Paper No. __
`Filed: January 15, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`________________
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`RANBAXY INC.
`Petitioner,
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`v.
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`JAZZ PHARMACEUTICALS IRELAND LTD.
`Patent Owner
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`________________
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`Case IPR2016-00024
`Patent 8,772,306
`________________
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`PATENT OWNER PRELIMINARY RESPONSE
`PURSUANT TO 35 U.S.C. § 313 AND 37 C.F.R. § 42.107
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`Patent Owner Preliminary Response
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`TABLE OF CONTENTS
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`Page
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`I.
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`INTRODUCTION ........................................................................................... 1
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`A.
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`Jazz’s Xyrem® Drug Product ................................................................ 3
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`B.
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`The ’306 Patent ..................................................................................... 4
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`II.
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`RANBAXY HAS FAILED TO SHOW A REASONABLE
`LIKELIHOOD THAT THE ’306 PATENT WOULD HAVE BEEN
`OBVIOUS ........................................................................................................ 6
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`A.
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`Ranbaxy ignores that the prior art’s teachings were inconsistent
`and contradictory, such that the effects of valproate on GHB in
`humans would have been unpredictable to a POSA ............................. 9
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`1.
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`2.
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`3.
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`4.
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`GHB is eliminated by many pathways other than
`GHB-DH ..................................................................................... 9
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`A POSA could not have expected valproate’s effect on
`GHB levels because of the unpredictability in the art .............. 12
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`Ranbaxy argues that the prior art discloses that valproate
`could lead to GHB toxicity, but ignores that the prior art
`discloses that valproate could also treat GHB toxicity ............ 19
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`Ranbaxy relies on rat studies without providing evidence
`that rat GHB-DH is the same as human GHB-DH ................... 23
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`B.
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`Ranbaxy ignores the express disclosures in the prior art that
`would have taught a POSA away from GHB and valproate
`co-administration and, thus, the claimed inventions ........................... 24
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`1.
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`2.
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`The Xyrem PI’s disclosures would have taught a POSA
`away from the claimed inventions ............................................ 25
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`Cagnin’s disclosure would have taught a POSA away
`from the claimed inventions ...................................................... 27
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`C.
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`Ranbaxy fails to show that a POSA would have been motivated
`to administer reduced GHB doses if valproate caused
`GHB-related side effects ..................................................................... 29
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`D.
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`E.
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`Ranbaxy fails to show that a POSA would have reasonably
`expected that the reduced GHB doses would treat the claimed
`sleep disorders, and do so without resulting side effects .................... 35
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`Ranbaxy’s arguments directed to the ’306 patent’s claims
`requiring the administration of aspirin do not add anything to
`its faulty Petition ................................................................................. 39
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`III. CONCLUSION .............................................................................................. 40
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`I.
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`INTRODUCTION
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`IPR2016-00024
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`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107(a), Patent Owner Jazz
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`Pharmaceuticals Ireland Ltd. and exclusive licensee Jazz Pharmaceuticals, Inc.
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`(together, “Jazz”) submit this Preliminary Response to Ranbaxy Inc.’s
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`(“Ranbaxy”) Petition for Inter Partes Review (the “Petition” or “Pet.”) of U.S.
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`Patent No. 8,772,306 (the “’306 patent”).
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`The ’306 patent describes and claims novel methods of treating patients with
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`certain sleep disorders using a reduced effective dosage amount of gamma-
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`hydroxybutyrate (“GHB”) when GHB is co-administered with valproate.
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`Ranbaxy’s Petition asserts four Grounds of alleged obviousness. Each
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`Ground fails to show a reasonable likelihood that the ’306 patent claims would
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`have been obvious. Ranbaxy’s obviousness arguments improperly use hindsight to
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`focus on select disclosures from the prior art. Specifically, each Ground in
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`Ranbaxy’s Petition is based on at least two unfounded assumptions: (1) the
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`assumption that the prior art would have disclosed to a person of ordinary skill in
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`the art (“POSA”) that valproate increases the negative effects of GHB in patients;
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`and (2) the assumption that a POSA would have chosen to titrate down the dose of
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`GHB as a result.
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`As explained below, at the time of the ’306 patent’s inventions, the prior art
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`would not have provided a POSA with any guidance concerning what effect
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`administering valproate would have on GHB in humans. Instead, the prior art
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`considered as a whole would have taught that valproate’s effect on both GHB
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`blood levels and GHB pharmacodynamic effects was entirely unpredictable.
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`Additionally, no prior art discloses, teaches, or suggests reducing the GHB
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`dose in a patient taking valproate. Rather, if a POSA were concerned with GHB-
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`related side effects occurring in humans concomitantly receiving valproate, then a
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`POSA would have done exactly what the references say to do—stop co-
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`administering the two drugs.
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`Each Ground of Ranbaxy’s Petition fails because: (1) Ranbaxy does not
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`show that the prior art would have taught a POSA what the effect of valproate
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`would be on GHB levels or GHB pharmacodynamic effects in human patients; (2)
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`Ranbaxy ignores that the prior art would have taught a POSA away from the
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`claimed inventions; (3) Ranbaxy does not show that a POSA would have been
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`motivated to administer reduced GHB doses even if the POSA believed that
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`valproate causes negative GHB-related side effects in humans; and (4) Ranbaxy
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`does not show that a POSA would have reasonably expected that the reduced GHB
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`doses would be effective for treating the claimed sleep disorders, and do so without
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`resulting side effects. Ranbaxy’s additional arguments directed to the ’306
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`patent’s claims that also require the administration of aspirin do not add anything
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`to its faulty Petition.
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`A.
`Jazz’s Xyrem® Drug Product
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`Jazz is a biopharmaceutical company that developed and markets Xyrem.
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`Xyrem is the only pharmaceutical that the U.S. Food and Drug Administration
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`(“FDA”) has approved for treatment of both cataplexy and excessive daytime
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`sleepiness in patients with narcolepsy. Ex. 1001 at 11:22-28. Xyrem contains the
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`sodium salt of GHB as its active ingredient. Id. at 11:25-27. GHB is a naturally-
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`occurring neurotransmitter that is found in many tissues of the human body.1 Id. at
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`11:26-29. When man-made GHB (Xyrem) is administered in effective dosage
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`amounts (i.e., 6-9 grams/night), it reduces excessive daytime sleepiness and
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`cataplexy in patients with narcolepsy.2 See Ex. 1005 at 1688 (“Description”),
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`1688-89 (“Clinical Trials”). While Xyrem is a life-changing therapy for many
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`narcoleptic patients, GHB is also a central nervous system (“CNS”) depressant
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`with potentially serious side effects. See id. at 1688 (“Warning”). Indeed, the
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`Xyrem PI teaches a POSA that GHB has a toxicity profile that includes “seizure,
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`respiratory depression, and profound decreases in level of consciousness, with
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`instances of coma and death.” See id.; see also Pet. 11.
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`1 Naturally-occurring GHB is referred to as “endogenous” GHB.
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`2 The GHB administered to patients is referred to as “exogenous” GHB.
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`B.
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`The ’306 Patent
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`The ’306 patent describes and claims specific methods of treating certain
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`patients receiving both GHB and valproate. Ex. 1001 at Abstract, 24:29-26:55.
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`Valproate, also called valproic acid or divalproex, does not occur naturally in the
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`human body but, instead, is solely a man-made product. See Ex. 2019 at 417.
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`Valproate is used as an anticonvulsant and mood-stabilizing drug, primarily in the
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`treatment of epilepsy and bipolar disorder. Ex. 1001 at 15:20-24. It is marketed
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`under various brand names, including Depakote®. Id. at 15:31-35.
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`In addition to its CNS effects, valproate can also act to inhibit certain
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`biological processes that have the potential to cause varying effects on GHB levels.
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`First, valproate can be a monocarboxylate transporter (“MCT”) inhibitor. MCTs
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`are molecules that transport substances like GHB in the body across cellular
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`membranes. Id. at 17:24-41. If MCT is inhibited, GHB levels are lower because
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`less GHB is transported into, and maintained in, the body. Id. at 17:37-40.
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`Although not disclosed in the prior art, the inventor of the ’306 patent found that
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`valproate inhibited the uptake of GHB into the body such that 30% more GHB was
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`excreted through the kidneys. Id. at 11:6-8 (“MCT inhibition caused renal
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`clearance to be increased 30%.”). Second, valproate can be a GHB dehydrogenase
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`(“GHB-DH”) inhibitor. Ex. 1003 at 340. GHB-DH is one of the many pathways
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`involved in the process of eliminating GHB from the body. Id. at 342.
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`If GHB-DH is inhibited, GHB levels are potentially higher because less GHB is
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`being broken down. Id. at 340-41. Although not disclosed in the prior art, the
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`inventor of the ’306 patent found that valproate inhibited the breakdown of GHB in
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`the body such that GHB levels were 26% higher. Ex. 1001 at 11:8-9 (“GHB
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`dehydrogenase inhibition caused systemic exposure (plasma AUC) to be increased
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`26%.”). Thus, the ’306 patent explains that valproate is involved in processes that
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`can both raise or lower the levels of GHB in the patient.
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`As discussed in more detail below, at the time of the ’306 patent’s
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`inventions, the prior art’s teachings on the interaction between GHB and valproate
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`were inconsistent and contradictory, and taught that valproate’s effects on orally-
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`administered GHB in the human body were unknown. Indeed, the prior art
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`highlighted the unpredictability of valproate’s effects. A POSA would not have
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`known how the co-administration of GHB and valproate would alter GHB blood
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`levels, nor would a POSA have known how valproate affects GHB
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`pharmacodynamic effects, in human patients. Indeed, some prior art recommended
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`using valproate to treat GHB overdose or GHB-induced seizures, while other prior
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`art expressly taught avoiding GHB and valproate co-administration altogether.
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`Thus, the prior art disclosures would not have allowed a POSA to draw any
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`conclusions about the effect of co-administering GHB and valproate, much less
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`draw any conclusions about whether or how to adjust the GHB dose as claimed in
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`the ’306 patent.
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`The ’306 patent describes and claims innovative methods for safely co-
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`administering GHB and valproate to treat patients with sleep disorders such as
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`cataplexy and excessive daytime sleepiness. The solution claimed by the ’306
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`patent uses specially-tailored GHB doses for co-administration with valproate that
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`could not have been derived from the prior art, both because: (1) the prior art
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`provided inconsistent and contradictory teachings, such that the effects of valproate
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`on patients taking GHB would be unpredictable; and (2) the prior art taught that
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`co-administration should be stopped if a substance (such as valproate) had the
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`potential to cause negative GHB pharmacodynamic effects in human patients.
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`II. RANBAXY HAS FAILED TO SHOW A REASONABLE
`LIKELIHOOD THAT THE ’306 PATENT WOULD HAVE
`BEEN OBVIOUS
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`Ranbaxy’s Petition improperly uses hindsight to ignore key disclosures that
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`would have led a POSA away from the claimed inventions.
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`Specifically, in each Ground of its Petition, Ranbaxy erroneously argues
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`that: (1) the prior art allegedly would have disclosed to a POSA that valproate
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`increases negative effects of GHB in patients; and (2) a POSA allegedly would
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`have chosen to titrate down the GHB dose as a result. See Pet. 11-15. When the
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`prior art is properly considered as a whole, however, it shows that Ranbaxy is
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`wrong on both counts.
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`First, the prior art Ranbaxy proffers concerning valproate’s effects on GHB
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`levels, as well as the prior art as a whole, would not have provided a POSA with
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`any understanding of the effects of valproate on either endogenous GHB or orally-
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`administered, exogenous GHB. Instead, Ranbaxy’s prior art would have taught a
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`POSA that the effects of valproate on a human patient also taking GHB were
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`unpredictable. This is because the prior art as a whole does not teach that
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`valproate increases negative effects of GHB in human patients. Instead, the prior
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`art as a whole actually discloses that:
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`(1)
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`a POSA cannot determine the overall effects of valproate on GHB
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`levels in humans because GHB is eliminated from the body by several
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`pathways that Ranbaxy does not consider (see infra at pp. 9-12);
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`(2) while certain prior art suggests that valproate may increase
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`endogenous GHB levels in the brain, other prior art suggests that
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`valproate may decrease endogenous GHB levels and GHB levels
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`achieved after oral administration of exogenous GHB, both in the
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`body as a whole and in the brain in particular, by: (a) its function in
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`the kidney; (b) inhibiting GHB formation; and (c) acting as an MCT
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`inhibitor, thereby both increasing renal clearance and lowering oral
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`absorption of GHB (see infra at pp. 12-18);
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`(3)
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`valproate could be a treatment for GHB overdose and GHB-induced
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`seizures and not a cause of GHB toxicity (see infra at pp. 19-23); and
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`(4)
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`valproate’s effect on GHB-DH in rats is not predictive of valproate’s
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`effect on GHB-DH in humans (see infra at pp. 23-24).
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`Second, the prior art as a whole, including references Ranbaxy relies upon,
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`expressly teach away from the claimed inventions. Specifically, the prior art
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`discloses that GHB and valproate should not be co-administered at all if negative
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`GHB-valproate interactions are a concern. See infra at pp. 24-29.
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`Third, the prior art teaches that a POSA would not have been motivated to
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`administer reduced GHB doses to patients concomitantly receiving valproate. No
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`prior art discloses, teaches, or suggests reducing the GHB dose in a patient taking
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`valproate. See infra at pp. 29-35.
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`Fourth, the prior art would have taught a POSA that lowering the GHB dose
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`to the doses Ranbaxy suggests (3 g/night, 4.5 g/night, 6 g/night, and 7.5 g/night)
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`would not have been a viable option. Specifically, the prior art teaches that GHB
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`doses lower than 6 g/night were known to be ineffective for treating sleep
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`disorders, including cataplexy and EDS, and side effects occurred in the prior art at
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`GHB doses as low as 3.5 g/night. See infra at pp. 35-39.
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`A. Ranbaxy ignores that the prior art’s teachings were inconsistent
`and contradictory, such that the effects of valproate on GHB in
`humans would have been unpredictable to a POSA
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`A claimed invention is nonobvious where it yields more than predictable
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`results. See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
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`Patent Litig., 678 F.3d 1063, 1072-73 (Fed. Cir. 2012); Crocs, Inc. v. U.S. Int’l
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`Trade Comm’n, 598 F.3d 1294, 1308-09 (Fed. Cir. 2010). Indeed, unpredictability
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`is an important indicia of nonobviousness. See United States v. Adams, 383 U.S.
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`39, 51-52 (1966); Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368, 1379 (Fed.
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`Cir. 2007). “To the extent an art is unpredictable, as the chemical arts often are,” it
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`is difficult to establish obviousness. See Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533,
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`F.3d 1353, 1359 (Fed. Cir. 2008). The prior art taken as a whole establishes that
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`the effect of valproate on a patient taking GHB was entirely unpredictable. This
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`unpredictability refutes Ranbaxy’s obviousness claim.
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`1. GHB is eliminated by many
`pathways other than GHB-DH
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`Ranbaxy’s Petition focuses solely on how GHB levels will allegedly be
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`affected by valproate’s interaction with GHB-DH to the exclusion of all other
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`relevant pathways. See, e.g., Pet. 12-14, 18, 35, 44, 49. Ranbaxy’s single-minded
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`focus on alleged increased GHB blood levels because of GHB-DH inhibition is
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`erroneous, however, because the prior art also would have taught a POSA that
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`GHB is eliminated from the body through several alternate pathways as well. In
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`fact, the prior art teaches that even if valproate decreases GHB elimination by
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`inhibiting GHB-DH, GHB is eliminated from the body through several alternate
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`pathways that are not inhibited (and that might even be accelerated) by valproate.
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`These alternate elimination pathways would decrease GHB levels. Accordingly,
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`prior art disclosing that valproate inhibits GHB-DH would not have led a POSA to
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`conclude anything about valproate’s effect on GHB blood levels and GHB
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`pharmacodynamic effects in human patients because other prior art discloses that
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`GHB could be eliminated from the body by one of the alternate elimination
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`pathways independent of GHB-DH. Ranbaxy ignores this fact.
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`Specifically, the prior art discloses that, in addition to GHB-DH, GHB is
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`also eliminated by: (1) mitochondrial oxidoreductase (Ex. 1015 at 757); (2)
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`hydroxyacid-oxoacid transhydrogenase (“HOT”) that “is active in a number of
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`mammalian species” (Ex. 1018 at 283); (3) β-oxidation via 3,4-dihydroxybutyrate
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`(Ex. 2001 at 3); and (4) renal clearance (Ex. 1028 at 317). Each of these disclosed
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`pathways demonstrates the unpredictability in the art and difficulty in extrapolating
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`a conclusion about valproate’s effect on GHB from the prior art that Ranbaxy
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`alleges shows that valproate inhibits GHB-DH.
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`First, mitochondrial oxidoreductase is similar to GHB-DH. Both eliminate
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`GHB from the body by catalyzing its oxidation to succinic semialdehyde (“SSA”).
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`See Ex. 1015 at 757. The mitochondrial oxidoreductase, however, differs from
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`GHB-DH in that it does not need the co-factor NADP+ and in that its activity is not
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`inhibited by valproate. See id. Second, the HOT enzyme reduces levels of GHB
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`by catalyzing the α-ketoglutarate-dependent oxidation of GHB to SSA. See Ex.
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`1018 at 283. Third, the body eliminates GHB through its partial β-oxidation via
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`3,4-dihydroxybutyrate to carbon dioxide and water. See Ex. 2001 at 3. Finally,
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`even if valproate inhibits the GHB-DH pathway of eliminating GHB, the body has
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`the ability to directly excrete GHB through the kidneys (i.e., renal clearance). See
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`Ex. 1028 at 317. Renal clearance becomes increasingly important as GHB levels
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`are increased above physiological levels. See id. Thus, aside from GHB-DH, there
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`are four additional pathways that remove GHB.
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`Ranbaxy does not explain, and the prior art would not have disclosed to a
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`POSA, how valproate would affect the overall level of GHB in the human body in
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`light of GHB’s several elimination pathways, or whether these other pathways
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`would nullify or compensate for valproate’s alleged inhibitory effects on
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`GHB-DH. Notably, the prior art does not uniformly show that valproate’s
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`inhibition of GHB-DH will significantly alter GHB levels at all. Ex. 1014 at 164.
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`The prior art, therefore, would not have provided any evidence for a POSA to
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`conclude that valproate would increase GHB levels in human patients, eliminating
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`the first link in Ranbaxy’s obviousness argument.
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`Ranbaxy has not established the next link in its obviousness argument either.
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`None of the prior art that Ranbaxy proffers establishes a relationship between
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`valproate’s effect on GHB levels and valproate’s effect on GHB pharmacodynamic
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`effects in human patients. Ranbaxy fails to show that the prior art disclosed a
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`known pharmacokinetic/pharmacodynamic (“PK/PD”) relationship for a valproate-
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`GHB interaction. Without the knowledge of such a PK/PD relationship, a POSA
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`would not know how changes in GHB levels (PK)—if they occur—would affect a
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`patient (PD), and whether such effects—if they occur—would be sufficient to
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`require any change in GHB dosing, let alone those claimed in the ‘306 patent.
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`Thus, the premise of Ranbaxy’s obviousness argument does not support its
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`conclusion that the ’306 patent claims would have been obvious. See In re
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`Cyclobenzaprine, 678 F.3d at 1072 (reversing obviousness holding for method of
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`treatment claims where the prior art failed to disclose a known PK/PD
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`relationship).
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`2.
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`A POSA could not have expected valproate’s effect on
`GHB levels because of the unpredictability in the art
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`Ranbaxy’s hindsight-focus on certain prior art that discloses that valproate
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`increases GHB levels through inhibition of GHB-DH (see, e.g., Pet. 12-14, 18, 35,
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`44, 49), leads it to ignore other prior art, which would have taught a POSA that
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`valproate decreases GHB levels. This focus is plainly insufficient to support a
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`challenge to validity. The prior art “must be considered in its entirety, i.e., as a
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`whole, including portions that would lead away from the invention in suit.”
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`Panduit Corp. v. Dennison Mfg., 810 F.2d 1561, 1568 (Fed. Cir. 1987) (emphasis
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`in original). Properly considered as a whole, the prior art discloses to a POSA that
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`valproate also decreases GHB levels by: (a) its function in the kidney;
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`(b) inhibiting GHB formation; and (c) acting as an MCT inhibitor, thereby both
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`increasing renal clearance and lowering oral absorption of GHB.
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`First, Ranbaxy fails to consider valproate’s effect on GHB levels in any
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`tissue other than the brain, and thus fails to consider valproate’s effect on the
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`overall GHB level in the body. Although Ranbaxy argues that “valproate . . .
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`would increase GHB levels in the body” because it “increase[s] GHB levels in the
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`brain” (see, e.g., Pet. 12-14), this is not correct. At least in the kidney, valproate
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`decreases GHB levels. Specifically, Ranbaxy’s own Kaufmann 1991 reference
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`discloses that valproate administration decreased endogenous GHB levels in the
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`kidney by approximately 8.55 nmole GHB/g tissue compared to a smaller increase
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`in the brain of approximately 0.85 nmole GHB/g tissue. See Ex. 1017 at 971,
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`Table VII. The overall decrease of GHB levels in this study would have provided
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`a POSA with uncertainty regarding whether valproate would result in an overall
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`increase or overall decrease of GHB levels in the human body. Thus, a POSA
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`would not have known how valproate affected GHB blood levels or GHB
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`pharmacodynamic effects in human patients.
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`Second, in addition to teaching that valproate increased GHB levels in rat
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`brain by inhibiting GHB metabolism by GHB-DH, the prior art also taught that
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`“valproate inhibited the formation of GHB” in rat brain homogenates. Ex. 1019 at
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`45; see also Ex. 1020 at 686 (“Inhibition of GHB formation by valproate could be
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`of considerable interest. . . .”); Ex. 2002 at 849-850 “Results” (discussing how
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`valproate “inhibited γ-hydroxybutyrate formation”). Disclosures that valproate
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`both inhibited GHB formation and inhibited GHB elimination via inhibition of
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`GHB-DH in rats would have presented a POSA with further uncertainty regarding
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`what valproate’s effect on GHB levels in the human body would be (e.g., a net
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`increase or net decrease of GHB levels).
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`Third, Ranbaxy erroneously argues that the ’306 patent’s applicant was
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`“incorrect when [he] asserted . . . that valproate’s possible function as an MCT
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`inhibitor might offset its possible function as a GHB dehydrogenase inhibitor.”
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`Pet. 12. Ranbaxy bases its argument on: (1) the ’306 patent’s own disclosure of
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`testing data which is not prior art, (id. (citing Ex. 1001 at 11:6-9)); and (2) certain
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`prior art that allegedly shows that valproate is not “transported” by MCT (id.
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`(citing Ex. 1019; Ex. 1020)).
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`As an initial matter, Ranbaxy’s reliance on the ’306 patent itself to argue
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`what a POSA allegedly would have known is improper as a matter of law. See
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`KSR Int’l v. Teleflex Inc., 550 U.S. 398, 421 (2007) (warning against a “temptation
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`to read into the prior art the teachings of the invention in issue” and instructing
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`courts to “guard against slipping into use of hindsight”); Life Techs. v. Clontech
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`Labs., 224 F.3d 1320, 1325 (Fed. Cir. 2000) (“[T]he path that leads an inventor to
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`the invention is expressly made irrelevant to patentability by statute.”). What
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`matters is what a POSA would have thought based upon the prior art at the time of
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`the ’306 patent’s invention. Ranbaxy has not shown—nor could it—that there was
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`any data in the prior art suggesting that valproate’s possible function as a GHB-DH
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`inhibitor was not offset by its function as an MCT inhibitor.
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`Moreover, the prior art at the time of the ’306 patent’s inventions would
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`have taught a POSA that valproate’s effect as an MCT inhibitor could have
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`potentially outweighed its effect as a GHB-DH inhibitor. Ranbaxy’s argument to
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`the contrary is based on a misstatement of the prior art’s disclosures.
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`Specifically, Ranbaxy cites Exs. 1019 and 1020 to argue that “[a]ny
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`potential function [of valproate] as a MCT inhibitor would have been minimal . . .
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`and at best, indirect.” Pet. 12. The disclosures Ranbaxy relies upon as alleged
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`support for its position, however, discuss whether valproate is transported by
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`MCT, not whether valproate inhibits MCT. See Ex. 1019 at 54 (discussing
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`whether valproate’s transport across the blood-brain barrier is mediated by MCT or
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`the fatty acid transporter); Ex. 1020 at 688 (same). Ranbaxy’s citations are
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`therefore entirely irrelevant. These references disclose the exact opposite of what
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`Ranbaxy claims they disclose. Specifically, the prior art establishes that valproate
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`acted as an MCT inhibitor; a teaching that would have predicted that valproate
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`would decrease, not increase, GHB levels.3
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`Monocarboxylate transporters (“MCT”) are membrane transport proteins
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`that can move molecules having one carboxylate group (such as GHB) across
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`biological membranes in the body. See Ex. 2004 at 227. Ranbaxy’s own prior art
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`explains the difference between valproate being transported by MCT and valproate
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`inhibiting MCT:
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`[V]alproic acid inhibited the BBB [blood-brain barrier]
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`influx of MCT substrates, but MCT substrates failed to
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`inhibit valproic acid BBB influx. This lack of mutual
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`inhibition suggested that valproic acid, although not
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`transported by MCT, can interact with MCT to prevent
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`substrate transport.
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`Ex. 1031 at 97 (emphasis added). In other words, valproate is an MCT inhibitor
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`whether or not it is transported by MCT. Thus, while Ranbaxy argues that
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`3 Further, Ranbaxy ignores other prior art that contradicts Exs. 1019 and 1020’s
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`disclosure that valproate is not transported by MCT. See Ex. 2003 at 1487 (citing
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`Halestrap 2004 (footnote 8)) (“Apart from endogenous moncarboxylates, MCTs
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`are also involved in the transport of some exogenous drugs such as salicylate,
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`valproic acid and atorvastatin.”). Regardless, valproate is an MCT inhibitor.
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`“valproate transport is not governed by the monocarboxylate carrier” (Pet. at 12
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`(emphasis added)), that fact is a red herring and completely irrelevant to the
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`patented inventions. Valproate still inhibits the transport of other MCT substrates
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`like GHB. Ranbaxy fails to appreciate this critical distinction.
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`Properly viewing the prior art, a POSA would have understood that it
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`discloses that valproate “significantly inhibited” GHB blood-brain barrier (“BBB”)
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`transport through its action as an MCT inhibitor. Ex. 1031 at 95; see also id. at 96
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`(Table 2) (disclosing that when rats were given valproate with GHB, the influx of
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`that exogenous GHB into the brain was reduced 40% to 75% compared to when
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`GHB was given without valproate). Ranbaxy’s own Morris reference also
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`discloses that, as an MCT inhibitor, valproate could also act upon the kidneys to
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`increase renal clearance of GHB and/or the digestive track to inhibit the absorption
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`of orally-administered (exogenous) GHB. See Ex. 1028 at 317. Thus, as described
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`below, even if some prior art suggested that valproate may increase GHB levels,
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`other prior art (that Ranbaxy relies upon) suggested the opposite position, i.e., “that
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`administration of GHB transport inhibitors [like valproate] may reduce brain GHB
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`concentrations.” Ex. 1031 at 98.
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`Accordingly, the ’306 applicant was correct during prosecution when he
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`stated, and the Patent Office agreed, that:
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`[I]t would not have been known prior to the present
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`application what [valproate’s] effect would be, such as an
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`increase or a decrease in the in vivo effect of GHB. For
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`example, valproate could have created an impact through
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`its activity as an MCT
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`inhibitor, or by another
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`mechanism, such as
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`inhibiting
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`the enzyme GHB
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`dehydrogenase.
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`Ex. 1027 at 10; see also Ex. 2005.
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`The unpredictability in the art weighs heavily against finding that a POSA
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`would have had a “reasonable expectation” that valproate would increase GHB
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`levels in humans. See Yamanouchi Pharm v. Danbury Pharmacal, 231 F.3d 1339,
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`1345 (Fed. Cir. 2000); see also Proctor & Gamble Co. v. Teva Pharm. USA, Inc.,
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`566 F.3d 989, 996 (Fed. Cir. 2009) (“In light of the Supreme Court’s instruction in
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`KSR, the Federal Circuit has stated that, ‘[t]o the extent an art is unpredictable, as
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`the chemical arts often are, KSR’s focus on [] ‘identified, predictable solutions’
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`may present a difficult hurdle because potential solutions are less likely to be
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`genuinely predictable.’”); Pfizer Inc. v. Teva Pharms. USA, Inc., 882 F. Supp. 2d
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`643, 664 (D. Del. 2012) (“[P]harmaceuticals can be an ‘unpredictable art.’”).
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`Here, the prior art would not have provided a POSA with guidance on how
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`valproate w