PTAB

IPR2016-01636

Torrent Pharmaceuticals Ltd v. UCB Pharma GmbH

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Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Stable Salts of Novel Derivatives of 3,3-Diphenylpropylamines
  • Brief Description: The ’650 patent is directed to derivatives of 3,3-diphenylpropylamines, specifically fesoterodine and its pharmaceutically acceptable salts, such as fesoterodine fumarate. Fesoterodine is a prodrug designed to metabolize into 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of the known overactive bladder drug tolterodine.

3. Grounds for Unpatentability

Ground 1: Obviousness over Postlind, Bundgaard, the Detrol® label, and Berge - Claims 1-5 and 21-24

  • Prior Art Relied Upon: Postlind (a 1998 journal article on tolterodine metabolism), Bundgaard (a 1985 textbook on prodrug design), the Detrol® label (approved 1998), and Berge (a 1977 journal article on pharmaceutical salts).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the prior art established 5-HMT as the known, primary active metabolite of tolterodine, a drug used to treat overactive bladder. Postlind and the Detrol® label disclosed that tolterodine administration presented known problems, including variable efficacy due to genetic polymorphism in the CYP2D6 metabolic pathway and potential adverse effects. While 5-HMT was the desired therapeutic agent, it was known to have poor bioavailability. Bundgaard taught that creating ester prodrugs from compounds containing hydroxyl groups, such as 5-HMT, was a well-known, routine, and predictable method to increase lipophilicity and improve bioavailability. Finally, Berge disclosed that fumaric acid was one of a limited number of FDA-approved, conventional options for forming a stable pharmaceutical salt. The limitations of claims 1-5 and 21-24, which cover the fesoterodine molecule (an ester prodrug of 5-HMT) and its fumarate salt, were therefore all disclosed or suggested in the prior art.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) would be motivated to design a therapy that avoided the known problems of tolterodine by starting with its known active metabolite, 5-HMT. To address 5-HMT’s poor bioavailability, a POSITA would logically apply the routine and predictable prodrug optimization strategies taught by Bundgaard, namely esterification of a hydroxyl group. The final step of forming a stable and effective drug product would lead a POSITA to select a conventional salt from the limited list of known options taught by Berge, such as fumarate.
    • Expectation of Success: Petitioner asserted that a POSITA would have a high expectation of success. The process involved applying a standard solution (esterification to create a prodrug) to a known problem (poor bioavailability) for a known active compound (5-HMT). The selection of a suitable salt form was also presented as a routine step in pharmaceutical development with predictable outcomes.

Ground 2: Obviousness over Brynne 1998, Bundgaard, and Johansson - Claims 1-5 and 21-24

  • Prior Art Relied Upon: Brynne 1998 (a 1998 clinical pharmacology journal article), Bundgaard (a 1985 textbook on prodrug design), and Johansson (International Publication No. WO 94/11337).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground presented a similar argument using a slightly different combination of art. Brynne 1998 also investigated the metabolic pathway of tolterodine to 5-HMT and critically disclosed that tolterodine is "tenfold more lipophilic than 5-HM," directly quantifying the bioavailability problem that would need to be solved to make 5-HMT a viable drug. The teachings of Bundgaard on using esterification to create more lipophilic prodrugs were again relied upon. Johansson was cited for disclosing a genus of compounds that included 5-HMT and for explicitly teaching that these compounds could be formulated with "physiologically acceptable acids," specifically including "hydrogen fumarate" as an example.
    • Motivation to Combine: The motivation was again to improve upon tolterodine by starting with its active metabolite, 5-HMT. Brynne's direct teaching of a tenfold difference in lipophilicity provided a strong and explicit motivation for a POSITA to pursue a prodrug strategy to improve 5-HMT’s membrane penetration and bioavailability. Bundgaard provided the well-known chemical pathway (esterification) to achieve this. Johansson provided an express motivation to combine 5-HMT with fumarate to form a stable salt, directly teaching the claimed salt form for the relevant class of compounds.
    • Expectation of Success: The combination of these references made the claimed invention particularly obvious and success highly predictable. The path from the known problem (poor lipophilicity of 5-HMT) to the known solution (ester prodrug) was clear from Brynne and Bundgaard, and the final claimed salt was explicitly suggested for the base compound by Johansson.

4. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-5 and 21-24 of Patent 6,858,650 as unpatentable under 35 U.S.C. §103.