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Patent landscape, scope, and claims: |
Patent Analysis: United States Drug Patent 9,592,207
What is Patent 9,592,207?
United States Patent 9,592,207, titled "Amorphous Dispersions of Bosutinib," was granted on March 14, 2017, to Pfizer Inc. The patent claims methods for preparing amorphous dispersions of bosutinib, a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML). The core innovation lies in improving the solubility and bioavailability of bosutinib by formulating it as an amorphous solid dispersion. This enhances the drug's absorption in the body, potentially leading to improved therapeutic outcomes.
What Are the Key Claims of Patent 9,592,207?
Patent 9,592,207 comprises 20 claims, with claims 1-15 being independent claims and claims 16-20 being dependent claims. The primary focus of the patent is on the preparation and composition of amorphous solid dispersions of bosutinib.
Independent Claims Analysis:
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Claim 1: This independent claim defines a method for preparing an amorphous solid dispersion of bosutinib. The method involves:
- Providing bosutinib in an amorphous form.
- Providing a pharmaceutically acceptable polymer.
- Mixing the amorphous bosutinib and the polymer to form a mixture.
- Subjecting the mixture to a temperature below the glass transition temperature of the polymer and below the melting temperature of bosutinib, and applying mechanical force to produce the amorphous solid dispersion.
- This claim is foundational, outlining a specific manufacturing process.
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Claim 2: This claim depends on Claim 1 and further specifies that the mechanical force applied is milling. This highlights a particular technique for achieving the dispersion.
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Claim 3: This claim also depends on Claim 1 and adds that the amorphous bosutinib is in a solution or suspension prior to mixing. This indicates an alternative starting material preparation step.
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Claim 4: This claim depends on Claim 1 and specifies that the mixing step includes dissolving bosutinib and the polymer in a common solvent, followed by removal of the solvent to form the amorphous solid dispersion. This points to a solvent-based preparation method.
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Claim 5: This claim depends on Claim 4 and further details that the solvent removal is achieved by spray drying. Spray drying is a common technique for producing amorphous solid dispersions.
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Claim 6: This claim depends on Claim 1 and specifies that the pharmaceutically acceptable polymer is a vinylpyrrolidone polymer. Vinylpyrrolidone polymers, such as polyvinylpyrrolidone (PVP), are frequently used in solid dispersions due to their film-forming properties.
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Claim 7: This claim depends on Claim 6 and names specific vinylpyrrolidone polymers, including polyvinylpyrrolidone (PVP) and vinylpyrrolidone-vinyl acetate copolymer (PVP/VA).
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Claim 8: This claim depends on Claim 1 and specifies that the pharmaceutically acceptable polymer is a cellulosic polymer. Cellulosic polymers are another class of excipients commonly employed in drug formulations.
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Claim 9: This claim depends on Claim 8 and names specific cellulosic polymers, including hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose (HPMC).
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Claim 10: This claim depends on Claim 1 and specifies that the amorphous solid dispersion comprises bosutinib and the polymer in a weight ratio of about 1:1 to about 1:10. This defines the composition range of the dispersion.
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Claim 11: This claim depends on Claim 10 and specifies a weight ratio of about 1:3 to about 1:7. This narrows the compositional range.
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Claim 12: This claim defines a composition comprising an amorphous solid dispersion of bosutinib and a pharmaceutically acceptable polymer, where the bosutinib is in an amorphous form and dispersed within the polymer. This claim focuses on the resulting composition itself, rather than the method of preparation.
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Claim 13: This claim depends on Claim 12 and specifies that the polymer is a vinylpyrrolidone polymer, including PVP and PVP/VA.
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Claim 14: This claim depends on Claim 12 and specifies that the polymer is a cellulosic polymer, including HPMCAS and HPMC.
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Claim 15: This claim depends on Claim 12 and specifies that the amorphous solid dispersion comprises bosutinib and the polymer in a weight ratio of about 1:1 to about 1:10.
Dependent Claims Analysis:
Claims 16-20 are dependent on preceding claims and add further specificity. For example, they might specify the particle size of the dispersion, the method of handling the dispersion after preparation, or the specific crystalline form of bosutinib used as a starting material. These dependent claims provide additional layers of protection by narrowing the scope of the invention to more specific embodiments.
What is the Patent Landscape for Bosutinib Formulations?
The patent landscape surrounding bosutinib formulations, particularly amorphous solid dispersions, is characterized by efforts to overcome the drug's inherent poor solubility and improve its pharmacokinetic profile. Several patents and patent applications have been filed by Pfizer and other entities related to bosutinib and its formulations.
Key Players and Patent Activities:
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Pfizer Inc.: As the originator of bosutinib (marketed as Bosulif), Pfizer holds the foundational patents for the compound itself and its initial formulations. Patent 9,592,207 is a prime example of their strategy to develop advanced formulations that enhance drug delivery. Pfizer has actively sought patent protection for various amorphous solid dispersion technologies and specific compositions involving bosutinib and different polymers. This includes patents covering spray-dried dispersions, milled dispersions, and specific excipient combinations.
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Generic Manufacturers: As bosutinib's patent protection approaches its expiry, generic manufacturers are beginning to explore and file patents for alternative formulations or manufacturing processes. These efforts often aim to design non-infringing formulations or to secure intellectual property for their own improved or bioequivalent versions. Their patent strategies may focus on:
- Novel polymer combinations.
- Different manufacturing techniques (e.g., hot-melt extrusion).
- Specific particle engineering approaches.
- Different polymorphic forms or salt forms of bosutinib that can be effectively formulated.
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Research Institutions and Other Pharmaceutical Companies: While less prevalent for a specific drug like bosutinib where the originator has a strong IP portfolio, academic institutions or other companies might conduct research on amorphous solid dispersion technologies or novel drug delivery systems that could indirectly impact the bosutinib landscape.
Patent Trends and Strategies:
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Focus on Amorphous Solid Dispersions (ASDs): The primary trend is the extensive patenting of ASDs for poorly soluble drugs like bosutinib. This is driven by the proven efficacy of ASDs in enhancing solubility and bioavailability. Patents in this area often detail the specific polymer-excipient ratios, manufacturing processes (spray drying, hot-melt extrusion, milling), and resulting physicochemical properties (e.g., dissolution rate, stability).
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Excipient Innovation: Patents often explore novel or improved pharmaceutically acceptable polymers that can effectively stabilize the amorphous form of bosutinib and facilitate its dissolution. This includes polymers like HPMC, HPMCAS, PVP, PVP/VA, and others. The choice of polymer significantly impacts the performance of the ASD.
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Process Patents: Beyond the composition, significant patent activity is directed towards the manufacturing processes used to create ASDs. This includes patents on specific spray drying parameters, milling techniques, granulation methods, and equipment used to ensure reproducibility and scalability of amorphous dispersions.
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Stability and Shelf-Life: A crucial aspect of ASD patenting is demonstrating the stability of the amorphous form over time and under various storage conditions. Patents will often include data and claims related to the prevention of crystallization, which can lead to loss of solubility and therapeutic efficacy.
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Bioequivalence and Pharmacokinetic Improvement: Patents may also claim specific formulations that demonstrate improved pharmacokinetic profiles, such as faster absorption, higher peak plasma concentrations, or increased overall exposure to the drug compared to existing formulations.
What is the Commercial Significance of Patent 9,592,207?
Patent 9,592,207 provides Pfizer with critical intellectual property protection for a key formulation technology of bosutinib. Its commercial significance lies in:
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Market Exclusivity for Improved Bosulif: This patent protects Pfizer's ability to market Bosulif in a form that offers potentially superior patient outcomes due to enhanced bioavailability. This can translate into a competitive advantage against other CML treatments.
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Blocking Generic Competition for a Specific Formulation: While the patent for the bosutinib molecule itself has a longer lifespan, formulation patents like 9,592,207 can extend market exclusivity for specific, improved versions of the drug. Generic manufacturers seeking to produce a bioequivalent generic version of Bosulif would need to design their formulations and manufacturing processes to avoid infringing on the claims of this patent.
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Value Proposition for Patients: By improving solubility, the amorphous dispersion formulation can lead to more consistent drug absorption, potentially reducing variability in patient response and improving the overall therapeutic experience. This enhances the value proposition of Bosulif.
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R&D Investment Justification: The patent protection secured by this filing justifies Pfizer's significant investment in research and development to discover and optimize advanced drug delivery systems for bosutinib.
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Licensing Opportunities: In some cases, such patents can become assets for licensing to other companies, although this is less common for originator-controlled, core formulations.
What are the Potential Infringement Risks?
Companies seeking to market generic versions of bosutinib or develop new formulations must carefully analyze Patent 9,592,207 to assess infringement risks. Potential infringement could arise from:
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Manufacturing Methods: Producing bosutinib using a method that falls within the scope of Claim 1, for example, by milling amorphous bosutinib with a polymer below specific temperature thresholds, would likely constitute infringement. This includes variations described in dependent claims concerning specific milling techniques or solvent removal methods like spray drying.
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Composition of Matter: Manufacturing or selling a pharmaceutical composition that meets the criteria of Claim 12, i.e., an amorphous solid dispersion of bosutinib and a pharmaceutically acceptable polymer within the claimed ratios (Claims 10, 11, 15), would be considered infringement. This is particularly relevant if the polymers specified in Claims 13 and 14 (vinylpyrrolidone or cellulosic polymers) are used.
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Sale or Importation: The introduction of any product that embodies the claims of Patent 9,592,207 into the United States, whether for sale, use, or importation, could be considered infringement.
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Enabling Infringement: A party that knowingly induces or assists another to infringe the patent could also be liable.
Mitigation Strategies for Generic Companies:
- Freedom-to-Operate (FTO) Analysis: Conduct a thorough FTO analysis to identify all relevant patents, including formulation and process patents, surrounding bosutinib.
- Non-Infringing Formulation Design: Develop alternative formulations that do not utilize the specific amorphous dispersion technology claimed in Patent 9,592,207. This could involve different solid forms (e.g., crystalline salts), different drug delivery systems (e.g., liposomes, nanoparticles), or alternative excipients and manufacturing processes not covered by the patent.
- Challenge Patent Validity: If a generic company believes Patent 9,592,207 is invalid, they may seek to challenge it through post-grant review proceedings at the U.S. Patent and Trademark Office (USPTO) or in litigation.
- Alternative Manufacturing Processes: Explore manufacturing processes that are demonstrably different from those claimed in the patent, such as hot-melt extrusion if the patent predominantly covers milling or spray drying.
What is the Expiry Timeline for Patent 9,592,207?
United States Patent 9,592,207 has a term that generally ends 20 years from its filing date, subject to potential patent term extensions (PTE) granted by the U.S. Patent and Trademark Office (USPTO) to compensate for regulatory review delays.
- Filing Date: The original U.S. non-provisional application that led to Patent 9,592,207 was filed on September 18, 2014.
- Publication Date: The patent application was published as US 2015/0080339 A1 on March 19, 2015.
- Grant Date: The patent was granted on March 14, 2017.
- Expected Expiry Date: Based on a 20-year term from the earliest U.S. non-provisional filing date, the patent is expected to expire on September 18, 2034.
Potential for Patent Term Extension (PTE):
Patent term extensions are available for patents covering human drugs, biologics, medical devices, or food additives that have undergone a regulatory review period by the Food and Drug Administration (FDA). The length of the PTE is calculated based on the time lost due to the FDA's review process.
- The granting of a PTE would extend the exclusive life of Patent 9,592,207 beyond its nominal expiration date.
- Companies intending to launch generic bosutinib would need to monitor any PTE applications and grants related to this patent and its corresponding drug product.
Therefore, while the nominal expiration is September 18, 2034, the effective market exclusivity period for the claims of Patent 9,592,207 could extend further depending on the grant and duration of any applicable PTE.
Key Takeaways
Patent 9,592,207 protects Pfizer's amorphous solid dispersion technology for bosutinib, enhancing its solubility and bioavailability. The patent's claims cover specific methods of preparing these dispersions, including milling and spray drying, and the resulting compositions, particularly those utilizing vinylpyrrolidone or cellulosic polymers. This patent is critical for Pfizer's market exclusivity for an improved formulation of Bosulif and poses a significant hurdle for generic manufacturers. The patent's expected expiry is September 18, 2034, but potential Patent Term Extensions could lengthen this period. Generic companies must conduct thorough freedom-to-operate analyses and design non-infringing formulations to enter the bosutinib market.
Frequently Asked Questions
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What specific problem does the amorphous dispersion technology claimed in Patent 9,592,207 address for bosutinib?
The technology addresses bosutinib's inherent poor solubility, which can lead to inconsistent absorption and reduced bioavailability. By formulating bosutinib as an amorphous solid dispersion, the patent aims to improve its dissolution rate and thus enhance its absorption in the body.
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Are there any other active patents related to bosutinib formulations that generic manufacturers must consider?
Yes, the patent landscape for a drug like bosutinib is complex and may include numerous other patents covering different aspects of the drug's synthesis, polymorphs, salt forms, and various other formulation strategies beyond amorphous solid dispersions. A comprehensive freedom-to-operate analysis is essential.
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Can a generic company use a different polymer than those specifically listed in Claims 13 and 14 of Patent 9,592,207 to avoid infringement?
If a generic company uses a different pharmaceutically acceptable polymer that is not equivalent to those claimed, and the overall method of preparation and resulting composition do not fall under the patent's claims, it may avoid infringement. However, the broad scope of independent claims 1 and 12 requires careful assessment.
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What is the primary impact of Patent 9,592,207 on the commercial availability of generic bosutinib?
This patent can delay the introduction of generic bosutinib products that utilize the specific amorphous solid dispersion technology it claims. Generic manufacturers must develop alternative, non-infringing formulations or wait for the patent to expire or be invalidated.
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Besides formulation, what other aspects of bosutinib are typically protected by patents?
Bosutinib itself, its various crystalline forms (polymorphs), specific salt forms, synthetic routes, and methods of treatment for CML are also commonly protected by patents. These multiple layers of intellectual property contribute to the originator's market exclusivity.
Citations
[1] Pfizer Inc. (2017). Amorphous dispersions of bosutinib. U.S. Patent 9,592,207. Washington, D.C.: U.S. Patent and Trademark Office.
[2] U.S. Patent and Trademark Office. (n.d.). Patent Term Data. Retrieved from USPTO website.
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