PTAB

IPR2016-01102

Roxane Laboratories Inc v. Novartis AG

Log In
Key Events
Petition
petition Intelligence

1. Case Identification

2. Patent Overview

  • Title: Rapamycin Derivatives
  • Brief Description: The ’772 patent discloses certain derivatives of the macrolide compound rapamycin, specifically those modified at the C40 position. The patent asserts these derivatives, such as 40-O-(2-hydroxyethyl)-rapamycin, exhibit improved properties like greater stability and bioavailability over rapamycin for use as immunosuppressants.

3. Grounds for Unpatentability

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

  • 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: Petitioner argued that a person of ordinary skill in the art (POSITA) would have been motivated to modify the known immunosuppressant rapamycin to solve its well-documented poor solubility. The combined teachings of the prior art provided a clear and predictable path to the specific derivatives claimed in the ’772 patent, rendering them obvious under 35 U.S.C. §103.
    • Prior Art Mapping: Petitioner asserted that Morris established rapamycin as an ideal lead compound for development due to its potent immunosuppressant activity but also identified its significant drawback of poor water solubility. This provided the motivation for a POSITA to seek improvements. Van Duyne, in conjunction with Rossmann’s method for deriving 3D coordinates from stereo diagrams, revealed the atomic structure of rapamycin bound to its biological target, FKBP-12. Petitioner contended this structural data clearly taught that the C40 hydroxyl group was located on the periphery of the binding interface, making it the optimal position for chemical modification without disrupting the compound's essential biological activity. In contrast, other potential sites like the C10 and C28 hydroxyl groups were shown to be critical to binding and thus unsuitable for modification. Having identified the problem (Morris) and the optimal location for a solution (Van Duyne), a POSITA would have turned to well-known chemical strategies for improving solubility. Yalkowsky taught that adding small, flexible side chains increases solubility, and Lemke taught that alcohol (hydroxyl) functional groups are effective solubilizing substituents.
    • Motivation to Combine: A POSITA would combine these references to solve a known problem with a promising drug. The motivation was not hindsight but a logical progression: select a lead compound with a known issue (Morris), use state-of-the-art structural biology to identify the safest place to modify it (Van Duyne), and apply standard medicinal chemistry principles to make the modification (Yalkowsky and Lemke). This path would lead a POSITA to add a small, flexible side chain containing a hydroxyl group, such as the 2-hydroxyethoxy group of claim 10, to the C40 position of rapamycin.
    • Expectation of Success: Petitioner argued a POSITA would have had a high expectation of success. The solubility-enhancing strategies taught by Yalkowsky and Lemke were predictable. Furthermore, the structural analysis from Van Duyne provided a strong basis to expect that modification at the C40 position would not disrupt the immunosuppressant activity, a fact later confirmed by other prior art.

Ground 2: Obviousness of Method and Composition Claims - Claims 7-9 are obvious over Morris, Van Duyne, Rossmann, Yalkowsky, and Lemke in further view of Hughes.

  • Prior Art Relied Upon: The same references as Ground 1, with the addition of Hughes (Patent 5,233,036).
  • Core Argument for this Ground: Petitioner argued that because the underlying compounds of claim 1 are obvious (as established in Ground 1), the claims directed to using these compounds for their known purpose (immunosuppression) and formulating them into a pharmaceutical composition are likewise obvious.
    • Prior Art Mapping: The argument for the obviousness of the underlying compound is identical to Ground 1. The petition introduced Hughes to address the specific limitations of claims 7, 8, and 9. Hughes explicitly taught that rapamycin derivatives modified at the C40 position retain potent immunosuppressant activity, are useful for preventing allograft rejection, and can be administered with a standard pharmaceutical carrier. Petitioner asserted this directly maps onto the limitations of claim 7 (a composition with a carrier), claim 8 (a method of inducing immunosuppression), and claim 9 (a method of preventing allograft rejection).
    • Motivation to Combine: The motivation to add Hughes was straightforward. Once a POSITA arrived at the obvious compounds of claim 1, it would have been an obvious next step to use them for the same purpose as the parent compound (rapamycin). Hughes confirmed that this was a fruitful path, showing that C40 modification preserved the desired activity and explicitly teaching the formulation of such derivatives into pharmaceutical compositions for administration to a mammal.
    • Expectation of Success: A POSITA would have reasonably expected the obvious compounds of claim 1 to function as immunosuppressants and to be suitable for formulation. The parent compound's activity was well-known, and Hughes demonstrated that similar C40-modified derivatives retained this activity and could be formulated in a standard manner.

4. Key Technical Contentions (Beyond Claim Construction)

  • Primacy of the C40 Position: A central technical contention was that the 3D structural data in Van Duyne, when properly interpreted, rendered the C40 position the only logical site for modification. Petitioner argued this data demonstrated other potential sites were integral to the binding with the FKBP-12 protein target. This analysis was crucial as it countered any argument of a vast, unpredictable number of modification options, instead presenting the selection of the C40 position as an obvious choice for a POSITA seeking to preserve biological activity.

5. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 1-3 and 7-10 of the ’772 patent as unpatentable.