PTAB

IPR2016-01596

Alembic Pharmaceuticals Ltd v. UCB Pharma GmbH

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1. Case Identification

2. Patent Overview

  • Title: Stable Salts of Novel Derivatives of 3,3-Diphenylpropylamines
  • Brief Description: The ’650 patent discloses derivatives of 3,3-diphenylpropylamines and their salt forms for treating overactive bladder. The claims encompass fesoterodine fumarate, a prodrug that metabolizes into 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of the known drug tolterodine.

3. Grounds for Unpatentability

Ground 1: Claims 1-5 and 21-24 are obvious over Postlind and Bundgaard in view of the Detrol® label and Berge.

  • Prior Art Relied Upon: Postlind (a 1998 journal article), Bundgaard (a 1985 textbook on prodrugs), 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 Detrol® label and Postlind established 5-HMT as the known, primary active metabolite of the drug tolterodine. These references also taught that tolterodine's metabolism to 5-HMT via the CYP2D6 enzyme was a known source of problems, including significant inter-patient variability and adverse side effects in poor metabolizers. Bundgaard taught that creating ester prodrugs was a routine and well-understood method to solve bioavailability and delivery issues for active compounds containing hydroxyl groups, such as 5-HMT. Petitioner contended that the claimed compound is an ester prodrug of 5-HMT. Finally, Berge taught that selecting a suitable salt, such as the claimed fumarate, was a routine optimization step for drug developers, disclosing fumaric acid as one of a limited number of FDA-approved options.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would have been motivated to overcome the known deficiencies of tolterodine (e.g., variable metabolism and side effects) by developing a drug based on its active metabolite, 5-HMT. Faced with 5-HMT's known poor bioavailability, a POSITA would have been motivated to apply the routine prodrug optimization techniques taught by Bundgaard to improve its lipophilicity and absorption. The final step of selecting a stable salt form would be a natural part of the drug development process, as taught by Berge.
    • Expectation of Success: Petitioner asserted that a POSITA would have had a reasonable expectation of success. The process of creating ester prodrugs to improve bioavailability was a well-established and predictable art. Similarly, selecting a suitable salt from the small, known list of pharmaceutically acceptable options disclosed in Berge was a routine practice with a high likelihood of success.

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

  • Prior Art Relied Upon: Brynne 1998 (a journal article), Bundgaard (the 1985 prodrug textbook), and Johansson (WO 94/11337).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Brynne 1998 identified 5-HMT as the active metabolite of tolterodine and critically disclosed that tolterodine is tenfold more lipophilic than 5-HMT. This teaching directly identified a lipophilicity and membrane penetration problem with 5-HMT itself. Bundgaard provided the well-known solution to such problems by teaching the creation of ester prodrugs to increase the bioavailability of compounds with poor lipophilicity. Johansson disclosed a genus of 3,3-diphenylpropylamine compounds that included 5-HMT and explicitly taught forming pharmaceutically acceptable salts of these compounds, specifically including hydrogen fumarate.
    • Motivation to Combine: A POSITA, motivated to develop a drug based on the active metabolite 5-HMT, would have been directly confronted with the lipophilicity problem described in Brynne 1998. This would have motivated the POSITA to turn to the conventional and predictable solution of esterification taught in Bundgaard. Johansson provided a direct reason to select the fumarate salt, as it expressly taught the use of hydrogen fumarate for the specific class of compounds to which 5-HMT belongs.
    • Expectation of Success: Petitioner contended there was a strong expectation of success. The combination involved applying a standard solution (esterification) to a clearly identified problem (poor lipophilicity). Johansson's disclosure of a fumarate salt for the 5-HMT chemical family made the successful creation of the claimed fesoterodine fumarate compound particularly predictable.

4. Relief Requested

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