PTAB

IPR2018-00182

Provepharm Inc. v. WisTa Laboratories Ltd.

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1. Case Identification

2. Patent Overview

  • Title: Methods of Synthesis and/or Purification of Diaminophenothiazinium Compounds
  • Brief Description: The ’220 patent discloses compositions of the compound methylene blue (a diaminophenothiazinium) purported to have exceptionally high purity. The claims recite compositions with at least 98% methylene blue and specific maximum levels for various organic and inorganic impurities.

3. Grounds for Unpatentability

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

  • Prior Art Relied Upon: EU Pharmacopoeia 5.4 (a 2005 monograph), Dean (a 1976 article on chromatography), and Akkermans (a 1999 article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the claimed diaminophenothiazinium compound is methylene blue. EU Pharmacopoeia 5.4 taught methylene blue compositions of at least 95.0% purity and suggested using liquid chromatography (HPLC) for analysis, identifying Azure B as a "related substance" (impurity). Akkermans disclosed commercially available methylene blue at 99% purity. Dean, a 1976 article, specifically taught that common organic impurities in methylene blue—including Azure A, Azure B, Azure C, and Methylene Violet Bernthsen (MVB)—could be effectively separated and resolved from methylene blue using HPLC. Petitioner asserted that these references collectively disclose or suggest methylene blue compositions meeting the "at least 98%" purity limitation and teach that the specific claimed impurities were known and separable.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would be motivated to improve the purity of a pharmaceutical compound like methylene blue to remove known impurities. Petitioner contended this is a routine and fundamental goal in chemistry, particularly for therapeutic compounds, to enhance safety and efficacy.
    • Expectation of Success: A POSITA would have a reasonable expectation of success in purifying methylene blue to the claimed levels. Dean demonstrated the successful separation of the exact claimed organic impurities using HPLC. Given the significant advancements in HPLC technology between 1976 and the patent's 2006 priority date, a POSITA would expect that achieving the claimed low impurity levels would be a matter of routine optimization.

Ground 2: Obviousness of Inorganic Impurity Claims - 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 article on dye purification).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground focused on the claims to specific low levels of inorganic metal impurities. Petitioner argued that claim 13 merely recites the exact maximum impurity limits for several metals as set forth in EU Pharmacopoeia 5.4. Claim 14 recites limits that are simply 50% of those same established standards. The Nerenberg reference was introduced to show that it was well-known that dyes contain inorganic contaminants and that they could be removed using conventional methods like ion-exchange resins and alumina columns.
    • Motivation to Combine: A POSITA would be motivated to reduce known inorganic impurities to meet or exceed established pharmaceutical standards, such as those explicitly laid out in the EU Pharmacopoeia.
    • Expectation of Success: Since conventional techniques like ion-exchange chromatography were known to be highly effective at removing trace metals, a POSITA would reasonably expect to achieve the impurity limits of claims 13 and 14. Achieving the limits of claim 13 was merely meeting a known standard, and achieving the 50% reduction in claim 14 was presented as an obvious optimization step.

Ground 3: Obviousness of Pharmaceutical Formulation Claims - 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: This ground addressed claims directed to pharmaceutical compositions (e.g., a tablet or capsule). The ’720 publication taught using methylene blue to treat tauopathies and explicitly disclosed formulating it with "pharmaceutically-acceptable excipients, carriers, buffers, stabilisers" into oral dosage forms like tablets and capsules. The publication also disclosed dosage amounts (e.g., 75 mg, 100 mg) that fall within or overlap the ranges recited in the challenged claims (20-300 mg or 30-200 mg).
    • Motivation to Combine: A POSITA, having arrived at a purified methylene blue composition based on the other references, would be motivated to formulate it into a standard pharmaceutical dosage form for its known therapeutic uses, as taught by the ’720 publication.
    • Expectation of Success: Formulating a known active ingredient into a standard tablet or capsule using well-known excipients is a routine, predictable, and conventional task in the pharmaceutical arts.

  • Additional Grounds: Petitioner asserted additional obviousness challenges (Grounds 2, 4, and 6) that were analogous to Grounds 1, 3, and 5, respectively. These grounds relied on the same core combinations of art but substituted the EU Pharmacopoeia 2001 for the EU Pharmacopoeia 5.4, arguing that the 2001 version also taught high-purity methylene blue and the use of HPLC, leading to the same conclusion of obviousness.

4. Key Claim Construction Positions

  • Petitioner argued that claim terms reciting a maximum impurity level, such as "less than 1% Azure B," should be construed to encompass compositions where the impurity is not present at all (i.e., 0%).
  • This construction was asserted to be critical because it allows prior art that teaches the complete removal or absence of an impurity to satisfy the claim limitation. Petitioner supported this position by pointing to the ’220 patent’s own examples, which describe embodiments having 0% of certain impurities.

5. Key Technical Contentions (Beyond Claim Construction)

  • Purity as a Difference in Degree, Not Kind: A central theme of the petition was that the claimed invention is merely a purer version of a known compound (methylene blue) with known impurities. Petitioner argued this is a difference in degree, not in kind, and thus insufficient to support non-obviousness. It was contended that a POSITA would ordinarily expect that a more purified ingredient retains the same basic properties, which may be amplified, but does not result in an unexpectedly new property.
  • Product-by-Process Claims Lack Patentable Weight: For claims 15-24, which recite process steps for obtaining the composition, Petitioner argued they are impermissible product-by-process claims. The argument was that the recited process steps do not impart any new or different structural or functional properties to the final product compared to the product of the prior art. As the resulting product is simply a purer form of a known compound, the process limitations should be given no patentable weight.

6. Relief Requested

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