PTAB

IPR2025-00505

CSPC Pharmaceutical Group Ltd v. Ipsen BioPharm Ltd

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Method of Treating Pancreatic Cancer
  • Brief Description: The ’552 patent is directed to methods of treating metastatic pancreatic cancer in human patients who have not previously received antineoplastic agents. The method comprises administering a specific combination chemotherapy regimen of liposomal irinotecan, oxaliplatin, leucovorin, and 5-fluorouracil at specific dosages once every two weeks.

3. Grounds for Unpatentability

Ground 1: Obviousness over FOLFIRINOX Prior Art - Claims 1, 3-6, and 8-14 are obvious over Conroy, Conroy Protocol, Conroy Appendix, and Mahaseth in combination with Bayever, Saif, Ko, and Cantore.

  • Prior Art Relied Upon: Conroy (a 2011 N. Engl. J. Med. article), Conroy Protocol (a 2011 clinical trial protocol), Conroy Appendix (a 2011 supplementary appendix), Mahaseth (a 2013 Pancreas journal article), Bayever (WO 2013/188586), Saif (a 2014 Journal of the Pancreas article), Ko (a 2013 British J. of Cancer article), and Cantore (a 2004 Oncology journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Conroy, its Protocol and Appendix, and Mahaseth collectively disclose the FOLFIRINOX regimen, which was the "gold standard" first-line therapy for metastatic pancreatic cancer. This regimen taught all elements of claim 1 except for the use of liposomal irinotecan instead of free irinotecan. Crucially, Petitioner asserted that Conroy’s disclosure of a 78% median dose intensity for oxaliplatin, combined with the Protocol’s explicit instruction to reduce the oxaliplatin dose from 85 mg/m² to 60 mg/m² due to toxicity, rendered the claimed 60 mg/m² dose obvious. Bayever disclosed a method of treating pancreatic cancer with 60 mg/m² of liposomal irinotecan (MM-398) in combination with the same doses of leucovorin and 5-fluorouracil as claimed.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) would combine these references to improve the established FOLFIRINOX regimen. Bayever taught that liposomal irinotecan had superior pharmacokinetic properties and toxicity profiles compared to free irinotecan. Saif and Ko explicitly suggested replacing the free irinotecan in the first-line FOLFIRINOX regimen with liposomal irinotecan (MM-398) based on its promising results in second-line therapy. A POSITA would have been motivated to make this substitution to improve the safety and tolerability of the gold-standard treatment. Lowering the oxaliplatin dose to the claimed 60 mg/m² was presented as routine dose optimization to manage known toxicities, a practice explicitly described in Conroy.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success in making this substitution. The underlying components were all well-known chemotherapy agents, and the specific substitution was suggested to improve a known therapy, not to create a new one. The claimed therapy was a predictable variation of the existing FOLFIRINOX standard of care.

Ground 2: Obviousness Regarding Administration Sequence - Claims 2, 7, and 15 are obvious over the prior art in Ground 1 in combination with Masi and Ginocchi.

  • Prior Art Relied Upon: All references from Ground 1, plus Masi (a 2004 Annals of Oncology article) and Ginocchi (a 2012 Annals of Oncology abstract).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground addresses dependent claims reciting the specific sequence of drug administration. Claim 2 requires administering oxaliplatin 2 hours after liposomal irinotecan. Masi and Ginocchi disclosed modified FOLFOXIRI regimens (irinotecan, oxaliplatin, leucovorin, 5-FU) where irinotecan was administered prior to oxaliplatin. Masi taught this sequence based on in vitro studies showing enhanced synergy. Ginocchi applied a similar regimen to metastatic pancreatic cancer patients, demonstrating it was well-tolerated and effective.
    • Motivation to Combine: A POSITA looking to optimize the combination therapy from Ground 1 would have been motivated by Masi and Ginocchi to administer irinotecan (in its liposomal form) before oxaliplatin to achieve synergistic effects. While the prior art did not specify a 2-hour delay, determining the optimal timing between infusions was argued to be a matter of routine optimization for a POSITA.
    • Expectation of Success: Given that Masi and Ginocchi demonstrated the benefits of the irinotecan-first sequence, a POSITA would have expected this administration order to be at least safe and potentially more effective when applied to the combination of liposomal irinotecan and the other FOLFIRINOX drugs.

Ground 3: Obviousness with a Later Priority Date - Claims 1-15 are obvious over the prior art in Grounds 1 and 2 in combination with Carnevale and Dean.

  • Prior Art Relied Upon: All references from Grounds 1 and 2, plus Carnevale (a 2016 Future Oncology review article) and Dean (a 2016 J. Clin. Oncol. abstract).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground is asserted under the premise that the challenged claims have a later effective filing date of November 10, 2017, if construed to require clinical efficacy (see §4 below). Carnevale explicitly stated that the optimized profile of liposomal irinotecan (MM-398) would make it an "ideal substitute for irinotecan in the first-line FOLFIRINOX regimen" and a "natural extension" of its use. Dean disclosed a phase 2 clinical trial evaluating the exact combination of liposomal irinotecan, 5-FU, leucovorin, and oxaliplatin for first-line therapy of pancreatic cancer.
    • Motivation to Combine: Carnevale and Dean provided even more direct and explicit motivation for a POSITA to make the claimed invention. They confirmed the field was already moving towards the exact substitution proposed by Petitioner’s obviousness theory, removing any doubt about the motivation to combine the primary references from Ground 1.

4. Key Claim Construction Positions

  • "treating" and "treat": Petitioner argued these terms should be construed as "attempting to cause a therapeutic improvement but not requiring actual efficacy." This construction is central to the petition because if adopted, the claims would not require a showing of clinical efficacy. Petitioner contended this would entitle the ’552 patent to an earlier priority date but would also significantly lower the bar for proving obviousness, as a POSITA would only need to have been motivated to try the combination, not to have expected superior clinical results. If the Board construes "treating" to require clinical efficacy, Petitioner argued the patent's effective filing date would be its actual filing date of November 10, 2017, which would make additional prior art like Carnevale and Dean available under Ground 3.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under §325(d) was inappropriate because the examiner made material errors during prosecution based on being misled by the Patent Owner. Key arguments included:
    • Patent Owner incorrectly argued that Bayever was limited to second-line therapy, thereby minimizing its relevance to the first-line FOLFIRINOX regimen. Petitioner asserted that Bayever’s disclosure and claims broadly cover first-line treatment.
    • The examiner failed to appreciate that Conroy disclosed dose reductions of oxaliplatin to the claimed 60 mg/m² level, making the claimed dose an obvious, routine optimization rather than an inventive step.
    • Patent Owner improperly relied on post-filing evidence of "unexpected results" (the Wainberg references) that were based on a flawed study and have since been refuted by more robust clinical trials (Nichetti and Nevala-Plagemann) showing identical efficacy to the prior art FOLFIRINOX regimen.

6. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-15 of the ’552 patent as unpatentable under 35 U.S.C. §103.