIDs and would
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`IPR2015-01773
`Patent No. 8,858,996
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`have motivated a POSA to develop safer NSAID treatments. (Chandramouli, Ex.
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`1009 at 38 (“NSAID induced gastropathy imposes considerable morbidity, cost
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`and a negative quality of life.”).) Moreover, Chandramouli discloses a number of
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`potential solutions including the acid-inhibitor combination tablet described within
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`the ’225 patent. (Id. at 37.)
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`A POSA would have known from Chandramouli that naproxen could benefit
`
`from combination with an acid inhibitor in the same manner as the ’225 patent.
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`Chandramouli expressly teaches naproxen was well known as of June 1, 2001, and
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`would have understood Chandramouli to teach that naproxen was associated with
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`NSAID-induced gastric injury. Chandramouli not only teaches efficacious dosages
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`of naproxen, it also teaches useful characteristics for formulation, such as half-life,
`
`pKa, and relative GI Toxicity. For example, Chandramouli teaches a common
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`dosage commercially marketed to consumers at the time under the brand name
`
`Naprosyn – the same dosage claimed in the ’996 patent: 250-500mg. Moreover, a
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`POSA would have known that naproxen’s pKa – the acidity at which naproxen
`
`dissociates – was at 4.2 and thus well-suited for enteric coating and release within
`
`a high pH portion of the gastrointestinal tract.
`
`As of June 1, 2001, naproxen, piroxicam, and diclofenac were all well
`
`known, common, available, and effective NSAIDs. Each was “similar with respect
`
`to therapeutic efficacy.” (Id. at 35.) As the USPTO has advised, “simple
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`IPR2015-01773
`Patent No. 8,858,996
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`substitution of one known element for another to obtain predictable results” may
`
`support a conclusion of obviousness.
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` USPTO Guidelines For Post-KSR
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`Consideration Of Obviousness (October 10, 2007) MPEP §2141 (2007). Here,
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`substitution of naproxen for another known NSAID is, at most, a predictable
`
`approach that renders the alleged invention obvious. This is clear at least from
`
`Chandramouli, which discloses common names, dosages, and characteristics of all
`
`three NSAIDs.
`
`E. A POSA Would Have Known How to Formulate a Combination
`Tablet with a Reasonable Expectation of Success
`
`The formation of a combination tablet was well known in the prior art, and
`
`Patent Owner’s arguments to the contrary have no merit. At the outset, the ’996
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`patent acknowledges that “[m]ethods for making appropriate formulations are well
`
`known in the art,” and that “[i]t is expected that a skilled pharmacologist may
`
`adjust the amount of a drug in a pharmaceutical composition . . . based upon
`
`standard techniques well known in the art.” (’996 patent, Ex. 1001 at 6:51-57.)
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`Thus, even the ’996 patent acknowledges that a POSA would have been able to
`
`successfully prepare a therapeutically effective tablet in accordance with the
`
`challenged claims.
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`As Dr. Banakar explained, [d]esigning . . . An uncoated buffered solid
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`dosage form tablet is a very routine thing. . . . It is pretty standard stuff. . . .
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`[involving] very standard procedures. Those are very standard steps that we take.
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`IPR2015-01773
`Patent No. 8,858,996
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`Those are very standard equipment. Those are very standard, routine formulation
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`exercises that we do.” (Banakar May 20, 2016 Deposition Transcript, Exhibit
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`2021 at 41:20-42:5.) Notably, the Patent Owner does not offer any testimony or
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`evidence to rebut Dr. Banakar’s assertion, but only attorney argument.
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`The prior art supports Dr. Banakar’s
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`testimony
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`that preparing a
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`therapeutically effective tablet would be routine. For example, the ’225 patent
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`expressly discloses “a pharmaceutical composition which is a core/mantle tablet
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`consisting of a core [NSAID]” surrounded by an anti-acid layer (Ex. 1013 at 3:8-
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`13) and explains that methods of preparing the NSAID core can be formulated by
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`“any suitable tableting equipment using compression tableting techniques well
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`known in the art.” (Id. at 4:8-11). Similarly, WO’185 explains that omeprazole
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`and bicarbonate can “be formed into a tablet . . . by methods well known to those
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`skilled in art.” (WO’185, Ex. 1015 at 26:1-4.) Preparations of enteric coating
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`were also “known to those skilled in the art and many of which are employed for
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`coating commercially available NSAIDs.” (’225 patent, Ex. 1013 at 6:29:33.) The
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`patent continues to explain that “various excipients” can be used “as is well known
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`in the art.” (Id. at 4:27-30.)
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`Instead of addressing these references, the Patent Owner sidesteps the
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`question and argues that “[p]etitioner fails to explain how one of skill in the art
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`would determine how much buffer is required in the dosage form or how the final
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`IPR2015-01773
`Patent No. 8,858,996
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`dosage form could be made at a size that could be ingested by the patient.” (PO
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`Response, Paper 22 at 17.) At the outset, the amount of buffer and size of the
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`tablet are not limitations of the challenged claims and therefore are wholly
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`irrelevant to the obviousness inquiry because the obviousness inquiry must focus
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`on the claims. See KSR, 500 U.S. at 419; Allergan, Inc. v. Sandoz Inc., 726 F.3d
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`1286, 1292–93 (Fed. Cir. 2013) (explaining that POSA “need only have a
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`reasonable expectation of success of developing the claimed invention” not
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`additional unclaimed elements contained in drug formulation).
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`Setting that aside, the prior art need not disclose the precise amount of buffer
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`or exact pill size to render the claims obvious. The prior art explicitly discloses a
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`solid formulation comprising bicarbonate buffer, esomeprazole, and NSAIDs, and
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`suggests that a POSA would have a reasonable likelihood of success in employing
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`the three in combination. See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165
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`(Fed. Cir. 2006) (“Obviousness does not require absolute predictability of
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`success,” but, rather“a reasonable expectation of success.” (quoting In re
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`O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)). Using “the application of a
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`well-known problem-solving strategy,” i.e. ordinary formulation experiments and
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`equipment, a POSA would have a reasonable expectation of success even if some
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`experimentation were required to verify the optimum amounts. Pfizer, Inc. v.
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`Apotex, Inc., 480 F.3d 1348, 1367–68 (Fed. Cir. 2007) (“[T]he discovery of an
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`IPR2015-01773
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`optimum value of a variable in a known process is usually obvious.”); In re Aller,
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`220 F.2d 454, 456 (C.C.P.A. 1955) (“[W]here the general conditions of a claim are
`
`disclosed in the prior art, it is not inventive to discover the optimum or workable
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`ranges by routine experimentation.”).
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`Finally, Patent Owner argues that “blindly appl[ying]” the prior art teachings
`
`would result in an oversized tablet. (PO Response, Paper 22 at 18.) But this
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`argument misstates the proper obvious inquiry. A POSA would not “blindly
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`apply” the teachings of the prior art. As the Supreme Court
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