PTAB

IPR2018-00323

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 ’621 patent discloses methods for treating conditions like tauopathies and methemoglobinemia by administering high-purity compositions of methylene blue (a diaminophenothiazinium compound), defined by specific low levels of organic and inorganic impurities.

3. Grounds for Unpatentability

Ground 1: Tauopathy Treatment Method - Claims 1-5 and 8-12 are obvious over the '720 publication, EU Pharmacopoeia 5.4, Dean, and Akkermans.

  • Prior Art Relied Upon: Wischik (WO 2002/055720, the '720 publication), European Pharmacopoeia 5.4, Dean (a 1976 journal article), and Akkermans (a 1999 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued the ’720 publication disclosed using methylene blue to treat tauopathies, including Alzheimer’s disease, and provided therapeutically effective amounts. EU Pharmacopoeia 5.4 described methylene blue compositions of at least 95% purity. Dean taught that known organic impurities like Azure A, B, C, and Methylene Violet Bernthsen (MVB) could be effectively separated from methylene blue using High-Performance Liquid Chromatography (HPLC). Akkermans disclosed commercially available 99% pure methylene blue. Petitioner contended these references collectively disclose all elements of the challenged claims.
    • Motivation to Combine: A POSITA would combine these references because it was a routine and desirable goal in the pharmaceutical arts to increase the purity of a known therapeutic compound to reduce potential side effects and improve consistency. Since the ’720 publication taught a therapeutic use and Dean showed how to remove known impurities, a POSITA would be motivated to apply Dean’s purification methods to the therapeutic compound.
    • Expectation of Success: A POSITA would have a high expectation of success because HPLC was a well-established, versatile, and powerful technique for separating closely related chemical compounds by 2006. The Dean reference demonstrated the successful separation of the exact impurities recited in the claims from methylene blue, making the outcome of applying this known purification technique entirely predictable.

Ground 2: Inorganic Impurity Limits - Claims 6-7 are obvious over the '720 publication, EU Pharmacopoeia 5.4, Dean, Akkermans, and Nerenberg.

  • Prior Art Relied Upon: The ’720 publication, EU Pharmacopoeia 5.4, Dean, Akkermans, and Nerenberg (a 1963 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground built upon the previous combination, adding Nerenberg to address the specific inorganic (metal) impurity limits of claims 6 and 7. Petitioner argued that EU Pharmacopoeia 5.4 itself set maximum allowable limits for the same metals recited in claim 6. Nerenberg taught that inorganic impurities were common in methylene blue and could be removed using conventional methods like ion-exchange resins. Claim 7 recites limits that are merely 50% of the maximums allowed by the pharmacopoeia.
    • Motivation to Combine: The motivation was to produce a methylene blue composition that met or exceeded established regulatory standards for purity, such as those in the EU Pharmacopoeia. A POSITA would seek to reduce known metal contaminants to the lowest feasible levels for a pharmaceutical product.
    • Expectation of Success: Success was expected because ion exchange and HPLC were well-known and effective methods for removing trace metals from chemical compositions. The petition cited prior art showing metal removal to parts-per-million (ppm) or parts-per-billion (ppb) levels, well below the claimed limits, making the claimed levels readily achievable through routine experimentation.

Ground 3: Methemoglobinemia Treatment Method - Claims 13-17 and 19-20 are obvious over Therapeutic Drugs, EU Pharmacopoeia 5.4, Dean, and Akkermans.

  • Prior Art Relied Upon: Therapeutic Drugs (a 1999 publication), EU Pharmacopoeia 5.4, Dean, and Akkermans.

  • Core Argument for this Ground:

    • Prior Art Mapping: This ground parallels Ground 1 but targets a different claimed method of use. Petitioner asserted that Therapeutic Drugs disclosed the well-known use of methylene blue for treating methemoglobinemia and provided effective dosage ranges (e.g., 70-280 mg) that overlap with the claimed ranges. The remaining references were used, as in Ground 1, to teach the claimed purity levels and the obviousness of achieving them via HPLC.
    • Motivation to Combine: The motivation was identical to Ground 1: to improve the purity of a known therapeutic agent. A POSITA would be motivated to apply standard purification techniques to methylene blue intended for treating methemoglobinemia for the same reasons as for treating tauopathies.
    • Expectation of Success: The expectation of success was based on the same rationale as in Ground 1. The application of the well-understood and effective HPLC purification technique taught by Dean to the methylene blue composition taught by Therapeutic Drugs would have been a routine and predictable task.

  • Additional Grounds: Petitioner asserted additional obviousness challenges based on combinations using the 2001 version of the EU Pharmacopoeia and targeting claim 18 with various reference sets, but these relied on similar purification theories.

4. Key Claim Construction Positions

  • Petitioner argued that claim terms reciting "less than __ %" of an impurity should be construed to include embodiments where the impurity is completely absent (i.e., 0%). This construction is important because it allows prior art that teaches the complete removal of an impurity via a separation technique like HPLC to satisfy such a claim limitation.

5. Key Technical Contentions (Beyond Claim Construction)

  • The petition's central technical argument, asserted across multiple grounds, was that by the patent's 2006 priority date, HPLC was a routine, conventional, and powerful tool for chemical purification. Petitioner contended that a person of ordinary skill in the art would have viewed the purification of methylene blue to the claimed high-purity levels not as an inventive step, but as a straightforward application of this standard technique to remove known impurities, with a predictable and successful outcome.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-20 of the ’621 patent as unpatentable.