Filed: March 10, 2016
`
`
`
`
`
`By:
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case No. TBD
`Patent 9,050,302
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,050,302
`
`
`
`
`
`
`
`
`
`By:
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case No. TBD
`Patent 9,050,302
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`brain, the Board should find that the claims of the ’302 patent are unpatentable.
`
`A. Level of Ordinary Skill in the Art
`The ʼ302 patent is directed to a collaborative team, spanning several
`
`disciplines in the pharmaceutical sciences. (Ex. 1002 at ¶34.) In particular, the
`
`person of ordinary skill in the art at the time of the alleged invention would have
`
`had an advanced degree, or access to those with advanced degrees, in medicine or
`
`pharmacy, including medical doctors and/or pharmacists. The person of ordinary
`
`skill would also have had advanced knowledge of medicinal chemistry, and would
`
`have collaborated with a person having advanced knowledge of pharmacology, and
`
`familiarity with, typical methods for evaluating the potential impact of drug-drug
`
`interactions. The person of ordinary skill in the art would have had an
`
`6
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`understanding of drug pharmacokinetics and pharmacodynamics, and the potential
`
`for drug-drug interactions. (Id.)
`
`B. Claim Construction
`Each claim of the ’302 patent pertains to methods of treating sleep disorders
`
`using GHB in patients also taking valproate. The terms in the challenged claims are
`
`presumed to take on their ordinary and customary meaning in view of the
`
`specification. Under the broadest reasonable interpretation standard, the Patentee
`
`has not acted as its own lexicographer, as it has not attributed any special meaning
`
`to any of the claim terms.
`
`When the Board’s approach to claim construction is applied:
`
`The term “concomitant” means the administration of at least two drugs to a
`
`patient either subsequently, simultaneously, or consequently within a time period
`
`during which the effects and/or measurable plasma levels of the first administered
`
`drug are still operative and subject to modulation of plasma levels in the patient.
`
`See, e.g., Ex. 1001 at 17 (col. 8:37-41).
`
`The term “divalproex sodium” means valproate, valproic acid, valproate
`
`semisodium, or divalproex. See, e.g., Ex. 1001 at 21 (col. 15:20-35). For clarity,
`
`Petitioner’s use the terms “valproate” and “divalproex sodium” interchangeably.
`
`7
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`Petitioner’s positions regarding the scope of the claims should not be
`
`construed as an assertion regarding the appropriate claim scope in other
`
`adjudicative forums, where a different claim interpretation standard may apply.
`
`C.
`
`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.,
`
`Ex. 1003 at 337), which is naturally present in the human brain, and was known to
`
`have dose-dependent sedative effects when administered to subjects. (Id.) More
`
`than a year prior to the effective filing date of the ’302 patent, GHB was known to
`
`be useful for treating cataplexy and excessive daytime sleepiness in narcolepsy
`
`(e.g., to improve sleep patterns). (See Ex. 1002 at ¶¶39, 44, and 45; see also, e.g.,
`
`Ex. 1003–Ex. 1007). Sodium oxybate, a known alternative for GHB, was marketed
`
`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
`
`(Ex. 1003), Okun (Ex. 1004), and the Xyrem®-TS (Ex. 1006) is prior art to the ’302
`
`patent under 35 U.S.C. § 102(b), as each was published more than one year before
`
`the earliest possible effective filing date of the ’302 patent (i.e., March 1, 2013).
`
`Patentee submitted Waszkielewicz and a package insert comparable to the Xyrem®
`
`PI in the Information Disclosure Statements, along with over 100 other references.
`
`8
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`But, neither Waszkielewicz nor the Xyrem® PI was used by the Examiner to
`
`support any rejection during prosecution. None of Okun, Maitre, or the Xyrem®-TS
`
`was submitted (or considered) during prosecution.
`
`Cataplexy is a sudden, transient, episode of muscle weakness associated with
`
`narcolepsy. (See Ex. 1002 at ¶38.) GHB was known to treat this symptom of
`
`narcolepsy. Numerous references, available as prior art under 35 U.S.C. § 102(b),
`
`disclose the well-known use of GHB to treat narcolepsy generally, and to treat
`
`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®-
`
`TS each teach a GHB titration schedule. (See, e.g., Ex. 1005 at 1692; see also, e.g.,
`
`Ex. 1006; Ex. 1002 at ¶46.) According to the Xyrem® PI and the Xyrem®-TS,
`
`dosing of GHB should be initiated at a starting dose of 4.5 g/night. (See, e.g., Ex.
`
`1005 at 1692; see also, e.g., Ex. 1006.) With monitoring, the dose of GHB is
`
`thereafter increased in 1.5 g/night increments to reach the desired effect, with “1 to
`
`2 weeks []recommended between dosage increases to evaluate clinical response and
`
`minimize adverse effects.” (See id.)
`
`9
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`3.
`
`Dangers of GHB Overdosing Were Known and Could Be
`Controlled By Adjusting Drug Dosing
`
`The prior art taught that excess GHB could lead to adverse effects, including
`
`coma or death. (See e.g., Ex. 1005 at 1688-1689; see also, e.g., Ex. 1002 at ¶42 and
`
`47.) These adverse effects were known to be dose dependent (see, e.g., Ex. 1005 at
`
`1692), and could become more severe when GHB was co-administered with
`
`alcohol or other drugs. (See id. at 1688.) Close monitoring of GHB dosing was
`
`recommended to “minimize adverse effects.” (Ex. 1005 at 1692; Ex. 1006.)
`
`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
`
`particular, a first drug that inhibits the metabolism of a second drug would lead to
`
`increased levels of the second drug. (See Ex. 1003 at 340, 342, 343; Ex. 1004 at
`
`170.) Such an increase in drug levels was understood, and known to increase the
`
`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
`
`avoid such interactions. This is incorrect. Drug-drug interactions are often
`
`encountered in the clinic, and, unless specifically instructed not to co-administer
`
`two or more drugs, a person of skill in the art would have addressed such drug
`
`10
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`interactions by using the strategies taught in the prior art – chiefly, adjusting the
`
`dose of one drug. (See generally Ex. 1030; see also, Ex. 1002 at ¶¶16, 34-37, 61, 62
`
`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
`
`and valproate were administered concomitantly; for example, “[a] dose-dependent
`
`11
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`increase in brain GHB content was demonstrated between 200 and 600 mg/kg
`
`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
`
`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
`
`physiologically relevant GHB levels, as illustrated in the chart below.
`
`Citation
`
`Quote
`
`GHB-DH “is strongly inhibited by various anti-epileptic drugs, short-
`
`Ex. 1003
`
`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
`
`accumulation of GHB is induced following acute treatment with this
`
`compound.
`
`Ex. 1003
`
`at 343
`
`12
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 9,050,302
`
`Ex. 1003
`
`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.
`
`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
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
