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`By:
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`
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`
`
`
`Filed on behalf of:
`Ranbaxy Inc.
`Joseph M. Reisman
`Carol Pitzel Cruz
`Kerry S. Taylor
`KNOBBE, MARTENS, OLSON & BEAR, LLP
`2040 Main Street, 14th Floor
`Irvine, CA 92614
`Tel.: (949) 760-0404
`Fax: (949) 760-9502
`E-mail: BoxRanbaxy332@knobbe.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`RANBAXY INC.,
`Petitioner,
`
`v.
`
`JAZZ PHARMACEUTICALS, INC. and
`JAZZ PHARMACEUTICALS IRELAND LTD
`Patent Owners.
`
`
`
`
`
`
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`
`
`
`
`Case No. TBD
`Patent 9,050,302
`
`
`
`
`
`
`
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`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,050,302
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page No.
`
`Exhibit List .............................................................................................................. vi
`I. MANDATORY NOTICES ........................................................................... 1
`A.
`Real Party-In-Interest .......................................................................... 1
`B.
`Related Matters .................................................................................... 2
`C.
`Lead and Back-Up Counsel ................................................................. 2
`D.
`Service Information ............................................................................. 3
`II. GROUNDS FOR STANDING ...................................................................... 3
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF
`III.
`THE PRECISE RELIEF REQUESTED ....................................................... 4
`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ........... 4
`
`V.
`
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED ............. 4
`A.
`Level of Ordinary Skill in the Art ....................................................... 6
`
`B.
`C.
`
`Claim Construction ............................................................................. 7
`Scope and Content of the Prior Art ..................................................... 8
`1.
`Use of GHB for Treating Cataplexy and Excessive
`Daytime Sleepiness in Narcolepsy was Known in the
`Art ............................................................................................. 8
`
`2.
`
`3.
`
`4.
`
`It was Known in the Art that GHB Should be
`Incrementally Titrated to Determine the Appropriate
`Dosage ....................................................................................... 9
`
`Dangers of GHB Overdosing Were Known and Could
`Be Controlled By Adjusting Drug Dosing .............................. 10
`
`The Potential for Drug-Drug Interactions Was Known
`and Could Be Controlled By Adjusting Drug Dosing ............ 10
`
`i
`
`
`
`D.
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`5.
`
`Valproate Was Known to Increase GHB Levels by
`Inhibiting GHB-DH which Dominates any MCT
`Inhibition ................................................................................. 11
`
`a.
`
`b.
`
`c.
`
`The Major Route of GHB Excretion is via
`Metabolism by GHB-DH .............................................. 11
`
`Valproate Increases Physiologically Relevant
`GHB Levels by Inhibiting GHB-DH ............................ 11
`
`Valproate’s Inhibition of GHB-DH Dominates
`Any Effect it has as a Substrate for MCT ..................... 16
`
`6.
`
`The Prior Art Taught That If Metabolism of GHB
`Was Compromised, Then The GHB Dose Should Be
`Decreased ................................................................................ 16
`The Challenged Claims are Unpatentable as Obvious ...................... 18
`Ground 1: Claims 1-31 are Obvious Over
`1.
`Waszkielewicz and the Xyrem® PI ........................................ 19
`a.
`Independent Claims 1, 8, 13, and 20 ............................ 19
`b.
`Independent Claim 27 ................................................... 25
`c.
`Independent Claim 31 ................................................... 27
`d.
`Dependent Claims 2, 10, 18, and 25 ............................. 30
`e.
`Dependent Claims 3, 5-7, 11, 19, and 26 ..................... 31
`f.
`Dependent Claim 9 ....................................................... 32
`g.
`Dependent Claims 4, 12, 14, and 21 ............................. 33
`h.
`Dependent Claims 15, 22, and 28 ................................. 35
`i.
`Dependent Claims 16, 17, 23, 24, 29, and 30 ............... 35
`
`ii
`
`
`
`2.
`
`3.
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`Ground 2: Claims 1-31 are Obvious Over Maitre and
`the Xyrem® PI ........................................................................ 37
`a.
`Independent Claims 1, 8, 13, and 20 ............................ 37
`b.
`Independent Claim 27 ................................................... 41
`c.
`Independent Claim 31 ................................................... 43
`d.
`Dependent Claims 2, 10, 18, and 25 ............................. 44
`e.
`Dependent Claims 3, 5-7, 11, 19, and 26 ..................... 45
`f.
`Dependent Claim 9 ....................................................... 46
`g.
`Dependent Claims 4, 12, 14, and 21 ............................. 47
`h.
`Dependent Claims 15, 22, and 28 ................................. 48
`i.
`Dependent Claims 16, 17, 23, 24, 29, and 30 ............... 49
`Ground 3: Claims 1-31 are Obvious Over Okun and
`the Xyrem®-TS ....................................................................... 50
`a.
`Independent Claims 1, 8, 13, and 20 ............................ 50
`b.
`Independent Claim 27 ................................................... 53
`c.
`Independent Claim 31 ................................................... 54
`d.
`Dependent Claims 2, 10, 18, and 25 ............................. 55
`e.
`Dependent Claims 3, 5-7, 11, 19, and 26 ..................... 55
`f.
`Dependent Claim 9 ....................................................... 56
`g.
`Dependent Claims 4, 12, 14, and 21 ............................. 57
`h.
`Dependent Claims 15, 22, and 28 ................................. 58
`
`iii
`
`
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`4.
`
`Dependent Claims 16, 17, 23, 24, 29, and 30 ............... 59
`i.
`No Secondary Considerations Support Non-
`Obviousness ............................................................................ 60
`VI. CONCLUSION ............................................................................................ 60
`
`
`iv
`
`
`
`TABLE OF AUTHORITIES
`
`Page No(s).
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) .....................................................................passim
`
`In re Applied Materials, Inc.,
`692 F.3d. 1289 (Fed. Cir. 2012) ......................................................................... 24
`
`AstraZeneca, L.P. v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2010) .............................................................. 24, 39, 51
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (U.S. 2007) .................................................................................... 18
`
`Leapfrog Enters., Inc. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 60
`
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 60
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003.) ..................................................................passim
`
`OTHER AUTHORITIES
`
`35 U.S.C. § 102 .......................................................................................... 8, 9, 12, 15
`
`35 U.S.C. § 103 .......................................................................................................... 4
`
`35 U.S.C. §§ 311–319 ................................................................................................ 1
`
`35 U.S.C. § 314 .......................................................................................................... 4
`
`37 C.F.R. § 42 ................................................................................................ 1, 2. 3, 4
`
`
`
`v
`
`
`
`EXHIBIT LIST
`
`Exhibit No.
`
`Description
`
`Ex. 1001
`
`U.S. Patent No. 9,050,302, issued June 9, 2015
`
`Ex. 1003 Maitre, M., The γ-Hydroxybutyrate Signalling System in
`Brain Organization and Functional Implications, Progress
`in Neurobiology, Vol. 51, pp. 337-361 (1997) (“Maitre”)
`Okun, M., GHB: An Important Pharmacologic and Clinical
`Update, J. Pharm. Pharmaceut. Sci., Vol. 4(2), pp. 167-175
`(2001) (“Okun”)
`
`Ex. 1004
`
`Ex. 1005
`
`Ex. 1006
`
`The Xyrem® Package Insert entry in the Physician’s Desk
`Reference Edition, pp. 1688-1692, (2007) (“the Xyrem® PI”)
`Xyrem® Titration Schedule published in 2008 (“the
`Xyrem®-TS”)
`Ex. 1007 Waszkielewicz, et al., γ-Hydroxybutyric acid (GHB) and its
`Chemical Modifications: A Review of the GHBergic System,
`Pol. J. Pharmacol., Vol. 56, pp. 43-49 (2004)
`(“Waszkielewicz”)
`Broughton, R., The Treatment of Narcolepsy-Cataplexy with
`Nocturnal Gamma-Hydroxybutyrate, Can. J. Neurol. Sci.,
`Vol. 6(1), pp. 1-6 (1979)
`
`Ex. 1008
`
`Ex. 1009
`
`Ex. 1010
`
`Broughton, R., Effects of Nocturnal Gamma-
`Hydroxybutyrate on Sleep/Waking Patterns in Narcolepsy-
`Cataplexy; Can. J. Neurol. Sci., Vol. 7(1), pp. 23-31 (1980)
`Cash, C. D., Gammahydroxybutyrate: An Overview of the
`Pros and Cons for it Being a Neurotransmitter And/Or a
`Useful Therapeutic Agent, Neurosci. Biobehavioral Rev.,
`Vol. 18(2), pp. 291-304 (1994)
`
`Ex. 1011 Mamelak, et al., Treatment of Narcolepsy with
`Hydroxybutyrate. A Review of Clinical and Sleep Laboratory
`Findings, Sleep, Vol. 9(1), pp. 285-289 (1986)
`
`vi
`
`
`
`
`
`Exhibit No.
`
`Ex. 1012
`
`Ex. 1013
`
`Ex. 1014
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1017
`
`Ex. 1018
`
`Description
`
`Scharf, et al., The Effects and Effectiveness of
`γ-Hydroxybutyrate in Patients with Narcolepsy; J. Clin.
`Psychiatry, Vol. 46, pp. 222-225 (1985)
`Scharf, et al., Pharmacokinetics of Gammahydroxybutyrate
`(GHB) in Narcoleptic Patients, Sleep, Vol. 21(5), pp. 507-514
`(1998)
`
`Bernasconi, et al., Experimental Absence Seizures: Potential
`Role of γ-Hydroxybutyric Acid and GABAB Receptors, J.
`Neural Transm., Vol. 35, pp. 155-177 (1992)
`
`Hechler, et al., γ-Hydroxybutyrate Conversion into GABA
`Induces Displacement of GABAB Binding that is Blocked by
`Valproate and Ethosuximide, JPET, Vol. 281(2), pp. 753-760
`(1997)
`
`Kaufman, et al., Evidence for the Participation of a Cytosolic
`NADP+-Dependent Oxidoreductase in the Catabolism of
`Gamma-Hydroxybutyrate In Vivo, J. Neurochem., Vol. 48(6),
`pp. 1935-1941 (1987)
`Kaufman, et al., An Overview of γ-Hydroxybutyrate
`Catabolism: The Role of the Cytosolic NADP+-Dependent
`Oxidoreductase EC 1.1.1.19 and a Mitochondrial
`Hydroxyacid-Oxoacid Transhydrogenase in the Initial, Rate-
`Limiting Step in This Pathway, Neurochem. Res., Vol. 16(9),
`pp. 965-974 (1991)
`
`Knerr, et al., Therapeutic Concepts in Succinate
`Semialdehyde Dehydrogenase (SSADH; ALDH5a1)
`Deficiency (γ-Hydroxybutyric Aciduria). Hypotheses
`Evolved From 25 Years of Patient Evaluation, Studies in
`Aldh5a1-/- Mice and Characterization of γ-Hydroxybutyric
`Acid Pharmacology, J. Inherit. Metab. Dis., Vol. 30, pp. 279-
`294 (2007)
`
`vii
`
`
`
`
`
`Exhibit No.
`
`Ex. 1019
`
`Description
`
`Löscher, W., Valproate: A Reappraisal of Its
`Pharmacodynamic Properties and Mechanisms of Action,
`Progress in Neurobiol., Vol. 58, pp. 31-59 (1999)
`
`Ex. 1020
`
`Ex. 1021
`
`Löscher, W., Basic Pharmacology of Valproate: A Review
`After 35 Years of Clinical Use for the Treatment of Epilepsy,
`CNS Drugs, Vol. 16(1), pp. 669-694 (2002)
`Vayer, et al., 3’-5’ Cyclic-Guanosine Monophosphate
`Increase in Rat Brain Hippocampus after Gamma-
`Hydroxybutyrate Administration. Prevention by Valoprate
`and Naloxone, Life Sciences, Vol. 41, pp. 605-610 (1987)
`Vayer, et al., Is the Anticonvulsant Mechanism of Valproate
`Linked to its Interaction with the Cerebral γ-Hydroxybutyrate
`System? TIPS, Vol. 9, pp. 127-129 (1988)
`Ex. 1023 Weiss, et al., Gamma-hydroxybutyrate (GHB) and
`Topiramate – Clinically Relevant Drug Interaction Suggested
`by a Case of Coma and Increased Plasma GHB
`Concentration, Eur. J. Clin. Pharmacol., Vol. 69, pp. 1193-94
`(2013)
`Cagnin, et al., γ-Hydroxybutyric Acid–Induced Psychosis
`Seizures, Epilepsy and Behav., Vol. 21, pp. 203-205 (2011)
`
`Ex. 1022
`
`Ex. 1024
`
`Ex. 1025 Morris, 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,
`AAPS J., 10(2), pp.311-321 (2008) (“Morris I”)
`
`Ex. 1026 Morris, et al., Monocarboxylate Transporter with Osmotic
`Diuresis Increases γ-Hydroxybutyrate Renal Elimination in
`Humans: A Proof-of-Concept Study, J. Clin. Tox., 1(2),
`1000105, pp. 1-4 (2011) (“Morris II”)
`
`viii
`
`
`
`
`
`Exhibit No.
`
`Ex. 1027
`
`Ex. 1028
`
`Ex. 1029
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`Ex. 1034
`
`Ex. 1035
`
`Ex. 1036
`
`Ex. 1037
`
`Ex. 1038
`
`Description
`
`Bhattacharya, et al., GHB (γ-Hydroxybutyrate) Carrier-
`Mediated Transport across the Blood-Brain Barrier, J. Pharm. &
`Experimental Therapeutics, 311(1), pp. 92-98 (2004)
`Curriculum Vitae for David Rotella, Ph.D.
`
`Depakene® Package Insert dated October 2011 (“Depakene®
`Package Insert”)
`
`Draft FDA Guidance dated February 2012 (“FDA Guidance”)
`Lamictal® Package Insert dated November 29, 2011
`(“Lamictal® Package Insert”)
`
`U.S. Patent No. 8,772,306 Patent File History, Supplemental
`Amendment and Response filed November 13, 2013
`U.S. Patent No. 8,772,306, issued July 8, 2014
`
`Petition for Inter Partes Review of U.S. Patent No. 8,772,306,
`Par Pharmaceutical, Inc. v. Jazz Pharmaceuticals, Inc.,
`IPR2016-00002
`Declaration of John W. Winkelman, Par Pharmaceutical, Inc.
`v. Jazz Pharmaceuticals, Inc., IPR2016-00002
`
`Petition for Inter Partes Review of U.S. Patent No.
`8,772,306, Ranbaxy, Inc. v. Jazz Pharmaceuticals, Inc.,
`IPR2016-00024
`Declaration of David Rotella,Ph.D., Ranbaxy, Inc. v. Jazz
`Pharmaceuticals, Inc., IPR2016-00024
`
`Vayer, et al., Gamma Hydroxybutyrate Distribution and
`Turnover Rates in Discrete Brain Regions of the Rat,
`Neurochem Int., 12(1), pp. 53-59 (1988)
`
`ix
`
`
`
`
`
`
`
`Exhibit No.
`
`Ex. 1039
`
`Description
`
`Havelaar, et al., Purification of the Lysosomal Sialic Acid
`Transporter, J. Biological Chem., 273(51), pp. 34568-34574
`(1998)
`
`Ex. 1040
`
`Chateauvieux, et al., Molecular and Therapeutic Potential and
`Toxicity of Valproic Acid, J. Biomed. Biotechnol., 2010,
`pp. 1-18 (2010)
`
`x
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`Pursuant to 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42, Ranbaxy Inc.
`
`(“Petitioner” or “Ranbaxy”) petitions for Inter Partes Review (“IPR”) of claims 1-
`
`31 of U.S. Patent No. 9,050,302 to Mark Eller, titled “Method of Administration
`
`of Gamma Hydroxybutyrate with Monocarboxylate Transporters” (“the ’302
`
`patent,” Ex. 1001). Concurrently filed herewith is a Power of Attorney pursuant to
`
`37 C.F.R. § 42.10(b). The Office is authorized to charge Deposit Account 11-1410
`
`for the fee set forth in 37 C.F.R. § 42.15(a) and is authorized to charge any
`
`additional fees to the same account.
`
`I. MANDATORY NOTICES
`A. Real Party-In-Interest
`Ranbaxy Inc., Ranbaxy Holdings (U.K.) Limited, Ranbaxy Netherlands
`
`(B.V.), and Sun Pharmaceutical Industries, Ltd., (collectively, “Sun”) are the real
`
`parties-in-interest for Petitioner.
`
`Ranbaxy, Inc. is not a publicly traded corporation, and is wholly owned by
`
`Ranbaxy Holdings (U.K.) Limited, which in turn is wholly owned by Ranbaxy
`
`Netherlands (B.V.), which in turn is wholly owned by Sun Pharmaceutical
`
`Industries, Ltd. Sun Pharmaceutical Industries, Ltd. is a publicly traded
`
`corporation, and no parent company or publicly traded corporation owns 10% or
`
`more of Sun Pharmaceutical Industries, Ltd.’s stock.
`
`1
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`B. Related Matters
`The ’302 patent is being asserted in the following patent infringement
`
`lawsuits: Jazz Pharm. Inc,. et al. v. Lupin Ltd., et al., 2:15-cv-06548 (D.N.J.), now
`
`consolidated into 2:13-cv-00319; Jazz Pharm., Inc., et al. v. Par Pharmaceutical
`
`Inc., 2:15-cv-07580 (D.N.J.); Jazz Pharm., Inc,. et al. v. Amneal Pharms., LLC,
`
`2:15-cv-06562 (D.N.J.); Jazz Pharm., Inc., et al. v. Sun Pharm. Industries Ltd., et
`
`al., 2:15-cv-08229 (D.N.J.); Jazz Pharm., Inc., et al. v. Wockhardt Bio AG, et al.,
`
`2:16-cv-00099 (D.N.J.); and Jazz Pharm., Inc., et al. v. Roxane Labs., Inc., 2:16-cv-
`
`00469 (D.N.J.).
`
`U.S. Patent No. 8,772,306 (“the ’306 patent”), which issued from a
`
`continuation of the application that became the ’302 patent, is the subject of the
`
`following pending petitions seeking Inter Partes Review: IPR2016-00002,
`
`IPR2016-00024, and IPR2016-00546. The ’306 patent is also being asserted in the
`
`consolidated patent infringement lawsuit Jazz Pharm., Inc., et al. v. Amneal
`
`Pharms., LLC, et al., 2:13-cv-00319 (D.N.J).
`
`C. Lead and Back-Up Counsel
`Pursuant to 37 C.F.R. § 42.8(b)(3) and 42.10(a), Ranbaxy provides the
`
`following designation of counsel:
`
`2
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`Lead Counsel
`Joseph M. Reisman
`Joseph.Reisman@knobbe.com
`(Reg. No. 43,878)
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
` 2040 Main Street, 14th Floor
` Irvine, CA 92614
` Tel.: (949) 760-0404
` Fax: (949) 760-9502
`Second Back-up Counsel
`Kerry S. Taylor
`Kerry.Taylor@knobbe.com
`(Reg. No. 43,947)
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
` 2040 Main Street, 14th Floor
` Irvine, CA 92614
` Tel.: (949) 760-0404
` Fax: (949) 760-9502
`
`First Back-up Counsel
`Carol Pitzel Cruz
`Carol.PitzelCruz@knobbe.com
`(Reg. No. 61,224)
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
` 2040 Main Street, 14th Floor
` Irvine, CA 92614
` Tel.: (949) 760-0404
` Fax: (949) 760-9502
`
`
`
`
`
`Service Information
`
`D.
`Please direct all correspondence to lead counsel at the contact information
`
`above.
`
`Petitioner
`
`consents
`
`to
`
`service
`
`by
`
`electronic mail
`
`at
`
`BoxRanbaxy332@knobbe.com.
`
`II. GROUNDS FOR STANDING
`As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’302
`
`patent is available for IPR and that the Petitioner is not barred or estopped from
`
`requesting IPR on the grounds identified herein.
`
`3
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`III. IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED
`
`Petitioner requests inter partes review and cancellation of claims 1–31 of the
`
`’302 patent on one or more of the grounds under 35 U.S.C. § 103 set forth herein.
`
`Petitioner’s detailed statement of the reasons for the relief requested is set forth
`
`below in the section titled “Statement of Reasons for Relief Requested.” In
`
`accordance with 37 C.F.R. § 42.6(c), copies of the exhibits are filed herewith. This
`
`Petition is accompanied by the declaration of Dr. David Rotella (Ex. 1002).
`
`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`A petition for inter partes review must demonstrate “a reasonable likelihood
`
`that the petitioner would prevail with respect to at least 1 of the claims challenged
`
`in the petition.” 35 U.S.C. § 314(a). This Petition meets this threshold. Because
`
`there is a reasonable likelihood that Petitioner will prevail with respect to at least
`
`one of the challenged claims, as explained herein.
`
`V. STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`The challenged claims of the ’302 patent are generally directed to various
`
`methods of treating patients suffering from “cataplexy in narcolepsy or excessive
`
`daytime sleepiness in narcolepsy,” by administering a reduced dose of gamma-
`
`hydroxybutyrate (GHB) in patients who are also receiving valproate (divalproex
`
`sodium). (Ex. 1001 at Claims 1, 8, 13, 20, and 27.) The alleged advance associated
`
`with every claim of the ’302 patent is administering a reduced dose of GHB in
`
`4
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`treating sleep disorders when valproate is also administered. The ’302 patent
`
`asserts that the inventors unexpectedly discovered that valproate increases “the
`
`effect of GHB in the body.” (Ex. 1001 at, e.g., Abstract; 18 (col. 10:47-53); 20
`
`(col. 13:9-12 and col. 13:48-50); cf. id. at 25 (col. 23:50-53) (stating that
`
`Applicants’ pharmacokinetic data “were consistent with the inhibition of GHB
`
`dehydrogenase.”)).
`
`There was no such “discovery.” Contrary to the statements in the ’302 patent,
`
`the art long recognized that concomitant administration of GHB and valproate
`
`would increase relevant physiologic GHB levels – as shown by increased plasma
`
`and brain GHB concentrations. Indeed, it was known in the art that valproate
`
`inhibited the activity of GBH dehydrogenase (“GBH-DH”), the enzyme primarily
`
`responsible for metabolizing GBH. Thus, because valproate was known to inhibit
`
`the major route of GBH metabolism, one of skill in the art would have expected
`
`concomitant administration of valproate to lead to increased amounts of GBH in the
`
`brain and blood.
`
`Furthermore, one of ordinary skill in the art would have recognized that, based
`
`on the valproate’s inhibitory effect on GHB’s major route of metabolism, dose
`
`reduction would be necessary in some instances to improve the safety of
`
`concomitant administration of GHB and valproate. In addition, because
`
`concomitant administration of GHB and valproate was known to elevate GHB
`
`5
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`levels in the brain relative to GHB administration alone, one of ordinary skill in the
`
`art would have also reasonably expected a lower dose of GHB to have the desired
`
`therapeutic effect. Thus, the claimed subject matter as a whole would have been
`
`obvious to a person of ordinary skill in the art at the time of the alleged invention.
`
`The Examiner’s understanding of the state of the prior art was simply
`
`incomplete, and the ’302 patent should not have issued. In light of a proper
`
`understanding of the scope and content of the prior art and, specifically, of
`
`valproate’s known ability to inhibit GHB-DH and to increase GHB levels in the
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`brain, the Board should find that the claims of the ’302 patent are unpatentable.
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`A. Level of Ordinary Skill in the Art
`The ʼ302 patent is directed to a collaborative team, spanning several
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`disciplines in the pharmaceutical sciences. (Ex. 1002 at ¶34.) In particular, the
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`person of ordinary skill in the art at the time of the alleged invention would have
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`had an advanced degree, or access to those with advanced degrees, in medicine or
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`pharmacy, including medical doctors and/or pharmacists. The person of ordinary
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`skill would also have had advanced knowledge of medicinal chemistry, and would
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`have collaborated with a person having advanced knowledge of pharmacology, and
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`familiarity with, typical methods for evaluating the potential impact of drug-drug
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`interactions. The person of ordinary skill in the art would have had an
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`understanding of drug pharmacokinetics and pharmacodynamics, and the potential
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`for drug-drug interactions. (Id.)
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`B. Claim Construction
`Each claim of the ’302 patent pertains to methods of treating sleep disorders
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`using GHB in patients also taking valproate. The terms in the challenged claims are
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`presumed to take on their ordinary and customary meaning in view of the
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`specification. Under the broadest reasonable interpretation standard, the Patentee
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`has not acted as its own lexicographer, as it has not attributed any special meaning
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`to any of the claim terms.
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`When the Board’s approach to claim construction is applied:
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`The term “concomitant” means the administration of at least two drugs to a
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`patient either subsequently, simultaneously, or consequently within a time period
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`during which the effects and/or measurable plasma levels of the first administered
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`drug are still operative and subject to modulation of plasma levels in the patient.
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`See, e.g., Ex. 1001 at 17 (col. 8:37-41).
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`The term “divalproex sodium” means valproate, valproic acid, valproate
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`semisodium, or divalproex. See, e.g., Ex. 1001 at 21 (col. 15:20-35). For clarity,
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`Petitioner’s use the terms “valproate” and “divalproex sodium” interchangeably.
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`Petitioner’s positions regarding the scope of the claims should not be
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`construed as an assertion regarding the appropriate claim scope in other
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`adjudicative forums, where a different claim interpretation standard may apply.
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`C.
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`Scope and Content of the Prior Art
`1.
`
`Use of GHB for Treating Cataplexy and Excessive Daytime
`Sleepiness in Narcolepsy was Known in the Art
`GHB is a neurotransmitter that acts on receptors in the brain (See, e.g.,
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`Ex. 1003 at 337), which is naturally present in the human brain, and was known to
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`have dose-dependent sedative effects when administered to subjects. (Id.) More
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`than a year prior to the effective filing date of the ’302 patent, GHB was known to
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`be useful for treating cataplexy and excessive daytime sleepiness in narcolepsy
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`(e.g., to improve sleep patterns). (See Ex. 1002 at ¶¶39, 44, and 45; see also, e.g.,
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`Ex. 1003–Ex. 1007). Sodium oxybate, a known alternative for GHB, was marketed
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`under the trade name Xyrem®. (See Ex. 1002 at ¶39; see also Ex. 1005 at 1688).
`
`Each of Waszkielewicz (Ex. 1007), the Xyrem® PI (Ex. 1005), Maitre
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`(Ex. 1003), Okun (Ex. 1004), and the Xyrem®-TS (Ex. 1006) is prior art to the ’302
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`patent under 35 U.S.C. § 102(b), as each was published more than one year before
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`the earliest possible effective filing date of the ’302 patent (i.e., March 1, 2013).
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`Patentee submitted Waszkielewicz and a package insert comparable to the Xyrem®
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`PI in the Information Disclosure Statements, along with over 100 other references.
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`But, neither Waszkielewicz nor the Xyrem® PI was used by the Examiner to
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`support any rejection during prosecution. None of Okun, Maitre, or the Xyrem®-TS
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`was submitted (or considered) during prosecution.
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`Cataplexy is a sudden, transient, episode of muscle weakness associated with
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`narcolepsy. (See Ex. 1002 at ¶38.) GHB was known to treat this symptom of
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`narcolepsy. Numerous references, available as prior art under 35 U.S.C. § 102(b),
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`disclose the well-known use of GHB to treat narcolepsy generally, and to treat
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`excessive daytime sleepiness and cataplexy in narcolepsy. (See Exs. 1008–1013.)
`
`2.
`
`It was Known in the Art that GHB Should be Incrementally
`Titrated to Determine the Appropriate Dosage
`
`The prior art taught that the effects of GHB are dose-dependent, and that
`
`doses of GHB should be titrated up to efficacy. The Xyrem® PI and the Xyrem®-
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`TS each teach a GHB titration schedule. (See, e.g., Ex. 1005 at 1692; see also, e.g.,
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`Ex. 1006; Ex. 1002 at ¶46.) According to the Xyrem® PI and the Xyrem®-TS,
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`dosing of GHB should be initiated at a starting dose of 4.5 g/night. (See, e.g., Ex.
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`1005 at 1692; see also, e.g., Ex. 1006.) With monitoring, the dose of GHB is
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`thereafter increased in 1.5 g/night increments to reach the desired effect, with “1 to
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`2 weeks []recommended between dosage increases to evaluate clinical response and
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`minimize adverse effects.” (See id.)
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`3.
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`Dangers of GHB Overdosing Were Known and Could Be
`Controlled By Adjusting Drug Dosing
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`The prior art taught that excess GHB could lead to adverse effects, including
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`coma or death. (See e.g., Ex. 1005 at 1688-1689; see also, e.g., Ex. 1002 at ¶42 and
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`47.) These adverse effects were known to be dose dependent (see, e.g., Ex. 1005 at
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`1692), and could become more severe when GHB was co-administered with
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`alcohol or other drugs. (See id. at 1688.) Close monitoring of GHB dosing was
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`recommended to “minimize adverse effects.” (Ex. 1005 at 1692; Ex. 1006.)
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`4.
`
`The Potential for Drug-Drug Interactions Was Known and
`Could Be Controlled By Adjusting Drug Dosing
`
`Concomitant administration of two drugs could reduce or enhance the effects
`
`of one, or both, of those drugs. (See, e.g., Ex. 1002 at ¶¶16, 36, and 37.) In
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`particular, a first drug that inhibits the metabolism of a second drug would lead to
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`increased levels of the second drug. (See Ex. 1003 at 340, 342, 343; Ex. 1004 at
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`170.) Such an increase in drug levels was understood, and known to increase the
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`risk of adverse events. (See, e.g., Ex. 1002 at ¶¶16, 36, and 37.) Patent Owner may
`
`argue that a skilled artisan would avoid the risks of drug-drug interaction by simply
`
`ceasing co-administration of the two drugs, or by switching drug combinations to
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`avoid such interactions. This is incorrect. Drug-drug interactions are often
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`encountered in the clinic, and, unless specifically instructed not to co-administer
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`two or more drugs, a person of skill in the art would have addressed such drug
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`interactions by using the strategies taught in the prior art – chiefly, adjusting the
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`dose of one drug. (See generally Ex. 1030; see also, Ex. 1002 at ¶¶16, 34-37, 61, 62
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`and 147-150; Ex. 1029 at 20-25.)
`
`5.
`
`a.
`
`Valproate Was Known to Increase GHB Levels by
`Inhibiting GHB-DH which Dominates any MCT Inhibition
`
`The Major Route of GHB Excretion is via Metabolism by
`GHB-DH
`
`GHB was known to be metabolized via multiple pathways, but the art
`
`explicitly taught that GHB “is eliminated mainly by metabolism,” rather than renal
`
`clearance. See Ex. 1005 at 1688. Moreover, it was known that the primary route of
`
`GHB metabolism was via a single enzyme, GHB-DH. See Ex. 1002 at ¶¶41, 48, 51,
`
`and 54. “The primary pathway involves a cytosolic NADP+-linked enzyme, GHB
`
`dehydrogenase, that catalyses the conversion of sodium oxybate to succinic
`
`semialdehyde . . . .” See Ex. 1005 at 1688. Likewise, “at low, therapeutic GHB
`
`doses[],
`
`the primary
`
`route of elimination
`
`is metabolism by GHB
`
`dehydrogenase. . . .” See Ex. 1026 at 3. Similarly, “[t]he main route for GHB
`
`degradation is its conversion into succinic semialdehyde (SSA) via [(GHB-DH)].”
`
`(See, e.g., Ex. 1003 at 342.)
`
`b.
`
`Valproate Increases Physiologically Relevant GHB Levels
`by Inhibiting GHB-DH
`The art taught that GHB concentrations increased in the brain when GHB
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`and valproate were administered concomitantly; for example, “[a] dose-dependent
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`increase in brain GHB content was demonstrated between 200 and 600 mg/kg
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`valproate, mainly due to GHB-DH inhibition.” (Ex. 1003 at 343; see also Ex. 1002
`
`at ¶¶41, 48, 50, 51, 54, and 143) (emphasis added). Likewise, the ’302 patent
`
`acknowledges that the effect of GHB-DH inhibition was “predominating” and states
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`that “GHB dehydrogenase inhibition caused systemic exposure (plasma AUC) to be
`
`increased 26%.” (Ex. 1001 at 19 (col. 11:3-9)).
`
`Numerous other 35 U.S.C. § 102(b) references, and the overwhelming
`
`teaching of the prior art as a whole, disclose valproate’s ability to inhibit the
`
`primary pathway for GHB metabolism, GHB-DH, and/or its ability to increase
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`physiologically relevant GHB levels, as illustrated in the chart below.
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`Citation
`
`Quote
`
`GHB-DH “is strongly inhibited by various anti-epileptic drugs, short-
`
`Ex. 1003
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`chain fatty acids []. When tested in vivo, these compounds induce a
`
`at 340
`
`significant increase in brain GHB levels, most probably by
`
`inhibiting GHB catabolism.”
`
`As the major route for GHB degradation is inhibited by valproate, an
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`accumulation of GHB is induced following acute treatment with this
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`compound.
`
`Ex. 1003
`
`at 343
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`Ex. 1003
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`at 344
`
`Ex. 1010
`
`at 294
`
`A dose-dependent increase in brain GHB content was demonstrated
`
`between 200 and 600 mg/kg valproate, mainly due to GHB-DH
`
`inhibition.
`
`Valproate is the most well-known agent that acutely increases
`
`cerebral GHB levels . . . . The mechanism of this increase might be
`
`due to inhibition of [] succinic semialdehyde dehydrogenase . . . .
`
`The nonspecific cytosolic aldehyde reductase with a high Km which
`
`Ex. 1010
`
`has been proposed as the enzyme that metabolizes GHB to GABA, in
`
`at 294
`
`vivo is inhibited by valproate, thus indicating another potential
`
`mechanism for elevating the endogenous GHB level.
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`Ex. 1013
`
`GHB is converted to succinate and then metabolized via the Krebs
`
`at 507
`
`cycle by a dehydrogenase.
`
`Ex. 1014
`
`at 171
`
`This increase of GHB levels is due to the fact that valproate does not
`
`alter the biosy