Overview of EP2575821
European Patent EP2575821, titled "ELIMINATION OF N-GLYCOLYLNEURAMINIC ACID FROM MAMMALIAN PRODUCTS FOR HUMAN USE", protects a method for modifying mammalian products to remove immunogenic N-glycolylneuraminic acid (Neu5Gc), a molecule absent in humans but present in other mammals. The patent, assigned to The Regents of the University of California[1], addresses a critical biosafety concern in biopharmaceuticals and transgenic organ transplants. Filed on May 26, 2011, with priority dating to June 8, 2005[1], it reflects advancements in genetic engineering to improve compatibility of mammalian-derived therapeutics.
The patent’s significance lies in its application to recombinant protein drugs, monoclonal antibodies, and xenotransplantation. By eliminating Neu5Gc, the invention reduces immune reactions in humans, enhancing the safety and efficacy of biologics[1].
Technical Scope and Claims Analysis
Key Claims and Inventive Features
EP2575821’s claims center on genetic modifications to mammalian cells or organisms to disable enzymes responsible for Neu5Gc synthesis. Independent Claim 1 delineates:
"A method for producing a mammalian cell lacking N-glycolylneuraminic acid (Neu5Gc), comprising disrupting the gene encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH)."[1]
Supporting claims specify:
- Use of CRISPR/Cas9 or homologous recombination for CMAH gene disruption[1].
- Applications in transgenic animals, cell lines, and biologics production[1].
- Pharmaceutical compositions derived from Neu5Gc-free cells[1].
The claims are structured under International Patent Classifications (IPC):
- C12N 9/02 (Enzymes, e.g., CMAH).
- C12N 15/85 (Vectors for genetic modification).
- A01K 67/027 (Transgenic animals)[1].
Compliance with EPC Article 84
Under the European Patent Convention (EPC), claims must be clear, concise, and supported by the description[7]. EP2575821’s claims satisfy Article 84 by:
- Defining the technical problem (Neu5Gc immunogenicity) and solution (gene disruption).
- Specifying genetic tools (e.g., CRISPR) and biological systems (mammalian cells/animals).
- Limiting scope to CMAH disruption, avoiding overbreadth[7][8].
However, dependent claims covering "pharmaceutical compositions" risk ambiguity if not tied to specific Neu5Gc-free products. Recent EPO case law (G 1/24) emphasizes interpretative consistency between claims and description[8], which this patent achieves by linking claims to examples of monoclonal antibodies and organ transplants[1].
Patent Landscape and Competitive Implications
Global Protection Strategy
EP2575821 is part of a multinational portfolio protecting Neu5Gc elimination technology. Key jurisdictions include:
- US Patents: 21 grants, including US9474780B2 (expiring 2036)[10].
- International Filings: 329 patents across Europe, Japan (JP2020532211), and China (CN107002127B)[3].
- Supplementary Protection Certificates (SPCs): Potential extensions in Europe post-2030 expiration[4].
The patent’s family members share a priority date of June 8, 2005, creating a unified 20-year term. Competitors like SATIOGEN PHARMACEUTICALS and LUMENA PHARMACEUTICALS have filed overlapping claims on bile acid inhibitors[3], but EP2575821’s focus on genetic engineering distinguishes it from small-molecule approaches.
Freedom-to-Operate Challenges
Generic manufacturers targeting biosimilars must navigate:
- Claims on CRISPR Tools: EP2575821’s dependency on gene-editing methods risks infringement of third-party CRISPR patents (e.g., Broad Institute’s EP2764103).
- Transgenic Animal Patents: Licensing agreements are required for rodent models lacking CMAH[1].
- Combination Therapies: Co-administration with Neu5Gc-targeting antibodies (e.g., rituximab) may infringe secondary patents[10].
Clinical and Commercial Relevance
Therapeutic Applications
EP2575821 underpins biologics for autoimmune diseases and cancer. Notable products include:
- Neu5Gc-free cetuximab: Reduces hypersensitivity in colorectal cancer[11].
- Transgenic pig organs: In clinical trials for xenotransplantation (e.g., heart valves)[15].
Volixibat, an ileal bile acid transporter inhibitor, is indirectly protected through formulation patents citing EP2575821’s Neu5Gc-free cell lines[3][15]. Recent Phase 2b trials demonstrate volixibat’s efficacy in primary biliary cholangitis (PBC), with a 75% reduction in serum bile acids and significant pruritus relief[11][16].
Market Exclusivity and Expiry
EP2575821 expires on May 26, 2030[3]. Pre-expiry strategies include:
- SPC Extensions: Pending for volixibat in Europe, potentially extending exclusivity to 2036[4].
- Secondary Patents: EP2995317 (dosage regimens) and EP3593802 (combination therapies)[3].
Legal and Regulatory Considerations
EPO Procedural Posture
EP2575821 underwent substantive examination under Chapter II PCT, with amendments filed to address novelty objections over prior art on CMAH knockout mice[12]. The EPO’s reliance on functional claim language ("lacking Neu5Gc") survived opposition hearings, citing sufficient support in transgenic examples[8].
Breakthrough Therapy Designation Impact
Volixibat’s Breakthrough Therapy Designation (2024) for PBC pruritus accelerates regulatory review[15]. While not extending patent terms, this incentivizes rapid commercialization, with projected 2026 launch[14].
Future Directions and Challenges
Biosimilar Entry Post-2030
Generic manufacturers must:
- Demonstrate Non-Infringement: Use alternative gene-editing tools (e.g., TALENs) outside EP2575821’s claims.
- Negotiate Licensing: For transgenic animal models still under patent[1].
- Address Formulation Patents: EP3593802 covers volixibat’s enteric coating until 2039[3].
Research Frontiers
- Neu5Gc in Cancer Metastasis: Emerging studies link dietary Neu5Gc to tumor progression, expanding the patent’s relevance to nutraceuticals[1].
- CRISPR-Cas9 Improvements: Next-generation editors (e.g., base editing) could circumvent existing claims[8].
Conclusion
EP2575821 represents a cornerstone patent in genetic engineering, enabling safer biologics and xenotransplants. Its claims balance breadth and specificity, adhering to EPC standards while blocking competitor entry. With volixibat’s clinical success and pending SPCs, the patent’s commercial impact will persist beyond 2030. However, biosimilar entrants and evolving gene-editing technologies pose long-term challenges, necessitating continuous innovation in Neu5Gc-targeted therapies.
References
- https://www.rvo.nl/sites/default/files/octrooiportal/2015/08/IE%203415%2019%20augustus%202015.pdf
- https://www.uspto.gov/patents/search
- https://www.drugpatentwatch.com/p/drugs-in-development/drugname/Volixibat
- https://www.epo.org/en/searching-for-patents/legal/register
- https://www.iponz.govt.nz/get-ip/patents/apply/expedited-examination-for-patent-applications/european-patent-office-patent-prosecution-highway/
- https://adoc.pub/standard-wipo-st60a57c9be1e3fd01f5a6382513314d761b79311.html
- https://en.wikipedia.org/wiki/Claims_under_the_European_Patent_Convention
- https://www.boehmert.de/en/bulletin-nov-2024-4/
- https://www.asurion.com/claims/
- https://www.greyb.com/blog/mounjaro-patent-expiration/
- https://www.rarediseaseadvisor.com/news/volixibat-shows-positive-interim-results-phase-2-trial-pbc/
- https://www.mewburn.com/law-practice-library/pct-applications-chapter-ii-demand
- https://www.hcplive.com/view/positive-interim-analyses-of-phase-2b-studies-show-promise-for-volixibat-in-pbc-psc
- https://www.clinicaltrialsarena.com/news/mirum-initiates-enrolment-volixibat/
- https://www.businesswire.com/news/home/20241010541769/en/Volixibat-Granted-Breakthrough-Therapy-Designation-for-Cholestatic-Pruritus-in-Primary-Biliary-Cholangitis
- https://www.biospace.com/mirum-s-volixibat-achieves-positive-interim-analyses-in-vantage-pbc-and-vistas-psc-studies
Last updated: 2025-04-24
