PTAB

IPR2016-01131

Mylan Pharmaceuticals Inc v. Allergan Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Method of Increasing Tear Production
  • Brief Description: The ’048 patent describes methods for treating dry eye disease, specifically keratoconjunctivitis sicca (KCS), by increasing tear production. The method involves 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: Obviousness over Ding and Sall - 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 trial publication).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Ding taught nearly all components of the claimed ophthalmic emulsion for treating KCS, including specific examples with 0.05% CsA and 1.25% castor oil, along with polysorbate 80, a cross-polymer, glycerine, sodium hydroxide, and water. Sall, a Phase 3 clinical trial, disclosed the claimed method of twice-daily administration of a 0.05% CsA-in-castor oil emulsion to treat KCS, demonstrating its safety and efficacy in increasing tear production. Sall further established that the 0.05% CsA emulsion was at least as effective as a 0.10% emulsion with fewer adverse events, meeting the limitations of claims 13, 14, 16, and 17.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would combine Ding’s detailed formulations with Sall’s clinical results. Sall’s trial used the very type of emulsion disclosed in Ding and provided the clinical evidence and rationale for selecting the specific 0.05% CsA concentration and twice-daily dosing regimen to optimize efficacy and safety. Petitioner noted that the Patent Owner had previously conceded during prosecution of a related application that the claimed formulation was "squarely within the teachings of the Ding reference" and would have been obvious to a POSITA.
    • Expectation of Success: A POSITA would have had a high expectation of success. Both references address the same problem (treating KCS) with the exact same active ingredient (CsA) in the same type of vehicle (castor oil emulsion). Combining Ding's preferred formulation components with Sall's clinically validated dosing regimen was a predictable combination of known elements for a known purpose.

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

  • Prior Art Relied Upon: Ding (Patent 5,474,979), Sall (a 2000 clinical trial publication), and Acheampong (a 1998 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground builds on the combination of Ding and Sall to address the limitation in claims 11 and 21 requiring "substantially no detectable concentration of cyclosporin A" in the blood. While Sall noted low blood concentrations, Acheampong explicitly studied the peak and trough blood concentrations of CsA after topical administration. Acheampong’s data showed that patients receiving a 0.05% CsA emulsion twice daily had no detectable concentration of CsA in their blood at any point.
    • Motivation to Combine: A POSITA, having selected the 0.05% CsA formulation from Ding and Sall for its safety and efficacy, would be motivated to confirm its systemic safety profile. Acheampong provided direct, published evidence of the blood concentration levels for that exact dosage, making it a natural reference to consult to ensure the formulation met the desired safety objective of minimal systemic exposure.
    • Expectation of Success: Based on Acheampong’s clear results for the 0.05% CsA emulsion, a POSITA would have fully expected that administering the formulation from Ding and Sall would result in substantially no detectable CsA in the blood.

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

  • Prior Art Relied Upon: Ding (Patent 5,474,979), Sall (a 2000 clinical trial publication), and Glonek (Patent 5,578,586).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground addresses claim 15, which requires the emulsion to "break down more quickly" than a comparable emulsion with 50% less castor oil, thereby reducing vision distortion. Glonek taught that for ophthalmic emulsions, blurring is caused by the time it takes the emulsion to differentiate on the eye's surface. Glonek explicitly disclosed that increasing the oil concentration in an emulsion while holding the surfactant constant increases its instability, causing it to "rapidly differentiate in the eye" and reduce blurring.
    • Motivation to Combine: A POSITA developing the formulation from Ding and Sall would seek to improve patient comfort and compliance by minimizing side effects like blurred vision. Glonek provided the known formulation principle that would motivate using a higher castor oil concentration (like the 1.25% in the primary combination) to achieve the desired faster breakdown and reduced vision distortion.
    • Expectation of Success: Given Glonek’s clear teaching on the relationship between oil concentration and emulsion breakdown rate, a POSITA would reasonably expect that an emulsion with 1.25% castor oil would break down faster and cause less blurring than one with only 0.625% castor oil.

4. Key Claim Construction Positions

  • "substantially no detectable concentration": Petitioner argued this term should be construed based on the patent’s specification, which identifies a detection limit of 0.1 ng/mL using LC-MS/MS. This construction was critical for mapping the term to the quantitative results disclosed in the Acheampong reference.
  • "breaks down": Petitioner asserted that a POSITA would understand this term, in the context of claim 15 and the specification, to mean the emulsion differentiates into separate aqueous and oil layers on the eye. This construction connected the claim language to the physical principles of emulsion stability taught by Glonek.

5. Key Technical Contentions (Beyond Claim Construction)

  • Rebuttal of "Unexpected Results": A core technical contention was that the Patent Owner’s evidence of "unexpected results," submitted during prosecution to overcome obviousness, was flawed and misleading. Petitioner argued that the data presented by the Patent Owner appeared to be repackaged from graphs previously published in the Sall reference. Furthermore, the data submitted to the examiner lacked necessary scientific parameters, such as error bars, making it impossible to determine statistical significance and rendering any conclusions of unexpected superiority unreliable.