PTAB

IPR2017-01434

Micro Labs Ltd v. SanTen Pharmaceutical Co Ltd

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1. Case Identification

2. Patent Overview

  • Title: Difluoroprostaglandin Derivatives and Their Use
  • Brief Description: The ’035 patent discloses a genus of fluorine-containing prostaglandin F2α (PGF2α) analogues, specifically those with two fluorine atoms at the C-15 position, and their use in medicines to treat eye diseases like glaucoma and ocular hypertension by lowering intraocular pressure (IOP).

3. Grounds for Unpatentability

Ground 1: Claims 1-14 are obvious over Klimko, Kishi, and Ueno Japan.

  • Prior Art Relied Upon: Klimko (European Patent Application # EP0639563A2), Kishi (Patent 5,292,754), and Ueno Japan (Japanese Patent Application # JP-A-7070054).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Klimko disclosed a structurally similar lead compound, "Compound C," for reducing IOP. Compound C is a PGF2α analogue that differs from the claimed tafluprost primarily at the C-15 position, where it has a hydroxyl (-OH) group instead of the two fluorine atoms (a difluoro group) of tafluprost. Kishi taught that removing the C-15 hydroxyl group from PGF2α analogues eliminates the negative side effect of hyperemia (eye redness) and improves compound stability, though it may slightly reduce IOP-lowering activity. Ueno Japan explicitly taught substituting the C-15 hydroxyl group on PGF2α analogues with a difluoro group to create 15-deoxy-15,15-difluoro compounds for treating ocular inflammatory diseases.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would select Klimko’s Compound C as a promising lead compound due to its demonstrated efficacy in lowering IOP, which was superior to the then-standard latanoprost. To address the known hyperemia side effect associated with such compounds, a POSA would be motivated by Kishi to remove the C-15 hydroxyl group. A POSA would then consult Ueno Japan, which taught replacing that hydroxyl group with two fluorine atoms to counteract any potential loss of IOP-lowering activity and improve the compound's biological profile.
    • Expectation of Success: A POSA would have a reasonable expectation of success because the proposed modification was a straightforward substitution at a known active site. The combination of Kishi and Ueno Japan taught that replacing the C-15 hydroxyl group with a difluoro group would predictably eliminate hyperemia while maintaining or restoring the desired therapeutic effect. The practical benefit of avoiding the creation of a new stereogenic center, thereby simplifying manufacturing, provided additional motivation and expectation of a successful outcome.

Ground 2: Claims 1-14 are obvious over Klimko, Kishi, and Ueno Japan in further view of Bezuglov 1982 and/or Bezuglov 1986.

  • Prior Art Relied Upon: Klimko (European Patent Application # EP0639563A2), Kishi (Patent 5,292,754), Ueno Japan (Japanese Patent Application # JP-A-7070054), Bezuglov 1982 (a journal article), and Bezuglov 1986 (a journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground presented a reinforcing or alternative line of reasoning for modifying Klimko’s Compound C. After being motivated by Kishi to replace the C-15 hydroxyl group to eliminate hyperemia, a POSA would also consider the teachings of Bezuglov. Bezuglov 1982 and 1986 taught that substituting the C-15 hydroxyl group with a single fluorine atom (monofluorination) resulted in prostaglandin analogues with greater stability, prolonged action, and increased activity. This provided an additional, well-documented rationale for replacing the hydroxyl group with fluorine.
    • Motivation to Combine: The initial motivation to select Klimko's Compound C as a lead compound and modify it based on Kishi's teachings remained the same as in Ground 1. Bezuglov provided further motivation by showing that fluorination at the C-15 position was a known and successful strategy for improving prostaglandin analogues. A POSA, having been taught by Bezuglov that monofluorination is beneficial, would then see Ueno Japan's teaching of difluorination as an obvious and superior alternative, as it provided the benefits of fluorination while also advantageously avoiding the creation of a new stereogenic center.
    • Expectation of Success: The teachings in Bezuglov, demonstrating the success of monofluorination, would strengthen a POSA's reasonable expectation of success in making a hydroxyl-to-fluorine substitution. This would make the subsequent, more advantageous step to difluorination as taught by Ueno Japan even more predictable and obvious.

4. Relief Requested

  • Petitioner requests institution of inter partes review (IPR) and cancellation of claims 1-14 of Patent 5,886,035 as unpatentable under 35 U.S.C. §103.