`
`
`
`
`
`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
`_____________________
`
`DECLARATION OF JOHN W. WINKELMAN, M.D., Ph.D.
`
`
`
`Page 1 of 116
`
`JAZZ EXHIBIT 2009
`Ranbaxy Inc. (Petitioner) v. Jazz Pharms. Ireland Ltd. (Patent Owner)
`Case IPR2016-00024
`
`

`

`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`OVERVIEW .................................................................................................... 1
`
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 7
`
`III.
`
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 10
`
`IV. THE ’306 PATENT AND ITS CLAIMS ...................................................... 11
`
`A. Overview of the ’306 Patent ................................................................ 12
`
`B.
`
`C.
`
`Claim Construction – “Concomitant” and “Concomitantly” .............. 17
`
`Orange Book listing of the ’306 patent ............................................... 19
`
`V.
`
`STATE OF THE ART ................................................................................... 19
`
`A. Narcolepsy and GHB .......................................................................... 20
`
`B.
`
`C.
`
`Valproic Acid/Divalproex Sodium ..................................................... 24
`
`Drug Interactions ................................................................................. 26
`
`D. GHB Metabolism and Valproate Interactions ..................................... 31
`
`VI. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS ......... 38
`
`A.
`
`The Scope and Content of the Prior Art .............................................. 40
`
`1.
`
`2.
`
`3.
`
`The Xyrem 2005 Label (PAR1006) .......................................... 40
`
`The Depakote 2011 Label (PAR1007) ..................................... 42
`
`Cagnin (PAR1008) .................................................................... 43
`
`4. Waszkielewicz (PAR1009) ....................................................... 44
`
`5. Weiss (PAR1010) ..................................................................... 45
`
`6.
`
`The FDA Guidance (PAR1011)................................................ 46
`
`B.
`
`Comparison of the Prior Art to the Claims ......................................... 47
`
`
`
`ii
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`Page 2 of 116
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`Claim 1 ...................................................................................... 49
`
`Claim 11 .................................................................................... 63
`
`Claim 19 .................................................................................... 73
`
`Claims 30 and 33....................................................................... 82
`
`Claims 2, 4, 12, 13, 18, and 28 ................................................. 98
`
`Claims 3 and 8 .........................................................................100
`
`Claims 5 and 16 .......................................................................100
`
`Claim 6, 17, and 27 .................................................................101
`
`Claims 7, 9, and 10 .................................................................102
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10. Claims 14, 15, 20, and 21 .......................................................103
`
`11. Claims 22 and 24.....................................................................104
`
`12. Claim 25 ..................................................................................105
`
`13. Claim 26 ..................................................................................105
`
`14. Claim 31 ..................................................................................105
`
`15. Claims 23, 29, 32 and 34 ........................................................106
`
`VII. SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ............ 107
`
`A. No commercial success. .................................................................... 107
`
`B.
`
`C.
`
`No long-felt but unmet need or failure of others. ............................. 108
`
`No unexpected superior results. ........................................................ 110
`
`VIII. CONCLUSION ............................................................................................ 112
`
`
`
`iii
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`Page 3 of 116
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`

`

`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`
`I, John W. Winkelman, M.D., Ph.D., do hereby declare as follows:
`
`I.
`
`OVERVIEW
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration. This declaration is based on my personal knowledge as an expert
`
`in treatment of sleep disorders with extensive experience treating patients for both
`
`excessive daytime sleepiness and cataplexy in narcolepsy. I understand that this
`
`declaration is being submitted together with a petition for an Inter Partes Review
`
`(“IPR”) of claims 1-34 of U.S. Patent No. 8,772,306 (“the ’306 patent,”
`
`PAR1001.)
`
`2.
`
`I have been retained as an expert witness on behalf of Par
`
`Pharmaceutical, Inc. (“Par”) for this IPR. I am being compensated for my time in
`
`connection with this declaration at my standard consulting rate of $600 per hour
`
`and $900 per hour for time at deposition or at trial. I have no personal or financial
`
`interest in the outcome of this proceeding.
`
`3.
`
`I understand that the ’306 patent issued on July 8, 2014, and resulted
`
`from U.S. Ser. No. 13/872,997, filed on April 29, 2013. I also understand that the
`
`U.S. Patent and Trademark Office (“USPTO”) records state that the ’306 patent is
`
`currently assigned to Jazz Pharmaceuticals, Inc. (“Jazz”).
`
`1
`
`Page 4 of 116
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`

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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`The face page of the ’306 patent lists another patent application. I
`
`4.
`
`understand that the ’306 patent is related to this patent application, which was
`
`filed on March 1, 2013.
`
`5.
`
`In preparing this declaration, I have reviewed the ’306 patent
`
`(PAR1001) and its file history (PAR1002). I have also considered each of the
`
`documents listed in the table below, in light of general knowledge in the art as of
`
`March 1, 2013.
`
`Par
`Exhibit #
`
`Description
`
`1001
`
`1002
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`Eller, M., U.S. Patent No. 8,772,306 (filed Apr. 29, 2013; issued
`Jul. 8, 2014)
`
`File History for U.S. Patent No. 8,772,306 (filed Apr. 29, 2013;
`issued Jul. 8, 2014)
`
`Orange Book Patent Exclusivity Listing for XYREM
`(http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew
`.cfm?Appl_No=021196&Product_No=001&table1=OB_Rx)
`
`Jazz Pharmaceuticals, Inc., Prescribing Information and
`Medication Guide for XYREM (sodium oxybate) (Nov. 18,
`2005)
`
`Abbvie, Inc., Prescribing Information and Medication Guide for
`DEPAKOTE (divalproex sodium) (Oct. 7, 2011)
`
`Cagnin, A. et al., γ-Hydroxybutyric Acid-Induced Psychosis and
`Seizures, 21(2) Epilepsy Behav. 203–05 (2011) (“Cagnin”)
`
`Waszkielewicz, A. et al., γ-Hydroxybutyric Acid (GHB) and Its
`Chemical Modifications: A Review of the GHBergic System,
`56(1) Pol. J. Pharmacol. 43–49 (2004) (“Waszkielewicz”)
`
`2
`
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`

`

`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`
`Par
`Exhibit #
`
`Description
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`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”)
`
`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”)
`
`Vayer, P. et al., Is the Anticonvulsant Mechanism of Valproate
`Linked to Its Interaction with the Cerebral γ-Hydroxybutyrate
`System?, 9(4) Trends Pharmacol. Sci. 127–29 (1988) (“Vayer”)
`
`Shinka, T. et al., Effect of Valproic Acid on the Urinary
`Metabolic Profile of a Patient with Succinic Semialdehyde
`Dehydrogenase Deficiency, 792(1) J. Chromatogr. B 99–106
`(2003) (“Shinka”)
`
`Hechler, V. et al., γ-Hydroxybutyrate Conversion into GABA
`Induces Displacement of GABAB Binding That Is Blocked by
`Valproate and Ethosuximide, 281(2) J. Pharmacol. Exp. Ther.
`735–60 (1997)
`
`Kaufman, E. et al., An Overview of γ-Hydroxybutyrate
`Catabolism: The Role of the Cytosolic NADP+-Dependent
`Oxidoreductase EC 1.1.1.19 and of a Mitochondrial
`Hydroxyacid-Oxoacid Transhydrogenase in the Initial, Rate-
`Limiting Step in This Pathway, 16(9) Neurochem. Res. 965–74
`(1991)
`
`Draft Guidance for Industry on Drug Interaction Studies—
`Study Design, Data Analysis, Implications for Dosing,
`and Labeling Recommendations, 77 Fed. Reg. 9,946 (Feb. 21,
`2012)
`
`1017
`
`FDA Approval Letter for Xyrem (Nov. 18, 2005)
`
`3
`
`Page 6 of 116
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`

`

`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`
`Par
`Exhibit #
`
`Description
`
`1018
`
`FDA Approval Letter for Depakote Label (Oct. 7, 2011)
`
`Bhattacharya, I. et al., Potential γ-Hydroxybutyric Acid (GHB)
`Interactions Through Blood–Brain Barrier Transport
`Inhibition: A Pharmacokinetic Simulation-Based Evaluation,
`33(5) J. Pharmacokinetics & Pharmacodynamics 657–81
`(2006) (“Bhattacharya”)
`
`Swann, A., Major System Toxicities and Side Effects of
`Anticonvulsants, 62(Suppl. 14) J. Clin. Psychiatry 16–21 (2001)
`(“Swann”)
`
`European Medicines Agency, Scientific Discussion: Sodium
`Oxybate (Aug. 9, 2006)
`
`European Medicines Agency, Find medicine – Xyrem –
`Assessment History (last visited Oct. 5, 2015), available at
`http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines
`/human/medicines/000593/human_med_001163.jsp&mid=WC0
`b01ac058001d124
`
`FDA Approval Letter for Xyrem (Jul. 17, 2002)
`
`Jazz Pharmaceuticals, Inc., Prescribing Information and
`Medication Guide for XYREM (sodium oxybate) (2014)
`
`Cipriani, A. et al., Valproic Acid, Valproate and Divalproex in
`the Maintenance Treatment of Bipolar Disorder (Review), 10
`Cochrane Database Syst. Rev. CD003196 (2013)
`
`Bhattacharya, I. et al., GHB (γ-Hydroxybutyrate) Carrier-
`Mediated Transport across the Blood-Brain Barrier, 311(1) J.
`Pharmacol. Exp. Ther. 92–98 (2004)
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`4
`
`Page 7 of 116
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`

`

`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`
`Par
`Exhibit #
`
`Description
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`Cui, D. et al., The Drug of Abuse γ-Hydroxybutyrate Is a
`Substrate for Sodium-Coupled Monocarboxylate Transporter
`(SMCT) 1 (SLC5A8): Characterization of SMCT-Mediated
`Uptake and Inhibition, 37(7) Drug Metab. Dispos. 1404–10
`(2009)
`
`Eller, M. et al., Evaluation of Drug–Drug Interactions of
`Sodium Oxybate with Divalproex: Results from a
`Pharmacokinetic/Pharmacodynamics Study, 14S Abs. Sleep
`Med. e302–e303 (2013)
`
`Harvey, P. et al., The Inhibitory Effect of Sodium n-Dipropyl
`Acetate on the Degradative Enzymes of the GABA Shunt, 52(2)
`FEBS Lett. 251–54 (1975)
`
`Kaufman, E. et al., Oxidation of γ-Hydroxybutyrate to Succinic
`Semialdehyde by a Mitochondrial Pyridine Nucleotide-
`Independent Enzyme, 51(4) J. Neurochem. 1079–84 (1988)
`
`Kaufman, E. et al., Evidence of the Participation of a Cytosolic
`NADP+-Dependent Oxidoreductase in the Catabolism of γ-
`Hydroxybutyrate in Vivo, 48(6) J. Neurochem. 1935–41 (1987)
`
`Kennedy, G. et al., CNS Adverse Events Associated with
`Antiepileptic Drugs, 22(9) CNS Drugs 739–60 (2008)
`
`Löscher, W., Basic Pharmacology of Valproate: A Review after
`35 Years of Clinical Use for the Treatment of Epilepsy, 16(10)
`CNS Drugs 669–42 (2002)
`
`Morris, M. et al., Overview of the Proton-Coupled MCT
`(SLC16A) Family of Transporters: Characterization, Function
`and Role in the Transport of the Drug of Abuse γ-
`Hydroxybutyric Acid, 10(2) AAPS J. 311–21 (2008)
`
`Rumigny, J. et al., Specific and Non-Specific Succinic
`Semialdehyde Reductases from Rat Brain: Isolation and
`Properties, 117(1) FEBS Lett. 111–16 (1980)
`
`5
`
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`

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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`
`Par
`Exhibit #
`
`Description
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`Schep, L. et al., The Clinical Toxicology of Gamma-
`Hydroxybutyrate, Gamma-Butyrolactone and 1,4-Butanediol,
`50(6) Clin. Toxicol. (Phila). 458–70 (2012)
`
`Thompson, P.J. et al., Sodium Valproate and Cognitive
`Functioning in Normal Volunteers, 12(6) Br. J. Clin.
`Pharmacol. 819–24 (1981)
`
`van der Laan, J.W. et al., Di-n-Propylacetate and GABA
`Degradation: Preferential Inhibition of Succinic Semialdehyde
`Dehydrogenase and Indirect Inhibition of GABA-Transaminase,
`32(4) J. Neurochem. 1769–80 (1979)
`
`Vayer, P. et al., 3'-5' Cyclic-Guanosine Monophosphate
`Increase in Rat Brain Hippocampus after Gamma-
`Hydroxybutyrate Administration: Prevention by Valproate and
`Naloxone, 41(5) Life Sci. 605–10 (1987)
`
`Whittle, S. et al., Effects of Anticonvulsants on the Formation of
`γ-Hydroxybutyrate from γ-Aminobutyrate in Rat Brain, 38(3) J.
`Neurochem. 848–51 (1982)
`
`Table 1 – List of Materials Considered
`Generally, the ’306 patent claims are directed to methods of treating
`
`6.
`
`patients suffering from excessive daytime sleepiness, cataplexy, narcolepsy, or
`
`other sleep disorders with reduced doses of gamma-hydroxybutyric acid (“GHB”)
`
`or its salts, when patients are also receiving concomitant administration of
`
`valproate. (See, e.g., PAR1001 at 24:29–39, 25:4–16, 25:37–49, 26:26–35, 26:43–
`
`51.)
`
`6
`
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`It is my opinion that a person of ordinary skill in the art (“POSA”)
`
`7.
`
`would have had a reason and the know-how to arrive at the subject matter recited
`
`in claims 1-34 of the ’306 patent in view of the Xyrem 2005 Label, the Depakote
`
`2011 Label, Cagnin, Waszkielewicz, and the FDA Guidance, as discussed in this
`
`declaration below, with a reasonable expectation of success.
`
`8.
`
`It is also my opinion that a POSA would have had a reason and the
`
`know-how to arrive at the subject matter recited in claims 1-34 of the ’306 patent
`
`in view of the Xyrem 2005 Label, the Depakote 2011 Label, Cagnin,
`
`Waszkielewicz, Weiss, and the FDA Guidance, as discussed in this declaration
`
`below, with a reasonable expectation of success.
`
`9.
`
`In formulating my opinions, I have relied upon my experience in the
`
`relevant art. In formulating my opinions, I have also considered the viewpoint of a
`
`POSA (i.e., a person of ordinary skill in the field of treatment of sleep disorders,
`
`including excessive daytime sleepiness in narcolepsy and cataplexy in narcolepsy)
`
`as of March 1, 2013.
`
`II. MY BACKGROUND AND QUALIFICATIONS
`10. My qualifications and credentials are fully set forth in my curriculum
`
`vitae, attached as PAR1004. I am an expert in the field of treatment of sleep
`
`disorders, with significant experience treating patients with narcolepsy, as well as
`
`experienced in psychopharmacology.
`
`7
`
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`I obtained a Ph.D. in Psychobiology in 1983 from Harvard
`
`11.
`
`University, Cambridge, MA. I then received an M.D. from Harvard Medical
`
`School in 1987. I was a resident in Psychiatry at Massachusetts General Hospital
`
`in Boston, MA from 1988 through 1991. From 1990-1991, I was the Chief
`
`Resident of the Clinical Psychopharmacology Unit at Massachusetts General
`
`Hospital. From 1991–1992, I was a Clinical Fellow in Neurology (Sleep
`
`Medicine) at Massachusetts General Hospital. Once my post-doctoral training was
`
`complete, I accepted a position as a Clinical Assistant in Psychiatry at
`
`Massachusetts General Hospital, as well as an Assistant Physician in Psychiatry at
`
`McLean Hospital in Belmont, MA. In 1996, I accepted a position as an Associate
`
`Physician of Medicine at Brigham and Women’s Hospital in Boston, MA. In
`
`2006, I also became a Psychiatrist at Brigham and Women’s Hospital. I accepted a
`
`position as Associate Psychiatrist at Massachusetts General Hospital in 2013 and
`
`was promoted to Psychiatrist in 2015.
`
`12. From 1991 through present, I have held a series of teaching positions
`
`at Harvard Medical School, primarily in the field of psychiatry, although I was an
`
`Instructor in Medicine at Harvard Medical School from 1996–2000. From 2000–
`
`2007, I was an Assistant Professor in Psychiatry at Harvard Medical School and
`
`have been an Associate Professor in Psychiatry at Harvard Medical School since
`
`2008.
`
`8
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`I currently split my time between clinical work, teaching, and clinical
`
`13.
`
`research, such that each takes up roughly one-third of my time. The focus of my
`
`clinical research, clinical work, and teaching lies in the neurobiological and
`
`psychiatric aspects of primary sleep disorders.
`
`14.
`
`In my clinical work, I see roughly 5 new referrals every week and
`
`follow over 500 patients at any given time with a variety of sleep disorders. In
`
`particular relevance to this case, I follow approximately 20 patients with
`
`narcolepsy (including both the symptoms of excessive daytime sleepiness and
`
`cataplexy in narcolepsy).
`
`15. My clinical work in sleep medicine uses an interdisciplinary
`
`approach, combining pharmacological and cognitive behavioral therapies in
`
`patients with sleep disorders, often with comorbid psychiatric illness.
`
`16. With respect to my teaching, I received a National Heart Lung and
`
`Blood Institute grant to develop a curriculum regarding sleep disorders for
`
`Harvard Medical School, and have been one of three faculty members in the
`
`“Sleep Medicine” elective since 2000. In connection with this work, I published a
`
`model curriculum for the teaching of sleep disorders (including narcolepsy) to
`
`psychiatry residents, and I continue to teach in multiple Harvard-affiliated
`
`psychiatric residency programs, to internal medicine residents, and to fellows in
`
`multiple disciplines. I have given invited presentations and been chair of multiple
`
`9
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`symposia and post-graduate courses at sleep, psychiatry, and neurology meetings
`
`both nationally and internationally. I was chair of the scientific committee for the
`
`Fourth International Symposium on Parkinson’s Disease and Restless Legs
`
`Syndrome in Stressa, Italy in 2005. I also chaired large symposia regarding sleep
`
`disorders at the American Psychiatric Association annual meeting every year from
`
`2001–2007, and chaired symposia and/or post-graduate courses at the Associated
`
`Professional Sleep Societies annual meetings yearly since 2004.
`
`17.
`
`I have served as the chair of the Nosology Committee (2004–2007),
`
`and as chair of the Movement Disorders section (2006–2008) of the American
`
`Academy of Sleep Medicine. I have been on the Medical Advisory Board of the
`
`Restless Legs Syndrome Foundation since 2000.
`
`18. Of particular relevance to this matter, I currently treat approximately
`
`25 patients with Xyrem, for conditions including excessive daytime sleepiness in
`
`narcolepsy and cataplexy in narcolepsy. I am a registered prescriber of Xyrem as
`
`well, and am generally familiar with the restricted distribution program through
`
`which it is made available.
`
`III. PERSON OF ORDINARY SKILL IN THE ART
`19.
`I understand that 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
`
`10
`
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`team and draw upon not only his or her own skills, but also take advantage of
`
`certain specialized skills of others in the team, to solve a given problem.
`
`20.
`
`In the case of the ’306 patent, a POSA would have at least a Ph.D.,
`
`Doctor of Pharmacy degree, or medical degree, and at least three to five years of
`
`experience of treating patients with neurologic disorders, including at least
`
`narcolepsy, cataplexy, and excessive daytime sleepiness in narcolepsy. As of
`
`March 1, 2013 and March 1, 2012, I consider myself at least a person of ordinary
`
`skill in the relevant art to which the ’306 patent pertains.
`
`IV. THE ’306 PATENT AND ITS CLAIMS
`21.
`I understand that this declaration is being submitted together with a
`
`petition for inter partes review of claims 1-34 of the ’306 patent.
`
`22.
`
`I have considered the disclosure of the ’306 patent in light of the
`
`general knowledge in the art as of the earliest possible priority date of the ’306
`
`patent, which I understand is claimed to be March 1, 2013.
`
`23.
`
`I have been informed that claim terms are given their broadest
`
`reasonable interpretation, as understood by a POSA, in view of their specification.
`
`After reading the ’306 patent’s specification, it is my opinion that a POSA reading
`
`the ’306 patent would have understood that all the terms of claims 1-34 should be
`
`given their ordinary meaning except as discussed below. It is also my
`
`11
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`understanding that a dependent claim contains all the limitations of the claim from
`
`which it depends.
`
`A. Overview of the ’306 Patent
`24. The ’306 patent is entitled “Method of Administration of Gamma
`
`Hydroxybutyrate with Monocarboxylate Transporters.” (PAR1001 at 1:1–3.) As
`
`stated above, the ’306 patent claims are directed to methods of treating patients
`
`suffering from excessive daytime sleepiness, cataplexy, narcolepsy, or other sleep
`
`disorders with reduced doses of gamma-hydroxybutyric acid (“GHB”) or its salts,
`
`when patients are also receiving concomitant administration of valproate. (See,
`
`e.g., PAR1001 at 24:29–39, 25:4–16, 25:37–49, 26:25–35, 26:43–51.) More
`
`broadly speaking, the ’306 patent states that “valproate increases the effect of
`
`GHB on the body, thereby potentially causing an unsafe condition.” (Id. at
`
`Abstract.) Broadly speaking, the ’306 patent generally claims methods of treating
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`patients concomitantly taking valproate with reduced doses of GHB in order to
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`avoid intensifying GHB’s effects on the body due to a drug interaction with
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`valproate.
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`25. The ’306 patent acknowledges that GHB is sold in the United States
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`under the brand name Xyrem. (Id. at 2:53–54.) Xyrem, more specifically, contains
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`sodium oxybate, or the sodium salt of GHB. As a prescription drug that is sold and
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`marketed in the United States, Xyrem has FDA-approved Prescribing Information
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
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`that provides information to doctors on its efficacy in its labeled indications
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`(cataplexy in narcolepsy and excessive daytime sleepiness in narcolepsy), safe
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`use, and dosage and administration. The Prescribing Information for Xyrem often
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`accompanies a “Medication Guide” to the patient, which includes directions to the
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`patient on how to safely take the drug on their own. Together, the Prescribing
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`Information and the Medication Guide make up what is called the “package
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`insert” or the “product insert” for Xyrem.
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`26. The specification of the ’306 patent states that the normal dose ranges
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`of GHB (i.e., in patients not taking valproate or other interacting drugs) is
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`disclosed in the product insert for Xyrem. (See id. at 2:52-54.) The “Dosing and
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`Administration” section of the Xyrem 2005 Label reflects the FDA-approved
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`doses of Xyrem at the time the ’306 patent was filed; this section states that
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`Xyrem is required to be taken at bedtime while in bed
`and again 2.5 to 4 hours later. The dose of Xyrem should
`be titrated to effect. The recommended starting dose is
`4.5 g/night divided into two equal doses of 2.25 g. The
`starting dosage can then be increased to a maximum of 9
`g/night in increments of 1.5 g/night (0.75 g per dose).
`One to two weeks are recommended between dosage
`increases to evaluate clinical response and minimize
`adverse effects. The effective dose range of Xyrem is 6 to
`9 g/night.
`
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
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`(PAR1006 at 22–23.) The label thus recommends starting therapy with Xyrem at a
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`subtherapeutic dose of 4.5 g/night and titrating the dose upwards in increments of
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`1.5 g/night in order to minimize adverse events and evaluate efficacy.
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`27. The ’306 patent specifically discloses a method for “treating a patient
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`who is suffering from excessive daytime sleepiness, cataplexy, sleep paralysis,
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`apnea, narcolepsy[,] sleep time disturbances, hypnagogic hallucinations, sleep
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`arousal, insomnia, and nocturnal myoclonus with gamma-hydroxybutyrate (GHB)
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`or a salt thereof, comprising: orally administering to the patient in need of
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`treatment, an adjusted dosage amount of the salt of GHB when the patient is
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`receiving a concomitant administration of valproate.” (PAR1001 at 1:24–32.) In
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`certain embodiments, the dosage adjustment is about a 1% to about a 50%
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`reduction in the amount of GHB “normally given to the patient.” (Id. at 1:32–36.)
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`28. The ’306 patent also states that one embodiment of the invention is
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`the “discovery of drug interactions that change either, or both, the efficacy or
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`safety profile of GHB.” (Id. at 10:47–49.) Specifically, the ’306 patent discloses
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`that GHB interacts with valproate, diclofenac, and ibuprofen. (Id. at 10:50–51.)
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`The ’306 patent discloses that to achieve the benefits of GHB use, the GHB dose
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`can be “administered in a reduced amount when a second compound, such as
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`valproate, is concomitantly administered with GHB.” (Id. at 10:51–54.)
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
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`29. The ’306 patent further discloses that the concomitant administration
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`of GHB with MCT inhibitors, such as valproate, can “effect GHB levels or
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`activity and alter the GHB safety and efficacy profile to create an unsafe
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`condition.” (Id. at 17:45–49.) Specifically, the ’306 patent states that valproate
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`“can increase or prolong GHB effects.” (Id. at 17:49–50.) The ’306 patent also
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`discloses that aspirin “may decrease the clearance of valproic acid, leading to
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`higher-than-intended serum levels of the anticonvulsant.” (Id. at 15:65-67.)
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`30. The ’306 patent notes that GHB is a central nervous system (CNS)
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`depressant. (Id. at 13:56.) Further, the ’306 patent also notes that the concurrent
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`use of GHB with other CNS depressants, including sedating antidepressants or
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`antipsychotics, may increase the risk of respiratory depression, hypotension,
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`profound sedation, syncope, and death. (Id. at 13:58–63.) The ’306 patent goes on
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`to state that if use of GHB with a CNS depressant is required, dose reduction of
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`one or more of the CNS depressants (including GHB) should be considered. (Id. at
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`13:63–66.)
`
`31. Example 2 of the ’306 patent discusses the results of a study
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`comparing the pharmacokinetic (PK) and pharmacodynamic (PD) endpoints of
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`Xyrem when administered with and without coadministration of divalproex
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`sodium extended release tablets. (Id. at 21:57–63.) The study was a randomized,
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`double-blind, placebo-controlled five-period crossover study in healthy male
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
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`subjects. (Id. at 22:6–8.) The PD measurements consisted of a battery Cognitive
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`Drug Research System tasks measuring, generally, cognitive impairment and
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`sedation (see id. at 21:63–67, 22:29–35, 22:63–65), while the PK measurements
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`were taken through measuring serum blood concentration of sodium oxybate and
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`valproate (see id. at 22:25–28, 22:58–62.) On days 1 and 3 of the study, the
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`subjects were administered a 3 g dose of either Xyrem or Xyrem placebo at 9 AM
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`and 1 PM (four hours apart), and PK and PD parameters were monitored for 24
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`hours post-dose. (Id. at 22:20–24.) On days 5–18, the subjects were administered
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`divalproex sodium extended release tablets (1250 mg) at approximately 8 AM
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`each day. (Id. at 22:37–47.) Then, on days 15 and 18, the subjects were
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`administered a 3 g dose of either Xyrem or Xyrem placebo at 9 AM and 1 PM,
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`and the PK and PD parameters were monitored. (See id. at 22:45–65.)
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`32. The study found
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`[PK] changes which were consistent with the inhibition
`of GHB dehydrogenase. This effect will increase the
`exposure of GHB to the subject and increase Cmax and
`AUC about 15%.
`
`The combination of Xyrem® dosed with
`divalproex sodium was compared to divalproex sodium
`alone, [sic] more consistent statistically significant
`impairments over time were seen with the combination,
`than when Xyrem® was compared to its placebo,
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
`
`
`indicating that the effects of co-administration, when
`they appeared, were in the direction of increased
`impairments.
`
`[* * *]
`Divalproex sodium alone showed no consistent or
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`notable effects on cognitive function or sleepiness. There
`were occasions when co-administration of Xyrem® and
`divalproex sodium produced greater deficits
`than
`Xyrem® alone. Further the combination also produced
`more consistent
`impairments when compared with
`divalproex sodium alone, than did Xyrem® when
`compared to its placebo. Thus this study has found
`evidence
`that co-administration of Xyrem® and
`divalproex produces greater impairments to cognitive
`function and sleepiness than were seen with Xyrem®
`alone.
`
`(Id. at 23:50–24:6.) As a result, the study showed both a pharmacokinetic
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`interaction between GHB and valproate, as well as a pharmacodynamic one.
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`B. Claim Construction – “Concomitant” and “Concomitantly”
`33.
`I understand that, in order to analyze whether a claim is obvious or
`
`not, the terms of the claim must be construed. I understand that the claim terms are
`
`to be given their broadest reasonable construction in light of the specification and
`
`file history of the patent.
`
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`Inter Partes Review of USPN 8,772,306
`Declaration of John W. Winkelman, M.D., Ph.D. (Exhibit 1003)
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`34. All of the claims of the ’306 patent recite that valproate and GHB
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`administration
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`is either “concomitant,” or
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`that valproate and GHB are
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`administered “concomitantly.” The specification of the ’306 patent defines the
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`claim terms “concomitant” 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 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.
`
`(Id. at 8:37–45 (emphasis added).) A POSA would find this as a reasonable
`
`definition of the terms “concomitant” or “concomitantly,” particularly in the case
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`of drug administration.
`
`35. 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.”
`
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`Inter