Paper No. __
`Filed: May 6, 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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`AMNEAL PHARMACEUTICALS LLC
`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 IPR2016-00546
`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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`TABLE OF CONTENTS
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`Page
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`I.
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`INTRODUCTION ...............................................................................................................1
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`II.
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`BACKGROUND .................................................................................................................3
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`A.
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`B.
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`Jazz’s Xyrem® Product.............................................................................................3
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`The ’306 Patent ........................................................................................................4
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`III.
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`AMNEAL 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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`Amneal 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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`Amneal’s Metabolic Pathway for GHB is Incomplete ................................9
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`A POSA could not have expected valproate’s effect on GHB
`levels because of the unpredictability in the art .........................................14
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`Amneal argues that the prior art discloses that valproate could lead
`to GHB toxicity, but ignores that the prior art also discloses that
`valproate could treat GHB toxicity............................................................19
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`B.
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`Amneal ignores the express disclosures in the prior art that it relies upon
`that would have taught a POSA away from GHB and valproate co-
`administration and, thus, the claimed inventions ...................................................23
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`1.
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`2.
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`The Xyrem Label’s disclosures would have taught a POSA away
`from the claimed inventions.......................................................................23
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`Cagnin’s disclosure would have taught a POSA away from the
`claimed inventions .....................................................................................26
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`C.
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`D.
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`Amneal fails to show that a POSA would have been motivated to
`administer reduced GHB doses if valproate caused GHB-related side
`effects .....................................................................................................................28
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`Amneal 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 .................................................................................33
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`1.
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`Amneal fails to rebut that the prior art discloses to a POSA that its
`proposed adjusted GHB doses would not have been effective for
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`treating the claimed sleep disorders, without resulting side effects,
`when co-administered with valproate ........................................................35
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`2.
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`Amneal’s argument that it would have been “obvious to try . . .
`routine pharmacokinetic studies” does not provide evidence of a
`reasonable expectation of success ..............................................................37
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`E.
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`Amneal’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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`IV.
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`CONCLUSION ..................................................................................................................40
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`I.
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`INTRODUCTION
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`IPR2016-00546
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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 Amneal Pharmaceuticals
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`LLC’s (“Amneal”) Petition for inter partes review (the “Petition” or “Pet.”) of
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`U.S. Patent No. 8,772,306 (the “’306 patent”).
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`Amneal’s Petition sets forth substantially the same art and arguments
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`considered and rejected by the Board in Par Pharmaceutical, Inc. v. Jazz
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`Pharmaceuticals Ireland Ltd. et al., IPR2016-00002, Paper 12 (Apr. 12, 2016) (the
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`“Par ’306 IPR”).1 Like Par, Amneal “does not account for the prior art’s teaching
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`away of the co-administration of GHB and valproate.” Id. at 12-13. Also like Par,
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`Amneal “has not identified a sufficient basis . . . to conclude that any increased
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`brain levels of endogenous GHB caused by valproate could have been predictably
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`compensated for by a corresponding decrease of at least 5% in the amount of GHB
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`orally administered to patients.” Id. at 13-14. For at least these reasons, Amneal’s
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`Petition should be denied.
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`1 In fact, all of the references asserted in Amneal’s Grounds of invalidity were
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`already considered in the Par ’306 IPR. See IPR2016-00002, PAR1006 (Xyrem
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`Label), PAR1014 (Hechler), PAR1013 (Shinka); PAR1007 (Depakote Label),
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`PAR1008 (Cagnin), PAR1015 (Kaufman).
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`As explained in more detail below, at the time of the ’306 patent’s
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`inventions, the prior art would not have provided a person of ordinary skill in the
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`art (“POSA”) with any guidance concerning what effect administering valproate
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`would have on GHB in humans. Instead, the prior art considered as a whole would
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`have taught that valproate’s effect on both GHB blood levels and GHB
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`pharmacodynamic effects was entirely unpredictable.
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`Amneal’s Petition makes it clear that no prior art disclosed, taught, or
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`suggested reducing the GHB dose in a patient taking valproate. Rather, if a POSA
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`were concerned with GHB-related side effects occurring in humans concomitantly
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`receiving valproate, then a POSA would have done exactly what the references say
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`to do—stop co-administering the two drugs. The prior art expressly teaches away
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`from the claimed inventions.
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`Each Ground of Amneal’s Petition fails because: (1) Amneal does not show
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`that the prior art would have taught a POSA what the effect of valproate would be
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`on GHB levels or GHB pharmacodynamic effects in human patients; (2) Amneal
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`ignores that the prior art would have taught a POSA away from the claimed
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`inventions; (3) Amneal does not show that a POSA would have been motivated to
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`administer reduced GHB doses even if the POSA believed that valproate causes
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`negative GHB-related side effects in humans; and (4) Amneal does not show that a
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`POSA would have reasonably expected that the reduced GHB doses would be
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`effective for treating the claimed sleep disorders, and do so without resulting side
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`effects, when co-administered with valproate. Amneal’s additional arguments
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`directed to the ’306 patent’s claims that also require the administration of aspirin
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`do not add anything to its faulty Petition.
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`II. BACKGROUND
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`A.
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`Jazz’s Xyrem® 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.2 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.3 See Ex. 1005 at 1 (“Description”), 4-7
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`(“Clinical Trials”). While Xyrem is a life-changing therapy for many narcoleptic
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`patients, GHB is also a central nervous system (“CNS”) depressant with potentially
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`serious side effects. See id. at 1 (“Warning”). Indeed, the Xyrem Label discloses
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`2 Naturally-occurring GHB is referred to as “endogenous” GHB.
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`3 The GHB administered to patients is referred to as “exogenous” GHB.
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`to a POSA that GHB has a toxicity profile that includes “seizure, respiratory
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`depression and profound decreases in level of consciousness, with instances of
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`coma and death.” See id.
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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. 2001 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. 1020 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. If
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`GHB-DH is inhibited, GHB levels are potentially higher because less GHB is
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`being broken down. See 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 overdoses or GHB-induced seizures, while other
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`prior art expressly taught avoiding GHB and valproate co-administration
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`altogether. Thus, the prior art disclosures would not have allowed a POSA to draw
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`any conclusions about the effect of co-administering GHB and valproate, much
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`less draw any conclusions about whether or how to adjust the GHB dose as
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`claimed in 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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`III. AMNEAL HAS FAILED TO SHOW A REASONABLE LIKELIHOOD
`THAT THE ’306 PATENT WOULD HAVE BEEN OBVIOUS
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`Amneal’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, Amneal erroneously argues that:
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`(1) the prior art allegedly would have disclosed to a POSA that valproate causes
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`negative pharmacokinetic and pharmacodynamic interactions with GHB through
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`its inhibition of certain enzymes; and (2) a POSA allegedly would have chosen to
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`reduce the GHB dose as a result. When the prior art is properly considered as a
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`whole, however, it shows that Amneal is wrong on both counts.
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`First, the prior art Amneal 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, the prior art would have taught a POSA
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`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 Amneal does not consider (see infra at 9-14);
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`(2) while certain prior art suggests that valproate may increase
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`endogenous GHB levels, other prior art suggests that valproate may
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`decrease endogenous GHB levels and GHB levels achieved after oral
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`administration of exogenous GHB by: (a) its function in the kidney;
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`(b) inhibiting GHB formation; and (c) acting as an MCT inhibitor,
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`thereby both increasing renal clearance and lowering oral absorption
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`of GHB (see infra at 14-19); and
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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 19-22).
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`Second, the prior art that Amneal relies upon expressly teaches away from
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`the claimed inventions. Specifically, the prior art discloses that GHB and
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`valproate should not be co-administered at all if negative GHB-valproate
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`interactions are a concern. See infra at 23-28.
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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 28-33.
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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 that Amneal suggests would not have been a viable option if co-
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`administered with valproate. Specifically, the prior art that Amneal relies upon
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`teaches that GHB doses lower than 6 g/night were known to be ineffective for
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`treating sleep disorders, including cataplexy and EDS, and also that side effects
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`occurred at GHB doses as low as 3.5 g/night when co-administered with valproate.
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`See infra at 33-39.
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`A. Amneal 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., 676 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. 2006). “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 Amneal’s obviousness claim.
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`1.
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`Amneal’s Metabolic Pathway for GHB is Incomplete
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`Amneal purports to set forth the metabolic pathway for GHB, and
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`valproate’s alleged effect on that pathway in its Petition. See, e.g., Pet. 8-10, 13-
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`16. Amneal argues that the prior art teaches that valproate increases GHB levels
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`by inhibiting GHB-DH, succinic semialdehyde dehydrogenase (“SSADH”), and
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`nonspecific succinic semialdehyde reductase (“nonspecific SSR”). See id. 8-10,
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`13-16, 25-26, 44-45, 57. Amneal further argues that “[v]alproate was known to not
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`inhibit specific SSR, which converts SSA [the abbreviation for succinic
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`semialdehyde] to GHB, further leading to increased accumulation of GHB.” Id.
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`15-16.
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`Amneal ignores, however, that the prior art also would have taught a POSA
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`that GHB is eliminated from the body through several alternate pathways that
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`Amneal does not consider. In fact, as detailed below, the prior art, including the
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`prior art that Amneal cites, teaches that even if valproate decreases GHB
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`elimination by inhibiting GHB-DH, SSADH, and nonspecific SSR, GHB is
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`eliminated from the body through several alternate pathways that are not inhibited
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`(and that might even be accelerated) by valproate. The prior art thus taught that
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`these alternate elimination pathways would decrease, rather than increase, GHB
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`levels. Accordingly, prior art disclosing that valproate inhibits GHB-DH, SSADH,
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`and/or nonspecific SSR, would not have led a POSA to conclude anything about
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`valproate’s effect on GHB levels and GHB pharmacodynamic effects in human
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`patients because other prior art discloses that GHB could be eliminated from the
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`body by one of the alternate elimination pathways independent of GHB-DH,
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`SSADH, and nonspecific SSR. Amneal ignores this fact in its oversimplified
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`depiction of the absorption, distribution, metabolism, and/or excretion (“ADME”)
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`of GHB. See Pet. Figs. 1 and 2.
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`Specifically, the prior art, including the Hechler reference and Xyrem Label
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`that Amneal relies upon, discloses that, in addition to GHB-DH, SSADH, and
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`nonspecific SSR, GHB is also eliminated by: (1) mitochondrial oxidoreductase
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`(Ex. 1006 at 757); (2) hydroxyacid-oxoacid transhydrogenase (“HOT”) that “is
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`active in a number of mammalian species” (Ex. 2002 at 283); (3) β-oxidation via
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`3,4-dihydroxybutyrate (Ex. 1005 at 3); and (4) renal clearance (Ex. 2003 at 317).
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`Each of these disclosed pathways demonstrates the unpredictability in the art and
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`difficulty in extrapolating a conclusion about valproate’s effect on GHB from the
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`prior art that Amneal alleges shows that valproate inhibits GHB-DH, SSADH, and
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`nonspecific SSR.
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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 SSA. See Ex. 1006 at 757. The
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`mitochondrial oxidoreductase, however, differs from GHB-DH in that it does not
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`need the co-factor NADP+ and in that its activity is not inhibited by valproate. See
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`id. Second, the HOT enzyme reduces levels of GHB by catalyzing the α-
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`ketoglutarate-dependent oxidation of GHB to SSA. See Ex. 2002 at 283. Third,
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`the body eliminates GHB through its partial β-oxidation via 3,4-dihydroxybutyrate
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`to carbon dioxide and water. See Ex. 1005 at 3. Fourth, even if valproate inhibits
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`the GHB-DH, SSADH, and nonspecific SSR pathways of eliminating GHB, the
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`body has the ability to directly excrete GHB through the kidneys (i.e., renal
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`clearance). See Ex. 2003 at 317. Renal clearance becomes increasingly important
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`as GHB levels are increased above physiological levels. See id. Thus, aside from
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`the enzymes Amneal mentions, the prior art teaches four additional pathways that
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`remove GHB.
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`Moreover, Amneal’s implication that valproate would necessarily increase
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`GHB levels because it does not inhibit specific SSR’s conversion of SSA to GHB
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`(see Pet. 15-16), is unsupported by the prior art. Conspicuously absent from
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`Amneal’s depiction of GHB’s metabolic pathway (Figure 2, Pet. 15) is the fact that
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`GABA Transaminase (“GABA-T”) is a “shunt” (or push-and-pull) enzyme,
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`meaning that it regulates both the conversion of GABA to SSA and the conversion
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`of SSA to GABA. See Ex. 1017 at 127 (Vayer article Amneal relies upon defining
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`GABA Transaminase as a “shunt” enzyme); Ex. 1020 at 339, 342 (Amneal’s
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`Maitre reference showing GABA-T regulating both the conversion of GABA to
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`SSA and the conversion of SSA to GABA). As Amneal and the Vayer article it
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`relies upon admit, valproate only inhibited the conversion of GABA to SSA,
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`thereby increasing concentrations of GABA. See Pet. at 13; Ex. 1017 at 127. As
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`the Maitre article explains, however, even in the presence of valproate, SSA could
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`be “converted into GABA by the mitochondrial GABA-T (GABA-Tm) or perhaps
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`by a cytosolic isoform of this enzyme (GABA-Tc).” Ex. 1020 at 342, Fig. 2.
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`Thus, valproate does not inhibit the conversion of SSA to GABA. Id.
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`Patent Owner Preliminary Response
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`IPR2016-00546
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`Accordingly, the prior art discloses that there remains an elimination pathway for
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`GHB once it is converted to SSA. Amneal is therefore wrong to imply that
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`valproate’s inability to inhibit specific SSR will lead to increased GHB levels
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`because SSA is converted solely back to GHB. As the prior art show, SSA will
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`also be converted to GABA.
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`Accordingly, Amneal does not explain, and the prior art would not have
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`disclosed to a POSA, how valproate would affect the overall level of GHB in the
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`human body in light of GHB’s several elimination pathways, or whether these
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`other pathways would nullify or compensate for valproate’s alleged inhibitory
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`effects on GHB-DH, SSADH, and nonspecific SSR. Notably, the prior art does
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`not uniformly show that valproate’s inhibition of enzymes like GHB-DH will
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`significantly alter GHB levels at all. Ex. 2004 at 164. The prior art, therefore,
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`would not have provided any evidence for a POSA to conclude that valproate
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`would increase GHB levels in human patients. Here, just as in the Par ’306 IPR,
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`because “Petitioner does not account for these other pathways by which GHB may
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`be eliminated[] Petitioner has not identified a sufficient basis . . . to conclude that
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`any increased brain levels of endogenous GHB caused by valproate would have
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`been predictably compensated for by a corresponding decrease . . . in the amount
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`of GHB orally administered to patients.” IPR2016-00002, Paper 12 at 13-14. This
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`eliminates the first link in Amneal’s obviousness argument.
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`Patent Owner Preliminary Response
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`IPR2016-00546
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`Amneal has not established the next link in its obviousness argument either.
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`None of the prior art Amneal 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. Amneal 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 Amneal’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, 676 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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`Amneal’s hindsight focus on certain prior art that discloses that valproate
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`increases GHB levels leads it to ignore other prior art, which would have taught a
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`POSA that valproate decreases GHB levels. This focus is fatal to Amneal’s
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`challenge. The prior art “must be considered in its entirety, i.e., as a whole,
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`including portions that would lead away from the invention in suit.” Panduit Corp.
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`Patent Owner Preliminary Response
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`IPR2016-00546
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`v. Dennison Mfg., 810 F.2d 1561, 1568 (Fed. Cir. 1987) (emphasis in original).
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`Properly considered as a whole, the prior art discloses to a POSA that valproate
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`also decreases GHB levels by: (a) its function in the kidney; (b) inhibiting GHB
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`formation; and (c) acting as an MCT inhibitor, thereby both increasing renal
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`clearance and lowering oral absorption of GHB.
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`First, Amneal fails to consider valproate’s effect on GHB levels in different
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`parts of the body, and thus fails to consider valproate’s effect on the overall GHB
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`level in the body. In at least the kidney, valproate decreases GHB levels.
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`Specifically, Amneal’s own Kaufman reference discloses that valproate
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`administration decreased endogenous GHB levels in the kidney by approximately
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`8.55 nmole GHB/g tissue compared to a smaller increase in the brain of
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`approximately 0.85 nmole GHB/g tissue. See Ex. 1015 at 971, Table VII. The
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`overall decrease of GHB levels in this study would have provided a POSA with
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`uncertainty regarding whether valproate would result in an overall increase or
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`overall decrease of GHB levels in the human body. Thus, a POSA would not have
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`known how valproate affected GHB levels or GHB pharmacodynamic effects in
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`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-DH, SSADH, and nonspecific SSR, the prior art also
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`taught that “valproate inhibited the formation of GHB” in rat brain homogenates.
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`Patent Owner Preliminary Response
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`Ex. 2005 at 45; see also Ex. 1022 at 686 (“Inhibition of GHB formation by
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`valproate could be of considerable interest. . . .”); Ex. 2006 at 849-850 “Results”
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`(discussing how valproate “inhibited γ-hydroxybutyrate formation”). Disclosures
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`that valproate both inhibited GHB formation and inhibited GHB elimination via
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`inhibition of GHB-DH, SSADH, and nonspecific SSR in rats would have presented
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`a POSA with further uncertainty regarding what valproate’s effect on GHB levels
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`in the human body would be (e.g., a net increase or net decrease of GHB levels).
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`Third, Amneal erroneously argues that the ’306 patent applicant’s
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`“characterization during prosecution that it was unpredictable what the effect of
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`valproate on GHB levels would be due to valproate’s inhibition of both GHB
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`dehydrogenase and MCT was incorrect.” See Pet. 17. Specifically, Amneal argues
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`“that renal elimination of GHB due to MCT was a minor pathway of GHB
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`elimination . . . [that] would not have had a significant impact on overall GHB
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`levels in vivo.” Id. at 18 (citing Ex. 1003 ¶ 84; Ex. 1033 at 62, 64). Amneal’s
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`argument, however, is based on its declarant’s misstatement of the Borgen
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`reference’s disclosure.
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`Contrary to Amneal’s declarant’s testimony, it is clear from the reference
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`itself that Borgen does not mention valproate, the inhibition of any of GHB’s
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`metabolic enzymes, or MCT. See generally Ex. 1033. In fact, the only thing that
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`Borgen discloses is that under typical dosing—without valproate—GHB “was
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`Patent Owner Preliminary Response
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`IPR2016-00546
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`rapidly absorbed and quickly eliminated” from the body where “[u]rinary excretion
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`. . . was a minor elimination pathway . . . rang[ing] from 1% to 7%.” Id. at 62.
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`Borgen’s results make sense because GHB is normally metabolized so quickly that
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`there is very little remaining in the body to be excreted by the kidneys.
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`As a result, Borgen is not predictive of GHB urinary excretion if GHB-DH,
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`nonspecific SSR, SSADH, and MCT are inhibited by valproate, let alone whether
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`the overall effect of valproate would be to increase or decrease GHB levels. On
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`the other hand, Amneal’s Shinka reference discloses that there is “increased
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`excretion of [GHB] following valproate administration.” See Ex. 1007 at Abstract.
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`Amneal has not shown—nor could it—that there was any data in the prior art
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`suggesting that valproate’s possible function as an inhibitor of GHB-DH,
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`nonspecific SSR, and SSADH was not offset by its function as an MCT inhibitor.
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`To the contrary, the clear disclosures of prior art at the time of the ’306
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`patent’s inventions would have taught a POSA that valproate’s effect as an MCT
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`inhibitor could have potentially outweighed its effect as a GHB-DH, nonspecific
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`SSR, and SSADH inhibitor.
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`Indeed, properly viewing the prior art, a POSA would have understood that
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`it discloses that valproate “significantly inhibited” GHB blood-brain barrier
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`(“BBB”) transport through its action as an MCT inhibitor. Ex. 1026 at 95; see also
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`id. at 96 (Table 2) (disclosing that when rats were given valproate with GHB, the
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`Patent Owner Preliminary Response
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`IPR2016-00546
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`influx of that exogenous GHB into the brain was reduced 40% to 75% compared to
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`when GHB was given without valproate). The prior art also discloses that, as an
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`MCT inhibitor, valproate could also act upon the kidneys to increase renal
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`clearance of GHB and/or the digestive track to inhibit the absorption of orally-
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`administered (exogenous) GHB. See Ex. 2003 at 317. Thus, as described below,
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`even if some prior art suggested that valproate may increase GHB levels, other
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`prior art suggested the opposite position, i.e., “that administration of GHB
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`transport inhibitors [like valproate] may reduce brain GHB concentrations.” Ex.
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`1026 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 prese