PTAB

IPR2018-00182

Provepharm Inc v. WiSTA Laboratories Ltd

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Methods of Synthesis and/or Purification of Diaminophenothiazinium Compounds
  • Brief Description: The ’220 patent relates to compositions of highly pure methylene blue (a diaminophenothiazinium compound) characterized by specific low levels of certain organic and inorganic impurities. The patent also covers pharmaceutical compositions containing this purified compound.

3. Grounds for Unpatentability

Ground 1: Obviousness of Organic Impurity Levels - Claims 1-12 and 15-24 are obvious over EU Pharmacopoeia 5.4, Dean, and Akkermans.

  • Prior Art Relied Upon: EU Pharmacopoeia 5.4 (copyright 2005), Dean (a 1976 journal article), and Akkermans (a 1999 publication).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the prior art collectively disclosed all limitations of the challenged claims regarding organic impurity levels. EU Pharmacopoeia 5.4 taught methylene blue compositions of at least 95.0% purity and suggested using High-Performance Liquid Chromatography (HPLC) for analysis, identifying Azure B as a known impurity. Akkermans disclosed commercially available methylene blue with 99% purity. Dean demonstrated that HPLC was capable of separating and resolving methylene blue from its common organic impurities, including Azures A, B, C, and Methylene Violet Bernthsen (MVB). Petitioner asserted that the claimed compositions, requiring at least 98% purity, were merely a purer version of what was already known and commercially available.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would be motivated to increase the purity of a known pharmaceutical compound to reduce contaminants. Given that the art identified specific organic impurities (Dean, EU Pharmacopoeia 5.4) and disclosed a known, effective technique for their removal (HPLC, per Dean), it would have been a matter of routine optimization to apply this technique to achieve the claimed purity levels.
    • Expectation of Success: A POSA would have had a high expectation of success. HPLC was a well-established and powerful purification technique at the time of the invention. The references demonstrated that HPLC could successfully resolve the exact impurities at issue from methylene blue, making the achievement of the claimed purity levels predictable.

Ground 2: Obviousness of Inorganic Impurity Levels - Claims 13-14 are obvious over EU Pharmacopoeia 5.4, Dean, Akkermans, and Nerenberg.

  • Prior Art Relied Upon: EU Pharmacopoeia 5.4, Dean, Akkermans, and Nerenberg (a 1963 publication).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner contended that claim 13 merely recited the maximum inorganic impurity limits for several metals (e.g., aluminum, chromium, copper) that were explicitly set forth in EU Pharmacopoeia 5.4. Claim 14 recited limits that were simply 50% of those same established levels. Nerenberg taught that inorganic impurities were common in such dyes and could be removed by conventional methods like ion-exchange resins. Petitioner pointed to other art demonstrating that ion exchange was a highly effective and well-known method for removing trace metals to parts-per-million (ppm) or parts-per-billion (ppb) levels, far exceeding the purity required by the claims.
    • Motivation to Combine: The motivation was the routine goal of meeting established regulatory standards and reducing known inorganic contaminants. EU Pharmacopoeia 5.4 provided the target purity levels, and Nerenberg taught the standard methods for removing such metal impurities. A POSA would combine these teachings to produce a composition that met the known safety limits.
    • Expectation of Success: Success was reasonably expected because the techniques for removing metal ions, such as ion exchange, were conventional and known to be effective. The fact that EU Pharmacopoeia 5.4 established specific impurity limits demonstrated that achieving such levels was considered possible and routine in the art.

Ground 3: Obviousness of Pharmaceutical Compositions - Claims 25-28 are obvious over EU Pharmacopoeia 5.4, Dean, Akkermans, and the ’720 Publication.

  • Prior Art Relied Upon: EU Pharmacopoeia 5.4, Dean, Akkermans, and the ’720 Publication (WO 2002/055720).

  • Core Argument for this Ground:

    • Prior Art Mapping: These claims cover pharmaceutical compositions (claims 25, 28) and specific tablets or capsules (claims 26, 27) comprising the purified methylene blue and a pharmaceutically acceptable carrier, within specified dosage ranges (e.g., 20-300 mg). The ’720 publication taught using methylene blue to treat tauopathies and explicitly disclosed formulating it with "pharmaceutically-acceptable excipients, carriers, buffers, stabilisers." Furthermore, the ’720 publication disclosed oral dosage amounts (e.g., 75 mg, 100 mg) that overlap with and teach within the claimed ranges.
    • Motivation to Combine: A POSA, having developed a purified active pharmaceutical ingredient as taught by the primary references, would be motivated to formulate it for administration to patients. The ’720 publication provided a clear reason (treatment of tauopathies) and a direct roadmap for combining purified methylene blue with standard excipients to create a final dosage form.
    • Expectation of Success: Formulating a known active ingredient with standard, well-known pharmaceutical carriers and excipients was a routine and predictable task for a POSA. The prior art provided both the purified ingredient and the instructions for its formulation, leaving nothing inventive to be done.

  • Additional Grounds: Petitioner asserted additional obviousness challenges based on combinations that substituted EU Pharmacopoeia 2001 for EU Pharmacopoeia 5.4, but these grounds relied on similar arguments and mappings for the respective claim groups.

4. Key Claim Construction Positions

  • Petitioner argued that claim terms reciting "less than [X]%" of a compound should be construed to include embodiments where none of the compound is present (i.e., 0%). This position was asserted to be consistent with the patent's own examples, which listed compositions having 0% of certain impurities, and with PTAB precedent.

5. Key Technical Contentions (Beyond Claim Construction)

  • A central technical contention was that HPLC was a routine, versatile, and powerful purification tool in the pharmaceutical industry well before the patent's 2006 priority date. Petitioner argued that HPLC was known to achieve purity levels far greater than 99% for a variety of compounds. This countered arguments made by the Patent Owner during prosecution that prior art purification methods were antiquated or inadequate, asserting that a POSA in 2006 would have naturally turned to HPLC for this exact task.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-28 of the ’220 patent as unpatentable.