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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`PAR PHARMACEUTICAL, INC.
`Petitioner,
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`v.
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`JAZZ PHARMACEUTICALS IRELAND LTD.
`Patent Owner
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`________________
`
`Case IPR2016-00002
`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 ............................................................................................. 2
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`A.
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`B.
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`Jazz’s Xyrem® Product .......................................................................... 2
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`The ’306 Patent ..................................................................................... 3
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`III. PAR HAS FAILED TO SHOW A REASONABLE LIKELIHOOD
`THAT THE ’306 PATENT CLAIMS WOULD HAVE BEEN
`OBVIOUS ........................................................................................................ 6
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`A.
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`Par’s invalidity grounds are premised on its erroneous
`“Background Regarding GHB/Valproate Interactions,” which
`fails to consider the unpredictability in the art and express
`disclosures of the prior art that would have led a POSA away
`from the claimed inventions .................................................................. 6
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`1.
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`Par 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 ............................................................. 8
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`(a) GHB is eliminated by many pathways other than
`SSADH and GHB-DH ...................................................... 9
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`(b) A POSA could not have expected valproate’s
`effect on GHB levels because of the
`unpredictability in the art ................................................ 12
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`(c)
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`(d)
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`Par 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 ................................................................... 17
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`Par relies on rat studies without providing
`evidence that rat enzymes are the same as human
`enzymes .......................................................................... 20
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`2.
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`Par ignores the express disclosures in the drug product
`labeling and patient case reports it relies upon that would
`have taught a POSA away from the claimed inventions .......... 21
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`B.
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`Par’s Ground 1 argument fails to show a reasonable likelihood
`that the ’306 patent claims would have been obvious ........................ 22
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`1.
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`Par has not shown that a POSA would have been
`motivated to combine the Ground 1 references ........................ 23
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`(a)
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`(b)
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`Par has not shown that a POSA would have been
`concerned with GHB-valproate interactions in
`patients with sleep disorders and thus that a POSA
`would have had a reason to even look to the prior
`art in the first place ......................................................... 24
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`Par has not shown that the FDA Guidance is
`relevant to drugs like Xyrem and Depakote and
`thus that a POSA would have been motivated to
`combine the FDA Guidance with the Ground 1
`references ........................................................................ 26
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`(c)
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`Par fails to address the prior art’s express
`disclosures that would have taught a POSA away
`from combining the Ground 1 references ....................... 28
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`i.
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`ii.
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`The Xyrem 2005 Label’s disclosures would
`have taught a POSA away from combining
`it with the Depakote 2011 Label .......................... 29
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`Cagnin’s disclosure would have taught a
`POSA away from combining it with the
`Xyrem 2005 Label and the Depakote 2011
`Label ..................................................................... 32
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`2.
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`3.
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`Par fails to show that a POSA would have been
`motivated to administer reduced GHB doses if valproate
`caused GHB-related side effects ............................................... 34
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`Par fails to show that a POSA would have reasonably
`expected that the reduced GHB doses would treat the
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`claimed sleep disorders, and do so without resulting side
`effects ........................................................................................ 41
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`(a)
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`(b)
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`Par fails to rebut that the prior art discloses to a
`POSA that Par’s proposed starting adjusted GHB
`doses would not have been effective for treating
`the claimed sleep disorders ............................................. 42
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`Par’s argument that a POSA would have titrated its
`proposed adjusted starting GHB doses up to effect
`fails because the prior art Par relies upon discloses
`side effects occurring at even very low,
`sub-therapeutic GHB doses ............................................ 43
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`C.
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`Par’s addition of Weiss in Ground 2 does not save its faulty
`Petition ................................................................................................. 45
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`IV. CONCLUSION .............................................................................................. 50
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`I.
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`INTRODUCTION
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`IPR2016-00002
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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 Par Pharmaceutical Inc.’s
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`(“Par”) Petition for Inter Partes Review (the “Petition” or “Pet.”) of U.S. Patent
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`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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`Par’s Petition fails to show a reasonable likelihood that the ’306 patent
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`claims would have been obvious. Par’s obviousness arguments improperly use
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`hindsight to focus on select disclosures from the prior art. Specifically, Par’s
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`Petition is based on at least two unfounded assumptions: (1) the assumption that
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`the prior art would have disclosed to a person of ordinary skill in the art (“POSA”)
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`that valproate causes negative pharmacokinetic and pharmacodynamic interactions
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`with GHB; and (2) the assumption that a POSA would have chosen to reduce the
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`GHB dose 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. The prior art expressly teaches away from the
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`claimed inventions.
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`Accordingly, for Ground 1, Par fails to establish that a POSA would have:
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`(1) been motivated to combine its asserted references; (2) 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 (3) reasonably expected that the
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`reduced GHB doses would be effective for treating the claimed sleep disorders,
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`and do so without resulting side effects. Ground 2 fails for all the same reasons.
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`Par’s addition of Weiss in Ground 2 does not save its flawed 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.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. 1006 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 2005 Label
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`discloses to 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.
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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. 2016 at 417.
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`Valproate is used as an anticonvulsant and mood-stabilizing drug, primarily in the
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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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`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. 2001 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. PAR HAS FAILED TO SHOW A REASONABLE LIKELIHOOD
`THAT THE ’306 PATENT CLAIMS WOULD HAVE BEEN
`OBVIOUS
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`A.
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`Par’s invalidity grounds are premised on its erroneous
`“Background Regarding GHB/Valproate Interactions,”
`which fails to consider the unpredictability in the art
`and express disclosures of the prior art that would have
`led a POSA away from the claimed inventions
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`Par’s “Background Regarding GHB/Valproate Interactions” (see Pet. 7-11),
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`improperly uses hindsight to ignore key disclosures that would have led a POSA
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`away from the claimed inventions.
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`Specifically, Par relies upon rat metabolism studies (Ex. 1012, Vayer; Ex.
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`1014, Hechler; Ex. 1015, Kaufman 1991), drug product labeling (Ex. 1006, the
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`Xyrem 2005 Label; Ex. 1007, the Depakote 2011), and single-patient case reports
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`(Ex. 1008, Cagnin; Ex. 1010, Weiss) to argue that: (1) the prior art allegedly
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`would have disclosed to a POSA that valproate causes negative pharmacokinetic
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`and pharmacodynamic interactions with GHB through its inhibition of succinic
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`semialdehyde dehydrogenase (“SSADH”)3 and GHB-DH; and (2) a POSA
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`allegedly would have chosen to reduce the GHB dose as a result. When the prior
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`art is properly considered as a whole, however, it shows that Par is wrong on both
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`counts.
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`First, Par’s cited metabolic studies, in light of the prior art as a whole, would
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`not have provided a POSA with any understanding of the effects of valproate on
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`either endogenous GHB or orally-administered, exogenous GHB. Instead, the
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`prior art would have taught a POSA that the effects of valproate on a human
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`patient also taking GHB were unpredictable. This is because the prior art as a
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`whole does not teach that valproate increases negative effects of GHB in human
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`patients. Instead, the prior 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 Par 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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`3 SSADH governs the metabolism of succinic semialdehyde (“SSA”). SSA is
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`both a metabolite, and direct precursor, of GHB. If SSADH is inhibited, SSA will
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`convert back to GHB. See Ex. 1012 at 128.
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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. 12-17);
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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. 17-20); and
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`(4)
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`valproate’s effect on SSADH and GHB-DH in rats is not predictive of
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`valproate’s effect on SSADH and GHB-DH in humans (see infra at
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`pp. 20-21).
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`Second, no prior art discloses, teaches, or suggests reducing the GHB dose in
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`a patient taking valproate. To the contrary, the prior art as a whole, including the
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`drug product labels and patient case reports that Par relies upon, expressly teach
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`away from the claimed inventions. Specifically, Par’s own cited references
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`disclose 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 21-22.
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`1.
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`Par 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 Par’s obviousness claim.
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`(a) GHB is eliminated by many pathways
`other than SSADH and GHB-DH
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`Par argues that the prior art teaches that valproate increases GHB levels by
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`inhibiting SSADH and GHB-DH. See Pet. 8-9. Par’s single-minded focus on
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`alleged increased GHB blood levels because of SSADH and 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 SSADH and GHB-DH, GHB is eliminated from the body through
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`several alternate pathways that are not inhibited (and that might even be
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`accelerated) by valproate. These alternate elimination pathways would decrease
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`GHB levels. Accordingly, prior art disclosing that valproate inhibits SSADH
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`and/or GHB-DH would not have led a POSA to conclude anything about
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`valproate’s effect on GHB blood levels and GHB pharmacodynamic effects in
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`human patients because other prior art discloses that GHB could be eliminated
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`from the body by one of the alternate elimination pathways independent of
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`SSADH and GHB-DH. Par ignores this fact.
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`Specifically, the prior art discloses that, in addition to SSADH and
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`GHB-DH, GHB is also eliminated by: (1) mitochondrial oxidoreductase (Ex. 1014
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`at 757); (2) hydroxyacid-oxoacid transhydrogenase (“HOT”) that “is active in a
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`number of mammalian species” (Ex. 2002 at 283); (3) β-oxidation via 3,4-
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`dihydroxybutyrate (Ex. 1006 at 3); and (4) renal clearance (Ex. 1034 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 Par alleges shows that valproate inhibits SSADH and 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. 1014 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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`2002 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. 1006 at 3. Finally,
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`even if valproate inhibits the SSADH and GHB-DH pathways of eliminating GHB,
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`the body has the ability to directly excrete GHB through the kidneys (i.e., renal
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`clearance). See Ex. 1034 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 Par mentions, there are four additional pathways that remove GHB.
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`Par does not explain, and the prior art would not have disclosed to a POSA,
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`how valproate would affect the overall level of GHB in the human body in light of
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`GHB’s several elimination pathways, or whether these other pathways would
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`nullify or compensate for valproate’s alleged inhibitory effects on SSADH and
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`GHB-DH. Notably, the prior art does not uniformly show that valproate’s
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`inhibition of enzymes like GHB-DH will significantly alter GHB levels at all. Ex.
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`2003 at 164. The prior art, therefore, would not have provided any evidence for a
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`POSA to conclude that valproate would increase GHB levels in human patients,
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`eliminating the first link in Par’s obviousness argument.
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`Par has not established the next link in its obviousness argument either.
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`None of the prior art Par proffers establishes a relationship between valproate’s
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`effect on GHB levels and valproate’s effect on GHB pharmacodynamic effects in
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`human patients. Par fails to show that the prior art disclosed a known
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`pharmacokinetic/pharmacodynamic (“PK/PD”) relationship for a valproate-GHB
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`interaction. Without the knowledge of such a PK/PD relationship, a POSA would
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`not know how changes in GHB levels (PK)—if they occur—would affect a patient
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`(PD), and whether such effects—if they occur—would be sufficient to require any
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`change in GHB dosing, let alone those claimed in the ‘306 patent. Thus, the
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`premise of Par’s obviousness argument does not support its conclusion that the
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`’306 patent claims would have been obvious. See In re Cyclobenzaprine, 676 F.3d
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`at 1072 (reversing obviousness holding for method of treatment claims where the
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`prior art failed to disclose a known PK/PD relationship).
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`(b) A POSA could not have expected valproate’s effect on
`GHB levels because of the unpredictability in the art
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`Par’s hindsight focus on certain prior art that discloses that valproate
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`increases GHB levels through inhibition of SSADH and GHB-DH (see Pet. 8-11),
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`leads it to ignore other prior art, which would have taught a POSA that valproate
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`decreases GHB levels. This focus is plainly insufficient to support a challenge to
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`validity. 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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`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, Par fails to consider valproate’s effect on GHB levels in any tissue
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`other than the brain, (see, e.g., Pet. 8 (arguing that GHB “could lead to increased
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`concentrations in the brain”)), and thus fails to consider valproate’s effect on the
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`overall GHB level in the body. In at least the kidney, valproate decreases GHB
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`levels. Specifically, Kaufmann 1991 discloses that valproate administration
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`decreased endogenous GHB levels in the kidney by approximately 8.55 nmole
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`GHB/g tissue compared to a smaller increase in the brain of approximately 0.85
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`nmole GHB/g tissue. See Ex. 1015 at 971, Table VII. The overall decrease of
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`GHB levels in this study would have provided a POSA with uncertainty regarding
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`whether valproate would result in an overall increase or overall decrease of GHB
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`levels in the human body. Thus, a POSA would not have known how valproate
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`affected GHB blood levels or GHB 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 SSADH and GHB-DH, the prior art also taught that “valproate
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`inhibited the formation of GHB” in rat brain homogenates. Ex. 2004 at 45; see
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`also Ex. 1033 at 686 (“Inhibition of GHB formation by valproate could be of
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`considerable interest. . . .”); Ex. 1040 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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`SSADH and GHB-DH in rats would have presented a POSA with further
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`uncertainty regarding what valproate’s effect on GHB levels in the human body
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`would be (e.g., a net increase or net decrease of GHB levels).
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`Third, Par’s Petition ignores valproate’s function as an MCT inhibitor.
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`Indeed, valproate’s function as an MCT inhibitor is only briefly discussed in Par’s
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`expert declaration. See Ex. 1003 ¶¶ 67-68. These paragraphs, however, are not
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`even cited in Par’s Petition, and they should be disregarded. See Fidelity Nat’l.
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`Info. Servs., Inc. v. Datatreasury Corp., IPR2014-00491, 2014 WL 4059222, at *5
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`(P.T.A.B. Aug. 13, 2014) (citing 37 C.F.R. § 42.6(a)(3)) (The Board’s rules
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`“prohibit arguments made in a supporting document from being incorporated by
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`reference into a petition.”). Par ignores these paragraphs because they are based on
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`a misinterpretation of the prior art, i.e., Bhattacharya 2006.
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`Par’s expert erroneously claims, citing Bhattacharya 2006, that “the effect of
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`MCT inhibition would likely not be significant in comparison to the effect of GHB
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`dehydrogenase inhibition.” Ex. 1003 ¶¶ 67-68. Specifically, Par’s expert relies on
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`Bhattacharya 2006’s conclusion, which states that salicylic acid, another GHB-DH
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`and MCT inhibitor, “is more likely to cause an undesirable drug interaction with
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`therapeutic use of GHB (for narcolepsy with cataplexy).” Ex. 1019 at 678. When
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`the snippets of Bhattacharya 2006 that Par’s expert chose to cite are read in context
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`of the rest of the paper, however, the “undesirable drug interaction” contemplated
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`by Bhattacharya 2006 is explained to be the reduction of GHB levels in the brain,
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`thereby reducing the effectiveness of GHB to treat narcolepsy. Thus, the
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`“undesirable drug interaction” is not the intensification of GHB’s negative effects,
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`but the opposite, i.e., the reduction of GHB levels, which is counter to Par’s theory.
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`See id. at Abstract (“Consistent with the prediction that reduced GHB
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`concentrations could translate to decreased pharmacodynamic effects, a pilot study
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`in rats showed that the pronounced GHB sedative/hypnotic effects . . . in the
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`control group . . . were significantly . . . abrogated by salicylic acid . . .
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`coadministration.”); id. at 676 (“Based on our simulations, salicylic acid pre-
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`administration, even 12hr prior to GHB dosing, leads to a decreased GHB brain
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`exposure.”); id. at 676-77 (“These pharmacological observations coupled with
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`pharmacokinetic simulations argue for a GHB-salicylic acid interaction occurring
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`via a transport (distributive) mechanism and against a metabolic inhibition
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`mechanism.”). In other words, Bhattacharya 2006 teaches that valproate
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`decreases, not increases, GHB levels.
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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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`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 (in prior art
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`post-dating Bhattacharya 2006) that, as an MCT inhibitor, valproate could also act
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`upon the kidneys to increase renal clearance of GHB and/or the digestive track to
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`inhibit the absorption of orally-administered (exogenous) GHB. See Ex. 1034 at
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`317. Thus, as described below, even if some prior art suggested that valproate may
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`increase GHB levels, other prior art 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. 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 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. 2005 at 10; see also Ex. 2006.
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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 would affect GHB levels, much less ho