Luitpold Pharmaceuticals Inc v. Apicore US LLC

1. Case Identification

• Case #: IPR2018-01640
• Patent #: 9,353,050
• Filed: August 31, 2018
• Petitioner(s): Luitpold Pharmaceuticals, Inc.
• Patent Owner(s): Apicore US LLC
• Challenged Claims: 1-18

2. Patent Overview

• Title: Process for Preparation of Isosulfan Blue
• Brief Description: The ’050 patent is directed to compositions of Isosulfan Blue (ISB) sodium salt, a triarylmethane dye used as a pharmaceutical tracing agent. The claims require a high level of purity, specifically at least 99.0% as measured by High-Performance Liquid Chromatography (HPLC).

3. Grounds for Unpatentability

Ground 1: Claims 1-18 are obvious over Kulkarni in view of Snyder

• Prior Art Relied Upon: Kulkarni (Application # 2006/0224003) and Snyder (a 1997 textbook, Practical HPLC Method Development).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Kulkarni disclosed a process for synthesizing the claimed ISB compound for pharmaceutical use, which inherently resulted in a product with a purity of approximately 86.4% by HPLC. Snyder was presented as a seminal "go-to" reference work that provided a detailed and routine roadmap for a Person of Ordinary Skill in the Art (POSITA) to develop and scale up analytical HPLC methods to preparative HPLC methods for the express purpose of obtaining highly purified (99%+) products. The combination, therefore, taught purifying Kulkarni's known but less pure ISB to the claimed purity level.
  • Motivation to Combine: A POSITA would combine Kulkarni and Snyder because it was well-known to seek purer forms of pharmaceutical products intended for human use. This motivation was strengthened by pharmaceutical regulations (e.g., ICH Q3A guidelines) that impose increasing regulatory burdens for impurities above certain thresholds, driving manufacturers to reduce them. Snyder provided the explicit, standard methodology to achieve this desired purification for a compound like ISB.
  • Expectation of Success: Petitioner asserted a high expectation of success, as preparative HPLC was a mature and well-developed purification technique by the patent's priority date. A POSITA would have found it routine to apply the step-by-step guidance in Snyder to scale up a known analytical HPLC method for ISB to a preparative method to achieve the claimed purity.

Ground 2: Claims 1-18 are obvious over Hirsch in view of Snyder

• Prior Art Relied Upon: Hirsch (a 1982 journal article, Use of Isosulfan Blue for Identification of Lymphatic Vessels) and Snyder.
• Core Argument for this Ground:
  • Prior Art Mapping: Hirsch disclosed Lymphazurin®, an FDA-approved, commercially available ISB product with a reported purity of 94.5% (later determined to be ~83.4%) that contained "closely related isomers." Hirsch noted that its makers welcomed FDA advice on removing these impurities. As in Ground 1, Snyder provided the standard roadmap for using preparative HPLC to achieve the claimed 99.0% purity.
  • Motivation to Combine: The motivation was similar to Ground 1 but augmented by Hirsch's explicit acknowledgment of known impurities in a long-marketed drug and the desire to remove them. Petitioner argued that significant advances in preparative chromatography between 1982 (Hirsch) and 2007 (the priority date), exemplified by Snyder's textbook, would have motivated a POSITA to apply modern purification techniques to this older product.
  • Expectation of Success: The expectation of success was based on the routine and predictable nature of applying the mature science of preparative HPLC, as detailed in Snyder, to a known purification problem.

Ground 3: Obviousness Further in View of Brown

• Prior Art Relied Upon: Kulkarni or Hirsch, in view of Snyder, and further in view of Brown (a 1980 journal article, Synthesis of 14C-Labeled FD & C Blue No. 1).

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner asserted that Brown provided a concrete, experimental example that reinforced the teachings of Snyder. Brown disclosed the successful purification of FD&C Blue No. 1—a triarylmethane dye structurally very similar to ISB—to "more than 99%" purity using conventional preparative HPLC.
  • Motivation to Combine: If a POSITA sought to purify the ISB from Kulkarni or Hirsch using the general roadmap from Snyder, they would have been motivated by Brown's successful application of the same techniques to a closely related dye. Brown served as an experimental proof of concept, confirming that such purification was not only possible but achievable with routine methods.
  • Expectation of Success: The addition of Brown was argued to significantly increase the expectation of success, as it demonstrated the successful purification of a structurally analogous compound to the claimed purity level using the very methods contemplated by the primary combination.

• Additional Grounds: Petitioner asserted that the same combinations of Kulkarni/Hirsch, Snyder, and Brown also rendered all dependent claims obvious. This included claims to specific purity ranges (e.g., 99.0-99.5%), low silver content, and product-by-process limitations, arguing these were either encompassed by or would have been obvious results of the primary purification strategy.

4. Key Claim Construction Positions

• "having a purity of at least 99.0% by HPLC": Petitioner proposed this term should be construed to mean that when the composition is analyzed by HPLC under appropriate conditions, it "results in 'a peak [representing ISB] having at least 99.0% of the area under the curve ('AUC') on a chromatogram.'" This construction was central to Petitioner's argument that achieving this purity level was a matter of routine separation technique.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) or §314(a) was inappropriate. It contended that the cited prior art and arguments were substantially different from those considered during prosecution. Further, it emphasized that a prior IPR on the ’050 patent filed by another party (Auromedics Pharma LLC, IPR2017-00762) was terminated pursuant to a settlement before an institution decision was made. Because the Board never previously issued an institution decision or FWD, and because this was Luitpold's first petition against the patent, Petitioner argued there was no basis for denial.

6. Relief Requested

• Petitioner requests institution of an inter partes review and cancellation of claims 1-18 of Patent 9,353,050 as unpatentable.