UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`AMNEAL PHARMACEUTICALS LLC
`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
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`TABLE OF CONTENTS
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`
`INTRODUCTION AND STATEMENT OF RELIEF REQUESTED ............... 1
`I.
`II. GROUNDS FOR STANDING ............................................................................ 1
`III. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ................. 1
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED .............................. 2
`V. STATEMENT OF REASONS FOR THE RELIEF REQUESTED ................... 2
`A. Level Of Ordinary Skill in the Art .................................................................... 4
`B. Claim Construction ........................................................................................... 4
`1. “Concomitant” and “Concomitantly”............................................................ 4
`2. “Therapeutically Effective Amount” ............................................................ 5
`C. Scope and Content of the Prior Art ................................................................... 6
`1. Background on GHB ..................................................................................... 6
`2. Background on the Metabolic Pathway of GHB........................................... 8
`3. Background on Drug-Drug Interactions ......................................................10
`4. Background on Valproate ............................................................................12
`5. Background on Drug-Drug Interactions Between GHB and Valproate .....13
`6. Background on Drug Interactions Associated with Aspirin .......................18
`D. Identification of Grounds of Unpatentability .................................................18
`1. Identification of Prior Art References For Grounds 1-4 .............................20
`2. Each of the References For Grounds 1-4 are Prior Art to the ’306 Patent .21
`E. Ground 1: Claims 1-34 of the ’306 Patent Would Have Been Obvious Over
`the Xyrem Label (AMN1005) in view of Hechler (AMN1006), Shinka
`(AMN1007), and the Depakote Label (AMN1009) .......................................22
`1. Comparison of the Claims of the ’306 Patent to the Prior Art - Independent
`Claim 1 ........................................................................................................23
`2. Independent Claim 11 .................................................................................29
`3. Independent Claim 19 .................................................................................30
`4. Independent Claim 30 .................................................................................32
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`5. Independent Claim 33 .................................................................................34
`6. Dependent Claims 2, 4, 12, 13, 18, and 28 .................................................34
`7. Dependent Claims 3 and 8 ..........................................................................36
`8. Dependent Claims 5 and 16 ........................................................................37
`9. Dependent Claims 6, 17, and 27 .................................................................37
`10. Dependent Claims 7, 9, and 10 ...................................................................38
`11. Dependent Claims 14, 15, 20, and 21 .........................................................39
`12. Claims 22 and 24 .........................................................................................41
`13. Dependent Claims 23, 29, 32, and 34 .........................................................41
`14. Dependent Claims 25 ..................................................................................42
`15. Dependent Claim 26 ....................................................................................42
`16. Dependent Claim 31 ....................................................................................43
`F. Ground 2: Claims 1-34 of the ’306 Patent Would Have Been Obvious Over
`the Xyrem Label (AMN1005) in view of Hechler (AMN1006), Shinka
`(AMN1007), Cagnin (AMN1008), and the Depakote Label (AMN1009) ....44
`1. Comparison of the Claims of the ’306 Patent to the Prior Art - Independent
`Claim 1 ........................................................................................................46
`2. Independent Claim 11 .................................................................................48
`3. Independent Claim 19 .................................................................................49
`4. Independent Claim 30 .................................................................................49
`5. Independent Claim 33 .................................................................................51
`6. Dependent Claims 2, 4, 12, 13, 18, and 28 .................................................51
`7. Dependent Claims 3 and 8 ..........................................................................52
`8. Dependent Claims 5 and 16 ........................................................................52
`9. Dependent Claims 6, 17, and 27 .................................................................52
`10. Dependent Claims 7, 9, and 10 ...................................................................53
`11. Dependent Claims 14, 15, 20, and 21 .........................................................53
`12. Claims 22 and 24 .........................................................................................54
`13. Dependent Claims 23, 29, 32, and 34 .........................................................54
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`14. Dependent Claims 25 ..................................................................................55
`15. Dependent Claim 26 ....................................................................................55
`16. Dependent Claim 31 ....................................................................................55
`G. Ground 3: Claims 6, 17, and 27 of the ’306 Patent Would Have Been
`Obvious Over the Xyrem Label (AMN1005) in view of Hechler (AMN1006),
`Shinka (AMN1007), and the Depakote Label (AMN1009), in Further View
`of Kaufman (AMN1015) ................................................................................56
`H. Ground 4: Claims 6, 17, and 27 of the ’306 Patent Would Have Been
`Obvious Over the Xyrem Label (AMN1005) in view of Hechler (AMN1006),
`Shinka (AMN1007), Cagnin (AMN1008), and the Depakote Label
`(AMN1009), in Further View of Kaufman (AMN1015)................................57
`I. No Secondary Considerations Support Non-Obviousness .............................58
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ........................................58
`VII.CONCLUSION .................................................................................................60
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`I.
`
`INTRODUCTION AND STATEMENT OF RELIEF REQUESTED
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`Amneal Pharmaceuticals LLC (“Petitioner”) submits this Petition for Inter
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`Partes review (“IPR”) seeking cancellation of claims 1-34 of U.S. Patent Number
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`8,772,306 (“the ’306 patent”) (AMN1001) as unpatentable under 35 U.S.C. §103(a)
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`in view of the prior art. Jazz Pharmaceuticals, Inc. and Jazz Pharmaceuticals Ireland
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`Limited (collectively, “Jazz”) have represented that they are the patent owners for
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`the ’306 patent. See IPR2016-00024, Paper No 7. (Oct. 28, 2015). Jazz
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`Pharmaceuticals, Inc. has represented itself as the exclusive licensee of the ’306
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`patent. (Id.).
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`As explained below, Petitioner is at least reasonably likely to prevail on each
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`asserted Ground with respect to the challenged claims. Accordingly, Petitioner
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`respectfully requests that the Board institute IPR and cancel each of challenged
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`claims 1-34 of the ’306 patent.
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`II. GROUNDS FOR STANDING
`In accordance with 37 C.F.R. § 42.104(a), Petitioner certifies that the ’306
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`patent is available for IPR and Petitioner is not barred or estopped from requesting
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`IPR of any of the challenged claims.
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`III. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`Pursuant to 35 U.S.C. § 314(a), this petition, supported by the Declaration of
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`Dr. John R. Horn, Pharm.D., F.C.C.P. (AMN1003), sufficiently demonstrates that
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`there is a reasonable likelihood that Petitioner will prevail with respect to at least
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`one of the claims challenged in the petition.
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED
`The Office should institute IPR under 35 U.S.C. §§ 311-319 and 37 C.F.R.
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`§§ 42.1-42.80 and 42.100-42.123, and cancel claims 1-34—all claims—of the ’306
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`patent as unpatentable under 35 U.S.C. § 103, as set forth herein.
`
`V.
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`STATEMENT OF REASONS FOR THE RELIEF REQUESTED
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`Claims 1-34 of the ’306 patent are generally directed to methods for treating
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`a patient who is suffering from disorders such as cataplexy and narcolepsy with a
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`decreased amount of gamma-hydroxybutyrate (“GHB”), or a salt thereof, when the
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`GHB is administered concomitantly with valproate. (AMN1001 at 1:24-32). The
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`alleged invention of the claims of the ’306 patent is administering a reduced dose of
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`GHB when valproate is also administered.
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`The ’306 patent alleges that that the Applicant discovered unexpected drug-
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`drug interactions between GHB and frequently prescribed drugs, such as valproate.
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`(Id. at 13:48-55). During prosecution, the Applicant argued that such drug-drug
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`interactions between GHB and valproate would have been unexpected. Specifically,
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`the Applicant stated in response to a rejection, that the cited prior art “would not
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`teach or suggest that there would be a change in the GHB in vivo effect caused by
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`valproate. Furthermore, it would not have been known prior to the present
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`application what that effect would be, such as an increase or decrease in the in vivo
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`effect of GHB.” (AMN1002 at 1103) (emphasis in original). In addition, the
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`Applicant argued that the interactions between GHB and valproate would not have
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`been obvious based on the alleged unpredictability of whether valproate affected
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`GHB through inhibition of GHB dehydrogenase or as a monocarboxylate transporter
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`(“MCT”) inhibitor. (Id.). However, as explained below, the drug-drug interactions
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`between GHB and valproate were predictable and would have been obvious to a
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`Person of Ordinary Skill in the Art (“POSA”).
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`It was well known in the art more than one year prior to the earliest effective
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`filing date of the ’306 patent that concomitant administration of valproate with GHB
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`would increase GHB levels in vivo due to inhibited GHB metabolism. Specifically,
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`it was well known in the art that valproate inhibited GHB dehydrogenase and
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`succinic semialdehyde dehydrogenase (“SSADH”), two enzymes involved in the
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`primary metabolic pathway for GHB. A POSA would have understood that the
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`inhibition of GHB metabolism by valproate would result in increases in GHB levels
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`in vivo, and that such increases in GHB levels could lead to adverse events in
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`patients. A POSA would have further understood that a dose of GHB could be
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`reduced to account for increases in GHB levels due to the drug-drug interactions and
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`to prevent adverse events. Therefore, as explained in more detail below, the subject
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`matter of claims 1-34 of the ’306 would have been obvious to a POSA at the time of
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`the invention.
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`A. Level Of Ordinary Skill in the Art
`The POSA to which the ’306 patent pertains would have at least a bachelor’s
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`degree, master’s degree, Ph.D., Doctor of Pharmacy degree, or medical degree, and
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`at least five years of experience in the field of drug interactions. A POSA would
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`have had an understanding of the pharmacokinetics and pharmacodynamics of
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`drugs, and the risks associated with concomitant administration of certain drug
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`combinations. (AMN1003 at ¶ 31). A POSA could have worked as a part of a multi-
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`disciplinary team and utilize his or her own skills, and also take advantage of certain
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`specialized skills of others in the team to solve a given problem. (Id. at¶ 30).
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`B. Claim Construction
`Unless otherwise construed herein, the terms of claims 1-34 of the ’306 patent
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`are to be given their broadest reasonable interpretation, as understood by one of
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`ordinary skill in the art in view of the ’306 patent’s specification. See 37 C.F.R.
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`§ 42.100(b).
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`“Concomitant” and “Concomitantly”
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`1.
`The specification of the ’306 patent defines the claim terms “concomitant”
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`and “concomitantly” as:
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`. . . 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
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`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.
`(AMN1001 at 8:37-45) (emphasis added).
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`Thus, the terms “concomitant” and “concomitantly” should be construed in
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`their broadest reasonable interpretation in light of the specification as “the
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`administration of at least two drugs to a patient either subsequently, simultaneously,
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`or consequently within a time period during which the effects of the first
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`administered drug are still operative in the patient.” (AMN1003 at ¶¶ 78-79).
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`“Therapeutically Effective Amount”
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`2.
`The specification of the ’306 patent defines the claim term “therapeutically
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`effective amount” as:
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`. . . an amount of a compound sufficient to treat,
`ameliorate, or prevent the identified disease or
`condition, or to exhibit a detectable therapeutic,
`prophylactic, or inhibitory effect. The effect can be
`detected by, for example, an improvement in clinical
`condition, or reduction in symptoms. The precise
`effective amount for a subject will depend upon the
`subject's body weight, size, and health; the nature and
`extent of the condition; and the therapeutic or
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`combination of therapeutics selected for administration.
`Where a drug has been approved by the U.S. Food and
`Drug Administration (FDA), a “therapeutically effective
`amount” refers to the dosage approved by the FDA or its
`counterpart foreign agency for treatment of the identified
`disease or condition.
`(AMN1001 at 9:8-22)(emphasis added).
`
`Therefore, the term “therapeutically effective amount” should be construed in
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`its broadest reasonable interpretation in light of the specification as “an amount of a
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`compound sufficient to treat, ameliorate, or prevent the identified disease or
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`condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect.”
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`(AMN1003 at ¶¶ 80-81).
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`C.
`
`Scope and Content of the Prior Art
`1.
`The ’306 patent is generally directed to methods for treating a patient who is
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`Background on GHB
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`suffering from disorders such as cataplexy and narcolepsy with a decreased amount
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`of GHB, or a salt thereof, when the GHB is administered concomitantly with
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`valproate. (AMN1001 at 1:24-32; AMN1003 at ¶¶ 7, 67, 71).
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`GHB is an endogenous neurotransmitter that is naturally occurring, and is
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`located in almost all regions of the mammalian brain. (AMN1003 at ¶ 38;
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`AMN1015 at 965; AMN1019 at 2721; AMN1011 at 44; AMN1006 at 753;
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`AMN1017 at 127; AMN1020 at 338). GHB functions as an inhibitory
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`neurotransmitter in the central nervous system (“CNS”). (AMN1003 at ¶ 38;
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`AMN1011 at 44; AMN1017 at 127). GHB is a metabolite of gamma-aminobutyric
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`acid (“GABA”), a major inhibitory neurotransmitter in the brain. (AMN1003 at ¶¶
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`39-40; AMN1018 at 47; AMN1020 at 338). It was well known in the art that
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`alterations to GABA levels in the brain can lead to adverse events, such as
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`convulsions, as well as several brain diseases, including epilepsy. (AMN1003 at ¶
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`40; AMN1022 at 681).
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`More than one year prior to the effective filing date of the ’306 patent, GHB
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`was commercially known as Xyrem and sold by Jazz Pharmaceuticals. (AMN1003
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`at ¶ 41; AMN1001 at 2:52-54; AMN1005 at 1). The United States Food and Drug
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`Administration’s Orange Book lists the ’306 patent for Xyrem. (AMN1003 at ¶¶
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`86-88; AMN1012). The active ingredient in Xyrem is sodium oxybate, the sodium
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`salt of GHB. (AMN1003 at ¶ 38, 40, 92; AMN1005 at 1, 7).1 Sodium oxybate was
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`known to be a CNS depressant. (AMN1003 at ¶ 41, 92; AMN1005 at 1, 7-8).
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`Xyrem is indicated for the treatment of excessive daytime sleepiness and
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`cataplexy in patients with narcolepsy. (AMN1003 at ¶ 41, 92; AMN1005 at 1, 7).
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`Xyrem was approved by the FDA on November 18, 2005. (AMN1003 at ¶ 91;
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`1 As sodium oxybate is the sodium salt of GHB, the terms “GHB” and “sodium
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`oxybate” are used interchangeably throughout this petition.
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`AMN1013 at 1, 4). The Xyrem Labeling Text (“Xyrem Label”) discloses doses of
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`GHB between 4.5 grams per day to 9 grams per day, administered in two equal
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`divided doses. (AMN1003 at ¶¶ 93-94; AMN1005 at 22-23). The recommended
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`starting dose is 4.5 grams per night, divided into two equal doses of 2.25 grams.
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`(Id.). Further, the Xyrem Label discloses that GHB should be titrated to effect.
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`(AMN1003 at ¶ 93; AMN1005 at 22). The starting dosage can then be titrated to a
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`maximum of 9 grams per night in increments of 1.5 grams per night. (AMN1003 at
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`¶¶ 94-95; AMN1005 at 22-23, 42). In addition, the Xyrem Label discloses that if
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`adverse events occur, the dose of GHB should be titrated down to decrease the dose
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`by 1.5 grams per night. (AMN1003 at ¶ 95; AMN1005 at 42-43).
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`Background on the Metabolic Pathway of GHB
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`2.
`The metabolism of GHB was known in the art more than one year prior to the
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`effective filing date of the ’306 patent. GHB is primarily metabolized in vivo by the
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`enzyme GHB dehydrogenase. (AMN1003 at ¶¶ 43-44, 96, 100-102, 119; AMN1005
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`at 2; AMN1006 at 754, 757; AMN1015 at 965, 967; AMN1019 at 2721; AMN1020
`
`at 338-339). Specifically, GHB is metabolized to succinic semialdehyde (“SSA”)
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`by GHB dehydrogenase. (Id.). In turn, SSA is metabolized by SSADH to succinic
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`acid. (Id.). Ultimately, succinic acid enters the Krebs cycle and is metabolized to
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`carbon dioxide and water. (Id.).
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`It was also known in the art that GHB can be alternatively metabolized to SSA
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`by non-specific succinic semialdehyde reductase to follow the same metabolic
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`pathway to the Krebs cycle. (AMN1003 at ¶ 45, 105-107; AMN1007 at 103-104,
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`106; AMN1022 at 686; AMN1020 at 338-39; AMN1017 at 128).
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`The metabolic pathway for GHB is summarized in Figure 1 below:
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`Figure 1: Metabolic Pathways for GHB (Sodium Oxybate)
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`(AMN1003 at ¶¶ 42-47; see, e.g., AMN1005 at 2; AMN1006 at 754, 757; AMN1007
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`at 103-104, 106; AMN1015 at 965; AMN1017 at 128; AMN1022 at 681).
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`In contrast to metabolism, GHB can be formed from SSA in the reverse
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`pathway by specific succinic semialdehyde reductase (“specific SSR”). (AMN1003
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`at ¶ 47; AMN1007 at 103-104; AMN1017 at 128; AMN at 681).
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`Background on Drug-Drug Interactions
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`3.
`It was well known in the art that a drug interaction occurs when a substance
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`(such as another drug) affects the activity of a drug when both are administered
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`concomitantly. (AMN1003 at ¶ 32). The drug that is affected is known as the object
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`drug, and the drug that causes the change is the precipitant drug. (Id.). A drug
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`interaction that affects the object drug may lead to changes in response to the object
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`drug, which are most commonly loss of efficacy or increased risk of drug toxicity.
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`(Id.; see, e.g., AMN1029 at 1-2).
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`Most drug interactions occur due to the precipitant drug altering the
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`absorption, distribution, metabolism, and/or excretion (“ADME”) of the object drug.
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`(AMN1003 at ¶ 33; see, e.g., AMN1029 at 1-2). Based on pharmacologic and
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`pharmacokinetic principles, it was well known to a POSA that if a drug is known to
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`be metabolized by a specific enzyme (such as GHB dehydrogenase), then there is a
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`predictable likelihood that the drug will interact with other drugs that either inhibit
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`or increase the activity of the same enzyme. (AMN1003 at ¶¶ 33-34).
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`Further, it was well known that pharmacodynamic interactions can result in
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`drug interactions by changing an object drug’s effect without a change in its
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`pharmacokinetics or plasma concentration. (Id. at ¶ 34). For example, if two drugs
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`have a sedative effect, increased sedation could occur if both drugs are administered
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`concomitantly. (Id.).
`
`Based on the pharmacologic and pharmacokinetic interactions between two
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`drugs, a POSA would have been able to predict appropriate dosage adjustments of
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`both the object drug and the precipitant drug to account for the drug-drug
`
`interactions.
`
` (Id. at ¶ 35).
`
` For example,
`
`if
`
`the pharmacokinetic or
`
`pharmacodynamics effects of the object drug were increased by a precipitant drug,
`
`a POSA would have understood that decreasing the dose of the object drug was an
`
`option to account for the drug-drug interactions between the object drug and the
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`precipitant drug. (Id.).
`
`A POSA would have also understood that it was routine practice to conduct
`
`drug interaction studies to further evaluate interactions between an object drug and
`
`drugs that are known to alter its metabolism or elimination based on the
`
`pharmacologic properties of the drugs. (Id.). Indeed, this routine approach to
`
`assessing drug interactions was well known in the art and has been incorporated into
`
`the FDA’s Draft Guidance to Industry on Drug Interaction Studies. (Id. at ¶ 36; see
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`generally AMN1010). The FDA recommends drug interaction studies to be done to
`
`examine the potential interaction between a new drug product and drugs that are
`
`known to alter its metabolism or elimination based on the pharmacologic properties
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`of the drugs. (AMN1003 at ¶ 36; AMN1010 at 1). Further, the FDA Draft Guidance
`
`also discloses procedures for conducting routine pharmacokinetic studies.
`
`(AMN1003 at ¶ 36; AMN1010 at 14-15, 18-20, 33-39, 52-55).
`
`In addition, it was routine practice for pharmaceutical and medical
`
`professionals to monitor for such potential drug-drug interactions, warn a patient of
`
`any potential drug-drug interactions, and adjust the dosages of the prescribed drugs
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`to account for any drug-drug interactions when appropriate. (AMN1003 at ¶ 37).
`
`Background on Valproate
`
`4.
`Valproate (which is also known as valproic acid or divalproex) is an
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`antiepileptic drug that has been used to treat seizures in adults and children for
`
`decades. (AMN1003 at ¶¶ 51, 54, 115; AMN1022 at 669-70; AMN1009 at 35;
`
`AMN1017 at 127). Valproate is marketed in the United States as Depakote, which
`
`was originally approved by the FDA in 1983. (AMN1003 at ¶ 52, 115; AMN1009
`
`at 1).
`
`The active ingredient in Depakote is divalproex sodium, which is a salt form
`
`of valproate. (AMN1003 at ¶¶ 52, 114; AMN1009 at 1, 48, 55). Valproate was
`
`known to be a CNS depressant. (AMN1003 at ¶ 116; AMN1009 at 1, 48). In
`
`addition, it was known that CNS depression may occur when valproate is
`
`administered with another CNS depressant. (Id.).
`
`The antiepileptic properties of valproate were known to be related to increases
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`in GABA concentrations in the brain. (AMN1003 at ¶ 54, 115; AMN1009 at 35).
`
`In particular, it was known that valproate increased concentrations of GABA by
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`inhibiting GABA transaminase, an enzyme which metabolizes GABA. (AMN1003
`
`at ¶ 54; AMN1017 at 127). Further, it was known that valproate also inhibits
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`SSADH and GHB dehydrogenase, which contributes to increases in GABA.
`
`(AMN1003 at ¶¶ 54-55, 57; AMN1017 at 12; AMN1006 at 759)
`
`The half-life of valproate is approximately nine to sixteen hours. (AMN1003
`
`at ¶ 55; AMN1009 at 37). Valproate is metabolized in vivo to metabolites 4-
`
`hydroxyvalproate (“4-HVPA”) and 5-hydroxyvalproate (“5-HVPA”). (AMN1003
`
`at ¶ 55; AMN1007 at 104, 106). Increased concentrations of these metabolites have
`
`been associated with elevated GHB concentrations. (Id.).
`
`5.
`
`Background on Drug-Drug Interactions Between GHB and
`Valproate
`
`Valproate was well known to be a GHB dehydrogenase inhibitor more than
`
`one year before the effective filing date of the ’306 patent. (AMN1003 at ¶¶ 57,
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`100; AMN1006 at 754, 757, 759; AMN1015 at 967; AMN1023 at 71). The
`
`inhibition of GHB dehydrogenase by valproate was known to increase levels of GHB
`
`in the brain, resulting in intensified effects after administration of GHB. (AMN1003
`
`at ¶¶ 57, 100; AMN1006 at 759; AMN1020 at 340, 342-343, 351).
`
`It was also known in the art that in addition to the inhibition of GHB
`
`dehydrogenase, that therapeutic levels of valproate also inhibit other aspects of the
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`GHB metabolic pathway. (AMN1003 at ¶¶ 58, 104-107; AMN1007 at 99-101, 103-
`
`104, 106). Valproate also inhibits SSADH, which in turn also results in
`
`accumulation of SSA, which is converted to GHB and increases levels of GHB.
`
`(AMN1003 at ¶ 58; AMN1007 at 103-104, 106; AMN1034 at 308). In addition,
`
`valproate was known as a potent inhibitor of nonspecific SSR, further leading to
`
`increased levels of GHB. (AMN1003 at ¶¶ 56, 58; AMN1007 at 103-104, 106;
`
`AMN1022 at 686). Valproate does not affect specific SSR, which further leads to
`
`increased levels of GHB. (Id.).
`
`The effect of concomitant valproate administration on the GHB metabolic
`
`pathway is shown in Figure 2 below.
`
`
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`14
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`
`
`Figure 2: Inhibitory Effect of Valproate on Metabolic Pathways for GHB
`
`(AMN1003 at ¶¶ 57-60; see, e.g., AMN1005 at 2; AMN1006 at 754, 757; AMN1007
`
`at 103-104, 106; AMN1015 at 965; AMN1017 at 128; AMN1022 at 681).
`
`The red X marks in Figure 2 indicate how valproate affects the metabolic
`
`pathway of GHB. Specifically, valproate inhibits GHB dehydrogenase, nonspecific
`
`SSR, and SSADH to prevent GHB metabolism, which results in increased GHB
`
`levels in the brain. (AMN1003 at ¶ 59; AMN1007 at 106; AMN1006 at 759;
`
`AMN1017 at 128; AMN1022 at 686). Valproate was known to not inhibit specific
`15
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`

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`SSR, which converts SSA to GHB, further leading to increased accumulation of
`
`GHB. (AMN1003 at ¶ 56, 107; AMN1007at 103-104, 106; AMN1022 at 686).
`
`
`
`It was also known in the art that the increased GHB levels in the brain due to
`
`valproate can result in absence-like epileptic seizures. (AMN1003 at ¶ 60;
`
`AMN1006 at 759; AMN1008 at 2005; AMN1022 at 686). The increase in brain
`
`GHB levels due to concomitant administration of valproate with GHB was known
`
`to be time-dependent and dose-dependent. (AMN1003 at ¶ 60; AMN1020 at 343;
`
`AMN1017 at 128; AMN1022 at 686).
`
`
`
`Thus, a POSA would have understood based on the prior art that the inhibition
`
`of GHB metabolism by valproate could lead to drug-drug interactions between
`
`valproate and GHB when the two drugs are concomitantly administered, which
`
`could lead to adverse events in patients. (AMN1003 at ¶ 61).
`
`
`
`Indeed, Cagnin disclosed a case report of a drug-drug interaction between
`
`GHB and valproate when the two drugs were administered concomitantly to a
`
`patient. (AMN1003 at ¶¶ 108-109; AMN1008 at 203). When the patient was
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`concomitantly administered 3.5 grams of GHB per day with 500 mg of valproate
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`twice per day, she developed daily tonic-clonic seizures and exhibited psychotic
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`behaviors. (AMN1003 at ¶ 109; AMN1008 at 203-204). After the GHB was
`
`discontinued, the seizures went into immediate remission. (AMN1003 at ¶ 109;
`
`AMN1008 at 205).
`
`
`
`16
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`

`
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`Cagnin suggested that the adverse events were caused by drug-drug
`
`interactions between GHB and valproate. (AMN1003 at ¶¶ 110-112; AMN1008 at
`
`205). Cagnin acknowledged the inhibition of the metabolic pathway of GHB by
`
`valproate as the cause of the adverse events, stating that valproate is a potent in vitro
`
`inhibitor of SSADH, which “catalyzes the production of succinate from succinic
`
`semialdehyde, an intermediate product in the metabolic pathway transforming GHB
`
`into GABA and vice versa.” (AMN1003 at ¶ 110; AMN1008 at 205). Cagnin
`
`concluded that their observations regarding adverse events resulting from
`
`administration of GHB with valproate outline the risk of drug-drug interactions
`
`when multiple drugs are prescribed to patients. (AMN1003 at ¶ 112; AMN1008 at
`
`205). Therefore, a POSA would have understood from Cagnin, in light of the prior
`
`art, that clinically relevant doses of GHB and valproate could lead to drug-drug
`
`interactions due to inhibited GHB metabolism, which could result in adverse events
`
`in patients.
`
`
`
`The Applicant’s characterization during prosecution that it was unpredictable
`
`what the effect of valproate on GHB levels would be due to valproate’s inhibition of
`
`both GHB dehydrogenase and MCT was incorrect. (AMN1003 at ¶ 83; 84;
`
`AMN1002 at 1103). A POSA would have understood that it was well known in the
`
`art that valproate inhibits GHB metabolism by inhibiting GHB dehydrogenase and
`
`SSADH, and that net increases of GHB in vivo after concomitant administration of
`
`
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`

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`valproate would have been predictable. (AMN1003 at ¶ 85; AMN1006 at 754, 757,
`
`759; AMN1007 at 99-100, 103-104, 106; AMN1015 at 967; AMN1008 at 203-205).
`
`Further, a POSA would have understood based on Borgen that renal elimination of
`
`GHB due to MCT was a minor pathway of GHB elimination, and that MCT
`
`inhibition would not have had a significant impact on overall GHB levels in vivo.
`
`(AMN1003 at ¶ 84; AMN1033 at 62, 64).
`
`Background on Drug Interactions Associated with Aspirin
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`6.
`It was also well known in the art that concomitant administration of valproate
`
`with aspirin can result in drug-drug interactions. (AMN1003 at ¶¶ 63, 118;
`
`AMN1009 at 1, 24). The Depakote Label recommended that valproate
`
`concentrations be monitored when aspirin is co-administered with valproate.
`
`(AMN1003 at ¶¶ 63, 118; AMN1009 at 24). In addition, the Depakote Label states
`
`that “[c]aution should be observed if valproate and aspirin are to be co-
`
`administered.” (Id.).
`
`It was also known in the art that salicylates, such as aspirin, inhibited GHB
`
`dehydrogenase. (AMN1003 at ¶¶ 64, 119-120; AMN1015 at 967). Thus, a POSA
`
`would have understood that co-administration of GHB and aspirin could lead to
`
`potential drug-drug interactions.
`
`Identification of Grounds of Unpatentability
`
`D.
`As detailed below, claims 1-34 of the ’306 patent would have been obvious in
`
`
`
`18
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`light of the prior art listed in the grounds for unpatentability below:
`
`Ground 35 U.S.C. Claims
`
`Prior Art References
`
`1
`
`§ 103(a)
`
`1-34
`
`2
`
`§ 103(a)
`
`1-34
`
`3
`
`§ 103(a)
`
`6, 17, 27
`
`4
`
`§ 103(a)
`
`6, 17, 27
`
`The Xyrem Label (AMN1005) in view of
`Hechler (AMN1006),
`Shinka (AMN1007), and
`the Depakote Label (AMN1009)
`The Xyrem Label (AMN1005) in view of
`Hechler (AMN1006),
`Shinka (AMN1007),
`Cagnin (AMN1008), and
`the Depakote Label (AMN1009)
`The Xyrem Label (AMN1005) in view of
`Hechler (AMN1006),
`Shinka (AMN1007),
`the Depakote Label (AMN1009), and in
`further view of Kaufman (AMN1015)
`The Xyrem Label (AMN1005) in view of
`Hechler (AMN1006),
`Shinka (AMN1007),
`Cagnin (AMN1008),
`the Depakote Label (AMN1009), and in
`further view of Kaufman (AMN1015)
`
`
`
`Pursuant to 37 C.F.R. § 42.6(c), copies of the exhibits to this petition are filed
`
`herewith. The grounds for unpatentability in this Petition are supported by the
`
`Declaration of Dr. John Horn, Pharm.D., F.C.C.P. (AMN1003).
`19
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`

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`For each asserted ground, the Petitioner details below where each limitation
`
`of the claims of the ’306 patent either exists in the prior art or is rendered obvious,
`
`by evaluating the scope and content of the prior art, any differences between the art
`
`and the challenged claims, the knowledge of person of ordinary skill in the art, and
`
`any available objectiv