PTAB

IPR2017-00762

AuroMedics Pharma LLC v. Apicore US LLC

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Petition
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1. Case Identification

2. Patent Overview

  • Title: Process for Preparation of Isosulfan Blue
  • Brief Description: The ’050 patent describes compositions of substantially pure isosulfan blue, a triarylmethane dye used as a diagnostic contrast agent for delineating lymphatic vessels. The patent claims compositions having at least 99.0% purity as measured by high-pressure liquid chromatography (HPLC) and methods for its preparation.

3. Grounds for Unpatentability

Ground 1: Anticipation of Claims 11 and 12 over Hirsch 1982

  • Prior Art Relied Upon: Hirsch et al., “Use of Isosulfan Blue for Identification of Lymphatic Vessels: Experimental and Clinical Evaluation,” Am. J. of Roentgenology (1982) (“Hirsch 1982”).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Hirsch 1982 inherently disclosed a solution of isosulfan blue meeting the purity limitations of claims 11 (≥99.0% pure) and 12 (99.0%-99.5% pure). Hirsch 1982 disclosed analyzing a sample of isosulfan blue using HPLC and determining it was 94.5% pure. Petitioner contended that the analytical HPLC process itself necessarily separated and isolated the isosulfan blue from its isomers, resulting in a transient solution within the HPLC column that met the claimed purity levels.
    • Key Aspects: The argument relied on the inherent properties of the disclosed analytical technique (HPLC), asserting that the act of measuring purity inherently created a purified form of the compound, even if only temporarily within the instrument.

Ground 2: Obviousness of Claims 1, 2, 11, 12, 15, and 16 over Hirsch 1982 in view of Waters

  • Prior Art Relied Upon: Hirsch 1982 and Waters Corp., “ACQUITY UPLC™ Separation of Triarylmethane Ink Dyes (Part 1)” (2005) (“Waters”).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner asserted that Hirsch 1982 disclosed the base compound, isosulfan blue, at 94.5% purity for pharmaceutical use. Waters taught a specific HPLC method for achieving baseline separation of six triarylmethane dyes structurally similar to isosulfan blue. The combination of Hirsch 1982's known compound and Waters’s purification technique for analogous compounds rendered the small increase in purity to ≥99.0% obvious.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would combine these teachings because there was a general motivation to increase the purity of any pharmaceutical compound. Higher purity was desirable to reduce potential side effects from impurities and to simplify the regulatory approval process with the FDA, which requires characterization of all impurities.
    • Expectation of Success: A POSA would have a reasonable expectation of success because Hirsch 1982 itself established that HPLC was a suitable analytical tool for isosulfan blue. Waters confirmed that HPLC was effective for separating structurally similar dyes, which would have assured a POSA that applying preparative HPLC to the known 94.5% pure compound would successfully yield a higher purity product.

Ground 3: Obviousness of Claims 5 and 8 over Thoraval

  • Prior Art Relied Upon: Thoraval et al., “Development Of Paper, Chemical Agent Detector, 3-Way Liquid Containing Non-Mutagenic Dyes” (2003) (“Thoraval”).

  • Core Argument for this Ground:

    • Prior Art Mapping: This ground challenged process claims 5 and 8, which recite preparing isosulfan blue by oxidizing its isoleuco acid precursor with silver oxide in a polar solvent. Petitioner argued that Thoraval disclosed the key chemical transformation for analogous triarylmethane compounds. Thoraval taught that the oxidation of triphenylmethane intermediates was "best performed using silver oxide as the oxidizing agent." Claim 8’s further limitation to using methanol as the polar solvent was also obvious, as methanol is a common polar organic solvent.
    • Motivation to Combine: A POSA seeking to synthesize isosulfan blue would have been motivated to use the method in Thoraval because the core chemical structure and required reaction (oxidation of a leuco precursor) were the same. Thoraval’s successful use of silver oxide for this exact type of reaction on similar molecules provided a direct reason to apply it to the synthesis of isosulfan blue.
    • Expectation of Success: A POSA would have expected success because the underlying chemistry is fundamentally the same. Thoraval reported that the silver oxide oxidations "proceeded well" for 11 different triphenylmethane intermediates, indicating the reaction was robust and broadly applicable to this class of compounds.

  • Additional Grounds: Petitioner asserted additional obviousness challenges, including claims 1, 2, 11, 12, 15, and 16 over Hirsch 1982 in view of Huber, Snyder, or Newton (all relating to standard HPLC purification); claims 6, 7, and 9 over Thoraval in view of the ’252 patent and the ’507 patent (relating to the synthesis of precursors); and claim 10 over Thoraval in view of the ’458 patent (relating to purification by recrystallization).

4. Key Claim Construction Positions

  • Petitioner argued that the term "having a purity of at least [99.0%] by HPLC" should be construed to mean "having not more than 1% extraneous material—i.e., material that is not isosulfan blue, sodium salt—as determined using HPLC with a reproducible set of conditions." This construction was presented as consistent with the broadest reasonable interpretation and how a POSA would understand purity measurements in the relevant art.

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-18 of the ’050 patent as unpatentable under 35 U.S.C. §§ 102 and 103.