PTAB

IPR2017-00600

Akorn, Inc. v. Allergan, Inc.

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1. Case Identification

2. Patent Overview

  • Title: Method of Providing Therapeutic Effect to a Patient
  • Brief Description: The ’048 patent describes methods for treating dry eye disease, specifically keratoconjunctivitis sicca (KCS), by increasing tear production. The methods involve the topical, twice-daily administration of an ophthalmic emulsion containing 0.05% cyclosporin A (CsA) and 1.25% 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 study on CsA ophthalmic emulsions).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Ding taught nearly every element of the claimed invention. Ding disclosed topical ophthalmic emulsions for treating KCS containing CsA, castor oil, polysorbate 80, glycerine, a cross-polymer, and sodium hydroxide, all within the concentrations recited in the ’048 patent. Specifically, Ding’s examples disclosed formulations with 0.05% CsA and 1.25% castor oil. Sall, a Phase 3 clinical trial, taught the missing element: the twice-daily administration of a 0.05% CsA-in-castor oil emulsion. Sall also established that the 0.05% CsA formulation was as therapeutically effective as a 0.10% CsA formulation for increasing tear production but resulted in fewer adverse side effects.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would combine Ding and Sall because both addressed the same problem of treating KCS with a CsA/castor oil emulsion. A POSITA looking to implement Ding’s formulation would have been motivated to adopt the twice-daily dosing regimen from Sall’s large-scale clinical trial to achieve the demonstrated efficacy and improved safety profile. Sall provided a strong rationale for selecting the 0.05% CsA concentration over 0.10% due to comparable efficacy and fewer side effects.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success in combining Ding and Sall. Ding provided the exact formulation, and Sall confirmed the clinical efficacy and safety of administering a nearly identical formulation on a twice-daily schedule to treat KCS and increase tear production.

Ground 2: Obviousness over Ding, Sall, and Acheampong - 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 CsA distribution).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground built upon the combination of Ding and Sall to address dependent claims 11 and 21, which added the limitation that administration results in "substantially no detectable concentration of cyclosporin A" in the blood. While Sall suggested low systemic absorption, Acheampong explicitly taught this limitation. Acheampong described a study where patients receiving a 0.05% CsA emulsion twice daily for three months had no detectable CsA concentration in their blood at either peak or trough levels (below a 0.1 ng/mL detection limit).
    • Motivation to Combine: A POSITA, having formulated the emulsion from Ding and Sall, would be concerned with systemic safety, a known issue with CsA. The motivation to consult Acheampong would be to confirm the systemic bioavailability of the chosen 0.05% topical formulation. Acheampong directly answered this question, teaching that such a formulation leads to undetectable blood levels of CsA.
    • Expectation of Success: A POSITA would have reasonably expected that the 0.05% CsA emulsion from Ding and Sall would result in no detectable blood concentration, as this is precisely what Acheampong demonstrated in a human study using the same CsA concentration.

Ground 3: Obviousness over Ding, Sall, and Glonek - 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 claimed emulsion "breaks down more quickly" than a second emulsion with only 50% as much castor oil (i.e., 0.625%). The combination of Ding and Sall provided the base emulsion. Glonek was introduced to teach the relationship between oil concentration and emulsion breakdown speed. Glonek disclosed that for ophthalmic emulsions, it is desirable for them to "rapidly differentiate in the eye" to reduce blurring and that increasing the oil concentration leads to faster differentiation.
    • Motivation to Combine: A POSITA formulating the emulsion from Ding and Sall would have been motivated to ensure patient comfort and minimize side effects like blurred vision. Glonek taught that faster emulsion breakdown reduces blurring. Therefore, a POSITA would have been motivated by Glonek’s teachings to understand that the higher (1.25%) castor oil concentration in Ding’s formulation would break down faster than a formulation with a lower oil concentration.
    • Expectation of Success: Based on Glonek’s teachings, a POSITA would have reasonably expected that the claimed emulsion with 1.25% castor oil would break down faster than an otherwise identical emulsion with 0.625% castor oil, thereby meeting the limitation of claim 15.

4. Key Claim Construction Positions

  • "substantially no detectable concentration": Petitioner argued this term, appearing in claims 11 and 21, should be interpreted in light of the specification, which stated that CsA concentrations below 0.1 ng/mL are considered "substantially undetectable." This construction was critical because prior art (Acheampong) explicitly disclosed measuring CsA blood levels below this exact 0.1 ng/mL threshold after administering a 0.05% CsA emulsion.
  • "breaks down": Petitioner asserted that this term from claim 15 should be construed to mean the emulsion "differentiates into separate aqueous and oil layers on the eye," based on the ’048 patent’s disclosure that a high concentration of the hydrophobic component (castor oil) provides for rapid "breaking down or resolving of the emulsion in the eye." This construction was essential for applying Glonek, which taught that higher oil concentrations lead to faster differentiation and reduced blurring.

5. Relief Requested

  • Petitioner requested the institution of an inter partes review and cancellation of claims 1-23 of Patent 8,648,048 as unpatentable under §103. Petitioner also requested joinder with IPR2016-01131.