PTAB

IPR2016-01131

Mylan Pharmaceuticals Inc. v. Allergan, Inc.

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1. Case Identification

2. Patent Overview

  • Title: Methods of Treating Dry Eye Disease
  • Brief Description: The ’048 patent claims methods for treating dry eye disease, specifically keratoconjunctivitis sicca (KCS), and increasing tear production. The methods involve the twice-daily topical administration of an ophthalmic emulsion containing specific concentrations of cyclosporin A (CsA) and castor oil, along with other excipients.

3. Grounds for Unpatentability

Ground 1: Claims 1-10, 12-14, 16-20, and 22-23 are obvious over Ding in view of Sall.

  • Prior Art Relied Upon: Ding (Patent 5,474,979) and Sall (a 2000 clinical study on cyclosporine ophthalmic emulsion).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Ding taught all compositional elements of the claimed emulsion, including methods for treating KCS and the specific concentrations of 0.05% CsA and 1.25% castor oil within its disclosed examples and preferred ranges. Ding also taught the use of polysorbate 80, a cross-polymer, glycerine, and sodium hydroxide at the claimed percentages. However, Ding did not explicitly teach a twice-daily administration frequency. Sall remedied this deficiency by disclosing a Phase 3 clinical trial for treating KCS with twice-daily administration of a 0.05% CsA castor oil emulsion. Sall further taught that the 0.05% concentration was as effective as a 0.10% concentration but resulted in fewer adverse side effects, providing a clear rationale for selecting the claimed lower dosage.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would combine Ding and Sall because both addressed the same problem (treating KCS) with the same core formulation (CsA in a castor oil emulsion). A POSITA, starting with Ding’s formulation, would have been motivated to consult a clinical study like Sall to determine an optimal and safe dosing regimen. Sall’s results, showing comparable efficacy and improved safety for the 0.05% dose administered twice daily, would have provided a strong motivation to adopt this specific method.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success because Ding taught the base emulsion was effective for treating KCS, and Sall confirmed that a nearly identical formulation was safe and effective when administered twice daily. The patent owner itself had previously conceded during prosecution of a related application that the claimed formulation was "squarely within the teachings of the Ding reference."

Ground 2: Claims 11 and 21 are obvious over Ding in view of Sall and Acheampong.

  • Prior Art Relied Upon: Ding (Patent 5,474,979), Sall (2000 clinical study), and Acheampong (a 1998 study on cyclosporine distribution).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground built upon Ground 1 to address dependent claims 11 and 21, which added the limitation that administration of the emulsion results in "substantially no detectable concentration of cyclosporin A" in the patient's blood. While Sall noted low systemic absorption, Acheampong explicitly taught this limitation. Acheampong described a study where patients receiving a 0.05% CsA emulsion twice daily showed no detectable CsA concentration (<0.1 ng/ml) in their blood at either peak or trough levels.
    • Motivation to Combine: A POSITA developing the formulation taught by Ding and Sall would have been motivated to investigate its systemic absorption and safety profile. Acheampong directly addressed this by studying the blood concentrations resulting from topical administration of the same active ingredient at the same concentration. The desire to ensure patient safety would motivate a POSITA to incorporate the teachings of Acheampong.
    • Expectation of Success: Given Acheampong's direct, empirical evidence showing no detectable blood concentration from a 0.05% CsA emulsion, a POSITA would have had a very high expectation of achieving this claimed result.

Ground 3: Claim 15 is obvious over Ding in view of Sall and Glonek.

  • Prior Art Relied Upon: Ding (Patent 5,474,979), Sall (2000 clinical study), and Glonek (Patent 5,578,586).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground targeted claim 15, which depended from claim 1 and added the limitation that the emulsion "breaks down more quickly" and reduces vision distortion compared to an emulsion with 50% less castor oil. Glonek taught that oil-in-water emulsions can cause blurring and that the duration of blurring is dependent on the time required for the emulsion to differentiate, or "break down." Crucially, Glonek taught that increasing the oil concentration in an emulsion (while holding surfactant constant) increases its instability, causing it to break down more rapidly in the eye and thereby reduce blurring.
    • Motivation to Combine: A POSITA formulating the emulsion from Ding and Sall would seek to optimize patient comfort and reduce side effects like blurred vision. Glonek provided a well-understood principle for achieving this: increasing the oil concentration. A POSITA would be motivated to apply Glonek’s teachings to the Ding/Sall formulation to improve its performance characteristics.
    • Expectation of Success: Because Glonek explicitly taught the direct relationship between higher oil concentration and a faster breakdown rate, a POSITA would have reasonably expected that the claimed emulsion (1.25% castor oil) would break down faster than one with half the oil (0.625%), as claimed.

4. Key Claim Construction Positions

  • "buffer": Petitioner argued the term should be construed to include sodium hydroxide, as disclosed in the patent, which is a specific ingredient taught by the prior art reference Ding.
  • "substantially no detectable concentration": Petitioner asserted this phrase should be construed as a CsA blood concentration below 0.1 ng/mL, as measured by LC-MS/MS. This construction was based on the patent’s own explicit definition and was critical to mapping the Acheampong reference in Ground 2.
  • "breaks down": Petitioner proposed this term means the emulsion differentiates into separate aqueous and oil layers on the eye. This construction, based on the patent's disclosure and expert testimony, was central to applying the teachings of Glonek in Ground 3.

5. Key Technical Contentions (Beyond Claim Construction)

  • Petitioner dedicated a substantial portion of its argument to rebutting the Patent Owner's claims of "unexpected results," which were relied upon to overcome obviousness during prosecution. The core technical contention was that the declaration data (from Schiffman and Attar) submitted by the Patent Owner were scientifically unreliable. Petitioner argued the data lacked necessary parameters for scientific interpretation, such as error bars and raw data, and appeared to be repackaged versions of graphs from the prior art reference Sall, which was published more than a year before the patent's priority date. Therefore, the results were neither "unexpected" nor supportive of non-obviousness.

6. Arguments Regarding Discretionary Denial

  • Petitioner argued that the Board should not defer to the examiner's prior allowance of the claims. The petition asserted that it presented new arguments and evidence, including expert testimony and prior art references (Acheampong and Glonek) that were not substantively analyzed during prosecution. Petitioner contended that the examiner's decision was based on one-sided, flawed evidence of unexpected results and that the new arguments presented a much stronger prima facie case of obviousness.

7. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-23 of Patent 8,648,048 as unpatentable under 35 U.S.C. §103.