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 a class of prodrugs of the HIV aspartyl protease inhibitor known as VX-478. The claims cover specific phosphate ester salts of VX-478, which are characterized by favorable aqueous solubility, high oral bioavailability, and facile in vivo generation of the active drug ingredient.

3. Grounds for Unpatentability

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

  • Prior Art Relied Upon: Hale (Patent 6,730,679) and WO ’269 (International Publication No. WO 95/07269).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the ’679 patent disclosed the base compound VX-478 as a potent HIV protease inhibitor but acknowledged its significant formulation challenges due to very low aqueous solubility. The WO ’269 publication taught a solution to this exact problem for structurally similar HIV protease inhibitors: creating a phosphate ester salt prodrug at a hydroxyl group to improve water solubility and oral absorption. Petitioner asserted that combining these teachings rendered obvious the claimed phosphate ester salt of VX-478, which is the subject of claims 1 and 2.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would have been motivated to address the known solubility and formulation problems of VX-478 identified in the ’679 patent. The inconveniently large number of capsules required for therapeutic dosing would have driven a search for a more soluble form. WO ’269 provided an express roadmap for achieving this by demonstrating that a phosphate ester prodrug strategy was successful for improving the solubility of a structurally related class of compounds.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success. The use of phosphate ester salts as a prodrug strategy was a well-known technique for improving drug solubility. WO ’269 provided working examples confirming the success of this strategy on a different but structurally similar HIV protease inhibitor, which also possessed a single hydroxyl group available for derivatization. The structural analogy, combined with the knowledge that non-specific enzymes (e.g., alkaline phosphatase) in the intestine cleave such prodrugs, provided a strong basis to expect that applying the same technique to VX-478 would yield a more soluble, orally bioavailable compound.

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

  • Prior Art Relied Upon: Hale (’679 patent), WO ’269, and Bighley (a 1996 encyclopedia chapter on pharmaceutical salt forms).

  • Core Argument for this Ground:

    • Prior Art Mapping: This ground extended the reasoning from Ground 1 to dependent claims 3-12, which recite specific salt forms and pharmaceutical compositions. Petitioner argued that after deciding to create a phosphate ester of VX-478, the selection of a specific cation for the salt form was a routine and obvious step. Bighley described standard procedures for salt selection, identifying sodium, potassium, calcium, and magnesium as the four most common cations used for acidic pharmaceutical compounds, accounting for approximately 85% of such salts. The remaining claims, directed to pharmaceutical compositions and methods of treatment, were argued to be obvious, as they recited standard elements (e.g., carriers, adjuvants, therapeutic dosages) that would naturally follow from the development of a new drug form and would involve only routine optimization.
    • Motivation to Combine: Once a POSITA created the phosphate ester of VX-478 (an acid), it would be a standard and necessary step in pharmaceutical development to select a suitable salt form for stability and handling. Bighley provided a well-established guide, or "decision tree," for this exact purpose, motivating a POSITA to select from the most common and well-characterized options.
    • Expectation of Success: The selection of a specific salt form from a finite list of well-known, predictable options was presented as a routine optimization with a high expectation of success. Bighley’s teachings confirmed that the claimed salts (e.g., calcium) were highly preferred and frequently used, making their selection an obvious choice rather than an inventive step.

  • Additional Grounds: Petitioner asserted additional obviousness challenges based on the ’587 publication (WO 97/35587) in combination with WO ’269 and Bighley. These grounds mirrored the arguments in Grounds 1 and 2, as Petitioner contended the ’587 publication contained disclosure almost identical to that of the ’679 patent.

4. Relief Requested

  • Petitioner requests institution of an inter partes review (IPR) and cancellation of claims 1-12 of Patent 6,436,989 as unpatentable under 35 U.S.C. §103.