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
`
`
`
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`Filed: October 7, 2015
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`RANBAXY INC.,
`Petitioner
`
`v.
`
`JAZZ PHARMACEUTICALS, INC.,
`Patent Owners
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case No. TBD
`Patent 8,772,306
`
`
`
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`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT 8,772,306
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Filed: October 7, 2015
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`RANBAXY INC.,
`Petitioner
`
`v.
`
`JAZZ PHARMACEUTICALS, INC.,
`Patent Owners
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case No. TBD
`Patent 8,772,306
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT 8,772,306
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page No.
`
`Exhibit list ............................................................................................................... vii
`
`I.
`
`MANDATORY NOTICES ............................................................................. 1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Party-In-Interest ............................................................................ 1
`
`Related Matters ...................................................................................... 2
`
`Lead and Back-Up Counsel ................................................................... 3
`
`Service Information ............................................................................... 3
`
`GROUNDS FOR STANDING ........................................................................ 4
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT
`OF THE PRECISE RELIEF REQUESTED ................................................... 4
`
`II.
`
`III.
`
`IV. THRESHOLD REQUIREMENT FOR INTER PARTES
`REVIEW .......................................................................................................... 4
`
`V.
`
`STATEMENT OF REASONS FOR THE RELIEF
`REQUESTED .................................................................................................. 5
`
`A.
`
`B.
`
`C.
`
`Level of Ordinary Skill in the Art ......................................................... 7
`
`Claim Construction ................................................................................ 8
`
`Scope and Content of the Prior Art ....................................................... 9
`
`The Use of GHB for Treating Narcolepsy and
`Cataplexy was Known ............................................................... 9
`
`It was Known that GHB Should be
`Incrementally Titrated When Determining
`Appropriate Doses for Patients ................................................ 11
`
`The Dangers of Overdosing and Co-
`administering Were Known ..................................................... 11
`
`1.
`
`2.
`
`3.
`
`
`
`i
`
`
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Valproate Was Known to Increase
`Physiological GHB Levels ....................................................... 12
`
`If Metabolism of GHB Was Compromised, the
`GHB Dose Should Be Titrated Down ..................................... 15
`
`It was Known That GHB Could be
`Administered as an Aqueous Solution .................................... 15
`
`It was Known That Aspirin Increased Free
`Valproate ................................................................................. 15
`
`D.
`
`The Challenged Claims are Unpatentable as Obvious
`Over the Prior Art ............................................................................... 16
`
`1.
`
`Ground 1: Claims 1-5, 7-16, 18-26, and 28-34
`are Obvious Over Maitre and the Xyrem® PI ........................ 17
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`g.
`
`h.
`
`i.
`
`j.
`
`k.
`
`Independent Claim 1 ..................................................... 17
`
`Independent Claim 11 ................................................... 21
`
`Independent Claim 19 ................................................... 21
`
`Independent Claim 30 ................................................... 24
`
`Independent Claim 33 ................................................... 26
`
`Dependent Claims 2, 4, 12, 13, 18, and 28 ................... 26
`
`Dependent Claims 3, 7, and 8 ....................................... 28
`
`Dependent Claims 5 and 16 .......................................... 29
`
`Dependent Claims 9, 10, and 31 ................................... 29
`
`Dependent Claims 14, 15, 20, and 21 ........................... 30
`
`Dependent Claims 22, 24, and 26 ................................. 31
`
`ii
`
`
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`l.
`
`Dependent Claim 25 ...................................................... 32
`
`m. Dependent Claims 23, 29, 32, and 34 ........................... 33
`
`2.
`
`Ground 2: Claims 1-5, 7-16, 18, 30 and 31 are
`Obvious Over Okun and the Xyrem® Titration
`Schedule ................................................................................... 34
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`g.
`
`h.
`
`i.
`
`Independent Claim 1 ..................................................... 34
`
`Independent Claim 11 ................................................... 37
`
`Independent Claim 30 ................................................... 37
`
`Independent Claim 33 ................................................... 39
`
`Dependent Claims 2, 4, 12, 13, and 18 ......................... 39
`
`Dependent Claims 3, 7, and 8 ....................................... 41
`
`Dependent Claims 5 and 16 .......................................... 41
`
`Dependent Claims 9, 10, and 31 ................................... 42
`
`Dependent Claims 14 and 15 ........................................ 43
`
`3.
`
`Ground 3: Claims 19-26, 28, 29, 32 and 34 are
`Obvious Over the Combination of Okun, the
`Xyrem® Titration Schedule, and Cook ................................... 44
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`Independent Claim 19 ................................................... 44
`
`Dependent Claims 20 and 21 ........................................ 46
`
`Dependent Claims 22-24, 26, 28, and 29 ...................... 47
`
`Dependent Claim 25 ...................................................... 48
`
`Dependent Claim 32 and 34 .......................................... 48
`
`iii
`
`
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`4.
`
`5.
`
`Ground 4: Claims 6, 17, and 27 are Obvious
`Over Maitre, the Xyrem® PI, and Sandson ............................ 49
`
`No Secondary Considerations Support Non-
`Obviousness ............................................................................. 50
`
`VI. CONCLUSION .............................................................................................. 51
`
`
`
`iv
`
`
`
`TABLE OF AUTHORITIES
`
`Page No(s).
`
`In re Aller,
`220 F.2d 272,276 (C.C.P.A. 1955) ........................................20, 23, 27, 36, 45
`
`In re Applied Materials, Inc.,
`692 F. 3d. 1289 (Fed. Cir. 2012) ................................................. 20, 23, 38, 40
`
`AstraZeneca, L.P. v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2011) ..................................................................... 27
`
`King Pharmaceuticals, Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) ..................................................................... 23
`
`Leapfrog Enters., Inc. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) ..................................................................... 51
`
`In re Ngai,
`367 F.3d 1336 (Fed. Cir. 2004) ............................................................... 23, 25
`
`Ormco Corp. v. Align Tech., Inc.,
`463, F.3d 1299, 1312-1313 (Fed. Cir. 2006) ................................................. 50
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ......................................................... 20, 36, 45
`
`OTHER AUTHORITIES
`
`35 U.S.C. § 102 .................................................................................................passim
`
`35 U.S.C. § 103 .................................................................................................passim
`
`35 U.S.C. § 311 .......................................................................................................... 1
`
`35 U.S.C. § 312 .......................................................................................................... 1
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 314 ...................................................................................................... 1, 4
`
`35 U.S.C. § 315 .......................................................................................................... 1
`
`v
`
`
`
`TABLE OF AUTHORITIES
`(cont’d)
`
`Page No(s).
`
`
`
`
`35 U.S.C. § 316 .......................................................................................................... 1
`
`35 U.S.C. § 317 .......................................................................................................... 1
`
`35 U.S.C. § 318 .......................................................................................................... 1
`
`35 U.S.C. § 319 .......................................................................................................... 1
`
`37 U.S.C. § 42 .................................................................................................... 1, 3, 4
`
`35 U.S.C. § 42.10 ....................................................................................................... 1
`
`35 U.S.C. § 42.15 ....................................................................................................... 1
`
`Rule 4(b)(4) of the Federal Rules of Civil Procedure ................................................ 2
`
`
`
`vi
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`
`EXHIBIT LIST
`
`Exhibit No.
`
`Description
`
`Ex. 1001
`
`U.S. Patent No. 8,772,306, issued July 8, 2014
`
`Declaration of David Rotella (“the Rotella Declaration”)
`Ex. 1002
`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”)
`
`Ex. 1004
`
`Ex. 1005
`
`Ex. 1006
`
`Ex. 1007
`
`Ex. 1008
`
`Okun, M., GHB: An Important Pharmacologic and Clinical
`Update, J. Pharm. Pharmaceut. Sci., Vol. 4(2), pp. 167-175
`(2001) (“Okun”)
`
`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®
`Titration Schedule”)
`U.S. Patent No. 6,780,889, issued August 24, 2004 to Cook et
`al. (“Cook”)
`Broughton R., The Treatment of Narcolepsy-Cataplexy with
`Nocturnal Gamma-Hydroxybutyrate, Can. J. Neurol. Sci., Vol.
`6(1), pp. 1-6 (1979)
`
`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 CD, 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)
`
`Exhibit List, Page vii
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`
`Exhibit No.
`
`Ex. 1012
`
`Ex. 1013
`
`Ex. 1014
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1017
`
`Ex. 1018
`
`Description
`
`Scharf M. et al., The Effects and Effectiveness of y-
`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., E.E., 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)
`
`Exhibit List, Page viii
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`
`Exhibit No.
`
`Ex. 1019
`
`Ex. 1020
`
`Ex. 1021
`
`Ex. 1022
`
`Ex. 1023
`
`Description
`
`Löscher, W., Valproate: A Reappraisal of Its
`Pharmacodynamic Properties and Mechanisms of Action,
`Progress in Neurobiol., Vol. 58, pp. 31-59 (1999)
`
`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)
`Sandson et al., An Interaction Between Aspirin and Valproate:
`The Relevance of Plasma Protein Displacement Drug-Drug
`Interactions, Am. J. Psychiatry, Vol. 163, pp. 1891-1896 (2006)
`
`Ex. 1024
`
`Curriculum Vitae for David Rotella
`
`Ex. 1025
`
`U.S. Patent No. 9,050,302, issued June 9, 2015
`
`Ex. 1026
`
`Ex. 1027
`
`’306 Patent Prosecution History, Amendment and Response filed
`October 31, 2013
`
`’306 Patent File History, Supplemental Amendment and Response
`filed November 13, 2013
`
`Ex. 1028 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”)
`
`Exhibit List, Page ix
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`
`Description
`Exhibit No.
`Ex. 1029 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”)
`Havelaar et al., Purification of the Lysosomal Sialic Acid
`Transporter, J. Biological Chem., 273(51), pp. 34568-34574
`(1998)
`Bhattacharya et al., GHB (γ-Hydroxybutyrate) Carrier-Mediated
`Transport across the Blood-Brain Barrier, J. Pharm. &
`Experimental Therapeutics, 311(1), pp. 92-98 (2004)
`
`Ex. 1030
`
`Ex. 1031
`
`Exhibit List, Page x
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`
`
`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 of
`
`U.S. Patent No. 8,772,306 to Mark Eller, titled “Method of Administration of
`
`Gamma Hydroxybutyrate with Monocarboxylate Transporters” (“the ’306 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. 8,772,306
`
`
`B. Related Matters
`
`The ’306 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.); Jazz
`
`Pharm. Inc. et al. v. Wockhardt Bio AG et al., 2:15-cv-05619 (D.N.J.); Jazz
`
`Pharm. Inc. et al. v. Roxane Laboratories, Inc., 2:15-cv-01360 (D.N.J.); Jazz
`
`Pharm. Inc. et al. v. Amneal Pharms., LLC, 2:15-cv-01043 (D.N.J.); Jazz Pharm.
`
`Inc. et al. v. Watson Laboratories, Inc., 2:14-cv-07757 (D.N.J.); Jazz Pharm. Inc.
`
`et al. v. Ranbaxy Laboratories Ltd. et al., 2:14-cv-06151 (D.N.J.); Jazz Pharm.
`
`Inc. et al. v. Par Pharmaceutical Inc., 2:14-cv-06150 (D.N.J.); Jazz Pharm. Inc. et
`
`al. v. Par Pharmaceutical Inc., 2:14-cv-05824 (D.N.J.). The Complaint alleging
`
`infringement of the ’306 patent in Jazz Pharm. Inc. et al. v. Ranbaxy Laboratories
`
`Ltd. et al., 2:14-cv-06151 (D.N.J.), was effectively served (pursuant
`
`to
`
`Rule 4(b)(4) of the Federal Rules of Civil Procedure) on October 17, 2014, by the
`
`filing on that day of a waiver of service in the District Court.
`
`On October 6, 2015, in IPR2016-0002, Par Pharmaceuticals, Inc. filed a
`
`Petition seeking institution of an IPR against Claims 1-34 of the ’306 patent.
`
`The ’306 patent is a continuation of U.S. Application 13/837,714, now U.S.
`
`Patent No. 9,050,302 (“the ’302 patent”). The ’302 patent is also asserted in the
`
`above-listed lawsuits.
`
`2
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`
`C.
`
`Lead and Back-Up Counsel
`
`Pursuant to 37 C.F.R. § 42.8(b)(3) and 42.10(a), Ranbaxy provides the
`
`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
`
`
`
`
`following designation of counsel:
`
`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. 43,974)
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
` 2040 Main Street, 14th Floor
` Irvine, CA 92614
` Tel.: (949) 760-0404
` Fax: (949) 760-9502
`
`
`D.
`
`Service Information
`
`
`
`Please direct all correspondence to lead counsel at the contact information
`
`above.
`
`Petitioner
`
`consents
`
`to
`
`service
`
`by
`
`electronic mail
`
`at
`
`BoxRanbaxy332@knobbe.com.
`
`3
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`II. GROUNDS FOR STANDING
`
`As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’306
`
`patent is available for IPR and that the Petitioner is not barred or estopped from
`
`requesting IPR on the grounds identified herein.
`
`III.
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED
`Petitioner requests inter partes review and cancellation of claims 1-34 of the
`
`’306 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. For each
`
`of the grounds of unpatentability proposed below, there is a reasonable likelihood
`
`that Petitioner will prevail with respect to at least one of the challenged claims.
`
`4
`
`
`
`Ranbaxy v. Jazz
`IPR Petition - U.S. Pat. 8,772,306
`
`V.
`
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`
`The challenged claims of the ’306 patent are generally directed to various
`
`methods of treating patients suffering from various sleep disorders, including
`
`narcolepsy, by administering a reduced dose of gamma-hydroxybutyrate (GHB) in
`
`patients who are concomitantly receiving valproate. The alleged advance recited in
`
`each and every claim of the ’306 patent is administering a reduced dose of GHB in
`
`treating sleep disorders when valproate is also administered. The ’306 patent asserts
`
`that the inventors unexpectedly discovered that valproate increases GHB in the body.
`
`(Ex. 1001 at, e.g., Abstract; Col. 10:47-51; Col. 13:9-12; Col. 13:48-50; Cf. id. at
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`Col. 23:50-51 (stating that Applicants’ pharmacokinetic data “were consistent with the
`
`inhibition of GHB dehydrogenase.”).) Applicants repeated this assertion during
`
`prosecution. (See, e.g., ’306 Patent File History Amendment and Response Filed
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`October 31, 2013 and Supplemental Amendment and Response filed November 13,
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`2013 (Ex. 1026 at 9, and Ex. 1027 at 9) (stating that the cited art “would not teach or
`
`suggest that there would be a change in the GHB in vivo effect caused by valproate.
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`Furthermore, it would not have been known prior to the present application what that
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`effect would be, such as an increase or decrease in the in vivo effect of GHB.”)
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`(emphasis in original).)
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`IPR Petition - U.S. Pat. 8,772,306
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`Applicants also, more specifically, suggested that it was unknown whether
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`valproate would inhibit GHB dehydrogenase. During prosecution Applicants
`
`asserted, without evidentiary support, that valproate might impact GHB levels
`
`“through its activity as an MCT inhibitor, or by another mechanism, such as
`
`inhibiting the enzyme GHB dehydrogenase,” (see Ex. 1026 at 9) and further
`
`suggested that this uncertainly made it impossible to predict the effect that
`
`concomitant administration of valproate might have on GHB levels.
`
`There was no such uncertainty. Contrary to Applicants’ repeated assertions, the
`
`art long recognized that concomitant administration with valproate would increase
`
`GHB levels. Prior to the ’306 patent, it was known that valproate inhibited the activity
`
`of GHB dehydrogenase, an enzyme responsible for metabolizing GHB, and that
`
`valproate would therefore increase the level of GHB in the brain and in the periphery.
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`Thus, it was known that GHB dosing should be reduced when a patient concomitantly
`
`receives valproate. Further, one of ordinary skill in the art would have recognized,
`
`based on the valproate’s inhibitory effect, dose reduction would be necessary in some
`
`instances to improve the safety of concomitant administration of GHB. The person of
`
`ordinary skill would have reasonably expected that the safety issues resulting from
`
`concomitant GHB and valproate administration could be addressed by lowering the
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`dose of GHB, and would have been motived to lower GHB dosing based on the prior
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`IPR Petition - U.S. Pat. 8,772,306
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`art. 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 prior art was simply incorrect, and the ‘306
`
`patent should not have issued. In light of a proper understanding of the prior art and,
`
`specifically, of valproate’s ability to inhibit GHB dehydrogenase and thus to increase
`
`GHB levels, the Board should find that the claims of the ‘306 patent are unpatentable.
`
`A. Level of Ordinary Skill in the Art
`
`The ʼ306 patent is directed to a collaborative team, spanning several
`
`disciplines in the pharmaceutical sciences. 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 a
`
`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 understanding of the drug’s
`
`pharmacokinetics and pharmacodynamics, and the risks of the pharmacokinetics of
`
`drug combinations. (Ex. 1002 at ¶30.)
`
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`IPR Petition - U.S. Pat. 8,772,306
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`B. Claim Construction
`
`Each claim of the ’306 patent pertains to methods of treating sleep disorders
`
`(including narcolepsy) using GHB or to methods of safely administering GHB to a
`
`patient. The terms in the challenged claims are presumed to take on their ordinary
`
`and customary meaning based on the broadest reasonable interpretation of the claim
`
`language 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 the any of the claim terms.
`
`When the broadest reasonable interpretation 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 “therapeutically effective amount” means an amount of a
`
`compound sufficient to treat, ameliorate, or prevent the identified disease or
`
`condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect
`
`on the disease or condition. See, e.g., Ex. 1001 at 18 (Col. 9:9-12).
`
`The
`
`term “valproate” means valproate, valproic acid, valproate
`
`semisodium, or divalproex. See, e.g., Ex. 1001 at 21 (Col. 15:20-35).
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`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.
`
`The Use of GHB for Treating Narcolepsy and Cataplexy was
`Known
`
`More than a year prior to the effective filing date of the ’306 patent, GHB
`
`
`
`was known to be useful for treating narcolepsy in patients (e.g., to improve sleep
`
`patterns).
`
`(See Ex. 1002 at ¶¶37-38; see also, e.g., Maitre M, The γ-
`
`Hydroxybutyrate Signalling System in Brain Organization and Functional
`
`Implications, Progress in Neurobiology, Vol. 51, pp. 337-361 (1997) (“Maitre,”
`
`Ex. 1003 at 352); see also, e.g., Okun, M., GHB: An Important Pharmacologic and
`
`Clinical Update, J. Pharm. Pharmaceut. Sci., Vol. 4(2), pp. 167-175 (2001)
`
`(“Okun,” Ex. 1004 at 167, 169); see also, e.g., Physician’s Desk Reference
`
`Edition, pp. 1688-1692, (2007) (Xyrem® Package Insert entry) (“the Xyrem® PI,”
`
`Ex. 1005 at 1688).) It was also known that GHB was marketed as sodium oxybate
`
`under the trade name Xyrem®. (See Ex. 1002 at ¶37; see also Ex. 1005 at 1688; see
`
`also Xyrem® Titration Schedule (Ex. 1006)(“the Xyrem® Titration Schedule”).)
`
`Each of Maitre, Okun, the Xyrem® PI, and the Xyrem® Titration Schedule is
`
`prior art under 35 U.S.C. § 102(b), as each was published more than one year
`
`9
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`IPR Petition - U.S. Pat. 8,772,306
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`before the earliest possible effective filing date of the ‘306 patent, March 1, 2013.
`
`Patentee submitted the Maitre reference and a package insert comparable to the
`
`Xyrem® PI in Information Disclosure Statements, along with over 100 other
`
`references; neither Maitre nor the submitted Xyrem® package insert were cited by
`
`the Examiner during prosecution. Neither Okun nor the Xyrem® Titration Schedule
`
`were submitted (or considered) during prosecution.
`
`Numerous other 35 U.S.C. § 102(b) prior art references disclose the use of
`
`GHB to treat narcolepsy. See, e.g., Broughton R., The Treatment of Narcolepsy-
`
`Cataplexy with Nocturnal Gamma-Hydroxybutyrate, Can. J. Neurol. Sci., Vol. 6(1),
`
`pp. 1-6 (1979) (Ex. 1008); Broughton R, Effects of Nocturnal Gamma-
`
`Hydroxybutyrate on Sleep/Waking Patterns in Narcolepsy-Cataplexy; Can J.
`
`Neural. Sci. Vol. 7(1), pp. 23-31
`
`(1980)
`
`(Ex. 1009); Cash CD,
`
`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. 1010); Mamelak et al., Treatment of
`
`Narcolepsy with Hydroxybutyrate. A Review of Clinical and Sleep Laboratory
`
`Findings, Sleep, Vol. 9(1), pp. 285-289 (1986) (Ex. 1011); Scharf M. et al., The
`
`Effects and Effectiveness of y-Hydroxybutyrate in Patients with Narcolepsy; J.
`
`Clin. Psychiatry, Vol. 46, pp. 222-225 (1985) (Ex. 1012); and Scharf et al.,
`
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`IPR Petition - U.S. Pat. 8,772,306
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`Pharmacokinetics of Gammahydroxybutyrate (GHB) in Narcoleptic Patients, Sleep,
`
`Vol. 21(5), pp. 507-514 (1998) (Ex. 1013).
`
`2.
`
`It was Known that GHB Should be Incrementally Titrated When
`Determining Appropriate Doses for Patients
`
`It was also understood in the prior art that doses of GHB should be titrated to
`
`efficacy. The Xyrem® PI and the Xyrem® Titration Schedule each teach a GHB
`
`titration schedule. (See, e.g., Ex. 1005 at 1692; see also, e.g., Ex. 1006 at 1; Ex.
`
`1002 at ¶39.) According to the Xyrem® PI and the Xyrem® Titration Schedule,
`
`the starting dose of GHB should be initiated at 4.5 grams per night (i.e., per day).
`
`(See, e.g., Ex. 1005 at 1692; see also, e.g., Ex. 1006 at 1.) The dose of GHB is
`
`thereafter increased in 1.5 g increments to reach the desired effect. (See, e.g., Ex.
`
`1005 at 1692; see also, e.g., Ex. 1006 at 1.)
`
`3.
`
`The Dangers of Overdosing and Co-administering Were Known
`
`It was also understood in the prior art that excess dosing of GHB could lead
`
`to adverse effects, including coma or death. (See e.g., Ex. 1004 at 167, 170; see
`
`also, e.g., Ex. 1005 at 1688-1689; Ex. 1002 at ¶40.) These harmful effects were
`
`known to be dose dependent (see, e.g., Ex. 1004 at 170; see also, e.g., Ex. 1005 at
`
`1692.), and could exacerbated when GHB was administered along with alcohol or
`
`other drugs. (See, e.g., Ex. 1004 at 167; see also, e.g., Ex. 1005 at 1688).
`
`11
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`IPR Petition - U.S. Pat. 8,772,306
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`4.
`
`Valproate Was Known to Increase Physiological GHB Levels
`
`Valproate – an anti-convulsant – could be co-administered with GHB
`
`(Ex. 1003 at 343; Ex. 1004 at 170) and was known to inhibit GHB dehydrogenase.
`
`(Ex. 1003 at 340, 342, 343; Ex. 1004 at 170.). Thus, a person of skill in the art
`
`would have understood that valproate, as a GHB dehydrogenase inhibitor, would
`
`increase GHB levels in the body relative to GHB administration alone. (Ex. 1002 at
`
`¶41; see also Ex. 1003 at 339-340.) Valproate was understood, specifically, to
`
`increase GHB levels in the brain, when co-administered with GHB. (See Ex. 1003
`
`at 340; see generally Ex. 1002 at ¶41.)
`
`Applicants’ were incorrect when they asserted, with no evidentiary support
`
`during prosecution, that valproate’s possible function as an MCT inhibitor might
`
`offset its possible function as a GHB dehydrogenase inhibitor. (Ex. 1002 at ¶41.)
`
`Properly understood in view of the prior art, concomitant administration of
`
`valproate and GHB would directly increase GHB levels through valproate’s known
`
`function as a GHB dehydrogenase inhibitor. Any potential function as a MCT
`
`inhibitor would have been minimal (See, e.g., Ex. 1019 at 54 and Ex. 1020 at 688
`
`(explaining that “recent experiments” show valproate transport is not governed by
`
`the monocarboxylate carrier)) and at best, indirect. (Ex. 1002 at ¶ 41.) Indeed, the
`
`data presented in the ’306 patent (Ex. 1001 at 19, Col. 11:6-9) allegedly related to
`
`MCT inhibition - a 30% increase in renal clearance rate upon concomitant
`
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`IPR Petition - U.S. Pat. 8,772,306
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`administration of valproate and GHB - is fully consistent with, and would have
`
`been accounted for by, the increase in G
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