Overview of Selinexor and Its Crystalline Polymorphs
Selinexor (C17H11F6N7O2) is a selective inhibitor of nuclear export (SINE) that targets exportin 1 (XPO1/CRM1), a protein critical for the transport of tumor suppressor proteins out of the nucleus. It is commercially marketed as Xpovio for treating relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma[11]. The compound’s therapeutic efficacy and pharmacokinetic properties are heavily influenced by its crystalline form, making polymorph protection a critical aspect of its intellectual property strategy[1][2].
Patent AU2020203246, filed by Karyopharm Therapeutics Inc., claims novel crystalline polymorphs of selinexor (Forms A, B, C, and D) and their use in pharmaceutical compositions[1][2]. This divisional application derives from the parent PCT/US2015/045395 (AU2015301484), emphasizing Australia’s role in the global protection strategy for selinexor[1][2].
Key Claims and Technical Scope of AU2020203246
1. Crystalline Form A
The patent’s primary focus is on Form A, characterized by X-ray powder diffraction (XRPD) peaks at 2θ angles of 4.4°, 19.0°, 21.3°, and 22.0° (±0.2°)[1]. Additional characterization includes differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), which confirm thermal stability and absence of solvent residues[1]. Form A is described as having a unimodal particle size distribution with a d(0.9) ≤100 μm, optimizing bioavailability and manufacturability[1].
2. Pharmaceutical Compositions and Methods of Use
Claims extend to pharmaceutical compositions comprising Form A for treating CRM1-mediated disorders, including cancer[1]. The specification highlights enhanced solubility and stability compared to amorphous selinexor, addressing challenges in formulation and shelf-life[1].
3. Methods of Preparation
Detailed synthetic pathways for Form A are provided, including solvent selection (e.g., ethyl acetate, heptane) and crystallization conditions[1]. Example 6 describes large-scale production (Lot No. 1405463) with reproducible particle size distribution[1].
Patent Landscape and Strategic Considerations
1. Global Patent Family
AU2020203246 is part of a sprawling patent family spanning 40+ jurisdictions, including the US (US10,519,139), EU (EP3180331), and Japan (JP6777626)[2]. This reflects Karyopharm’s strategy to secure polymorph-specific protection worldwide, leveraging Australia’s robust pharmaceutical patent system[2][10].
2. Divisional Strategy
As a divisional of AU2015301484, AU2020203246 exemplifies tactical segmentation of claims to extend protection beyond the parent’s compound coverage[1][6]. This approach mitigates risks of invalidation by isolating polymorph-specific innovations, which are often challenged for obviousness[6][12].
3. Competitive Threats and Generic Entry
Australia’s therapeutic goods framework lacks a formal patent linkage system, allowing generics to seek regulatory approval without prior patent clearance[5]. However, importing selinexor generics manufactured using patented processes (e.g., Form A crystallization) constitutes infringement under §117 of the Patents Act 1990[8]. Generics must either invalidate AU2020203246 or design around the patented polymorphs, which is non-trivial given the specificity of XRPD claims[1][8].
4. Validity Challenges
The patent’s validity hinges on:
- Novelty: Forms A–D are distinct from prior art disclosures (e.g., WO2013/019548)[1][11].
- Inventive Step: Demonstrating non-obviousness requires evidence that the polymorphs’ properties (e.g., stability) were unforeseeable[6][12].
- Support and Sufficiency: Detailed XRPD and DSC data in the specification satisfy §40(3) requirements for claim support[6].
Australia’s Pharmaceutical Patent Ecosystem
1. Trends in Patent Filings
In 2020, 92% of Australian standard patent applications were filed by non-residents, with the US (13,122 applications), China (2,358), and Japan (1,643) leading[10]. Medical technology and pharmaceuticals dominate, accounting for 3,701 applications[10]. Karyopharm’s filings align with this trend, prioritizing Australia for its strong IP enforcement and alignment with US/EU standards[10][12].
2. Policy Pressures
The 2016 Productivity Commission Report criticized Australia’s patent system for granting low-quality patents, particularly in pharmaceuticals[12]. Recommendations to raise the inventive step threshold and abolish innovation patents could heighten scrutiny of polymorph patents like AU2020203246[12].
3. Extension of Term Considerations
Selinexor’s extension of term (EoT) under §70–79 of the Patents Act is critical for maximizing market exclusivity. However, proposed reforms to limit EoT to one patent per product may complicate strategies for secondary patents covering polymorphs[12].
Commercial Implications and Market Dynamics
1. Bioequivalence Hurdles
Generics seeking to replicate Form A must demonstrate bioequivalence, which is challenging due to the polymorph’s unique dissolution profile[1][8]. Regulatory requirements under the Therapeutic Goods Act 1989 (§26B certificates) necessitate careful analysis of infringement risks[5][8].
2. Litigation Precedents
Australian courts have upheld polymorph patents where claims are narrowly defined and supported by data. In AstraZeneca v Apotex [2014], the Federal Court invalidated a patent for lack of inventive step, underscoring the need for AU2020203246 to demonstrate unexpected advantages over prior art[6][12].
3. Strategic Collaborations
Karyopharm’s partnerships with Australian research institutions (e.g., CSIRO) for preclinical testing could strengthen the patent’s enforceability by linking Form A to clinical efficacy data[11].
Conclusion
AU2020203246 represents a strategic asset in Karyopharm’s global IP portfolio, leveraging Australia’s robust patent system to protect selinexor’s crystalline polymorphs. The patent’s detailed characterization and claim structure mitigate invalidation risks, while Australia’s evolving policy landscape necessitates vigilance against systemic reforms. For generics, navigating this landscape requires a dual focus on invalidation strategies and formulation innovation to circumvent polymorph-specific claims.
Key Takeaways
- Polymorph patents like AU2020203246 are critical for extending market exclusivity.
- Australia’s lack of patent linkage increases reliance on litigation to enforce rights.
- Validity hinges on robust data demonstrating novelty and non-obviousness.
FAQs
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What distinguishes Form A of selinexor?
Form A is characterized by XRPD peaks at 4.4°, 19.0°, 21.3°, and 22.0°, with optimized stability and solubility[1].
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How does AU2020203246 fit into Karyopharm’s global strategy?
It is part of a 40+ jurisdiction family, ensuring polymorph protection in key markets[2].
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Can generics bypass this patent in Australia?
Yes, but they risk infringement if using Form A or its patented manufacturing processes[8].
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What are the main validity challenges?
Demonstrating inventiveness over prior art and sufficient disclosure of experimental data[6][12].
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How does Australia’s patent system affect pharmaceutical innovation?
Strong protections attract filings, but reforms may heighten scrutiny of secondary patents[10][12].
“Crystalline forms of selinexor, particularly Form A, exhibit superior physicochemical properties critical for therapeutic efficacy.” – AU2020203246 specification[1]
References
- https://patentimages.storage.googleapis.com/94/a1/79/10e270f89b6891/AU2020203246A1.pdf
- https://pubchem.ncbi.nlm.nih.gov/patent/KR-20170043561-A
- https://www.opticsplanet.com/v/200193-burris-6-5x-20x-50mm-fullfield2.html
- https://www.climatechangeauthority.gov.au/sites/default/files/Targets%20and%20Progress%20Review%20Final%20Report_Chapter%209.pdf
- https://www.griffithhack.com/insights/publications/whats-going-on-with-australias-proposed-patent-notification-scheme-for-generic-and-biosimilar-medicines/
- http://manuals.ipaustralia.gov.au/patent/5.6.7.3-support-for-the-claims
- https://eastasiaforum.org/2020/07/19/australias-defence-strategic-update-when-all-you-have-is-a-hammer/
- https://www.fbrice.com.au/ip-news-insights/importing-antibody-drug-conjugates-challenge-or-opportunity/
- https://auth0.com/docs/get-started/apis/scopes/sample-use-cases-scopes-and-claims
- https://www.gemaker.com.au/wp-content/uploads/2021/05/patentbreakout.pdf
- https://newdrugapprovals.org/2019/07/16/selinexor/
- https://www.pc.gov.au/inquiries/completed/intellectual-property/report
- https://blog.patentology.com.au
- https://www.youtube.com/watch?v=y113Gl-5a8s
- https://www.wipo.int/en/web/patentscope
Last updated: 2025-04-23
