Paper No. __
`Date: February 16, 2016
`
`
`
`
`
`Filed on behalf of:
`
`Pozen Inc.
`Pernix Therapeutics Holdings, Inc.
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`GRAY SQUARE PHARMACEUTICALS, LLC
`
`Petitioner,
`
`v.
`
`POZEN INC.,
`
`Patent Owner.
`
`
`
`
`
`
`
`Case IPR2016-00191
`U.S. Patent No. 7,332,183
`
`
`
`
`
`
`
`PATENT OWNER PRELIMINARY RESPONSE
`UNDER 35 U.S.C. § 313 and 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`THE PARTIES ................................................................................................ 4
`
`A.
`
`Pozen and Pernix ................................................................................... 4
`
`B.
`
`Gray Square Is a Shell Company Formed by a Hedge
`Fund Manager ........................................................................................ 4
`
`III. DEVELOPMENT OF THE INVENTION ...................................................... 5
`
`A.
`
`The ’183 Patent and TREXIMET® .......................................................... 5
`
`B.
`
`C.
`
`D.
`
`TREXIMET® Was Developed to Treat Rebound Migraine .................... 6
`
`The ’183 Patent’s Inventors Identified and Solved a
`Problem Previously Unrecognized in the Art ....................................... 7
`
`The Prior Art Fails to Recognize the Problem Solved by
`the ’183 Patent’s Inventors and Teaches Dosage Forms
`That Are Contrary to the ’183 Patent .................................................... 9
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`The ’499 Patent ........................................................................... 9
`
`The ’779 Patent ......................................................................... 11
`
`The ’907 Patent ......................................................................... 13
`
`The ’325 Patent ......................................................................... 15
`
`The ’125 Patent ......................................................................... 17
`
`The Bandelin Reference and EP ’182 ....................................... 18
`
`IV. CHALLENGED CLAIMS AND CLAIM INTERPRETATION ................. 19
`
`A.
`
`The Challenged Claims ....................................................................... 19
`
`Claim Interpretation ............................................................................ 20
`
`Construction of “Dissolution of said naproxen occurs
`independently of said triptan”............................................................. 21
`
`B.
`
`C.
`
`
`
`

`
`
`
`V.
`
`INSTITUTION SHOULD BE DENIED UNDER 35 U.S.C.
`§325(d) ........................................................................................................... 24
`
`VI. PETITIONER’S PROPOSED OBVIOUSNESS GROUNDS
`ARE FLAWED .............................................................................................. 27
`
`A.
`
`Legal Background ............................................................................... 27
`
`B.
`
`Ground 1 .............................................................................................. 29
`
`1.
`
`A skilled artisan would not have been motivated to
`combine the ’499 and ’779 Patents, and because
`those patents do not recite all of the required
`elements, that person would not have reached the
`challenged claims ...................................................................... 30
`
`2.
`
`Petitioner’s Arguments Regarding Ground 1 Are
`Unsupported .............................................................................. 33
`
`C.
`
`Ground 2 .............................................................................................. 38
`
`1.
`
`A skilled artisan would not have been motivated to
`combine the ’499 and ’907 Patents, and because
`those patents do not recite all of the required
`elements, that person would not have reached the
`challenged claims ...................................................................... 39
`
`2.
`
`Petitioner’s Arguments Regarding Ground 2 Are
`Unsupported By Its References ................................................ 42
`
`D. Ground 3 .............................................................................................. 45
`
`1.
`
`A skilled artisan would not have been motivated to
`combine the ’325 and ’907 Patents, and because
`those patents do not recite all of the required
`elements, that person would not have reached the
`challenged claims ...................................................................... 45
`
`2.
`
`Petitioner’s Arguments Regarding Ground 3 Are
`Unsupported By Its References ................................................ 48
`
`E.
`
`Ground 4 .............................................................................................. 51
`
`
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`- ii -
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`

`
`
`
`1.
`
`A skilled artisan would not have been motivated to
`combine the ’499 and ’125 Patents, and because
`those patents do not recite all of the required
`elements, that person would not have reached the
`challenged claims ...................................................................... 52
`
`2.
`
`Petitioner’s Arguments Regarding Ground 4 Are
`Unsupported By Its References ................................................ 54
`
`VII. CONCLUSION .............................................................................................. 63
`
`
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`- iii -
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`

`
`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Amgen Inc. v. F. Hoffmann-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) .....................................................................28
`
`CCS Fitness, Inc. v. Brunswick Corp.,
`288 F.3d 1359 (Fed. Cir. 2002) .....................................................................21
`
`Coalition for Affordable Drugs VII LLC v. Pozen Inc.,
`IPR2015-01680, Paper 18 (Feb. 11, 2016) ............... 31, 33, 40, 41, 47, 53, 54
`
`Coalition for Affordable Drugs VII LLC, v. Pozen Inc.,
`IPR2015-01241 (Dec. 8, 2015), Paper 22 .................................. 33, 41, 48, 54
`
`Dr. Reddy’s Labs., Inc. v. Pozen, Inc.,
`IPR2015-00802, Paper 28 ..............................................................................35
`
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .............................................................. 32, 33
`
`Excelsior Med. Corp. v. Lake,
`IPR2013-00494, Paper No. 10 (Feb. 6, 2014) ...............................................24
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ...........................................................................................27
`
`Hulu LLC v. Intertainer, Inc.,
`IPR2014-01456, Paper No. 8 (Mar. 6, 2015) ................................................24
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .....................................................................21
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) .....................................................................21
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) .......................................................................27
`
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008) .................................................. 28, 31, 39, 46
`
`
`
`- iv -
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`

`
`
`
`InSite Vision, Inc. v. Sandoz,
`783 F.3d 853 (Fed. Cir. 2015) .......................................................................28
`
`Interconnect Planning Corp. v. Feil,
`774 F.2d 1132 (Fed. Cir. 1985) .....................................................................32
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007).................................................................... 27, 28, 34, 42
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................. 28, 31, 39, 46
`
`Microsoft Corp. v. Proxyconn, Inc.,
`IPR2012-00026, Paper 17 (Dec. 21, 2012) ...................................................21
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .....................................................................28
`
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) .......................................................................29
`
`Mylan Pharm. Inc. v. Gilead Sciences, Inc.,
`IPR2014-00885, Paper 15 (Dec. 9, 2014) ............................................. 43, 56
`
`Pozen Inc. v. Par Pharm., Inc.,
`719 F.Supp.2d 718 (E.D. Tex. 2011) ............................................................21
`
`Pozen Inc. v. Par Pharm., Inc.,
`800 F. Supp. 2d 789 (E.D. Tex. 2011), aff’d Pozen Inc. v.
`Par Pharm., Inc., 696 F.3d 1151 (Fed. Cir. 2012) .......................................... 1
`
`Praxair Distribution, Inc. v. INO Therapeutics, Inc.,
`IPR2015-00522, Paper 12 (July 29, 2015) ....................................... 32, 35, 44
`
`Prism Pharma Co. v. Choogwae Pharma Corp.,
`IPR2014-00315, Paper No. 14 (July 8, 2014) ...............................................24
`
`Rohm and Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) .............................................................. 43, 56
`
`Smiths Indus. Med. Sys., Inc. v. Vital Signs, Inc.,
`183 F.3d 1347 (Fed. Cir. 1999) .....................................................................20
`
`
`
`- v -
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`

`
`
`
`Rules
`
`35 U.S.C. §103 .........................................................................................................25
`
`35 U.S.C. §103(a) ....................................................................................................27
`
`35 U.S.C. §311(b) ....................................................................................................43
`
`35 U.S.C. §313 ........................................................................................................... 1
`
`35 U.S.C. §325(d) ............................................................................................. 24, 27
`
`37 C.F.R. §42.107 ...................................................................................................... 1
`
`Publications
`
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations ................................................................................. 6
`
`- vi -
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`
`
`
`Patent
`Owner’s
`Exhibit
`No.
`
`LIST OF EXHIBITS
`
`
`Description of Exhibit
`
`2001
`
`Pozen Inc. v. Par Pharm., Inc., 800 F. Supp. 2d 789 (E.D. Tex. 2011)
`
`2002
`
`Pozen Inc. v. Par Pharm., Inc., 696 F.3d 1151 (Fed. Cir. 2012)
`
`2003
`
`Pozen Inc. v. Par Pharm., Inc., 719 F. Supp. 2d 718 (E.D. Tex. 2011)
`
`2004 Gray Square Pharmaceuticals, LLC – Corporate Entity Information
`
`2005
`
`Ferrum Ferro Capital, LLC – Website Information
`
`2006
`
`Trial Testimony of Dr. John Plachetka, Oct. 12, 2010, Morning Session
`
`2007
`
`Trial Testimony of Dr. John Plachetka, Oct. 12, 2010, Afternoon
`Session
`
`2008 Orange Book Listing for TREXIMET®
`
`2009 Notice of Allowance dated Nov. 20, 2007
`
`2010 Arthur Kibbe Lecture Notes
`
`
`
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`- i -
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`
`
`Pozen Inc. (“Pozen”) and Pernix Therapeutics Holdings Inc. (“Pernix”)
`
`submit this Preliminary Response to the Petition filed by Graybar Pharmaceuticals,
`
`LLC1 on November 12, 2015 seeking inter partes review (“IPR”) of U.S. Patent
`
`No. 7,332,183 (“the ’183 Patent”) (Ex. 1001).2 The Petition was accorded a filing
`
`date in a notice dated November 16, 2015 (Paper No. 3), and thus this Preliminary
`
`Response is timely filed under 35 U.S.C. §313 and 37 C.F.R. §42.107.
`
`I.
`
`INTRODUCTION
`
`The ’183 Patent claims a single specific dosage form for delivering naproxen
`
`and sumatriptan. In developing the claimed dosage form, Pozen observed an
`
`unexpected problem not previously known in the art: naproxen formed a gel-like
`
`matrix that inhibited the release of sumatriptan when the two ingredients were
`
`mixed together in a single tablet. Though the prior art taught that many dosage
`
`
`1 Petitioner’s updated Mandatory Notices (Paper No. 7) state that Petitioner
`
`changed its name to Gray Square Pharmaceuticals, LLC (“Gray Square”).
`
`2 The validity of the ’183 Patent was upheld in Pozen Inc. v. Par Pharm., Inc., 800
`
`F. Supp. 2d 789, 819-21 (E.D. Tex. 2011) (Ex. 2001), aff’d Pozen Inc. v. Par
`
`Pharm., Inc., 696 F.3d 1151, 1165-66 (Fed. Cir. 2012) (Ex. 2002) after
`
`consideration of arguments and references identical or substantially identical to
`
`those raised in the Petition.
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`
`
`

`
`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
`
`forms could be used to deliver two active ingredients, overcoming the newly-
`
`identified release problem that the ’183 Patent’s inventors observed required a
`
`“very specific tablet architecture,” namely a bilayer tablet that “provide[d] for
`
`independent and immediate release of each component.” (Ex. 1004 at 6; Ex. 1001
`
`at col. 3:62-63.)
`
`During prosecution, Applicants overcame rejections based on references that
`
`disclosed co-administration of naproxen and sumatriptan combined with references
`
`that disclosed bilayer tablets. Applicants explained that nothing in the prior art
`
`taught or suggested that the problem faced by the inventors could be solved by
`
`using only the “very specific tablet architecture” that they claimed. (Ex. 1004 at 6-
`
`8.) Now, Petitioner, a non-practicing entity owned by a hedge fund principal, seeks
`
`to institute an IPR using the same basic arguments already rejected by the
`
`Examiner, a District Court and the Federal Circuit. In particular, Petitioner uses
`
`references that are either identical (the ’499 Patent) or cumulative (the ’779, ’907,
`
`’125, and ’325 Patents) to the references the Examiner considered in allowing the
`
`claims. Because fundamentally Petitioner does not rely on new arguments or new
`
`art, institution should be denied.
`
`Moreover, Petitioner fails to identify any motivation to combine the asserted
`
`references to reach the claimed invention. None of the asserted references
`
`addresses the problem identified by the ’183 Patent’s inventors, namely that
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
`
`naproxen forms a gel-like matrix that inhibits the release of sumatriptan. Nor do
`
`the asserted references identify any motivation to limit the configuration of a
`
`naproxen-sumatriptan dosage form to a bilayer tablet.
`
`To the contrary, Petitioner’s references disclose an expansive array of
`
`potential configurations, including configurations that caused the problem
`
`identified by the inventors, which are excluded by the ’183 Patent’s claims.
`
`Moreover, Petitioner’s references disclose configurations wherein active
`
`ingredients are provided in modified-release form in order to achieve release over
`
`an extended period of time. That is contrary to the ’183 Patent’s requirement that
`
`both ingredients be released immediately. (Ex. 1001 at col. 3:61-63.) Thus,
`
`Petitioner’s references fail to provide any motivation to combine, and fail to
`
`disclose key elements of the ’183 Patent’s claims, i.e., that only a bilayer tablet
`
`having two immediate release active ingredients may be used.
`
`Finally, Petitioner’s rationales for combining the asserted references are
`
`unsupported and are contradicted by the asserted references themselves. For
`
`example, Petitioner argues that some of its references teach that a bilayer tablet
`
`provides a solution for separating incompatible ingredients, when in fact those
`
`same references expressly teach that single layer tablets or capsules—which the
`
`’183 Patent expressly precludes—may also be used. (See, e.g., infra Section
`
`III.D.3.) Likewise, the Petition states that a bilayer tablet configuration solved the
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
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`“disintegration” problem addressed in the ’907 Patent, when in fact that patent
`
`shows in detail that bilayer tablets had the same “disintegration” problem as single-
`
`layer tablets, and that the problem was solved only after an excipient, magnesium
`
`stearate, was removed. (See id.)
`
`For these reasons, discussed in detail below, Patent Owner respectfully
`
`requests that institution be denied.
`
`II. THE PARTIES
`
`A.
`
`Pozen and Pernix
`
`Pozen is a pharmaceutical company headquartered in Chapel Hill, North
`
`Carolina. Since its founding in 1996, Pozen has had a long, successful history
`
`creating novel pharmaceuticals by combining existing drug therapies that result in
`
`superior patient outcomes. Pernix is a specialty pharmaceutical business based in
`
`Morristown, New Jersey, with a focus on acquiring and developing prescription
`
`drugs primarily for the U.S. market. Pernix targets underserved therapeutic areas
`
`including neurology and psychiatry, and in 2014 acquired TREXIMET®, which is
`
`covered by the ’183 Patent and is approved for treating acute migraine.
`
`B. Gray Square Is a Shell Company
`Formed by a Hedge Fund Manager
`
`Gray Square’s principal is Mr. Kevin Barnes. Gray Square was formed less
`
`than nine months ago, on June 9, 2015 (Ex. 2004), and publicly available
`
`information suggests that it is a shell company existing for the sole purpose of
`
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
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`conducting transactions for the enrichment of its principal, with no address apart
`
`from the address of its corporate agent in Delaware. Mr. Barnes is also the
`
`principal of Ferrum Ferro Capital, LLC (“FFC”), which is a self-described
`
`“privately-held venture focused on innovation, application, and monetization.”
`
`(Ex. 2005.) FFC filed IPR2015-00858, which was not instituted.
`
`In contrast to Patent Owner, Petitioner appears to have no marketed
`
`products. Despite calling itself a “pharmaceutical” company, Patent Owner is
`
`aware of no information to suggest that Petitioner has developed or sought
`
`approval from the United States Food and Drug Administration (“FDA”) to market
`
`any product, or even to suggest that Petitioner’s business has a physical location.
`
`III. DEVELOPMENT OF THE INVENTION
`
`A. The ’183 Patent and TREXIMET®
`
`The ’183 Patent protects TREXIMET®, a highly successful drug for treating
`
`acute migraine, a condition characterized by severe headaches, nausea, and
`
`sensitivity to light and sound. (Ex. 2006, Plachetka Oct. 12, 2010 Trial Testimony
`
`at 70:20-71:9.) TREXIMET® is a bilayer tablet that delivers two active ingredients:
`
`naproxen sodium, a non-steroidal anti-inflammatory drug (“NSAID”) and
`
`sumatriptan, used specifically to treat migraines. (See, e.g., Ex. 2001 at 796; 808-
`
`812; 819-21.)
`
`TREXIMET® was invented by Dr. John Plachetka and his colleagues at
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
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`Pozen. (Ex. 2006 at 65:15-66:12.) Dr. Plachetka is also the sole inventor of the
`
`’499 Patent. (Ex. 1007, U.S. Pat. No. 6,060,499.) The ’183 Patent and the ’499
`
`Patent are both listed in the FDA’s Orange Book: Approved Drug Products with
`
`Therapeutic Equivalence Evaluations (“Orange Book”) as covering TREXIMET®.
`
`(Ex. 2008, Orange Book Listing for TREXIMET®.)
`
`B.
`
`TREXIMET® Was Developed to Treat Rebound Migraine
`
`In addition to being a named inventor on the ’183 and ’499 Patents, Dr.
`
`Plachetka played a key role in the development of the first sumatriptan formulation
`
`that was brought to market for the treatment of migraine, IMITREX® (sumatriptan
`
`succinate). (Ex. 2006 at 67:18-68:6; 74:1-16.) IMITREX® was considered to be the
`
`“gold-standard” in migraine treatment. (Id. at 69:16-23.)
`
`After the launch of IMITREX®, it was noted that some patients suffered from
`
`“relapse” or “rebound” migraine. For those patients, the migraine would return,
`
`often more severe than before, after taking sumatriptan alone. (Id. at 79:8-13; Ex.
`
`1007, col. 2:44-65.) Rebound migraine is thought to be caused by inflammation of
`
`blood vessels that remains after sumatriptan treatment, and was found to be
`
`treatable by the co-administration of an NSAID and sumatriptan. (Ex. 2006 at
`
`84:23-87:22; Ex. 1007, col. 1:27-33; col. 4:50-62.)
`
`The existence of rebound migraine and a method of treating it by combining
`
`an NSAID and sumatriptan are taught in the ’499 Patent, as the ’183 Patent’s
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
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`specification expressly acknowledges. (Ex. 1001 at col. 1:28-33, citing, inter alia,
`
`the ’499 Patent: “combination therapies in which triptans are combined with
`
`NSAIDs greatly improve the relief available to migraine patients.”)
`
`C. The ’183 Patent’s Inventors Identified and
`Solved a Problem Previously Unrecognized in the Art
`
`Prior to the ’183 Patent, combination therapy using an NSAID and a triptan
`
`relied on NSAIDs that were delivered orally (e.g., as tablets), and triptans that were
`
`delivered orally, intranasally, or by injection. (Ex. 1001, col. 1:33-42.)
`
`As development work continued, Pozen encountered an unexpected
`
`problem: naproxen formed a gel-like matrix that significantly slowed the rate of
`
`dissolution of sumatriptan in a tablet where the two ingredients were mixed
`
`together. (See, e.g., Ex. 1001, col. 2:11-15; col. 10:4-51; Ex. 2007 at 38:9-39:7.)
`
`For tablets comprising a physical admixture of naproxen sodium and sumatriptan,
`
`the rate of release of sumatriptan was significantly impaired, as shown in Table 7
`
`of the ’183 Patent (Ex. 1001, Table 7, col. 10:35-51):
`
`Such a slowed rate of dissolution was contrary to the inventors’ goal of
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
`
`developing a dosage form that could “provide[] for independent and immediate
`
`release of each component,” meaning that release “should occur at approximately
`
`the same rate as would occur if the drugs were given separately.” (Ex. 1001 at
`
`col. 3:62-63; col. 2:48-49; emphasis added.)
`
`During prosecution, the inventors explained that their invention was limited
`
`to a “very specific tablet architecture,” requiring that “naproxen and triptan be in a
`
`tablet in which they are segregated from one another in a ‘side by side
`
`arrangement’ and in which their dissolution occurs independently of one another.”
`
`(Ex. 1004 at 6.) The inventors also explained that the claimed dosage form aimed
`
`to “combin[e] two separate drugs in a single dosage form, where both drugs are
`
`formulated for immediate release.” (Id. at 7.) In allowing the claims, the Examiner
`
`cited Applicants’ arguments, stating that after “very carefully consider[ing] these
`
`comments,” “the claims are limited to one very specific tablet architecture.” (Ex.
`
`2009, Notice of Allowance dated Nov. 20, 2007, at 3.)
`
`Because the undesirability of making a single-layer tablet containing
`
`sumatriptan and naproxen was not previously known—as demonstrated, e.g., by
`
`the ’499 Patent, which, as discussed below mixed both ingredients in a single
`
`layer—a person of ordinary skill in the art (“skilled artisan”) as of the earliest
`
`priority date of the ’183 Patent would not have been motivated to develop the
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
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`specifically claimed bilayer tablet architecture.3
`
`D. The Prior Art Fails to Recognize the
`Problem Solved by the ’183 Patent’s Inventors and
`Teaches Dosage Forms That Are Contrary to the ’183 Patent
`
`None of Petitioner’s references disclose the problem solved by the ’183
`
`Patent. Nor do they limit the structure of their dosage forms to a single
`
`architecture, i.e., a bilayer tablet.
`
`1.
`
`The ’499 Patent
`
`The ’499 Patent addresses the problem of rebound migraine, and teaches that
`
`it may be treated by co-administering an NSAID and a triptan. (See, e.g., Ex. 1007,
`
`col. 1:28-33; col. 4:50-62.) But, the ’499 Patent does not recognize the dissolution
`
`problem later observed by the ’183 Patent’s inventors, and does not even mention a
`
`bilayer tablet. In fact, the ’499 Patent does not require that naproxen and
`
`sumatriptan be administered in the same dosage form or even by the same route,
`
`stating “[i]n some instances, multiple routes of administration will be employed.”
`
`(Ex. 1007, col. 7:41-43).
`
`
`3 The unfeasibility of making a single-layer tablet was confirmed by the generic
`
`challengers to the ’183 Patent during litigation, who “acknowledg[ed] a single
`
`layer dosage form was not feasible thus a bilayer tablet of sumatriptan and
`
`naproxen sodium was formulated.” (Ex. 2001 at 811.)
`
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`Case No. IPR2016-00191
`U.S. Patent No. 7,332,183
`
`And, the ’499 Patent discloses many dosage forms that can be used without
`
`limiting its invention to any particular structure. The ’499 Patent states:
`
`For parenteral application, particularly suitable are
`
`injectable, sterile solutions, preferably oily or aqueous
`
`solutions, as well as suspensions, emulsions, or implants,
`
`including suppositories. Ampules, vials, and injector
`
`cartridges are convenient unit dosages.
`
`Also for parenteral application, particularly suitable are
`
`tablets, dragees, liquids, drops, suppositories, or capsules.
`
`A syrup, elixir, or the like can be used wherein a
`
`sweetened vehicle is employed. Sublingual and buccal
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`forms are also noted.
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`Sustained or directed release compositions can be
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`formulated, e.g., liposomes or those wherein the active
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`component is protected with differentially degradable
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`coatings, e.g., by microencapsulation, multiple coatings,
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`etc. It is also possible to freeze-dry the new
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`compositions and use the lyophilizates obtained, for
`
`example, for the preparation of products for injection.
`
`(Ex. 1007, col. 12:56-col. 13:5; see also col. 4:1-4.) The ’499 Patent’s Examples
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`and claims also encompass multiple routes of administration, including “a single
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`subcutaneous injection of sumatriptan . . . and at the same time orally ingest[ing] a
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`tablet containing naproxen sodium.” (Id., col. 11:10-13.) And, unlike the ’183
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`Patent, the ’499 Patent is not limited to immediate release forms of the active
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`ingredients. Rather, “[s]ustained or directed release compositions can be
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`formulated, e.g., liposomes or those wherein the active component is protected
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`with differentially degradable coatings, e.g., by microencapsulation, multiple
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`coatings, etc.” (Ex. 1007, col. 12:66-col. 13:2.)
`
`The ’499 Patent thus does not limit its dosage form to the “very specific
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`tablet architecture” taught by the ’183 Patent, wherein “both drugs are formulated
`
`for immediate release,” resulting in the “independent and immediate release of
`
`each component.” (Ex. 1004 at 6-7; Ex. 1001 at col. 3:62-63.)
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`2.
`
`The ’779 Patent
`
`U.S. Pat. No. 6,183,779 (“the ’779 Patent”) addresses the chemical
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`incompatibility of NSAIDs and prostaglandins by stabilizing the prostaglandin
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`with HPMC and applying an enteric coating to the NSAID. (See, e.g., Ex. 1011,
`
`col. 2:30-35; 8:39-40.) The problem addressed by the ’779 Patent is unrelated to
`
`the gelling of naproxen during dissolution that was recognized by the ’183 Patent’s
`
`inventors, and solving it does not require a bilayer tablet with a “very specific
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`tablet architecture.”
`
`To the contrary, the ’779 Patent contemplates using one of the precise
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`dosage forms that the ’183 Patent avoids. The ’779 Patent states that “the
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`enterically coated NSAID and the stabilized prostaglandin are mixed into a single
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`granulation, and the admixture is compressed into a tablet or filled into a
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`capsule.” (Ex. 1011, col. 7:65-col. 8:1; emphasis added.) With this “admixture,
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`there is a random possibility of the NSAID and the prostaglandin coming into
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`contact with each other. However, the enteric coating on the NSAID granules
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`provides a physical barrier between the NSAID and the prostaglandin.” (Id., col.
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`8:1-5; emphasis added). It is the enteric coating that solves the problem addressed
`
`by the ’779 Patent, which states that bilayer tablets were used merely because they
`
`provide “manufacturing advantages.” (Id., col. 7:38-49.) Indeed, some of the ’779
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`Patent claims do not require a bilayer tablet, and expressly require either a capsule
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`(claim 4) or an admixture formed into a single layer tablet (claims 5 and 6)—
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`dosage forms excluded from the ’183 Patent claims. (Ex. 1011, col. 10:18-22.)
`
`Moreover, the ’779 Patent does not provide for “independent and immediate
`
`release of each component” or that “both drugs are formulated for immediate
`
`release” as required by the ’183 Patent. Instead, it teaches only dosage forms
`
`wherein one of the ingredients is not immediately released. The NSAID
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`component of the ’779 invention must be enterically coated: “the NSAID is
`
`enterically coated and the prostaglandin is present along with an effective
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`stabilizing amount of a prostaglandin stabilizing agent such as [HPMC] or [PVP].”
`
`(Ex. 1011 Abstract; see also col. 2:25-42; col. 5:1-2; claims 1-35.) Such a
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`formulation is contrary to the ’183 Patent, which requires “independent and
`
`immediate release” of each component and that “both drugs are formulated for
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`immediate release.” (Ex. 1001 at col. 3:62; Ex. 1004 at 7.)
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`The ’779 Patent thus addresses a problem different from the one addressed
`
`by the ’183 Patent, and does not teach the “very specific tablet architecture”
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`required by the ’183 Patent that provides the “independent and immediate release”
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`of both active ingredients, which are “formulated for immediate release.” (Ex.
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`1004 at 6-7; Ex. 1001 at col. 3:62) Indeed, the ’779 Patent is designed to avoid
`
`independent and immediate release.
`
`3.
`
`The ’907 Patent
`
`U.S. Pat. No. 4,844,907 (“the ’907 Patent”) addresses problems of
`
`“incompatibility, poor crushing strength, and long disintegration times” (Ex. 1012,
`
`col. 1:35-40) that occur when chemically incompatible ingredients and certain
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`excipients, including magnesium stearate, are used. (Id., col. 3:25-43.) The
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`problems addressed by the ’907 Patent are unrelated to the gelling of naproxen.
`
`Instead, the ’907 Patent “remov[es] stearic acid and/or stearate salts (especially
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`magnesium stearate) from the composition,” and “add[s] at least one self-
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`lubricating, direct compression aid” to address its issues. (Id.)
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`The ’907 Patent is not limited to bilayer tablets. Its specification states that
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`“[p]referably the composition is in the form of a layered tablet, especially a bilayer
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`tablet,” but its claims broadly recite a “multiphase tablet” (e.g., Ex. 1012, claims 1-
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`10; emphasis added), which is limited only in some claims to a multilayer tablet.
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`(Ex. 1012, col 2:1-2; claims 11-12; emphasis added.)
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`Significantly, a review of the ’907 Patent’s examples shows that most do not
`
`involve naproxen, and that a bilayer tablet did not solve the stated problems. Only
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`one of the 17 examples includes naproxen. The other 16 are combinations of
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`codeine and ibuprofen or flurbiprofen. (Ex. 1012, col. 5:54-col. 10:41.) Examples
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`1-6, which were formulated without magnesium stearate (and involve ibuprofen,
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`not naproxen), “exhibited pharmaceutically acceptable properties with regard to
`
`stability, disintegration times and dissolution rates.” (Ex. 1012, col. 9:1-4.) No
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`such statement appears for the example using naproxen. (Id. col.10:19-28.)
`
`While those examples use bilayer tablets, the ’907 Patent makes clear that
`
`the bilayer structure was not required, and was not the reason the compositions
`
`were acceptable. That is because Comparative Examples C and D show that simply
`
`separating the narcotic analgesic and the NSAID into separate layers did not
`
`solve the stated problems:
`
`When the two layers were compressed together the
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`codeine content decreased markedly after short term
`
`stability at room and elevated temperatures. Also a brown
`
`colour formed, especially at the interface between the
`
`two layers. . . When the codeine layer was compressed it
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`was found that crushing strengths above 6 kp were
`
`difficult to achieve even with increasing compression
`
`forces.
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`(Ex. 1012, col. 6:32-col. 7:15.) The desired properties were obtained only when
`
`magnesium stearate was removed. (See, e.g., Ex. 1012, Examples 4 and 7.)
`
`The ’907 Patent also does not teach that two immediate release active
`
`ingredients must be used, stating that a “controlled release” formulation may be
`
`used. (Id., col. 4:13-17; 44-46