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 diagnostic agent. The claims require a high level of purity—at least 99.0% as measured by High Performance Liquid Chromatography (HPLC)—which Petitioner asserted is the only allegedly novel feature.

3. Grounds for Unpatentability

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

• Prior Art Relied Upon: Kulkarni (Application # 2006/0224003) and Snyder (a 1997 book titled “Practical HPLC Method Development”).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Kulkarni discloses a process for making ISB sodium salt for pharmaceutical use, which inherently results in a product with a purity of approximately 86.4% by HPLC. Snyder was presented as a well-known, seminal reference work that provides a detailed "roadmap" for a person of ordinary skill in the art (POSITA) to develop and scale up HPLC methods. Petitioner contended that Snyder explicitly teaches scaling up analytical HPLC to preparative HPLC for the "[c]onvenient recovery of highly purified (99%+) product." The combination, therefore, taught purifying the known ISB from Kulkarni to the purity level required by the claims.
  • Motivation to Combine: A POSITA would combine Kulkarni's disclosure of a useful but impure pharmaceutical product (ISB) with Snyder's standard purification methodology. The motivation was driven by the well-known need to increase the purity of any pharmaceutical compound intended for human use and to meet regulatory standards for impurity levels.
  • Expectation of Success: Petitioner asserted a POSITA would have had a reasonable expectation of success because, by the 2007 priority date, preparative HPLC was a mature, routine, and well-understood technique. Scaling an analytical HPLC method to a preparative one to achieve higher purity was a standard practice with predictable results, not an inventive step.

Ground 2: Obviousness over Kulkarni, Snyder, and Brown - Claims 1-18 are obvious over Kulkarni and Snyder, further in view of Brown.

• Prior Art Relied Upon: Kulkarni (Application # 2006/0224003), Snyder (1997 book), and Brown (a 1980 journal article titled “Synthesis of 14C-Labeled FD & C Blue No. 1...”).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground supplements Ground 1 with Brown. Petitioner argued Brown provides a specific, experimental example that reinforces the teachings of Snyder. Brown disclosed the purification of FD&C Blue No. 1—a triarylmethane dye structurally very similar to ISB—to "more than 99%" purity using conventional preparative HPLC. Brown's success in purifying a closely related compound would have confirmed to a POSITA that the general principles in Snyder were applicable to ISB and would yield a high-purity product.
  • Motivation to Combine: The motivation was the same as in Ground 1, with Brown providing an additional, powerful reason. Brown served as an experimental proof of concept, demonstrating that preparative HPLC was successfully used to achieve high purity for a dye of the same chemical class as ISB. This would have further motivated a POSITA to apply the same techniques to the ISB from Kulkarni.
  • Expectation of Success: Brown's successful purification of a structurally analogous compound to >99% purity would have significantly strengthened a POSITA's expectation of success in purifying ISB to the claimed purity levels.

Ground 3: Obviousness over Hirsch and Snyder - Claims 1-18 are obvious over Hirsch in view of Snyder.

• Prior Art Relied Upon: Hirsch (a 1982 journal article titled “Use of Isosulfan Blue for Identification of Lymphatic Vessels...”) and Snyder (1997 book).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground asserted that Hirsch disclosed an FDA-approved, commercially available ISB product (Lymphazurin®) with a reported purity of 94.5% by HPLC (which was later determined to be ~83.4%). Hirsch thus established that a lower-purity version of ISB was known and in use. As in Ground 1, Snyder provided the standard roadmap for purifying such a compound to 99%+ purity using preparative HPLC. The combination of a known, impure commercial product (Hirsch) and a standard purification guide (Snyder) rendered the high-purity claimed product obvious.
  • Motivation to Combine: A POSITA would have been motivated to improve the purity of the existing, FDA-approved ISB product described in Hirsch. This motivation stemmed from general pharmaceutical principles, evolving regulatory requirements for purity, and the fact that the maker of the Hirsch product had welcomed FDA's advice on removing organic impurities. The significant advances in chromatography between 1982 (Hirsch) and 2007 (priority date) would have made applying Snyder's modern techniques a logical step.
• Additional Grounds: Petitioner asserted an additional obviousness challenge where claims 1-18 are obvious over Hirsch and Snyder, further in view of Brown, relying on the same logic as Ground 2.

4. Key Claim Construction Positions

• "having a purity of at least 99.0% by HPLC": Petitioner argued this central claim phrase should be construed to mean "the composition, when analyzed by HPLC under appropriate conditions, results in 'a peak [representing ISB] having at least 99.0% of the area under the curve ('AUC') on a chromatogram.'" This construction was critical because the claimed purity level is the sole point of novelty. Petitioner contended this interpretation is consistent with how a POSITA would understand HPLC purity measurements and with the patent's prosecution history, where the applicant distinguished the invention based on this purity value.

5. Key Technical Contentions (Beyond Claim Construction)

• Routine Nature of HPLC Purification: A central technical argument underpinning all grounds was that scaling up an analytical HPLC method to a preparative one was a routine, mature, and well-developed procedure for a POSITA by 2007. The petition asserted there were no fundamental technical differences between the two, and that achieving higher purity for a known compound using standard techniques like preparative HPLC was merely the application of ordinary skill and common sense, not invention.

6. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under either §314(a) or §325(d) would be inappropriate.
  • §325(d): The petition asserted that the primary references (Snyder, Hirsch, Brown) were never considered by the Examiner during prosecution of the ’050 patent. While Kulkarni was cited in the prosecution of a parent application, it was in the context of method claims, not the product claims at issue. Therefore, the art and arguments were substantially different.
  • §314(a) (General Plastics): Petitioner argued that the General Plastics factors weigh against denial. This was Luitpold's first petition challenging the ’050 patent, so it is not a "follow-on" or serial petition by the same party. Furthermore, a prior IPR filed by a different party (Auromedics Pharma) was terminated via settlement before an institution decision, meaning the Board never considered the merits or issued a decision.

7. Relief Requested

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