PTAB

IPR2013-00024

Ranbaxy Laboratories Ltd v. Vertex PharmaceuTicals Inc

Log In

1. Case Identification

2. Patent Overview

  • Title: Prodrugs of HIV Protease Inhibitors
  • Brief Description: The ’989 patent is directed to phosphate ester salt prodrugs of VX-478, a known HIV aspartyl protease inhibitor. The invention aimed to solve the problem of VX-478’s poor aqueous solubility, which made it difficult to formulate, required large amounts of excipients, and resulted in a high pill burden for patients seeking a therapeutic dose. The claimed prodrugs were designed to improve solubility and oral bioavailability while readily converting back to the active VX-478 ingredient in vivo.

3. Grounds for Unpatentability

Ground 1: Obviousness of Claims 1-2 - Claims 1 and 2 are obvious over the ’679 patent in view of the ’269 publication.

  • Prior Art Relied Upon: the ’679 patent (Patent 6,730,679) and the ’269 publication (WO 95/07269).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the ’679 patent established VX-478 as an effective HIV protease inhibitor but explicitly taught its significant formulation challenges due to poor solubility (0.095 mg/mL). This problem necessitated formulations with large amounts of excipients, limiting the active drug per capsule and leading to inconveniently large daily doses. Petitioner asserted that the ’269 publication directly addressed this type of problem by teaching the use of phosphate ester salts as a prodrug strategy to enhance the water solubility of HIV protease inhibitors. The ’269 publication included working examples demonstrating that a disodium phosphate ester of a structurally similar HIV inhibitor was water-soluble, could be prepared via a straightforward synthesis, and exhibited oral absorption in animal models. The combination of the known problem in the ’679 patent and the explicit solution in the ’269 publication taught the claimed phosphate ester salts of VX-478.
    • Motivation to Combine: A POSITA, faced with the well-defined solubility and dosing problems of the promising drug VX-478 described in the ’679 patent, would have been motivated to consult the art for known solutions. The ’269 publication provided a clear and successful example of improving the solubility of a structurally related HIV protease inhibitor using a phosphate ester prodrug approach, thus providing a strong motivation to apply the same proven technique to VX-478.
    • Expectation of Success: Petitioner contended that a POSITA would have had a high expectation of success. This was based on the fact that phosphate ester prodrugs were a well-established strategy for improving drug solubility. Furthermore, the structural similarities between VX-478 and the inhibitor modified in the ’269 publication—both possessing a single, accessible hydroxyl group suitable for derivatization—would provide confidence. The known non-specific mechanism of in vivo cleavage by the enzyme alkaline phosphatase further supported the predictability of the outcome.

Ground 2: Obviousness of Claims 3-12 - Claims 3-12 are obvious over the ’679 patent, the ’269 publication, and Bighley.

  • Prior Art Relied Upon: ’679 patent (Patent 6,730,679), ’269 publication (WO 95/07269), and Bighley (a 1996 encyclopedia chapter on salt forms).

  • Core Argument for this Ground:

    • Prior Art Mapping: This ground built upon Ground 1 by adding Bighley to render the dependent claims obvious. Petitioner argued Bighley taught that selecting a specific salt form for a new acidic compound (like the phosphate ester of VX-478) was a routine optimization procedure. For claim 3, which recites the calcium salt, Bighley identified calcium as the second most frequent choice among the four most common cations (Na, Ca, Mg, K) that comprise 85% of all salts for such compounds. For claims 4-12, directed to pharmaceutical compositions and methods of use, Petitioner mapped these elements to teachings in the ’679 patent and ’269 publication. These references disclosed formulating HIV protease inhibitors with pharmaceutically acceptable carriers, administering them in effective amounts to treat HIV, and combining them with other anti-viral agents.
    • Motivation to Combine: After forming the phosphate ester prodrug as motivated by the ’679 and ’269 references, a POSITA would be motivated by routine pharmaceutical development principles to select an optimal salt form. Bighley provided a "decision tree" and a finite, predictable set of preferred options, motivating the selection and testing of common salts like calcium to optimize for properties such as stability and hygroscopicity.
    • Expectation of Success: The selection of a salt from a small, well-known list of preferred candidates described in Bighley was presented as a predictable activity with a high expectation of success, constituting an obvious-to-try experiment with a finite number of known choices.

  • Additional Grounds: Petitioner asserted additional obviousness challenges for claims 1-12 based on combinations including the ’587 publication (WO 97/35587). The petition argued the ’587 publication contained disclosure almost identical to the ’679 patent and was thus substitutable in the primary invalidity arguments.

4. Relief Requested

  • Petitioner requests that the Board institute an inter partes review and cancel claims 1-12 of Patent 6,436,989 as unpatentable.