Apotex Inc v. Ipsen Biopharm Ltd

1. Case Identification

• Case #: IPR2025-01531
• Patent #: 11,344,552
• Filed: September 12, 2025
• Petitioner(s): Apotex Inc.
• Patent Owner(s): Ipsen Biopharm Ltd.
• Challenged Claims: 1-15

2. Patent Overview

• Title: Methods of Treating Metastatic Pancreatic Cancer
• Brief Description: The ’552 patent is directed to methods for the first-line treatment of metastatic pancreatic adenocarcinoma. The method comprises administering a specific combination therapy of liposomal irinotecan (60 mg/m²), oxaliplatin (60 mg/m²), leucovorin, and 5-fluorouracil (5-FU) once every two weeks.

3. Grounds for Unpatentability

Ground 1: Claims 1, 3-6, and 8-14 are obvious over Conroy, Mahaseth, Bayever, Saif, Ko, and Cantore.

• Prior Art Relied Upon: Conroy (a 2011 N. Engl. J. Med. article), Conroy Protocol, Conroy 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 the claimed method was an obvious modification of the then-gold standard FOLFIRINOX regimen for first-line pancreatic cancer treatment, as disclosed by Conroy and Mahaseth. The FOLFIRINOX regimen taught all elements of the claimed combination except for using non-liposomal irinotecan instead of liposomal irinotecan. Conroy taught the use of oxaliplatin, leucovorin (400 mg/m²), and 5-FU (2,400 mg/m²) administered every two weeks. Critically, Conroy's disclosure of a 78% median dose intensity for oxaliplatin, combined with the Conroy Protocol's instructions for dose reduction to 60 mg/m² due to toxicity, rendered the claimed 60 mg/m² dose obvious. Bayever disclosed a method of treating pancreatic cancer by administering the claimed 60 mg/m² dose of liposomal irinotecan (MM-398) with the same claimed doses of leucovorin and 5-FU.
  • Motivation to Combine: A POSITA would combine the teachings because Saif and Ko, commenting on the success of liposomal irinotecan (MM-398) in second-line therapy, explicitly suggested it should be studied as a replacement for standard irinotecan in the first-line FOLFIRINOX regimen. Bayever further motivated this substitution by disclosing the improved pharmacokinetic and toxicity profiles of liposomal irinotecan over the standard form. The combination amounted to substituting a known, improved version of a drug into an established, gold-standard therapy to solve a known problem (toxicity).
  • Expectation of Success: A POSITA would have had a clear expectation of success in making this substitution. The base FOLFIRINOX regimen was already the standard of care, and substituting an improved version of one component (liposomal irinotecan) was a predictable path for optimization. Cantore demonstrated that a 60 mg/m² dose of oxaliplatin in combination with irinotecan was well-tolerated and effective in metastatic pancreatic cancer patients.

Ground 2: Claims 2, 7, and 15 are obvious over the prior art of Ground 1 in view of 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 targets dependent claims reciting a specific drug administration sequence (irinotecan, then oxaliplatin, then leucovorin, then 5-FU) and pre-treatment with a corticosteroid. Masi taught a modified FOLFOXIRI regimen where irinotecan was administered before oxaliplatin to achieve synergy. Ginocchi applied a similar modified FOLFOXIRI regimen (irinotecan before oxaliplatin) to metastatic pancreatic cancer patients and found it to be well-tolerated and effective. Bayever taught that liposomal irinotecan should be administered first and also disclosed pre-treatment with a corticosteroid (dexamethasone) and an anti-emetic.
  • Motivation to Combine: A POSITA seeking to optimize the combination from Ground 1 would look to established administration sequences. Masi provided a rationale for the irinotecan-first sequence (synergy), and Ginocchi confirmed its tolerability in the specific patient population. A POSITA would apply this known, beneficial sequence to the therapy from Ground 1.

Ground 3: Claims 1-15 are obvious over the prior art of Grounds 1 and 2 in view of 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 contingent on the Board determining the patent's effective filing date is November 10, 2017. Carnevale explicitly stated that based on its optimized safety profile, liposomal irinotecan (MM-398) would be an "ideal substitute" for standard irinotecan in the first-line FOLFIRINOX regimen. Dean disclosed a phase 2 clinical trial protocol to evaluate the exact combination of liposomal irinotecan, 5-FU, leucovorin, and oxaliplatin in first-line therapy.
  • Motivation to Combine: If the later filing date applies, Carnevale and Dean provide overwhelming and explicit motivation. They remove any doubt by directly proposing the claimed combination as a "natural extension" of therapy and the subject of a clinical trial, confirming it was obvious to try.

4. Key Claim Construction Positions

• "treating" and "treat" (claims 1-15): Petitioner argued this term should be construed as "attempting to cause a therapeutic improvement but not requiring actual efficacy." Petitioner contended the patent specification distinguishes between "treatment" and "effective treatment," using only the former in the claims. This construction is critical, as it impacts the patent's effective filing date and undermines the Patent Owner's arguments regarding unexpected results, which rely on a presumption of proven clinical efficacy.

5. Arguments Regarding Discretionary Denial

• Petitioner argued against discretionary denial under §325(d), asserting that the Patent Owner misled the Examiner during prosecution. Key alleged errors included:
  • Arguing that Bayever was limited to second-line therapy, when its disclosure and claims covered first-line therapy, thereby obscuring a primary motivation to combine.
  • Obscuring that Conroy's data and protocols effectively disclosed the claimed 60 mg/m² dose of oxaliplatin, leading the Examiner to incorrectly believe the dose was novel.
  • Relying on flawed "unexpected results" arguments that were only relevant if the claims were improperly construed to require proven clinical efficacy.

6. Relief Requested

• Petitioner requested institution of an inter partes review, joinder with IPR2025-00505, and cancellation of claims 1-15 of Patent 11,344,552 as unpatentable.