`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`GRAYBAR PHARMACEUTICALS, LLC
`Petitioner,
`v.
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`POZEN INC.
`Patent Owner
`
`U.S. Patent No. 7,332,183
`Issue Date: Feb. 19, 2008
`Inventors: John R. Plachetka, Venkata Markandeya Kothapalli,
`Donna L. Gilbert
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`Title: MULTILAYER DOSAGE FORMS CONTAINING NSAIDS AND
`TRIPTANS
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`
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`
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`Case Number: Unassigned
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
`7,332,183 UNDER TO 35 U.S.C. §§ 311 ET SEQ. AND
`37 C.F.R. § 42.100 ET SEQ.
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`Table of Contents
`I. Introduction ................................................................................................... 1
`II. Notice of Real-Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ................ 3
`III. Notice of Related Matters Under 37 C.F.R. § 42.8(b)(2) ......................... 3
`IV. Notice Under 37 C.F.R. § 42.8(b)(3) and (b)(4) ........................................ 3
`V. Payment of Filing Fee Under 37 C.F.R. § 42.103 ....................................... 4
`VI. Grounds For Standing Under 37 C.F.R. § 42.104(a) ............................... 4
`VII. Statement of Precise Relief Requested Under 37 C.F.R. § 42.104(b)(1)-
`(2) ................................................................................................................. 4
`VIII. Background ............................................................................................... 5
`A. The ‘183 Patent ........................................................................................ 5
`B. Prosecution History of the ‘183 Patent .................................................... 8
`C. Background of the Prior Art ................................................................... 11
`1) Naproxen sodium and sumatriptan were each well-known for migraine
`relief. ................................................................................................... 11
`2) Combination therapies of naproxen sodium and sumatriptan were well
`known for migraine relief. .................................................................. 12
`3) Single tablet combinations of naproxen sodium and sumatriptan were
`well-known for migraine relief. .......................................................... 14
`4) Rapid release of naproxen sodium and sumatriptan was well-known
`for faster migraine relief. .................................................................... 15
`5) Multilayer tablets were well-known in the art. ................................... 17
`6) Multilayer tablets containing naproxen sodium and another active
`ingredient were well-known for release of each ingredient at
`approximately the same time. ............................................................. 18
`7) Multilayer tablets containing naproxen and sumatriptan were well-
`known in the art. ................................................................................. 22
`8) Multilayer tablets containing naproxen sodium were well-known for
`reducing gastric damage. .................................................................... 23
`D. Person of Ordinary Skill in the Art ........................................................ 25
`IX. Claim Construction Under 37 C.F.R. § 42.104(b)(3) ............................. 25
`A. “side-by-side arrangement” .................................................................... 26
`B. “naproxen” ............................................................................................. 27
`X. Analysis ........................................................................................................ 28
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`Attorney Docket No. 2015-GBP-0001  
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`A. GROUND 1: Claims 1 and 2 are rendered obvious under 35 U.S.C. §
`103 over the ‘499 Patent in view of the ‘779 Patent. ............................. 28
`B. GROUND 2: Claims 1 and 2 are rendered obvious under 35 U.S.C. §
`103 over the ‘499 Patent in view of the ‘907 Patent. ............................. 40
`C. GROUND 3: Claims 1 and 2 are rendered obvious under 35 U.S.C. §
`103 over the ‘325 Patent in view of the ‘907 Patent. ............................. 47
`D. GROUND 4: Claims 1 and 2 are rendered obvious under 35 U.S.C. §
`103 over the ‘499 Patent in view of the ‘125 Patent. ............................. 51
`XI. Objective Indicia of Non-Obviousness .................................................... 59
`XII. Conclusion ................................................................................................. 60
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`Patent No. 7,332,183
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`Attorney Docket No. 2015-GBP-0001  
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`Exhibit
`1001
`1002
`1003
`1004
`1005
`1006
`1007
`1008
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`1009
`1010
`1011
`1012
`1013
`1014
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`EXHIBIT LIST
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`Description
`U.S. Patent No. 7,332,183 (“the ‘183 Patent”)
`Declaration of Arthur Kibbe, Ph.D. (“Kibbe Decl.”)
`‘183 Patent File History (“FH183”) Office Action 12/20/2006
`‘183 Patent File History (“FH183”) Amendment 4/5/2007
`U.S. Patent No. 5,872,145 (“Plachetka ‘145”)
`U.S. Patent No. 2,951,792 (“Swintosky ‘792”)
`U.S. Patent No. 6,060,499 (“the ‘499 Patent”)
`Bandelin , F., Compressed Tablets by Wet Granulation, Pharmaceutical
`Dosage Forms: Tablets, Vol. 1, 2nd Ed., Herbert Lieberman, et al. eds.,
`Marcel Dekker, Inc., New York (1989) (“Bandelin”)
`U.S. Patent No. 5,756,125 (“the ‘125 Patent”)
`U.S. Patent No. 6,365,184 (“the ‘184 Patent”)
`U.S. Patent No. 6,183,779 (“the ‘779 Patent”)
`U.S. Patent No. 4,844,907 (“the ‘907 Patent”)
`U.S. Patent No. 6,730,325 (“the ‘325 Patent”)
`European Patent Application EP 1020182 A2 (“EP182”)
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`This is a petition for Inter Partes Review pursuant to 35 U.S.C. §§ 311 et
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`seq. and 37 C.F.R. §§ 42.100 et seq., of claims 1 and 2 of U.S. Patent No.
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`7,332,183 (“the ‘183 Patent”) filed Dec. 22, 2003. (Ex. 1001).
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`I.  
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`Introduction
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`The ‘183 Patent purports to claim a novel dosage formulation for the treatment
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`of migraine and other pain relief. (Ex. 1001, ‘183 Patent col. 1:12-18). The
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`challenged claims are directed to a combination of two well-known active
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`ingredients, naproxen and a triptan. (Id. at col. 18:30-39). Yet, the purported novelty
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`of the patent is not the combination of naproxen and a triptan. Rather, it is
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`formulating naproxen and triptan in a bilayer form, with one layer of naproxen and
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`another layer of a triptan in a “side-by-side arrangement.” (Ex. 1001, ‘183 Patent col.
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`18:30-39). This is illustrated from FIG. 1 of the patent below.
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`Nothing, however, about this dosage form is novel. The applicants
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`acknowledged that combination therapies of naproxen and triptans were well-
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`known for migraine relief long before the ‘183 Patent’s priority date. (Ex. 1001,
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`Patent No. 7,332,183
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`‘183 Patent col. 1:28-30; (Ex. 1004, FH183 Amendment 4/5/2007 at 6). Multi-
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`layer and bilayer tablet formulations, such as the “side by side” arrangement
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`depicted above, were well-known before the earliest priority date of the ‘183
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`Patent. (Ex. 1008, Bandelin at 131; Ex. 1009, ‘125 Patent col. 3:41-44).
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`Additionally, combining naproxen sodium along with another ingredient into
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`bilayer tablets was also well-known. (Ex. 1009, ‘125 Patent col. 4:25-53). Indeed,
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`bilayer tablets containing both naproxen and a triptan were already disclosed in the
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`prior art. (Ex. 1013, ‘325 Patent col. 6:30-32, col. 6:45-47; col. 10:41-46).
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`The ‘183 Patent claims a bilayer tablet for “independent” dissolution of the
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`naproxen and triptan. However, this is an inherent property of a bilayer tablet
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`including those ingredients that is already disclosed in the art. (Ex. 1002, Kibbe
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`Decl. ¶68). That is not a patentable distinction. (See infra Ground 1). Even it was,
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`it was well-known before the ‘183 Patent that bilayer tablets, including those with
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`naproxen and another active ingredient, allowed for independent dissolution of
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`each ingredient. (See infra Grounds 1 and 2).
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`Thus, at the time of filing the ‘183 Patent, it would have been obvious to
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`formulate the well-known combination therapies of naproxen and a triptan in a
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`bilayer dosage form for independent dissolution of each ingredient.
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`II.   Notice of Real-Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
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`
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`The real-party-in-interest for this Petition is Graybar Pharmaceuticals, LLC
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`(“GBP” or “Petitioner”). No other entity or person has authority to direct or
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`control Petitioner’s actions or decisions relating to this petition. GBP is funding all
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`of the fees and costs of this petition for Inter Partes Review.
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`III.   Notice of Related Matters Under 37 C.F.R. § 42.8(b)(2)
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`Petitioner Identifies the following related matters: District Court and
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`C.A.F.C. Matters: Pozen Inc. v. Teva Pharmaceuticals USA Inc., Civil Action No.
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`6:09-cv-00182-LED (E.D. Tex.); Pozen Inc. v. Alphapharm Pty Ltd. et al, Civil
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`Action No. 6:09-cv-00003-LED (E.D. Tex.); Pozen Inc. v. Par Pharmaceutical,
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`Inc., Civil Action No. 6:08-cv-00437-LED (E.D. Tex.); Pozen Inc. v. Par
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`Pharmaceutical, Inc., et al., Nos. 11-1584, 1585, 1586 (Fed. Cir.); Pozen Inc. v.
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`Par Pharmaceutical, Inc., et al., No. 12-1023 (Fed. Cir.). This petition contains
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`arguments regarding the patentability of the ‘183 Patent not previously presented to
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`the United States Patent and Trademark Office.
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`IV.   Notice Under 37 C.F.R. § 42.8(b)(3) and (b)(4)
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`
`Lead Counsel
`Zachary D. Silbersher
`Kroub, Silbersher & Kolmykov PLLC
`305 Broadway 7th Fl.
`New York, NY 10007
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`Backup Counsel
`Sergey Kolmykov
`Kroub, Silbersher & Kolmykov PLLC
`305 Broadway 7th Fl.
`New York, NY 10007
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`Patent No. 7,332,183
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`Attorney Docket No. 2015-GBP-0001  
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`(212) 323-7442
`zsilbersher@kskiplaw.com
`(Reg. No. 62,090)
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`(212) 323-7442
`skolmykov@kskiplaw.com
`(Reg. No. 47,713)
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`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney has been filed with
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`this Petition. Petitioner consents to electronic service by email at:
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`zsilbersher@kskiplaw.com, skolmykov@kskiplaw.com, ipr@kskiplaw.com.
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`V.   Payment of Filing Fee Under 37 C.F.R. § 42.103
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`A fee set forth in 37 C.F.R. § 42.15(a) accompanies this petition.
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`VI.   Grounds For Standing Under 37 C.F.R. § 42.104(a)
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`Petitioner hereby certifies that the patent for which review is sought is
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`available for inter partes review and that the Petitioner is not barred or estopped
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`from requesting an inter partes review challenging the patent claims on the
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`grounds identified in the petition.
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`VII.   Statement of Precise Relief Requested Under 37 C.F.R. § 42.104(b)(1)-
`(2)
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`Petitioner respectfully requests that claims 1 and 2 of the ‘183 Patent be
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`cancelled based upon the following grounds of unpatentability:
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`GROUND 1: Claims 1 and 2 are rendered obvious under 35 U.S.C. § 103
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`over the ‘499 Patent in view of the ‘779 Patent.
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`GROUND 2: Claims 1 and 2 are rendered obvious under 35 U.S.C. § 103
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`over the ‘499 Patent in view of ‘907 Patent.
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`GROUND 3: Claims 1 and 2 are rendered obvious under 35 U.S.C. § 103
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`the ‘325 Patent in view of the ‘907 Patent.
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`GROUND 4: Claims 1 and 2 are rendered obvious under 35 U.S.C. § 103
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`over the ‘499 Patent in view of the ‘125 Patent.
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`VIII.   Background
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`A.
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`The ‘183 Patent
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`The ‘183 Patent generally relates to treatment for pain, and particularly
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`treatment for pain associated with migraine headaches. (Ex. 1001, ‘183 Patent col.
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`1:12-15). The patent is directed to multi-dosage forms (such as tablets containing
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`two active ingredients) containing nonsteroidal anti-inflammatory drugs (NSAIDs)
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`and triptans for the treatment of migraines. (Ex. 1001, ‘183 Patent, Title). The
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`preferred NSAIDs include naproxen and naproxen sodium. (Ex. 1001, ‘183 Patent
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`col. 1:54-60).1
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`1 ALEVE®, available on an over-the-counter basis since 1994, is a popular example
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`of an NSAID containing naproxen sodium as the active ingredient.
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`The patent does not claim to have invented combination therapies of
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`NSAIDs and triptans. Indeed, the patent acknowledges at the outset that
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`combination therapies of NSAIDs and triptans were well-known in the prior art for
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`treating migraines at the time of filing. (Ex. 1001, ‘183 Patent col. 1:28-30
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`(“Recently, reports have indicated that combination therapies in which triptans are
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`combined with NSAIDs greatly improve the relief available to migraine patients.”)
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`(citations omitted).
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`Instead, the patent identifies the purported novelty of its invention in a
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`specific dosage form. This dosage form requires that the naproxen and triptan “are
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`segregated into separate layers of a multilayer tablet.” (Ex. 1001, ‘183 Patent col.
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`1:54-57). The two layers are in a “side-by-side arrangement”. (Ex. 1001, ‘183
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`Patent col. 2:7-10). Below is FIG. 1 (Panel A) from the ‘183 Patent, which shows
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`“a side-by-side type configuration encompassed by the present invention.” (Ex.
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`1001, ‘183 Patent col. 3:31-35).
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`The patent distinguishes this “side-by-side” arrangement from a matrix
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`formulation that contains both agents or a core with one agent surrounded by a
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`coating containing another agent. The patent states, “a side-by-side arrangement,
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`as opposed, for example, in a single layer tablet matrix containing both agents or
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`one layer forming a core surrounded by the other layer.” (Ex. 1001, ‘183 Patent
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`col. 2:55-58). Instead, in the preferred embodiment, the layers are “juxtaposed
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`symmetrically along a single planar surface” and “essentially all of the triptan-
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`containing layer is on one side of the plane and essentially all of the NSAID-
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`containing layer is on the other side.” (Ex. 1001, ‘183 Patent col. 2:58-63).
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`According to the ‘183 Patent, separating triptan and an NSAID into a side-
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`by-side arrangement allows “the dissolution of the naproxen [to] occur[]
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`independently of the dissolution of triptan.” (Ex. 1001, ‘183 Patent col. 2:7-10).
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`The patent claims that this arrangement supposedly has “better properties than
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`other tablet arrangements” because “in the stomach, naproxen forms a gel-like
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`matrix that retards the dissolution of triptans (or other drugs) unless the two agents
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`are maintained in distinct side by side layers.” (Ex. 1001, ‘183 Patent col. 2:9-15).
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`The patent continues:
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`Applicants believe that naproxen and similar NSAIDs possess poor
`solubility in vivo due, in part, to the stomach’s low pH environment.
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`This poor solubility may impart slower drug release properties for a
`given dosage form. Because of the slow eroding nature of naproxen
`sodium tablets and similar NSAIDs, triptans may become entrapped,
`and, as a result, their release may be delayed when non-segregated
`tablets are used. By maintaining the triptan and NSAID in separate
`layers, this problem is avoided.
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`(Ex. 1001, ‘183 Patent col. 3:50-61).
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`The patent also claims “[e]xperiments discussed in the Examples section
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`have shown that, in other types of tablets, the dissolution of triptan was delayed.”
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`(Ex. 1001, ‘183 patent col. 2:9-15).
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`B.
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`Prosecution History of the ‘183 Patent
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`The ‘183 Patent issued from U.S. Patent Application No. 10/741,592, filed
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`Dec. 22, 2003, which purportedly claimed priority to U.S. Provisional Application
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`No. 60/436,000, filed on Dec. 26, 2002. Accordingly, the earliest priority date for
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`the ‘183 Patent is not earlier than Dec. 26, 2002.
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`During prosecution, the claims were originally rejected under 35 U.S.C. §
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`103 as unpatentable over U.S. Patent No. 5,872,145 to Plachetka (“Plachetka
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`‘145”) in view of U.S. Patent No. 2,951,792 to Swintosky (“Swintosky ‘792”).
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`(Ex. 1003, FH183 Office Action 12/20/2006 at 2-3). John R. Plachetka, the
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`Patent No. 7,332,183
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`inventor on the Plachetka ‘145 patent, is the first named inventor on the ‘183
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`Patent, the patent challenged in this petition. (Ex. 1005, Plachetka ‘145).
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`The Examiner asserted that Plachetka ‘145 “discloses the migraine
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`combination naproxen and triptan in the amounts claimed” and Swintosky
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`discloses the concept of “separating tablet ingredients into various layers to control
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`delivery rates, prevent interference between the two compounds.” (Ex. 1003,
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`FH183 Office Action 12/20/2006 at 2). Notably, the Examiner asserted these
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`concepts taught by Swintosky, which was originally filed in 1954, exemplify how
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`“notoriously old” they are. (Id. citing Ex. 1006, Swintosky ‘792).
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`In response, Applicants acknowledged that a combination therapy of
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`naproxen and triptan in a single dosage form was not novel. Applicants stated that
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`“drug combinations utilizing triptans and naproxen were known in the prior art.”
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`(Ex. 1004, FH183 Amendment 4/5/2007 at 6). Applicants also acknowledged that
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`bilayer tablets were not novel. Applicants stated, “the concept of putting drugs in
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`separate layers of dosage forms was well established.” (Id.).
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`Instead, Applicants suggested that the purported novelty in their invention is
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`because it is a “selection invention.” (Ex. 1004, FH183 Amendment 4/5/2007 at
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`6). In particular, their claimed combination of naproxen and triptan in a tablet was
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`purportedly novel because it requires a “side by side arrangement” in which the
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`naproxen and triptan “dissolution occurs independently of one another.” (Id.).
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`Yet, despite acknowledging that bilayer tablets were not novel, Applicants
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`did not purport to claim any specific or unique “side-by-side arrangement”.
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`Rather, Applicants suggested that their invention encompassed any side-by-side
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`arrangement. Indeed, applicants argued that dosage forms falling outside the
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`claims would include “admixtures; any dosage forms other than tablets; tablets in
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`which one drug is in a core and surrounded by a layer or coating containing the
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`second drug; and tablets containing multiple drug release pellets or
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`microparticles.” (Ex. 1004, FH183 Amendment 4/5/2007 at 6).
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`Applicants further argued “the claimed tablet arrangement does not represent
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`an arbitrary selection.” (Ex. 1004, FH183 Amendment 4/5/2007 at 7). This,
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`applicants claimed, is due to an alleged “advantage in the specific dosage form that
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`Applicants have claimed that sets it apart from other dosage forms that could have
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`been chosen.” (Id. at 6). That advantage was allegedly demonstrated by the
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`Examples in the ‘183 Patent’s specification. Applicants argued that, “[t]he results
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`[of these examples] demonstrate that naproxen is released much more rapidly
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`from the bilayer tablet” and “sumatriptan is also released more rapidly from the
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`bilayer tablet.” (Id. at 7) (emphasis added).
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`Applicants reasoned that rapid release of both naproxen and sumatriptan is
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`advantageous. They stated, “[s]ince the claimed drug combinations would be used
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`in treating patients for pain, especially pain associated with migraine headache, the
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`rate at which drugs are released after ingestion by a patient is a very important
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`consideration, and the claimed dosage forms are thus clearly superior to other
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`tested formulations.” (Id.).
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`Despite the Examples within the patent’s specification, and Applicants’
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`arguments during prosecution, Applicants never contended that the release
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`properties of a bilayer tablet—which Applicants’ admit was an old concept—was
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`not an inherent property of a bilayer formulation of naproxen and sumatriptan,
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`which as disclosed below, already existed in the art.
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`C.
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`Background of the Prior Art
`1)  
`Naproxen sodium and sumatriptan were each well-known
`for migraine relief.
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`Prior to filing of the ’183 Patent, naproxen and naproxen sodium were
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`known to provide migraine relief. (Ex. 1002, Kibbe Decl. ¶21). Naproxen sodium
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`was “thought to relieve migraine pain through [its] known analgesic action, but
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`may also relieve symptoms by reducing the neurogenic and vascular inflammation
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`secondary to their known anti-inflammatory actions or by other mechanisms such
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`as, but not limited to, platelet inhibition or inhibition of prostaglandin synthesis.”
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`(Ex. 1007, ‘499 Patent col. 10:21-28).
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`Prior to the filing of the ‘183 Patent, sumatriptan was also known to provide
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`migraine relief. (Ex. 1002, Kibbe Decl. ¶22). The ‘499 Patent discloses the
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`compound 5-hydroxytryptamine (5-HT or 5HT), which acts on receptors within the
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`central nervous system. (Ex. 1007, ‘499 Patent col. 1:45-50). Drugs acting on
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`these receptors are known as 5-HT agonists, and have been further classified into
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`sub-classes including 5-HT1 agonists. (Ex. 1007, ‘499 Patent col. 1:50-54). The
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`‘499 Patent teaches that “5-HT1-like agonists and agonists” are notable for
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`migraine therapy. (Ex. 1007, ‘499 Patent col. 1:55-57). Sumatriptan is a
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`representative member of 5-HT1-like agonists and agonists. (Ex. 1007, ‘499
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`Patent col. 1:57-60). The ‘499 Patent teaches that sumatriptan is a drug that is
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`“structurally similar to 5-HT agonists.” (Ex. 1007, ‘499 Patent col. 4:50-53).
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`Sumatriptan was believed to provide migraine relief by “either reducing the relase
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`of pro-inflammatory mediators around certain nerves and blood vessels or by
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`vasoconstriction of selected blood vessels in the head or both.” (Ex. 1007, ‘499
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`Patent col. 10:8-14).
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`Combination therapies of naproxen sodium and
`sumatriptan were well known for migraine relief.
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`2)  
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`Combination therapies using NSAIDs, such as naproxen sodium, and
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`triptans for the treatment of migraines long preceded the earliest priority date of the
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`‘183 Patent. (Ex. 1002, Kibbe Decl. ¶23). The ‘183 Patent acknowledges this at
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`the outset of the Background of the Invention by disclosing that “reports have
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`indicated that combination therapies in which triptans are combined with NSAIDs
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`greatly improve the relief available to migraine patients.” (Ex. 10001, ‘183 Patent
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`col. 1:28-33) (citing references). By at least 1998, persons of ordinary skill knew
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`that combination therapies of triptans, such as sumatriptan, and NSAIDs, such as
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`naproxen sodium, were therapeutically effective for treatment of migraines. (Ex.
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`1007, ‘499 Patent col. 4:50-63; Ex. 1002, Kibbe Decl. ¶23).
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`Persons of skill in the art also knew that combining sumatriptan and
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`NSAIDs could have increased benefits for migraine therapy. (Ex. 1002, Kibbe
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`Decl. ¶24). The ‘499 Patent teaches, “because NSAIDs and 5-HT agonists,
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`including those of both the 5-HT like structure and the ergot structure, have
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`different pharmacologic properties and may relieve migraine through their own
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`unique mechanisms, in some instances their combined use results in a greater
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`beneficial therapeutic effect compared with the effect one achieves with the same
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`doses of each agent used singly.” (Ex. 1007, ‘499 Patent col. 10:46-53).
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`The ‘499 Patent teaches combination therapies of NSAIDs, including
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`naproxen and naproxen sodium, and 5-HT agonists and 5-HT-like agonists,
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`including sumatriptan. The patent states, “[i]t has now been discovered that a
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`combination therapy of a 5-HT agonist, including drugs structurally similar to 5-
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`HT agonists like sumatriptan or like members of the ergot family of compounds,
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`combined with a long acting nonsteroidal anti-inflammatory drug (NSAID)” can
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`be therapeutically effective for migraine therapy. (Ex. 1007, ‘499 Patent col. 4:49-
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`57). “[C]ombination of the two agents results in an enhanced therapeutic effect
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`allowing for greater and/or longer lasting efficacy and/or lower doses than can be
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`obtained with the conventional doses of either individual agent.” (Ex. 1007, ‘499
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`Patent col. 4:57-60). The patent expressly teaches the combination of naproxen
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`sodium and sumatriptan: “Naproxen sodium is one such long acting NSAID and
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`sumatriptan is one such 5-HT agonist.” (Ex. 1007, ‘499 Patent col. 4:60-62).
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`3)  
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`Single tablet combinations of naproxen sodium and
`sumatriptan were well-known for migraine relief.
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`The ‘499 Patent also teaches dosage of sumatriptan and naproxen sodium in
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`a single tablet formulation. (See Ex. 1007, ‘499 Patent col. 10:65-67 (“single oral
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`tablet containing sumatriptan 25 mg and naproxen sodium 550 mg”); col. 11:22-25
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`(“single oral tablet containing sumatriptan 12.5 mg and naproxen sodium 550
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`mg”); col. 12:4-13 (listing “combined compositions” of naproxen sodium and
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`sumatriptan in single tablet of different “tablet strengths”); col. 13:6-11 (“the
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`compositions of this invention are dispensed in unit dosage form comprising 1-100
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`mg of sumatriptan . . . and 200-600 mg of naproxen sodium . . . in a
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`pharmaceutically acceptable carrier per unit dose”)).
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`4)  
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`Rapid release of naproxen sodium and sumatriptan was
`well-known for faster migraine relief.
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`Prior to filing the ‘183 Patent, persons of skill in the art were aware that
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`rapid release of naproxen sodium and sumatriptan was helpful for faster migraine
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`relief. (Ex. 1002, Kibbe Decl. ¶27). The ‘499 Patent suggests that rapid
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`dissolution of combined sumatriptan and naproxen sodium is desirable. The patent
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`teaches, “[i]t is preferred that the dosage form provides blood levels consistent
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`with rapid initial migraine relief . . . .” (Ex. 1007, ‘499 Patent col. 9:14-16). The
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`patent also teaches, “[a]nother example includes a rapidly dissolving tablet of 12.5
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`mg of sumatriptan combined with 550 mg of naproxen sodium.” (Ex. 1007, ‘499
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`Patent col. 11:63-64). The patent also teaches tablets containing sumatriptan and
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`naproxen sodium of varying tablet strengths, where “[e]ach tablet dissolves within
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`20 minutes rapidly producing effective blood levels of each component as listed
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`herein.” (Ex. 1007, ‘499 Patent col. 12:4-13).
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`Similarly, the ‘907 Patent also teaches the desirability of rapid release of
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`naproxen for pain relief. The inventors of the ‘907 Patent found that a single tablet
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`containing a mixture of an analgesic and an NSAID did not dissolve quickly.
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`Specifically, they exhibited “serious incompatability . . . and long disintegration
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`times.” (Ex. 1012, ’907 Patent col. 1:35-40). Single layer tablets containing
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`ibuprofen (an NSAID) and codeine phosphate had “poor disintegration times” or
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`“unacceptably long disintegration times.” (Id. col. 5:59-6:30). To solve this
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`problem, for pain relief, the inventors of the ‘907 Patent disclosed a bilayer tablet
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`containing both ingredients, including a bilayer tablet specifically containing a
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`naproxen layer and a codeine layer. (Id. col. 1:6-9; col. 10:18-30).
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`Similarly, the ‘125 patent teaches delayed release of naproxen sodium is
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`undesirable for migraine relief. The patent states, “[s]uch a delay in reaching
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`therapeutic blood levels is unsuitable for use as an analgesic and antipyretic in the
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`treatment of mild to moderate pain such as dysmenorrhea or arthritis, where fast
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`onset of action is necessary to obtain pain relief.” (Ex. 1009, ‘125 Patent col. 2:13-
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`17). For this reason, the ‘125 Patent—which discloses naproxen sodium in a
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`bilayer tablet form—is directed to a formulation that provides for rapid release of
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`naproxen sodium. “A particularly beneficial aspect of the invention herein, as
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`shown in the graphs, is that the immediate release naproxen sodium layer allows
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`for faster absorption thereby providing for pain relief within an hour.” (Ex. 1009,
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`‘125 Patent col. 10:57-60).
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`5)   Multilayer tablets were well-known in the art.
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`Multilayer and bilayer tablets were well-known among persons of skill in the
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`art long before the priority date of the ‘183 Patent. (Ex. 1002, Kibbe Decl. ¶30).
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`For instance, in 1989, Bandelin disclosed “multilayer tablets”, which “are called
`
`layer tablets and usually consist of two and sometimes three layers.” (Ex. 1008,
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`Bandelin at 131). Bandelin taught that multilayer tablets can serve many
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`functions, including “separat[ing] incompatible ingredients by formulating them in
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`separate layers,” or “to make sustained or dual-release products.” (Id. at 131). In
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`the latter case, one layer can be for immediate release, and another layer for
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`extended release. (Id. at 180). In this way, each layer dissolves independently of
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`the other. (Ex. 1002, Kibbe Decl. ¶30).
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`More specifically, bilayer tablets comprising naproxen and naproxen sodium
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`were well-known in the art. The ‘125 Patent also teaches a multi-layer
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`pharmaceutical composition. (Ex. 1009, ‘125 Patent col. 4:25-53). As shown
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`below, the layers are side-by-side.
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`(Ex. 1009, ‘125 Patent, FIG. 1).
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`The ’125 Patent describes this composition as “multilayered.” (Ex. 1009,
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`‘125 Patent col. 1:10-12). The patent further teaches that “multilayered”
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`compositions can consist of “two or more adjacent layers”, and specifically in the
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`form of “bilayer” tablets. (Ex. 1009, ‘125 Patent, col. 3:37-41). Importantly, the
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`‘125 Patent illustrates that bilayer tablets were well-known in the art prior to the
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`‘183 Patent. The patent states that these types of “multilayer pharmaceutical
`
`compositions and methods of manufacturing such compositions are well known in
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`the pharmaceutical art.” (Ex. 1009, ‘125 Patent col. 3:41-44).
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`6)   Multilayer tablets containing naproxen sodium and another
`active ingredient were well-known for release of each
`ingredient at approximately the same time.
`
`Prior to the filing of the ‘183 Patent, persons of skill also knew that bilayer
`
`
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`tablets containing naproxen sodium and another ingredient allowed for immediate
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`Attorney Docket No. 2015-GBP-0001  
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`Patent No. 7,332,183
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`release, or release at approximately the same time, of each respective ingredient.
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`(Ex. 1002, Kibbe Decl. ¶33).
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`The ‘779 Patent discloses a bilayer tablet where one layer comprises
`
`naproxen or naproxen sodium, and the other layer comprises a different active
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`ingredient, namely prostaglandin and a prostaglandin stabilizing agent. (Ex. 1011,
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`‘779 Patent col. 4:25-50). Prostaglandins reduce the “undesirable gastrointestinal
`
`effects of oral administration of NSAIDs,” such as naproxen sodium. (Id.).
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`However, “prostaglandins are unstable compounds and degrade readily in the
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`presence of NSAIDs, thus requiring a stabilizing agent . . . which can, in turn,
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`lessen the activity of the NSAID.” (Id. col. 1:65-2:3). Yet, the stabilizing agents
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`for prostaglandins, such as hydroxypropyl methylcellulose, “lessen the activity of
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`an NSAID.” (Id. at 1:65-2:4). An illustration of the bilayer tablet containing
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`naproxen sodium, on the one hand, and prostaglandin and a prostaglandin
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`stabilizing agent, on the other hand, is illustrated below. (Id. at FIG. 1).
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`Attorne