PTAB

IPR2016-00024

Ranbaxy Inc v. Jazz Pharmaceutical Inc

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Petition
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1. Case Identification

2. Patent Overview

  • Title: Method of Administration of Gamma Hydroxybutyrate with Monocarboxylate Transporters
  • Brief Description: The ’306 patent discloses methods for treating sleep disorders, such as narcolepsy, by administering a reduced dose of gamma-hydroxybutyrate (GHB) to patients who are concomitantly receiving valproate. The patent is based on the asserted discovery that valproate increases physiological GHB levels, necessitating a dose reduction for safety and efficacy.

3. Grounds for Unpatentability

Ground 1: Claims 1-5, 7-16, 18-26, and 28-34 are obvious over Maitre and the Xyrem® PI.

  • Prior Art Relied Upon: Maitre (a 1997 journal article on the γ-Hydroxybutyrate signalling system) and the Xyrem® PI (the 2007 FDA-approved package insert for sodium oxybate, a GHB salt).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of these references taught every element of the challenged claims. Maitre explicitly taught that valproate inhibits GHB dehydrogenase, the primary enzyme responsible for metabolizing GHB, and thereby increases GHB levels in the brain. The Xyrem® PI, the official prescribing information for a commercial GHB product, taught that excessive doses of GHB could lead to severe adverse effects, including coma and death. The Xyrem® PI also provided a standard titration schedule for GHB, starting at 4.5 g/night and increasing in 1.5 g increments to a maximum of 9 g/night.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would have been motivated to combine the teachings to ensure patient safety. Knowing from Maitre that valproate impairs GHB metabolism and from the Xyrem® PI that elevated GHB levels are dangerous, a POSITA would have found it necessary and obvious to reduce the GHB dosage for any patient receiving concomitant valproate treatment.
    • Expectation of Success: A POSITA would have had a high expectation of success in safely reducing the dose. The Xyrem® PI provided a clear, incremental titration schedule (1.5 g adjustments), which offered a predictable and routine method for dose modification. Petitioner argued that applying a single standard dose reduction from the titration schedule (e.g., from 7.5 g/night to 6.0 g/night) would result in a 20% decrease, meeting the specific percentage reduction limitations recited in numerous dependent claims (e.g., "at least 15%").

Ground 2: Claims 19-26, 28, 29, 32 and 34 are obvious over Okun, the Xyrem® Titration Schedule, and Cook.

  • Prior Art Relied Upon: Okun (a 2001 journal article on GHB), the Xyrem® Titration Schedule (a document published in 2008), and Cook (Patent 6,780,889).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground specifically targeted claims reciting formulation parameters. Petitioner asserted that Okun and the Xyrem® Titration Schedule provided the same core teachings as the references in Ground 1: GHB is used for narcolepsy, valproate inhibits its metabolism, and established titration schedules exist. The Cook patent was added to teach the specific formulation limitations of claim 19, which requires a GHB salt concentration between 350 and 750 mg/mL and a pH between 6 and 10. Cook explicitly disclosed stable, aqueous GHB formulations with a concentration of 500 mg/mL and a pH of 7.5, falling squarely within the claimed ranges.
    • Motivation to Combine: The motivation to combine Okun and the Xyrem® Titration Schedule was again driven by patient safety. A POSITA seeking to implement the obvious dose reduction would then be motivated to use a known, stable, and effective formulation for oral administration, as taught by Cook.
    • Expectation of Success: There was a high expectation of success, as combining the references merely involved using a well-characterized formulation from Cook to administer a dose of GHB that was adjusted according to routine clinical safety principles taught by Okun and the Xyrem® Titration Schedule.

Ground 3: Claims 6, 17, and 27 are obvious over Maitre, the Xyrem® PI, and Sandson.

  • Prior Art Relied Upon: Maitre (1997 journal article), the Xyrem® PI (2007 package insert), and Sandson (a 2006 journal article on drug interactions).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground addressed claims requiring the additional step of administering aspirin. Building on the foundation of Maitre and the Xyrem® PI, Petitioner introduced Sandson, which taught the known drug-drug interaction between valproate and aspirin. Sandson explained that aspirin increases the concentration of "free valproate," the pharmacologically active form of the drug.
    • Motivation to Combine: A POSITA would have been motivated to combine these teachings to manage a three-way drug interaction. The POSITA would understand that: (1) valproate increases GHB levels (from Maitre), and (2) aspirin increases the effective amount of valproate (from Sandson). The logical conclusion was that administering aspirin would potentiate the effect of valproate, which in turn would further potentiate the effect of GHB, making a downward dose adjustment of GHB even more critical to avoid toxicity.
    • Expectation of Success: Adjusting a drug dosage to account for known metabolic interactions was a standard and predictable practice in pharmacology and medicine, ensuring a high expectation of success.
  • Additional Grounds: Petitioner asserted an additional obviousness challenge (Ground 2) based on Okun and the Xyrem® Titration Schedule, which relied on the same core safety motivation and dose-titration logic as Ground 1.

4. Key Claim Construction Positions

  • "valproate": Petitioner argued that under the broadest reasonable interpretation, this term should encompass not only valproate but also its related forms, including valproic acid, valproate semisodium, and divalproex. This construction was crucial for applying prior art references that discussed any of these chemical entities to the claims.

5. Key Technical Contentions (Beyond Claim Construction)

  • Petitioner’s central technical contention was that the ’306 patent was based on a false premise of an "unexpected" discovery. Petitioner argued that the prior art, particularly Maitre, had long established the underlying biochemical mechanism: valproate was a known inhibitor of GHB dehydrogenase. Therefore, the resulting increase in physiological GHB levels upon co-administration was not a surprising discovery but a direct, known, and entirely predictable pharmacological consequence.

6. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 1-34 of Patent 8,772,306 as unpatentable under 35 U.S.C. § 103.