PTAB

IPR2016-00084

Par Pharmaceutical Inc v. Novartis AG

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1. Case Identification

2. Patent Overview

  • Title: O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
  • Brief Description: The ’772 patent discloses O-alkylated derivatives of the immunosuppressant compound rapamycin. The patent asserts these derivatives, such as 40-O-(2-hydroxyethyl)-rapamycin, exhibit improved properties like enhanced solubility and bioavailability over the parent compound.

3. Grounds for Unpatentability

Ground 1: Obviousness over Core Chemical References - Claims 1-3 and 10 are obvious over Morris, Van Duyne, Rossmann, Lemke, and Yalkowsky.

  • Prior Art Relied Upon: Morris (a 1992 review article), Van Duyne (a 1991 journal article), Rossmann (a 1980 journal article), Yalkowsky (a 1979 journal article), and Lemke (a 1988 book chapter).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Morris established rapamycin as a potent immunosuppressant with a known solubility problem, making it a prime lead compound for optimization. Van Duyne, using stereo diagrams that Rossmann taught how to interpret, disclosed the three-dimensional structure of rapamycin bound to its target (FKBP-12), revealing the C40 hydroxyl group is exposed and peripheral to the binding interface. Yalkowsky and Lemke taught established principles for improving solubility, specifically by adding flexible side chains (Yalkowsky) containing known solubilizing functional groups like alcohols (Lemke). Petitioner contended a POSITA would combine these teachings to add a small, flexible, alcohol-containing chain at the optimal C40 position, directly leading to the 2-hydroxyethoxy substituent of claim 10.
    • Motivation to Combine: A POSITA would combine these references to solve the known problem of rapamycin's poor solubility. The motivation was to modify the lead compound (Morris) at a site that would not disrupt its critical biological activity (identified via Van Duyne/Rossmann) using standard, predictable techniques to improve solubility (taught by Yalkowsky/Lemke).
    • Expectation of Success: Petitioner asserted a high expectation of success because modifying the C40 position was structurally favored to preserve immunosuppressant activity, and the techniques for improving solubility were routine and known to be effective for molecules like rapamycin.

Ground 2: Obviousness of Method Claims - Claims 8 and 9 are obvious over Morris, Van Duyne, Rossmann, Lemke, Yalkowsky, and in further view of Hughes.

  • Prior Art Relied Upon: The references from Ground 1, plus Hughes (Patent 5,233,036).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground built on the argument that the compound of claim 1 is obvious. The method claims (8 and 9) recite using this compound for immunosuppression and preventing allograft rejection—activities for which the parent compound, rapamycin, was well-known (Morris). Hughes was cited to demonstrate that other rapamycin derivatives modified at the C40 position were already known to retain immunosuppressant and anti-rejection activity, as confirmed by standard pharmacological assays.
    • Motivation to Combine: A POSITA, having created the obvious compound from the Ground 1 references, would be motivated to confirm its expected biological activity using routine methods. Hughes provided a template by disclosing that other C40-modified derivatives retained such activity and described the standard pharmacological assays through which this could be evaluated, confirming both the utility and the predictability of the outcome.
    • Expectation of Success: The expectation of success was high because the modification was designed to preserve the known activity of the parent compound. Hughes provided direct evidence that similar C40 modifications did, in fact, result in compounds with the desired immunosuppressant activity, confirming a POSITA would reasonably expect the claimed methods to be effective.

Ground 3: Obviousness via Computer-Aided Drug Design - Claims 1-3 and 10 are obvious over the routine use of computer-aided drug design software in view of Morris, Van Duyne, Lemke, and Yalkowsky.

  • Prior Art Relied Upon: The references from Ground 1, combined with the routine use of computer-aided drug design (CADD) software available at the time.
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground presented an alternative rationale, arguing a POSITA would use the 3D coordinates derivable from Van Duyne as an input for CADD software. Such routine modeling would have quantitatively confirmed that the C40 position was the optimal site for modification and could accommodate small, solubilizing substituents (as suggested by Lemke and Yalkowsky) without interfering with FKBP-12 binding. This analysis would have directly led to candidates like the 2-hydroxyethoxy derivative of claim 10.
    • Motivation to Combine: The motivation was to leverage a known and powerful tool (CADD) for rational drug design to efficiently screen and validate modifications aimed at solving the known solubility problem of rapamycin.
    • Expectation of Success: The quantitative evaluation available from known CADD software—calculating hydrogen bonding potential and free energy interactions—would have provided additional, robust evidence to support a reasonable expectation of success that the selected C40 modifications would bind effectively to FKBP-12.
  • Additional Grounds: Petitioner asserted an additional obviousness challenge for claims 8 and 9 (Ground 4) based on the CADD rationale in combination with Hughes, relying on a similar theory as Ground 2.

4. Key Claim Construction Positions

  • The Petitioner did not propose constructions for specific claim terms but based its analysis on the chemical structure shown in a pending Certificate of Correction for claim 1. This corrected structure, which aligns with the specification, was assumed to be the broadest reasonable construction of the claimed compounds.

5. Key Technical Contentions (Beyond Claim Construction)

  • The petition's core technical argument, central to all grounds, was the interpretation of the rapamycin/FKBP-12 complex structure disclosed in Van Duyne. Petitioner contended that this prior art structure unambiguously taught a POSITA that the C40 position was located on the molecule's periphery, exposed to solvent and away from the critical binding interface, making it the clear and optimal site for chemical modification to improve properties like solubility without disrupting immunosuppressant activity.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-3 and 8-10 of the ’772 patent as unpatentable.