PTAB

IPR2026-00176

Halozyme Inc v. Alteogen Inc

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Key Events
Petition

1. Case Identification

2. Patent Overview

  • Title: Method for Producing Recombinant Protein
  • Brief Description: The ’638 patent discloses a method for producing recombinant hyaluronidase PH20 protein in cultured animal cells. The method involves a two-stage temperature-shift protocol: a first culturing stage at 35-38°C to increase cell density, followed by a second, longer culturing stage at a lower temperature of 28-34°C to enhance protein production with specific enzymatic activity and sialylation levels.

3. Grounds for Unpatentability

Ground 1: Claims 1-15 are obvious over Wei and Zmuda

  • Prior Art Relied Upon: Wei (European Patent No. EP3037529) and Zmuda (International Publication No. WO2017/011598).
  • Core Argument for this Ground: Petitioner argued that the claimed method is an obvious optimization of a well-known temperature-shift protocol for producing recombinant PH20. Wei taught all the essential elements of the claimed method but used a second culturing temperature (35.5°C) just outside the claimed range. Zmuda taught that a second culturing temperature of approximately 32°C was optimal for improving protein yields in the same type of cells. Petitioner asserted that combining these teachings was a matter of routine optimization.
    • Prior Art Mapping: Petitioner contended that Wei disclosed a method for producing recombinant human PH20 (rHuPH20) in CHO cells using a temperature shift from 37°C to a lower temperature (35.5°C) for protein production. Wei's process allegedly produced rHuPH20 meeting the limitations of claim 1, including enzymatic activity greater than 10,000 units/mL (17,000 U/mL crude), N-glycan sialylation of 25% (within the claimed 1-38% range), and conventional pH (7.2) and glucose levels. The only significant deviation was Wei's second temperature of 35.5°C, which is close to the claimed upper limit of 34°C. Zmuda disclosed improving recombinant protein production in CHO cells by shifting from 37°C to a sub-physiologic temperature range of "less than 37°C and greater than 30°C," specifically exemplifying 32°C as optimal.
    • Motivation to Combine: Petitioner argued a POSITA would combine the specific rHuPH20 production method of Wei with the general temperature optimization teachings of Zmuda. Since temperature downshifting was a well-known strategy to improve protein productivity, a POSITA would have been motivated to adjust the second culturing temperature in Wei's method to the more optimal range taught by Zmuda (e.g., 32°C) to enhance the yield of rHuPH20. This adjustment was presented as a predictable and routine optimization step, not an inventive leap.
    • Expectation of Success: Petitioner asserted a POSITA would have a high expectation of success. The principle that a mild hypothermic shift improves protein production in CHO cells was well-established. Modifying Wei's temperature from 35.5°C to the overlapping and exemplified range in Zmuda (30-34°C) was a minor adjustment within a known result-effective variable. A POSITA would reasonably expect this change to maintain or improve the favorable protein characteristics already achieved by Wei, such as high enzymatic activity and proper glycosylation.

Ground 2: Claims 4 and 7 are obvious over Wei, Zmuda, and Wei 2013

  • Prior Art Relied Upon: Wei (European Patent No. EP3037529), Zmuda (International Publication No. WO2017/011598), and Wei 2013 (International Publication No. WO2013/102144).
  • Core Argument for this Ground: This ground built upon Ground 1, adding Wei 2013 to address the specific limitations of claims 4 and 7. Claim 4 requires specific enzymatic activity at least 10% higher than wild-type PH20, and claim 7 requires substitution of one or more amino acid residues. Petitioner argued that Wei 2013 explicitly taught PH20 variants with these exact features, and it would have been obvious to produce these known, improved variants using the optimized manufacturing process established by the combination of Wei and Zmuda.
    • Prior Art Mapping: Wei and Zmuda established the obviousness of the base method in claim 1. Wei 2013 disclosed a large number of PH20 polypeptide variants designed to have "increased stability and/or increased activity" compared to wild-type PH20. This reference explicitly taught variants with amino acid substitutions (meeting claim 7) that exhibited enzymatic activity more than 10% higher—often over 300% higher—than wild-type PH20 (meeting claim 4).
    • Motivation to Combine: Petitioner argued a POSITA seeking to produce a more active or modified form of PH20 would have been motivated to use the optimized production process from Wei and Zmuda to manufacture the improved PH20 variants disclosed in Wei 2013. The motivation was straightforward: to apply a known, efficient production platform to a known, superior protein variant to achieve predictable, high-yield production of that superior protein.
    • Expectation of Success: A POSITA would have had a high expectation of success because the combination involved using a standard, optimized biomanufacturing process to create a protein variant explicitly designed for enhanced activity. There was no technical uncertainty suggesting the production method would fail or that the resulting protein would not exhibit its known, enhanced properties.

4. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-15 of the ’638 patent as unpatentable.