PTAB

IPR2014-00899

Kamada Ltd v. Grifols SA

Log In

1. Case Identification

2. Patent Overview

  • Title: Purification of Alpha-1 Proteinase Inhibitor
  • Brief Description: The ’180 patent relates to methods for purifying α-1 proteinase inhibitor (α-1 PI) from aqueous solutions, such as Cohn Fraction IV-1, through a multi-step process involving precipitation and chromatography.

3. Grounds for Unpatentability

Ground 1: Anticipation over Ralston - Claims 1, 2, 5, 6, 10, 11, 12, 16, 17, 18, 21, 22, 26, 27, 32, and 33 are anticipated under 35 U.S.C. §102 by Ralston.

  • Prior Art Relied Upon: Ralston (Patent 6,093,804).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Ralston expressly taught every element of the challenged claims. Ralston disclosed a method of purifying α-1 PI from aqueous solutions, including the independent claim steps of: (a) removing contaminating proteins by precipitation using a lipid removal agent (LRA); (b) passing the purified solution through an anion exchange resin; (c) eluting the α-1 PI; (d) passing the eluted solution through a cation exchange resin; and (e) collecting the α-1 PI in the flow-through. Petitioner asserted that Ralston also disclosed the limitations of the challenged dependent claims, including starting with Cohn Fraction IV-1, washing the anion resin, performing viral inactivation and removal steps (including nanofiltration), and adjusting the pH of the solution prior to anion exchange.

Ground 2: Anticipation over Lebing - Claims 1, 6, 10, 17, 22, 26, and 33 are anticipated under §102 by Lebing.

  • Prior Art Relied Upon: Lebing (Patent 5,610,285).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner contended that Lebing, like Ralston, disclosed all elements of the method recited in the challenged claims. Lebing’s method included removing contaminants by precipitation, passing the solution through an anion exchange resin to bind the α-1 PI, eluting the α-1 PI, passing the eluate through a cation exchange resin, and collecting the α-1 PI in the flow-through. Petitioner also asserted that Lebing taught using Cohn Fraction IV-1 as the starting material and incorporating viral inactivation and removal steps, thereby anticipating the recited independent and dependent claims. This ground was presented as a non-cumulative alternative to the Ralston ground, as Lebing qualified as prior art under §102(b) while Ralston qualified under §102(e).

Ground 3: Obviousness over Ralston and Coan - Claims 3, 4, 19, and 20 are obvious over Ralston in view of Coan.

  • Prior Art Relied Upon: Ralston (Patent 6,093,804) and Coan (Patent 4,379,087).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Ralston taught the core purification process. To the extent Ralston did not explicitly teach the specific precipitation method of claims 3 and 19 (adding a polyalkylene glycol and adjusting pH to 5.0-6.0), Coan supplied this teaching. Coan disclosed precipitating contaminants from an α-1 PI solution by adding polyethylene glycol (claim 4) and adjusting the pH to a range of 4.6 to 5.9, which meets the claimed limitation.
    • Motivation to Combine: A POSITA would combine Coan’s precipitation step with Ralston’s process to improve the purification method. It was well-known that removing contaminants before chromatography could prevent column fouling, improve flow rates, and increase the binding of the target protein to the resin. A POSITA seeking to enhance the yield and purity of α-1 PI, a stated goal in Ralston, would have been motivated to incorporate Coan's effective pre-treatment step.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success because both references were directed to purifying α-1 PI and used the same sequence of steps: precipitation followed by anion exchange chromatography. Combining them would not alter the fundamental operation of either step and would be expected to yield a predictable improvement in purity and efficiency.

Ground 4: Obviousness over Ralston and Hwang - Claims 7, 8, 12, 23, 24, and 28 are obvious over Ralston in view of Hwang.

  • Prior Art Relied Upon: Ralston (Patent 6,093,804) and Hwang (Patent 5,616,693).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner asserted that Ralston taught the main purification method, while Hwang supplied the specific viral inactivation and dilution steps recited in these dependent claims. Hwang disclosed treating crude α-1 PI with a non-ionic detergent (Tween 80) and adjusting the pH to 8.5 to inactivate viruses, meeting the limitations of claims 7, 8, 23, and 24. Hwang also taught a dilution step before passing the solution through the anion exchange resin, as recited in claims 12 and 28.
    • Motivation to Combine: A POSITA would have been motivated to include Hwang’s viral inactivation step in Ralston’s method to comply with regulatory requirements (e.g., from the FDA) that plasma-derived products be substantially free of active virus. This was a standard and necessary step in the field. Additionally, a POSITA would have added Hwang's dilution step as a known technique to improve protein binding to the anion exchange column by reducing the solution's conductivity.
    • Expectation of Success: Combining a standard, widely used viral inactivation method with a purification process would have been straightforward for a POSITA. Since both Ralston and Hwang shared an anion exchange step, and Hwang demonstrated successful viral inactivation prior to this step, the combination was expected to be successful and produce a predictable, safe, and purified product.

  • Additional Grounds: Petitioner asserted numerous additional obviousness challenges. These grounds relied on similar rationales but added further references to teach more specific limitations, such as adding Neurath (Patent 4,540,573) for its teaching of Tween 20 as a detergent, Chen (Vox Sanguinis, 1998) for specific conductivity ranges, and Coan II (American Journal of Medicine, 1988) for dilution with sodium phosphate. A parallel set of grounds (Grounds 8-12) was also presented, using Lebing as the primary reference in combination with Coan, Hwang, Neurath, Chen, and Coan II.

4. Key Claim Construction Positions

  • Petitioner argued for applying the plain and ordinary meaning for the term "precipitation," defining it as a process where a solid comprising proteins is separated from an aqueous solution.
  • Petitioner noted that claims 6 and 22 contained a typographical error, reading "viral activation," and for the purposes of the IPR, interpreted the term as "viral inactivation" consistent with the patent's disclosure and a subsequent housekeeping amendment filed by the Patent Owner.

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-33 of the ’180 patent as unpatentable.