Exhibit 1002
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`Declaration of Arthur Kibbe, Ph.D.
`(“Kibbe Decl.”)
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`
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`Declaration of Arthur Kibbe, Ph.D.
`(“Kibbe Decl.”)
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`
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`DECLARATION OF DR. ARTHUR H. KIBBE, PH. D.
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`I, Dr. Arthur H. Kibbe, Ph.D., declare that:
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`1.
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`I am over 18 years of age. I have personal knowledge of the facts
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`stated in this Declaration and could testify competently to them if asked to do so.
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`2.
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`I received a Bachelors of Science in pharmacy in 1966 from
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`Columbia University. I attended graduate school at the University of Florida and
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`received a Masters of Science in pharmacy in 1968 and a doctorate in pharmacy /
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`pharmacokinetics in 1973.
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`3.
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`During my career, I worked in both the private sector and academia.
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`I was the Senior Director of Scientific and Professional Affairs for the American
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`Pharmacists Association – the national professional society of pharmacists. While
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`at the American Pharmacists Association, I managed the Journal of
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`Pharmaceutical Science. I served as a Scientific Consultant to the House of
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`Representative’s Committee on Energy and Commerce, Subcommittee on
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`Oversight and Investigations, in its review of the generic drug industry practices
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`and the FDA’s generic drug review activities. I was a member of the FDA’s
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`Generic Drug Advisory Committee and served as Chair of a special panel
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`appointed by the FDA Commissioner to investigate Fairness in the Generic Drug
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`Approval Process. That committee issued findings which became known as the
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`“Kibbe Report.”
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`4.
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`Currently, I am Chair of the Department of Pharmaceutical Sciences
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`at Wilkes University, Nesbitt School of Pharmacy in Wilkes-Barre, Pennsylvania.
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`During my tenure at Wilkes University, I was elected President of the American
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`Pharmacists Association. I also served as the Editor-in-Chief of the internationally
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`recognized reference text, Handbook of Pharmaceutical Excipients, 3rd Edition. I
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`have been a consultant to Commerce Committee of United States Congress and
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`currently serves as Chair of the Governor’s Renal Disease Advisory Panel and am
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`the Chair of the Food and Drug Administration’s Scientific Advisory Committee.
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`5.
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`Previously, I was a Professor of Pharmaceutics at the University of
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`Mississippi, School of Pharmacy. While at the University of Mississippi, I
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`conducted research in the areas of formulation development, pharmacokinetics of
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`drugs of abuse (including, cocaine and amphetamine), bioequivalency evaluations
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`and impact of formulation changes on bioavailability.
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`6.
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`Between professorships, I was also the Director of Pharmaceutical
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`Development Services at the National Institutes of Health in Bethesda, Maryland.
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`During my time at the NIH, I developed delivery systems for Phase I clinical trials
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`and provided pharmacokinetics and analytical support for NIH intramural clinical
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`research programs.
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`7.
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`In 1994, I was elected a Fellow of the Academy of Pharmaceutical
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`Research and Science. Fellows have a minimum of 10 years of exemplary
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`professional experience and achievements in professional practice.
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`8.
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`9.
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`My full CV is attached as Exhibit A.
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`I have been retained by Graybar Pharmaceuticals, LLC to provide
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`technical analysis of prior art references and prepare this declaration. If I am asked
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`to provide live deposition testimony it will be at a rate of $750 an hour.
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`10.
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`In preparation for this declaration, I have reviewed U.S. Patent No.
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`7,332,183 (“the ‘183 Patent”) along with the prior art references and portions from
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`the file history of the ‘183 Patent set forth below:
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`1) ‘183 Patent File History (“FH183”) Office Action 12/20/2006;
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`2) ‘183 Patent File History (“FH183”) Amendment 4/5/2007;
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`3) U.S. Patent No. 5,872,145 (“Plachetka ‘145”);
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`4) U.S. Patent No. 2,951,792 to Swintosky (“Swintosky ‘792”);
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`5) U.S. Patent No. 6,060,499 (“the ‘499 Patent”);
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`6) Bandelin , F., Compressed Tablets by Wet Granulation,
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`Pharmaceutical Dosage Forms: Tablets, Vol. 1, 2nd Ed., Herbert
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`Lieberman, et al. eds., Marcel Dekker, Inc., New York (1989)
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`(“Bandelin”);
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`7) U.S. Patent No. 5,756,125 (“the ‘125 Patent”);
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`8) U.S. Patent No. 6,365,184 (“the ‘184 Patent”);
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`9) U.S. Patent No. 6,183,779 (“the ‘779 Patent”)
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`10) U.S. Patent No. 4,844,907 (“the ‘907 Patent”)
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`11) U.S. Patent No. 6,730,325 (“the ‘325 Patent”)
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`12) European Patent Application EP 1 020 182 A2 (“EP182”)
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`11.
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`I understand that a patent claim is evaluated from the perspective of
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`a “person of ordinary skill in the art,” which I understand is a hypothetical person
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`considered to have the skill level and knowledge of a particular field related to an
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`alleged invention claimed in a patent. I further understand that this hypothetical
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`skilled artisan is presumed to have before him or her all of the relevant prior art. I
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`understand that this “hypothetical person” can be more than one person or a team
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`of people of different disciplines. The discussions in this declaration are intended
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`to convey the state of the art and the knowledge of a person of ordinary skill in the
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`art generally prior to the earliest priority date of the patent application that issued
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`as the respective ‘183 patent.
`In view of the subject matter of the ‘183 Patent, a person of ordinary
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`12.
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`skill in the art as of the patent’s filing date would typically be a pharmaceutical
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`formulator with at least a master’s degree in pharmaceutics or a related discipline
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`and four to six years of experience.
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`13.
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`As of the priority date of the ‘183 Patent, I have been a person of
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`ordinary skill in the art as defined above.
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`14.
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`The ‘183 Patent generally relates to treatment for pain, and
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`particularly treatment for pain associated with migraine headaches. (Ex. 1001,
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`‘183 Patent col. 1:12-15). The patent is directed to multi-dosage forms (such as
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`tablets containing two active ingredients) containing nonsteroidal anti-
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`inflammatory drugs (NSAIDs) and triptans for the treatment of migraines. (Ex.
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`1001, ‘183 Patent, Title). The preferred NSAIDs include naproxen and naproxen
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`sodium. (Ex. 1001, ‘183 Patent col. 1:54-60).1
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`15.
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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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`16.
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`Instead, the patent identifies the purported novelty of its invention in
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`a specific dosage form. This dosage form requires that the naproxen and triptan
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`“are segregated into separate layers of a multilayer tablet.” (Ex. 1001, ‘183 Patent
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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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`col. 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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`17. The patent distinguishes this “side-by-side” arrangement from a
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`matrix formulation that contains both agents or a core with one agent surrounded
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`by a coating containing another agent. The patent states, “a side-by-side
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`arrangement, as opposed, for example, in a single layer tablet matrix containing
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`both agents or one layer forming a core surrounded by the other layer.” (Ex. 1001,
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`‘183 Patent col. 2:55-58). Instead, in the preferred embodiment, the layers are
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`“juxtaposed symmetrically along a single planar surface” and “essentially all of the
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`triptan-containing layer is on one side of the plane and essentially all of the
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`NSAID-containing layer is on the other side.” (Ex. 1001, ‘183 Patent col. 2:58-
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`18. According to the ‘183 Patent, separating triptan and an NSAID into a
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`6
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`63).
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`side-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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`19.
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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.
`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.
`
`
`(Ex. 1001, ‘183 Patent col. 3:50-61).
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`20. The patent also claims “[e]xperiments discussed in the Examples
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`section have shown that, in other types of tablets, the dissolution of triptan was
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`delayed.” (Ex. 1001, ‘183 patent col. 2:9-15).
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`21. Prior to filing of the ’183 Patent, naproxen and naproxen sodium were
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`known to provide migraine relief. Naproxen sodium was “thought to relieve
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`migraine pain through [its] known analgesic action, but may also relieve symptoms
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`by reducing the neurogenic and vascular inflammation secondary to their known
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`anti-inflammatory actions or by other mechanisms such as, but not limited to,
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`platelet inhibition or inhibition of prostaglandin synthesis.” (Ex. 1007, ‘499 Patent
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`col. 10:21-28).
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`22. Prior to the filing of the ‘183 Patent, sumatriptan was also known to
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`provide migraine relief. The ‘499 Patent discloses the compound 5-
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`hydroxytryptamine (5-HT or 5HT), which acts on receptors within the central
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`nervous system. (Ex. 1007, ‘499 Patent col. 1:45-50). Drugs acting on these
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`receptors are known as 5-HT agonists, and have been further classified into sub-
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`classes including 5-HT1 agonists. (Ex. 1007, ‘499 Patent col. 1:50-54). The ‘499
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`Patent teaches that “5-HT1-like agonists and agonists” are notable for migraine
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`therapy. (Ex. 1007, ‘499 Patent col. 1:55-57). Sumatriptan is a representative
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`member of 5-HT1-like agonists and agonists. (Ex. 1007, ‘499 Patent col. 1:57-60).
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`The ‘499 Patent teaches that sumatriptan is a drug that is “structurally similar to 5-
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`HT agonists.” (Ex. 1007, ‘499 Patent col. 4:50-53). Sumatriptan was believed to
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`provide migraine relief by “either reducing the relase of pro-inflammatory
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`mediators around certain nerves and blood vessels or by vasoconstriction of
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`selected blood vessels in the head or both.” (Ex. 1007, ‘499 Patent col. 10:8-14).
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`23. 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. The ‘183 Patent acknowledges this at the outset of the Background of
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`the Invention by disclosing that “reports have indicated that combination therapies
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`in which triptans are combined with NSAIDs greatly improve the relief available
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`to migraine patients.” (Ex. 10001, ‘183 Patent col. 1:28-33) (citing references).
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`By at least 1998, persons of ordinary skill knew that combination therapies of
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`triptans, such as sumatriptan, and NSAIDs, such as naproxen sodium, were
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`therapeutically effective for treatment of migraines. (Ex. 1007, ‘499 Patent col.
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`4:50-63).
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`24. Persons of skill in the art also knew that combining sumatriptan and
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`NSAIDs could have increased benefits for migraine therapy. The ‘499 Patent
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`teaches, “because NSAIDs and 5-HT agonists, including those of both the 5-HT
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`like structure and the ergot structure, have different pharmacologic properties and
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`may relieve migraine through their own unique mechanisms, in some instances
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`their combined use results in a greater beneficial therapeutic effect compared with
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`the effect one achieves with the same doses of each agent used singly.” (Ex. 1007,
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`‘499 Patent col. 10:46-53).
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`25. 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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`26. The ‘499 Patent also teaches dosage of sumatriptan and naproxen
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`sodium in a single tablet formulation. (See Ex. 1007, ‘499 Patent col. 10:65-67
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`(“single oral tablet containing sumatriptan 25 mg and naproxen sodium 550 mg”);
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`col. 11:22-25 (“single oral tablet containing sumatriptan 12.5 mg and naproxen
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`sodium 550 mg”); col. 12:4-13 (listing “combined compositions” of naproxen
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`sodium and sumatriptan in single tablet of different “tablet strengths”); col. 13:6-
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`11 (“the compositions of this invention are dispensed in unit dosage form
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`comprising 1-100 mg of sumatriptan . . . and 200-600 mg of naproxen sodium . . .
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`in a pharmaceutically acceptable carrier per unit dose”)).
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`27. Prior to filing the ‘183 Patent, persons of skill in the art were aware
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`that rapid release of naproxen sodium and sumatriptan was helpful for faster
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`migraine relief. The ‘499 Patent suggests that rapid dissolution of combined
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`sumatriptan and naproxen sodium is desirable. The patent teaches, “[i]t is
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`preferred that the dosage form provides blood levels consistent with rapid initial
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`migraine relief . . . .” (Ex. 1007, ‘499 Patent col. 9:14-16). The patent also
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`teaches, “[a]nother example includes a rapidly dissolving tablet of 12.5 mg of
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`sumatriptan combined with 550 mg of naproxen sodium.” (Ex. 1007, ‘499 Patent
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`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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`28. Similarly, the ‘907 Patent also teaches the desirability of rapid release
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`of naproxen for pain relief. The inventors of the ‘907 Patent found that a single
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`tablet 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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`29. Similarly, the ‘125 patent teaches delayed release of naproxen sodium
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`is 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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`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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`30. Multilayer and bilayer tablets were well-known among persons of
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`skill in the art long before the priority date of the ‘183 Patent. For instance, in
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`1989, Bandelin disclosed “multilayer tablets”, which “are called layer tablets and
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`usually consist of two and sometimes three layers.” (Ex. 1008, Bandelin at 131).
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`Bandelin taught that multilayer tablets can serve many functions, including
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`“separat[ing] incompatible ingredients by formulating them in separate layers,” or
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`“to make sustained or dual-release products.” (Id. at 131). In the latter case, one
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`layer can be for immediate release, and another layer for extended release. (Id. at
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`180). In this way, each layer dissolves independently of the other.
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`31. More specifically, bilayer tablets comprising naproxen and naproxen
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`sodium 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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`
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`(Ex. 1009, ‘125 Patent, FIG. 1).
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`32. The ’125 Patent describes this composition as “multilayered.” (Ex.
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`1009, ‘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
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`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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`33. Prior to the filing of the ‘183 Patent, persons of skill also knew that
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`bilayer tablets containing naproxen sodium and another ingredient allowed for
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`immediate release, or release at approximately the same time, of each respective
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`ingredient.
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`34. The ‘779 Patent discloses a bilayer tablet where one layer comprises
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`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
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`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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`35. Accordingly, the ‘779 Patent preserves the efficacy of each active
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`ingredient, i.e., NSAID for pain relief, and prostaglandin for reduction of
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`gastrointestinal effects, by separating the NSAID from the stabilizing agent so that
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`the prostaglandin stabilizing agent does not interfere with the NSAID when they
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`each respectively dissolve at the same time. (Ex. 1011, ‘779 Patent col. 2:15-23).
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`This is accomplished by separating the two ingredients into different layers—
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`“discrete regions of the composition, such as in a bilayer tablet”. (Id. at col. 2:38-
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`39). The purpose of segregating naproxen sodium and prostaglandin is because
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`when they dissolve together, the prostaglandin degrades. (Ex. 1011, ‘779 Patent
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`col. 1:65-67). Moreover, the purpose of segregating naproxen sodium and the
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`prostaglandin stabilizing agent is because the stabilizing agent can “lessen the
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`activity of the NSAID.” (Id. col. 1:65-2:3). Thus, the ‘779 Patent puts the
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`respective ingredients into a bilayer tablet in order to avoid the deleterious effects
`
`of when they dissolve at the same time—i.e., “independently”.
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`36. Similarly, EP182 also teaches that separating an NSAID and a
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`prostaglandin into “in the form of a tablet comprising two layers” so that each
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`ingredient dissolves at approximately the same time. (Ex. 1014, EP182 at ¶0010).
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`EP182 was published on July 19, 2000, and is therefore prior art under 35 U.S.C. §
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`102(b). The EP182 teaches,
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`It is desirable to provide a pharmaceutical composition which exhibits
`the beneficial properties of an NSAID and which also exhibits the
`beneficial properties of misoprostol for countering the ulcerogenic
`side effects attendent [sic] to NSAID administration. This can be
`achieved by combining an NSAID and misoprostol in a single
`pharmaceutical tablet. However this is not easy to do, because
`misoprostol is highly unstable, and it is thus desirable not to have the
`misoprostol and NSAID mixed together, so as to prevent any
`deleterious effect of the NSAID on the stability of the misoprostol.
`(Id. at ¶¶0004-05).
`
`37. Additionally, the ‘907 Patent also teaches a bilayer tablet with two
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`active ingredients where each ingredient dissolves at approximately the same time,
`
`i.e., independently. Specifically, the ‘907 Patent teaches a pharmaceutical
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`composition in the form of a “bilayered” tablet containing a narcotic analgesic and
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`an NSAID, such as naproxen. (Ex. 1012, ‘907 Patent, Abstract, col. 2:1-4, col.
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`2:16-25). The inventors of the ‘907 Patent found that a single tablet containing a
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`mixture of an analgesic and an NSAID did not dissolve quickly, but exhibited
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`“long disintegration times,” “poor disintegration times” or “unacceptably long
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`disintegration times.” (Id. col. 1:35-40; col. 5:59-6:30). To solve this problem, the
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`inventors of the ‘907 Patent disclosed a bilayer tablet containing both ingredients,
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`including a naproxen layer and a codeine layer. (Id. col. 10:18-30). The disclosed
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`tablet avoids long disintegration times by putting each ingredient into a bilayer
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`formulation.
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`38. Prior to filing the ‘183 Patent, persons of skill in the art were also
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`aware that naproxen and a triptan (sumatriptan) were disclosed in a multilayer
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`tablet. (Ex. 1013, ‘325 Patent). The ‘325 Patent was filed on May 7, 2001, and
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`published on May 9, 2002, and is therefore prior art under 35 U.S.C. § 102.
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`39. The ‘325 Patent discloses a pharmaceutical tablet. “The present
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`invention also provides solid oral dosage forms comprising a composition
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`according to the invention.” (Ex. 1013, ‘325 Patent col. 4:62-64). The
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`composition has a “first component comprising a first population of active
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`ingredient-containing particles,” and “a second component comprising a second
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`population of active ingredient-containing particles.” (Id. col. 4:10-15). The
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`active ingredients in the first and components can be different. “The active
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`ingredient contained in the first and second components can be the same or
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`different . . . .” (Id. col. 4:15-16). Compositions with different first and second
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`active ingredients “may be desirable for combination therapies.” (Id. col. 6:65-
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`17
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`7:1). The ‘325 Patent discloses both ingredients can be in a “multilayer tablet.”
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`(Id. col. 10:41-46). The multilayer tablet “maybe used to deliver a number of
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`drugs including, . . . naproxen . . . [and] anti-migraine agents such as sumatriptan.”
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`(Id. at col. 6:30-32, col. 6:45-47).
`
`40. Prior to the filing of the ‘183 Patent, persons of skill knew that
`
`naproxen and naproxen sodium can be irritants to the gastrointestinal tract. The
`
`‘125 Patent teaches, “naproxen and naproxen sodium are known to be irritants to
`
`the gastrointestinal tract . . . .” (Ex. 1009, ‘125 Patent col. 2:25-26). The ‘184
`
`Patent teaches, “NASAIDs including acetyl salicyclic acid are among the most
`
`commonly prescribed and used drugs world-wide. Despite the therapeutic benefits
`
`of NSAIDs, their use is frequently limited by an increased risk of gastrointestinal
`
`side-effects, mainly upper gastrointestinal side-effects like peptic ulceration and
`
`dyspeptic symptoms.” (Ex. 1010, ‘184 Patent col. 1:23-29). The ‘779 Patent
`
`teaches, “high dosages and chronic use of NSAIDs are associated with problems
`
`such as gastrointestinal and duodenal bleeding, ulceration and perforation.” (Ex.
`
`1011, ‘779 Patent col. 1:36-39).
`
`41. Persons of skill also knew that matrix formulations of drugs
`
`containing naproxen or naproxen sodium could exacerbate gastric damage. For
`
`instance, The ‘125 Patent teaches,
`
`matrix systems described in the art are designed to remain intact, and
`
`18
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`
`
`
`
`
`
`since naproxen and naproxen sodium are known to be irritants to the
`gastrointestinal tract, such systems may not empty from the stomach
`due to its large size. The retention of such systems in the stomach may
`thereby cause gastric damage.
`(Ex. 1009, ‘125 Patent col. 2:24-29).
`
`42. For this reason, persons of skill were motivated to design drug
`
`formulations for administering naproxen and naproxen sodium that would reduce
`
`the potential for gastric irritation and damage. To avoid gastric damage
`
`exacerbated by administering naproxen sodium through matrix systems, persons of
`
`skill were aware of bilayer side-by-side formulations comprising naproxen sodium.
`
`(Id.). For instance, the ‘125 Patent teaches a multi-layer pharmaceutical
`
`composition naproxen and naproxen sodium. (Ex. 1009, ‘125 Patent col. 4:25-53;
`
`FIG. 1).
`
`43. The ‘125 Patent further teaches that the design of a bilayer tablet
`
`comprising naproxen sodium helps avoid gastric damage. The patent teaches, “the
`
`design of the tablet provides for total disintegration of the tablet thereby reducing
`
`the potential for gastric irritation and damage.” (Ex. 1009, ‘125 Patent col. 10:65-
`
`67).
`
`44. Similarly, the ‘779 Patent discloses a bilayer tablet where one layer
`
`comprises naproxen or naproxen sodium, and the other layer comprises another
`
`ingredient (prostaglandin.) (Ex. 1011, ‘779 Patent col. 4:25-50). The purpose of
`
`19
`
`
`
`
`
`
`
`co-administering naproxen and prostaglandin in a single tablet is “to reduce the
`
`undesirable gastrointestinal effects resulting from the oral administration of
`
`NSAIDs.” (Id. col. 1:55-57).
`
`45. The ‘499 Patent discloses a pharmaceutical composition comprising
`
`naproxen and a triptan. (Ex. 1007, ‘499 Patent col. 1:21-33 (“This invention also
`
`comprises a unit dosage form comprising a co-timely delivered therapeutically
`
`effective amount of a 5HT agonist coordinated and a therapeutically effective
`
`amount of an NSAID or non-NSAID analgesic. . . . In some embodiments of the
`
`unit dosage form the 5HT agonist is sumatriptan, . . . A long-acting NSAID useful
`
`in the unit dosage form is naproxen, or pharmaceutically acceptable salt thereof
`
`such as naproxen sodium.”)).
`
`46. The ‘499 Patent teaches dosage of sumatriptan and naproxen sodium
`
`in a single pharmaceutical tablet formulation. (See Ex. 1007, ‘499 Patent col.
`
`10:65-67 (“single oral tablet containing sumatriptan 25 mg and naproxen sodium
`
`550 mg”); col. 11:22-25 (“single oral tablet containing sumatriptan 12.5 mg and
`
`naproxen sodium 550 mg”); col. 12:4-13 (listing “combined compositions” of
`
`naproxen sodium and sumatriptan in single tablet of different “tablet strengths”);
`
`col. 13:6-11 (“the compositions of this invention are dispensed in unit dosage form
`
`comprising 1-100 mg of sumatriptan . . . and 200-600 mg of naproxen sodium . . .
`
`in a pharmaceutically acceptable carrier per unit dose”)).
`
`20
`
`
`
`
`
`
`
`47. The ‘779 Patent teaches “high dosages and chronic use of NSAIDs are
`
`associated with problems such as gastrointestinal and duodenal bleeding,
`
`ulceration and perforation.” (Ex. 1011, ‘779 Patent col. 1:36-39). The ‘779 Patent
`
`discloses a bilayer tablet where one layer comprises naproxen or naproxen sodium,
`
`and the other layer comprises a different active ingredient, namely prostaglandin
`
`and a prostaglandin stabilizing agent. (Ex. 1011, ‘779 Patent col. 4:25-50).
`
`48. Thus, similar to the claims of the challenged ‘183 Patent, the ‘779
`
`Patent discloses a bilayer tablet with two different active ingredients, where one
`
`ingredient is naproxen sodium. An illustration of the ‘779 Patent’s bilayer tablet is
`
`illustrated below. (Id. at FIG. 1).
`
`
`
`49.
`
`[Reserved]
`
`50. The purpose of co-administering naproxen sodium, on the one hand,
`
`and prostaglandin, on the other hand, in a single tablet is to “to reduce the
`
`undesirable gastrointestinal effects resulting from the oral administration of
`
`21
`
`
`
`
`
`
`
`NSAIDs.” (Id. col. 1:55-57). Prostaglandins reduce these undesirable effects.
`
`(Id.). However, “prostaglandins are unstable compounds and degrade readily in
`
`the presence of NSAIDs, thus requiring a stabilizing agent . . . which can, in turn,
`
`lessen the activity of the NSAID.” (Id. col. 1:65-2:3). Yet, the stabilizing agents
`
`for prostaglandins, such as hydroxypropyl methylcellulose, “lessen the activity of
`
`an NSAID.” (Id. at 1:65-2:4).
`
`51. Thus, in view of the ‘779 Patent, for at least the following reasons, it
`
`would have been obvious to persons of ordinary skill as of the earliest priority date
`
`of the ‘183 Patent to formulate the single tablet containing naproxen and a triptan,
`
`as disclosed in the ‘499 Patent, into a multilayer formulation, as disclosed in the
`
`‘779 Patent.
`
`52. Bilayer tablet formulations were well-known to persons of skill in the
`
`art. (Ex. 1011, ‘779 Patent FIG. 1; Ex. 1008, Bandelin at 131, 180 (disclosing
`
`“multilayer tablets”, which “are called layer tablets and usually consist of two and
`
`sometimes three layers”); Ex. 1009, ‘125 Patent col. 1:37-44 (disclosing
`
`“multilayered” compositions consisting of “two or more adjacent layers”,
`
`specifically in the form of “bilayer” tablets; and teaching that these types of
`
`“multilayer pharmaceutical compositions and methods of manufacturing such
`
`compositions are well known in the pharmaceutical art”)).
`
`53. The ‘779 Patent teaches that a bilayer tablet formulation is a solution
`
`22
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`
`
`
`
`
`for incompatible ingredients. The ‘779 Patent suggests that NSAIDs and
`
`prostaglandins are “incompatible”, which is defined therein to mean two drugs that
`
`“in close physical proximity a first drug may have a deleterious effect on the
`
`physical or chemical stability of a second drug . . . .” (Ex. 1011, ‘779 Patent col.
`
`3:60-65). Indeed, prostaglandins degrade in the presence of NSAIDs. (Id. col.
`
`1:65-67). And the stabilizing agent lessens the efficacy of the NSAID. (Id. col.
`
`1:65-2:3). Thus, the goal of the ‘779 Patent is to formulate a pharmaceutical
`
`composition that overcomes the incompatibility of ingredients in a single tablet by
`
`separating the ingredients into “discrete regions of the composition, such as in a
`
`bilayer tablet”. (Id. at).
`
`54. Persons of ordinary skill as of the earliest priority date of the ‘183
`
`Patent knew that bilayer formulations were a solution for incompatible ingredients
`
`in a single tablet. (Ex. 1011, ‘779 Patent col. 1:65-67; col. 1:65-2:3; col. 2:38-39;
`
`col. 3:60-65; Ex. 1008, Bandelin at 131 (teaching that multilayer tablets “separate
`
`incompatible ingredients by formulating them in separate layers”); Ex. 1014,
`
`EP182 at ¶¶0010, 0004-04 (teaching that separating an NSAID and a prostaglandin
`
`into “in the form of a tablet comprising two layers” so that each ingredient
`
`dissolves at approximately the same time because “it is thus desirable not to have
`
`the m
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