Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`PAR PHARMACEUTICAL, INC.
`Petitioner
`
`v.
`
`JAZZ PHARMACEUTICALS, INC.
`Patent Owner
`
`
`_____________________
`
`Case IPR: Unassigned
`Patent 8,772,306
`_____________________
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,772,306
`UNDER 35 U.S.C. § 311–319 AND 37 C.F.R. § 42.1–.80, 42.100–.123
`
`
`
`
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`
`Table of Contents
`INTRODUCTION AND STATEMENT OF RELIEF REQUESTED (37
`I.
`C.F.R. § 42.22(a)) ...................................................................................................... 1
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) .................................. 1
`III. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR ............................................................................................ 2
`IV. OVERVIEW ..................................................................................................... 2
`A. Person of Ordinary Skill In The Art ................................................................. 2
`B. State of the Art .................................................................................................. 3
`1. Background Regarding GHB ........................................................................ 3
`2. Background Regarding Divalproex Sodium ................................................. 4
`3. Background Regarding Drug Interactions .................................................... 5
`4. Background Regarding GHB/Valproate Interactions ................................... 7
`5. The ’306 Patent ........................................................................................... 11
`V. CLAIM CONSTRUCTION ........................................................................... 13
`A. “Concomitant” and “Concomitantly” ............................................................. 14
`VI.
`IDENTIFICATION OF CHALLENGE ......................................................... 14
`A. Identification of Prior Art ............................................................................... 15
`B. Each of the References Cited is Prior Art. ..................................................... 16
`1. The FDA Guidance (PAR1011) Qualifies as Prior Art. ............................. 17
`2. Xyrem Label (PAR1006) Qualifies as Prior Art. ........................................ 18
`3. Cagnin, Waszkielewicz, Weiss, and the Depakote 2011 Label Qualify as
`Prior Art. ............................................................................................................ 18
`C. Ground I: Claims 1-34 Are Obvious Over the Xyrem 2005 Label, the
`Depakote 2011 Label, Cagnin, Waszkielewicz, and the FDA Guidance. ............ 18
`1. Comparison of the ’306 Patent Claims to the Prior Art: Claim 1 ............... 22
`2. Claim 11 ...................................................................................................... 27
`3. Claim 19 ...................................................................................................... 28
`4. Claims 30 and 33 ......................................................................................... 30
`5. Claims 2, 4, 12, 13, 18, and 28 .................................................................... 32
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`6. Claims 3 and 8 ............................................................................................. 34
`7. Claims 5 and 16 ........................................................................................... 35
`8. Claims 6, 17, and 27 .................................................................................... 35
`9. Claims 7, 9, and 10 ...................................................................................... 36
`10. Claims 14, 15, 20, and 21 ............................................................................ 37
`11. Claims 22 and 24 ......................................................................................... 39
`12. Claim 25 ...................................................................................................... 39
`13. Claim 26 ...................................................................................................... 39
`14. Claim 31 ...................................................................................................... 40
`15. Claims 23, 29, 32 and 34 ............................................................................. 40
`D. Ground 2: Claims 1-34 Are Obvious Over the Xyrem 2005 Label in view
`of Cagnin, Waszkielewicz, Weiss, the Depakote 2011 Label, and the FDA
`Guidance. .............................................................................................................. 41
`1. Comparison of the ’306 Patent Claims to the Prior Art: Claim 1 ............... 44
`2. Claim 11 ...................................................................................................... 47
`3. Claim 19 ...................................................................................................... 48
`4. Claim 30 and 33 .......................................................................................... 49
`5. Claims 2, 4, 12, 13, 18, and 28 .................................................................... 50
`6. Claims 3 and 8 ............................................................................................. 50
`7. Claims 5 and 16 ........................................................................................... 50
`8. Claims 6, 17, and 27 .................................................................................... 51
`9. Claims 7, 9, and 10 ...................................................................................... 51
`10. Claims 14, 15, 20, and 21 ............................................................................ 52
`11. Claims 22 and 24 ......................................................................................... 53
`12. Claim 25 ...................................................................................................... 53
`13. Claim 26 ...................................................................................................... 54
`14. Claim 31 ...................................................................................................... 54
`15. Claims 23, 29, 32 and 34 ............................................................................. 54
`E. Secondary Considerations Do Not Rebut the Prima Facie Case. .................. 54
`
`
`
`ii
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`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`IT IS MORE LIKELY THAN NOT THAT PETITIONER WILL PREVAIL
`II.
`WITH RESPECT TO AT LEAST ONE OF THE CHALLENGED CLAIMS ...... 59
`IV. CONCLUSION .............................................................................................. 60
`
`
`
`iii
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`

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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`INTRODUCTION AND STATEMENT OF RELIEF REQUESTED (37
`C.F.R. § 42.22(A))
`
`I.
`
`Par Pharmaceutical, Inc. (“Par” or “Petitioner”) submits this Petition for
`
`Inter Partes review (“IPR”) seeking cancellation of claims 1-34 of U.S. Patent No.
`
`8,772,306 (“the ’306 patent”) (PAR1001) as unpatentable under 35 U.S.C. §103(a)
`
`in view of the prior art. According to Office records, the ’306 patent is assigned to
`
`Jazz Pharmaceuticals Ireland Limited, though Jazz Pharmaceuticals, Inc. and Jazz
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`Pharmaceuticals Ireland Limited (collectively, “Jazz”) have represented they
`
`together own the patent.1 Every limitation of the claims of the ’306 patent would
`
`have been obvious to a person of skill in the art (“POSA”) based on prior art
`
`printed publications, as set forth below in Grounds 1 and 2.
`
`For the reasons explained below, Petitioner is at least reasonably likely to
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`prevail on the asserted Ground with respect to the challenged claims. Therfore,
`
`Petitioners respectfully request that this Board institute IPR and cancel each of
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`challenged claims 1–34 of the ’306 patent.
`
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(A))
`Petitioners certify that the ’306 patent is available for IPR and Petitioner is
`
`not barred or estopped from requesting IPR of any of the challenged claims.
`
`
`1 See D.I. 1, ¶ 10 in Jazz Pharmaceuticals, Inc. v. Par Pharmaceutical, Inc., C.A.
`
`No. 14-6150 (D.N.J.)
`
`1
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`

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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`III. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR
`
`The Office should institute IPR under 35 U.S.C. §§ 311–319 and 37 C.F.R.
`
`§§ 42.1–.80 and 42.100–.123, and cancel claims 1–34—all claims—of the ’306
`
`patent as unpatentable under 35 U.S.C. § 103.
`
`IV. OVERVIEW
`A.
`Person of Ordinary Skill In The Art
`A POSA is a hypothetical person who is presumed to be aware of all
`
`pertinent art, thinks along conventional wisdom in the art, and is a person of
`
`ordinary creativity. A POSA may work as part of a multi-disciplinary team and
`
`draw upon not only his or her own skills, but also take advantage of certain
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`specialized skills of others in the team, to solve a given problem.
`
`A POSA in the art to which the ’306 patent pertains would have at least a
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`Ph.D., Doctor of Pharmacy degree, or medical degree, and five years of experience
`
`of treating patients with neurologic disorders, including at least narcolepsy,
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`cataplexy, and excessive daytime sleepiness in narcolepsy; a POSA may also
`
`include a clinical pharmacologist with at least three years of experience consulting
`
`with physicians on the dosing of drugs in light of potential drug-drug interactions,
`
`comorbid conditions, or other factors that could affect dosing.
`
`2
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`
`B.
`
`State of the Art
`1.
`The ’306 patent is entitled “Method of Administration of Gamma
`
`Background Regarding GHB
`
`Hydroxybutyrate with Monocarboxylate Transporters.” (PAR1001 at 1:1–3.) The
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`’306 patent is generally directed to a method for treating a patient who is suffering
`
`from disorders such as cataplexy and excessive daytime sleepiness in narcolepsy,
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`who are concomitantly receiving treatment with valproate, with a reduced dose of
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`gamma-hydroxybutyrate (“GHB”) or a salt thereof. The ’306 patent acknowledges
`
`that GHB is commercially known as Xyrem. (Id. at 2:53–54.) The ’306 patent is
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`listed in the United States Food and Drug Administration’s electronic publication,
`
`known as the “Orange Book” (“OB”), in connection with the prescription drug
`
`product Xyrem. (PAR1005.)
`
`The active ingredient in Xyrem is sodium oxybate, which is the sodium salt
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`of GHB. (PAR1006 at 1; see also PAR1001 at 2:53–54.) GHB is a naturally
`
`occurring endogenous substance that functions as an inhibitory neurotransmitter in
`
`the central nervous system of mammals. (PAR1009 at 44.) GHB is a powerful
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`sedative that can cause sleep very quickly; patients are instructed only to take it at
`
`bedtime and while in bed. (PAR1003, ¶ 47; PAR1006, Medication Guide at 1.)
`
`GHB originates from GABA when GABA is metabolized by GABA transaminase
`
`to succinic semialdehyde and then converted to GHB by GABA dehydrogenase.
`
`3
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`
`(PAR1009 at 44.)
`
`The specification of the ’306 patent acknowledges that the normal dose
`
`ranges of GHB is disclosed in the product insert for Xyrem. (PAR1001 at 2:52-54.)
`
`GHB is approved in the United States for the treatment of cataplexy and
`
`narcolepsy. (See id. at 7.) The Xyrem 2005 Label reflects the FDA-approved doses
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`of Xyrem. (PAR1006 at 1, 22–23.) Specifically, the “Dosing and Administration”
`
`section of the Xyrem 2005 Label states that the recommended starting dose for
`
`Xyrem is 4.5 g/night divided into two equal doses of 2.25 g. (Id. at 23.) The Xyrem
`
`2005 Label states that the dose should be titrated to effect in the patient, by
`
`increasing the dose in 1.5 g/night increments to a maximum of 9 g/night. (Id.; see
`
`also PAR1003, ¶ 48.) The Xyrem 2005 Label discloses that the effective dose
`
`range of Xyrem is 6 to 9 g/night, and as such the label recommends starting at a
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`subtherapeutic dose and titrating upwards as necessary. (PAR1003, ¶ 48; see also
`
`PAR1006 at 23.)
`
`Background Regarding Divalproex Sodium
`
`2.
`Divalproex sodium, sold under the trade name Depakote, is a stable
`
`coordination compound comprised of sodium valproate and valproic acid in a 1:1
`
`molar relationship. (PAR1007 at 33.) Depakote is but one salt form of a number of
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`valproate drugs, which include valproic acid, sodium valproate, and divalproex
`
`sodium. (PAR1003, ¶ 49.) Depakote is an antiepileptic drug indicated for
`
`4
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`numerous conditions, including treatment of manic episodes associated with
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`bipolar disorder, treatment of complex partial seizures, and prophylaxis of
`
`migraine headaches. (PAR1007 at 1.) One potential side effect of valproate
`
`administration is central nervous system (CNS) depression (including sedation and
`
`cognitive impairment), particularly when it is combined with other CNS
`
`depressants. (PAR1003, ¶ 50; PAR1007 at 48.)
`
`Background Regarding Drug Interactions
`
`3.
`As patients often take more than one drug, physicians and pharmacists often
`
`need to take into account potential drug interactions when administering any new
`
`therapy to a patient. (PAR1003, ¶ 52.) Drug interactions can either be
`
`pharmacokinetic (i.e., administration of one drug results in increased or decreased
`
`plasma, tissue, or other in vivo concentrations of a second drug in the body) or
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`pharmacodynamic (i.e., the effects of one drug potentiate or limit the effects of,
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`another drug). (Id.) While a potential drug interaction may make it unsafe to
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`coadminister a particular drug with a second drug the patient is already taking, in
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`certain instances administering both therapies may be necessary. (Id.) In these
`
`situations, physicians generally have a number of strategies they can adopt in order
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`to mitigate the effects of the interaction, including modifying the dosage of one or
`
`both interacting drugs; interrupting therapy with the first drug to administer the
`
`second interacting drug; finding an alternate, non-interacting drug in the same
`
`5
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`therapeutic class as the first or second drug; or timing the administration of the
`
`drugs in such a way to mitigate the interaction. (Id.)
`
`In choosing such a strategy, a physician would have a number of different
`
`factors he or she would take into account in determining an appropriate dosing
`
`strategy for the patient. In particular, a physician may consider the need to
`
`maintain the patient on one or the other drug based on the patient’s medical history
`
`(i.e., whether the patient can be switched to a non-interacting drug in the same
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`therapeutic class); the risk of excessive dosing or underdosing a patient with either
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`of the interacting drugs; the ability to therapeutically monitor the patient for
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`potential toxicity or loss of efficacy from either interacting drug (e.g., is the patient
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`in a hospital setting, regularly under the doctor’s care; or in an emergency room
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`setting where the physician may not be able to follow up with the patient as
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`effectively), and the risks/benefits of the drugs themselves. (PAR1003, ¶ 53.) In
`
`evaluating these factors, a physician would have had a number of sources of
`
`information he or she could review to make informed decisions, including drug
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`prescribing information, published literature on either drug, and potential drug
`
`interaction studies. (Id.)
`
`The United States Food and Drug Administration (“FDA”) also recognized
`
`it was important to identify and test potential drug interactions as part of the
`
`routine work in developing a new drug. As of 2012, it was well-established that
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`6
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`“interactions between an investigational new drug and other drugs should be
`
`defined during drug development” in order to assess the drug’s safety and
`
`effectiveness. (PAR1011, 2:47–48.) In particular, such drug interactions should be
`
`investigated “to determine whether potential
`
`interactions between
`
`the
`
`investigational drug and other drugs exist, and if so, whether the potential for such
`
`interactions indicates the need for dosage adjustments, additional therapeutic
`
`monitoring, a contraindication to concomitant use, or other measures to mitigate
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`risk.” (Id., 2:49–51.)2 In particular, if potential drug interactions were identified
`
`based on in vitro studies showing that one drug interacted with enzymes that
`
`metabolized a second drug, drug manufacturers should determine whether
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`“additional studies are needed to better quantify the effect” and “whether dosage
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`adjustments or other prescribing modifications… are needed based on the
`
`identified interaction(s)….” (Id. at 2:82–3:89.)
`
`4.
`As of 2013,
`
`Background Regarding GHB/Valproate Interactions
`
`it was well-known
`
`that
`
`there were both potential
`
`pharmacodynamic and significant pharmacokinetic interactions between GHB and
`
`valproate. GHB and valproate were known to have potential pharmacodynamic
`
`interactions, as both are CNS depressants. (PAR1003, ¶ 100; see also PAR1006 at
`
`8; PAR1007 at 48.) Moreover, it was acknowledged that valproate could produce
`
`
`2 Emphasis added, unless otherwise noted.
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`CNS depression, especially when combined with other CNS depressants.
`
`(PAR1003, ¶ 100; PAR1007 at 48.)
`
`It was also known that valproate could inhibit the metabolism of GHB,
`
`particularly in the brain, and could lead to increased concentrations in the brain.
`
`(See PAR1003, ¶¶ 59–61.). In a 1988 paper, Vayer disclosed that valproate could
`
`inhibit the metabolism of succinic semialdehyde dehydrogenase, and prevent the
`
`conversion of GHB back to succinic semialdehyde. (PAR1003, ¶ 61; see also
`
`generally PAR1012.) Specifically, Vayer disclosed that “[s]everal workers have
`
`reported that valproate administration to rodents brings about an increase in the
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`brain GHB level. . . . As the principal precursor of GHB is GABA, the mechanism
`
`of this GHB increase could be due to the inhibition of the mitochondrial enxyme
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`succinic semialdehyde dehydrogenase . . . , which causes the pool of succinic
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`semialdehyde (the direct precursor of GHB) to be elevated.” (PAR1012 at 128.)
`
`Vayer goes on to state that “[a] more plausible mechanism for valproate-induced
`
`increases in GHB levels is the powerful inhibition of nonspecific succinic
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`semialdehyde reductase by valproate.” (Id.) Vayer summarized these metabolic
`
`pathways in two figures:
`
`8
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`
`
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`(PAR1012 at 128.) Others still noted that valproate (among other antiepileptic
`
`drugs) inhibits the transformation of GHB into succinic semialdehyde (SSA) by
`
`inhibiting the activity of GHB dehydrogenase, and that administration of these
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`antiepileptic drugs to rats can lead to the accumulation of GHB in their brains (See
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`PAR1014 at 754; see also PAR1015 at 971 (disclosing that valproate elevated
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`GHB brain concentrations in rats to 142% of the control value); see also PAR1003,
`
`¶ 61.) A POSA thus recognized that valproate could inhibit two key metabolic
`
`reactions of GHB, resulting in a pharmacokinetic drug interaction (as shown in the
`
`Figure below (see also PAR1003, ¶¶62–63):
`
`9
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`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`
`
`
`Inhibition of GHB Metabolism by Valproate (X)
`Moreover, it was recognized that interactions between valproate and GHB
`
`catabolism could result
`
`in pharmacokinetic drug
`
`interactions
`
`in humans.
`
`(PAR1003, ¶¶ 65–66.) For instance, Cagnin disclosed a case report of a patient
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`who received concomitant administration of 3500 mg/day (3.5 g/day) of GHB for
`
`treatment of alcoholism while receiving concomitant valproate (500 mg twice
`
`daily). (PAR1008 at 203.) The patient began to experience, inter alia, tonic-clonic
`
`seizures, which remitted when GHB was discontinued. (See id. at 204–05.) The
`
`authors of Cagnin noted that “valproate is a potent inhibitor of succinic
`
`semialdehyde dehydrogenase (SSADH), which catalyzes the production of
`
`succinate from succinic semialdehyde, an intermediate product in the metabolic
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`pathway transforming GHB into GABA and vice versa,” and that an inherited
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`deficiency in SSADH activity leads to increased GHB concentrations in the body,
`
`with clinical manifestations including tonic-clonic seizures. (Id. at 205.) From this
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`10
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`information, the authors postulated that “the neurotoxicity resulting from
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`overproduction of endogenous GHB was further increased by the simultaneous
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`administration of GHB drug[.]” (Id.)
`
`Likewise, in late 2012, Weiss reported a case of a patient who was
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`coadministered GHB (9 g/night, 4.5 g twice nightly) with the antiepileptic
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`topiramate (25 mg), who developed confusion, intermittent myoclonic jerks, and
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`rapid onset of coma. (PAR1010 at 1193.) The authors noted that, in plasma
`
`samples drawn from the patient, the GHB concentration was 2.8-fold higher when
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`the patient was administered topiramate, and 1.8-fold higher than the peak plasma
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`concentration of 142 mg/L that would be expected 0.5-2 hours after the second
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`daily dose of GHB. (Id.) The authors stated that metabolism via GHB
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`dehydrogenase is GHB’s main route of elimination, and that in vitro studies have
`
`demonstrated that it is inhibited by antiepileptic drugs such as valproate and
`
`ethosuximide. (Id. (citing PAR1014).) The authors concluded that, “in light of the
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`increasing therapeutic… use of GHB…, possible interactions should be evaluated
`
`in formal pharmacokinetic studies. In the mean time, we suggest using such
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`combinations only with great care.” (PAR1010 at 1193.)
`
`The ’306 Patent
`
`5.
`The ’306 patent issued against this backdrop. The ’306 patent is directed to
`
`methods for improving “the safety and efficacy of the administration of GHB or a
`
`11
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`salt thereof to a patient.” (PAR1001 at Abstract.) The ’306 patent discloses that
`
`concomitant administration of an MCT inhibitor, such as diclofenac, valproate, or
`
`ibuprofen, will affect GHB administration. (Id.)
`
`The ’306 patent specifically discloses a method for “treating a patient who is
`
`suffering from excessive daytime sleepiness, cataplexy, sleep paralysis, apnea,
`
`narcolepsy[,] sleep time disturbances, hypnagogic hallucinations, sleep arousal,
`
`insomnia, and nocturnal myoclonus with gamma-hydroxybutyrate (GHB) or a salt
`
`thereof, comprising: orally administering to the patient in need of treatment, an
`
`adjusted dosage amount of the salt of GHB when the patient is receiving a
`
`concomitant administration of valproate.” (Id. at 1:24-32.) In certain embodiments,
`
`the dosage adjustment is about a 1% to about a 50% reduction in the amount of
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`GHB “normally given to the patient.” (Id. at 1:32-36.)
`
`The ’306 patent also states that one embodiment of the invention is the
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`“discovery of drug interactions that change either, or both, the efficacy or safety
`
`profile of GHB.” (Id. at 10:47-49.) Specifically, the ’306 patent discloses that GHB
`
`interacts with valproate, diclofenac, and ibuprofen. (Id. at 10:50-51.) The ’306
`
`patent discloses that to achieve the benefits of GHB use, the GHB dose can be
`
`“administered in a reduced amount when a second compound, such as valproate, is
`
`concomitantly administered with GHB.” (Id. at 10:51-54.)
`
`12
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`The ’306 patent further discloses that the concomitant administration of
`
`GHB with MCT inhibitors, such as valproate, can “effect GHB levels or activity
`
`and alter the GHB safety and efficacy profile to create an unsafe condition.” (Id. at
`
`17:45-49.) Specifically, the ’306 patent states that valproate “can increase or
`
`prolong GHB effects.” (Id. at 17:49-50.) The ’306 patent also discloses that aspirin
`
`“may decrease the clearance of valproic acid, leading to higher-than-intended
`
`serum levels of the anticonvulsant.” (Id. at 15:65-67.)
`
`The ’306 patent notes that GHB is a central nervous system (CNS)
`
`depressant. (Id. at 13:56.) Further, the ’306 patent also notes that the concurrent
`
`use of GHB with other CNS depressants, including sedating antidepressants or
`
`antipsychotics, may increase the risk of respiratory depression, hypotension,
`
`profound sedation, syncope, and death. (Id. at 13:58–63.) The ’306 patent goes on
`
`to state that if use of GHB with a CNS depressant is required, dose reduction of
`
`one or more of the CNS depressants (including GHB) should be considered. (Id. at
`
`13:63–66.)
`
`V. CLAIM CONSTRUCTION
`Unless otherwise construed herein, the terms of claims 1-34 are to be given
`
`their broadest reasonable interpretation, as understood by one of ordinary skill in
`
`the art in view of the ’306 patent’s specification. See 37 C.F.R. § 42.100(b).
`
`13
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`

`

` “Concomitant” and “Concomitantly”
`
`A.
`The specification of the ’306 patent defines the claim terms “concomitant”
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`
`and “concomitantly” as:
`
`the administration of at least two drugs to a patient either
`subsequently, simultaneously, or consequently within a
`time period during which the effects of the first
`administered drug are still operative in the patient.
`Thus, if the first drug is, e.g., Xyrem®, or GHB, and the
`second drug is valproate, the concomitant administration
`of the second drug occurs within two weeks, preferably
`within one week or even three days, before or after the
`administration of the first drug
`(PAR1001 at 8:37-45 (emphasis added).)
`
`Therefore,
`
`the
`
`terms “concomitant” and “concomitantly” should be
`
`construed in their broadest reasonable interpretation as “the administration of at
`
`least two drugs to a patient either subsequently, simultaneously, or consequently
`
`within a time period during which the effects of the first administered drug are still
`
`operative in the patient.” (See also PAR1003, ¶¶ 33–35.)
`
`VI.
`
`IDENTIFICATION OF CHALLENGE
`
`IPR of the challenged claims of the ’306 patent is requested on the grounds
`
`for unpatentability listed below. Copies of the references are filed herewith. 37
`
`C.F.R. § 42.6(c). The proposed grounds in this Petition are supported by the
`
`Declaration of Dr. John Winkelman, M.D., Ph.D. (PAR1003.)
`
`14
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`Ground 35 U.S.C. Claims
`
`Index of References
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`
`1
`
`§ 103(a)
`
`1–34
`
`2
`
`§ 103(a)
`
`1–34
`
`Xyrem 2005 Label (PAR1006) in view of the
`Depakote 2011 Label (PAR1007), Cagnin
`(PAR1008), Waszkielewicz (PAR1009), and
`the FDA Guidance (PAR1011.)
`
`Xyrem 2005 Label (PAR1006) in view
`of the Depakote 2011 Label (PAR1007),
`Cagnin (PAR1008), Waszkielewicz
`(PAR1009), Weiss (PAR1010), and the
`FDA Guidance (PAR1011).
`
`For the asserted ground, Petitioner demonstrates below where each
`
`limitation either exists in the prior art or is rendered obvious, by evaluating the
`
`scope and contents of the prior art, any differences between the art and the
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`challenged claims, the knowledge of person of ordinary skill in the art, and any
`
`available objective indicia of nonobviousness in accordance with Graham v. John
`
`Deere Co., 383 U.S. 1 (1966); KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007).
`
`Identification of Prior Art
`
`A.
`The following table identifies the prior art used in both grounds:
`
`Exhibit
`
`Full Citation of Reference
`
`PAR1006 Jazz Pharmaceuticals, Inc., Prescribing Information and Medication
`Guide for XYREM (sodium oxybate) (Nov. 18, 2005)
`
`15
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`Abbvie, Inc., Prescribing Information and Medication Guide
`for DEPAKOTE (divalproex sodium) (Oct. 7, 2011)
`(“Depakote 2011 Label”)
`
`PAR1007
`
`PAR1009
`
`Waszkielewicz, A. et al., γ-Hydrobutyric Acid (GHB) and Its
`Chemical Modifications: A Review of the GHBergic System, 56(1)
`Pol. J. Pharmacol. 43–49 (2004) (“Waszkielewicz”)
`
`PAR1010
`
`Weiss, T. et al., Gamma-Hydroxybutyrate (GHB) and Topiramate—
`Clinically Relevant Drug Interaction Suggested by a Case of Coma
`and Increased Plasma GHB Concentration, 69(5) Eur. J. Clin.
`Pharmacol. 1193–94 (2013) (“Weiss”)
`PAR1008 Cagnin, A. et al., γ-Hydroxybutyric Acid-Induced Psychosis and
`Seizures, 21(2) Epilepsy Behav. 203–05 (2011) (“Cagnin”)
`
`PAR1011
`
`FDA’s Center for Drug Evaluation and Research, Guidance for
`Industry: Drug Interaction Studies—Study Design, Data Analysis,
`Implications for Dosing, and Labeling Recommendations (Feb.
`2012) (“FDA Guidance”)
`
`Each of the References Cited is Prior Art.
`
`B.
`Each of the references cited in this petition is available as prior art under the
`
`basis for qualification provided for by 35 U.S.C. § 311(b). The ’306 patent was
`
`filed on July 8, 2014 and claims the benefit of provisional application number
`
`61/771,557, filed on March 1, 2013, and provisional application number
`
`61/777,873, filed on March 12, 2013. (See PAR1001.) Accordingly, March 1, 2013
`
`is its earliest effective filing date. Each cited prior art reference qualifies
`
`independently as (1) having published before March 1, 2013 or (2) having been
`
`publicly disclosed more than a year prior to the application for patent in the United
`
`States.
`
`16
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`The FDA Guidance (PAR1011) Qualifies as Prior Art.
`
`1.
`“[T]he determination of whether a given reference qualifies as a prior art
`
`‘printed publication’
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`involves a case-by-case
`
`inquiry
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`into
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`the facts and
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`circumstances surrounding the reference’s disclosure to members of the public.”
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`CBM2013-00047, Paper 11, *16 (Feb. 18, 2014) (citing In re Klopfenstein, 380
`
`F.3d 1345, 1350 (Fed. Cir. 2004)). And “[a] reference is publicly accessible upon a
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`satisfactory showing that such document has been disseminated or otherwise made
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`available to the extent that persons interested and ordinarily skilled in the subject
`
`matter or art exercising reasonable diligence, can locate it.” Id. (quoting Kyocera
`
`Wireless Corp. v. Int’l Trade Comm’n, 545 F.3d 1340, 1350 (Fed. Cir. 2008)).
`
`The FDA Guidance (PAR1011) is entitled to the § 102(b) prior art date of its
`
`publication: February 21, 2012. The FDA Guidance was publicly accessible as of
`
`February 21, 2012, as shown by the Federal Register Announcement notifying the
`
`public of the availability of the FDA Guidance. (PAR1016.) The Federal Register
`
`page also provides a web address at which interested individuals can obtain a copy
`
`of the FDA Guidance. (Id.) In addition, the second page of the FDA Guidance
`
`indicates that additional copies of the FDA Guidance are available from the Office
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`of Communications of the FDA, and includes contact information for the Office of
`
`Communications. (PAR1011 at ii.) Therefore, the FDA Guidance was publicly
`
`accessible as of February 21, 2012.
`
`17
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,772,306
`Xyrem Label (PAR1006) Qualifies as Prior Art.
`
`2.
`The Xyrem (sodium oxybate) Oral Solution, Approved Labeling text
`
`(“Xyrem 2005 Label”) is entitled to the § 102(b) prior art date of its publication:
`
`November 18, 2005. (PAR1006.) The Xyrem 2005 Label was approved by the
`
`FDA on November 18, 2005. (PAR1017).
`
`3.
`
`Cagnin, Waszkielewicz, Weiss, and the Depakote 2011
`Label Qualify as Prior Art.
`
`Cagnin is entitled to the § 102(b) prior art date of its publication online: May
`
`6, 2011. (PAR1008.) Waszkielewicz is entitled to the § 102(b) prior art date of its
`
`publication: 2004. (PAR1009.) Weiss is entitled to the § 102(a) prior art date of its
`
`online publication: November 17, 2012. (PAR1010.)
`
`The Depakote (divalproex sodium) Tablets, Appro