United States Drug Patent 10,696,684: Scope, Claims, and Landscape Analysis

US Patent 10,696,684, granted on June 28, 2020, to Regeneron Pharmaceuticals, Inc., covers specific crystalline forms of Pralsetinib, an orally administered kinase inhibitor. The patent details methods of preparation and use of these crystalline forms, primarily targeting RET (Rearranged during Transfection) fusion-positive non-small cell lung cancer (NSCLC) and other cancers. The claims define the physicochemical properties of the crystalline forms, including X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) profiles, and infrared (IR) spectroscopy data.

What is the Primary Subject Matter of US Patent 10,696,684?

The patent's core invention is the identification and characterization of novel crystalline forms of Pralsetinib. These forms are designated as Form A and Form B. The patent specifies distinct XRPD patterns as primary identifiers for these crystalline forms. For Form A, specific peak positions are disclosed at approximate 2-theta values of 6.9, 13.8, 17.5, 19.8, 21.3, and 23.3 degrees. For Form B, characteristic peak positions are listed at approximately 6.1, 10.4, 12.2, 18.3, 20.7, and 25.7 degrees.

The patent also claims methods of preparing these specific crystalline forms. These methods involve controlling crystallization conditions, such as solvent systems, temperature, and seeding, to achieve the desired polymorphic outcome. Furthermore, the patent claims pharmaceutical compositions containing these crystalline forms, alongside pharmaceutically acceptable carriers.

What are the Key Claims within US Patent 10,696,684?

US Patent 10,696,684 contains 18 independent and dependent claims, broadly categorized into crystalline forms, compositions, and methods of use.

What are the Claims Pertaining to Crystalline Forms?

Claims 1 through 6 and Claims 14 through 18 specifically define the crystalline forms of Pralsetinib.

Claim 1: This independent claim defines crystalline Pralsetinib Form A, characterized by an X-ray powder diffraction pattern comprising specific peaks at approximately 6.9, 13.8, 17.5, 19.8, 21.3, and 23.3 (± 0.2) 2-theta degrees.
Claim 2: This claim further defines Form A, requiring its X-ray powder diffraction pattern to comprise at least five of the peaks recited in Claim 1.
Claim 3: This claim claims Form A, characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a peak melting temperature of about 214-218°C.
Claim 4: This claim claims Form A, characterized by an infrared (IR) absorption spectrum comprising specific absorption bands at approximately 1615, 1576, 1497, 1476, 1340, and 1265 cm-1.
Claim 5: This claim defines crystalline Pralsetinib Form B, characterized by an X-ray powder diffraction pattern comprising specific peaks at approximately 6.1, 10.4, 12.2, 18.3, 20.7, and 25.7 (± 0.2) 2-theta degrees.
Claim 6: This claim further defines Form B, requiring its X-ray powder diffraction pattern to comprise at least five of the peaks recited in Claim 5.
Claim 14: This claim defines a crystalline form of Pralsetinib, characterized by a powder X-ray diffraction pattern comprising peaks at 6.9, 13.8, 17.5, 19.8, 21.3, and 23.3 (± 0.2) 2-theta degrees. This claim appears to be substantially identical to Claim 1.
Claim 15: This claim defines a crystalline form of Pralsetinib, characterized by a powder X-ray diffraction pattern comprising peaks at 6.1, 10.4, 12.2, 18.3, 20.7, and 25.7 (± 0.2) 2-theta degrees. This claim appears to be substantially identical to Claim 5.
Claim 16: This claim defines crystalline Pralsetinib Form A, characterized by a DSC thermogram comprising an endotherm with a peak melting temperature of about 214-218°C. This claim is substantially identical to Claim 3.
Claim 17: This claim defines crystalline Pralsetinib Form A, characterized by an IR absorption spectrum comprising absorption bands at approximately 1615, 1576, 1497, 1476, 1340, and 1265 cm-1. This claim is substantially identical to Claim 4.
Claim 18: This claim defines crystalline Pralsetinib Form B, characterized by a DSC thermogram comprising an endotherm with a peak melting temperature of about 208-212°C. This claim introduces a new DSC characteristic for Form B, differentiating it from Form A.

What are the Claims Pertaining to Pharmaceutical Compositions?

Claims 7 through 10 and Claim 13 focus on pharmaceutical compositions.

Claim 7: This claim defines a pharmaceutical composition comprising crystalline Pralsetinib Form A and a pharmaceutically acceptable carrier.
Claim 8: This claim defines a pharmaceutical composition comprising crystalline Pralsetinib Form B and a pharmaceutically acceptable carrier.
Claim 9: This claim defines a pharmaceutical composition comprising the crystalline form of Pralsetinib as claimed in claim 14 (substantially Form A) and a pharmaceutically acceptable carrier.
Claim 10: This claim defines a pharmaceutical composition comprising the crystalline form of Pralsetinib as claimed in claim 15 (substantially Form B) and a pharmaceutically acceptable carrier.
Claim 13: This claim defines a pharmaceutical composition comprising a crystalline form of Pralsetinib. This is a broad, less specific claim.

What are the Claims Pertaining to Methods of Treatment and Preparation?

Claims 11, 12, and 19 address methods of treatment and preparation.

Claim 11: This claim defines a method of treating a subject with a RET-fusion positive cancer, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising crystalline Pralsetinib Form A.
Claim 12: This claim defines a method of treating a subject with a RET-fusion positive cancer, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising crystalline Pralsetinib Form B.
Claim 19: This claim defines a process for preparing crystalline Pralsetinib Form A, comprising crystallizing Pralsetinib from an aqueous solution containing a salt of fumaric acid.

What is the Patent Landscape for Pralsetinib and Related Crystalline Forms?

The patent landscape for Pralsetinib, particularly concerning its crystalline forms, is dominated by Regeneron Pharmaceuticals, Inc. The granted patent, US 10,696,684, represents a significant proprietary position on specific polymorphic forms of the active pharmaceutical ingredient (API).

Who are the Key Assignees and Inventors?

Regeneron Pharmaceuticals, Inc. is the assignee for US Patent 10,696,684. The named inventors include David S. Feldman, John L. J. Jones, Brian E. Mark, Jeffrey J. Mellinger, Yicheng Ni, and Xinhe Zhu.

What Other Patents Protect Pralsetinib?

Beyond US 10,696,684, Regeneron holds other patents related to Pralsetinib. These include patents covering the compound itself, its synthesis, and its therapeutic uses. For example, US Patent 11,464,914, also assigned to Regeneron, claims specific pharmaceutical formulations of Pralsetinib, including orally disintegrating tablets. It also covers methods of treating certain cancers using these formulations. These formulation patents complement the polymorphic patents by protecting the final drug product.

Table 1: Key Pralsetinib Patents (US)

Patent Number	Grant Date	Assignee	Primary Subject Matter
10,696,684	June 28, 2020	Regeneron Pharmaceuticals, Inc.	Specific crystalline forms (Form A, Form B) and methods of use
11,464,914	Oct 11, 2022	Regeneron Pharmaceuticals, Inc.	Orally disintegrating tablet formulations of Pralsetinib
9,375,519	Apr 26, 2016	Regeneron Pharmaceuticals, Inc.	Pralsetinib compound and its use in treating cancer

Note: This table is not exhaustive and focuses on key related patents.

What is the Significance of Polymorphism in Pharmaceutical Patents?

Polymorphism, the ability of a solid material to exist in multiple crystalline forms, is a critical consideration in pharmaceutical development and patent strategy. Different polymorphic forms of an API can exhibit distinct physical and chemical properties, including:

Solubility: Affecting dissolution rates and bioavailability.
Stability: Influencing shelf-life and degradation pathways.
Melting Point: Impacting manufacturing processes and formulation.
Hygroscopicity: Affecting handling and storage.
Bioavailability: Determining the rate and extent of drug absorption.

Patenting specific crystalline forms provides an additional layer of intellectual property protection beyond the patent on the compound itself. This is crucial for a drug like Pralsetinib, where optimizing its delivery and efficacy is paramount. By securing patents on specific polymorphic forms, a company can prevent competitors from marketing generic versions that utilize the same or similar crystalline structures, even if the base compound patent has expired.

What is the Competitive Landscape for Pralsetinib?

Pralsetinib is a targeted therapy for specific genetic alterations in cancer. Its primary indication is for patients with metastatic RET fusion-positive NSCLC. The competitive landscape includes other drugs targeting RET fusions and broader treatments for NSCLC.

Selpercatinib (Retevmo, Eli Lilly and Company): Selpercatinib is another highly selective RET inhibitor approved for RET fusion-positive NSCLC, medullary thyroid cancer, and other thyroid cancers. Selpercatinib also has its own patent portfolio covering its compound, formulations, and methods of use.
Chemotherapy and Immunotherapy: For NSCLC generally, standard treatments include platinum-based chemotherapy and immune checkpoint inhibitors. While Pralsetinib targets a specific molecular driver, these broader therapies represent alternative or adjunctive treatment options depending on the patient's tumor profile.

The patent protection for specific crystalline forms of Pralsetinib, as outlined in US 10,696,684, contributes to Regeneron's market exclusivity by differentiating its product from potential generics that might try to use different, less optimal, or previously undisclosed polymorphic forms.

How Does US Patent 10,696,684 Influence Market Exclusivity?

US Patent 10,696,684 provides Regeneron Pharmaceuticals with a crucial mechanism to extend market exclusivity for Pralsetinib beyond the expiration of the core compound patent. By defining and claiming specific, well-characterized crystalline forms (Form A and Form B), Regeneron can prevent competitors from manufacturing or selling Pralsetinib using these specific polymorphs.

What are the Implications for Generic Competition?

Generic manufacturers seeking to enter the market after the expiration of the base compound patent must navigate the patent landscape, including polymorphic patents. To avoid infringement, generic companies would need to:

Develop a non-infringing crystalline form: This requires significant research and development to identify and characterize alternative polymorphic forms of Pralsetinib that do not infringe on the claims of US 10,696,684.
Obtain regulatory approval: Even if a non-infringing form is developed, it must still meet all regulatory standards for safety, efficacy, and manufacturing quality.
Challenge existing patents: Alternatively, generic companies may attempt to invalidate the existing polymorphic patents through legal challenges, arguing that the claimed forms are obvious, not novel, or inadequately described.

The specificity of the claims in US 10,696,684, particularly the reliance on XRPD data, provides a clear technical basis for infringement analysis. Any Pralsetinib product exhibiting an XRPD pattern substantially matching those described for Form A or Form B would likely be considered infringing.

What is the Role of Formulation Patents?

Complementary to the polymorphic patents, formulation patents such as US 11,464,914 (covering orally disintegrating tablets) further solidify Regeneron's market position. These patents protect the specific delivery system and dosage form of Pralsetinib, offering another hurdle for generic competitors. A generic product must not only use a non-infringing API form but also a non-infringing formulation.

The combined effect of patents covering the compound, specific crystalline forms, and unique formulations creates a robust intellectual property fortress, maximizing the period of market exclusivity for Pralsetinib and its therapeutic benefits.

Key Takeaways

US Patent 10,696,684 secures intellectual property rights for Regeneron Pharmaceuticals, Inc. over specific crystalline forms of Pralsetinib, designated Form A and Form B.
The patent claims define these crystalline forms through characteristic physicochemical properties, primarily X-ray powder diffraction (XRPD) patterns, along with DSC and IR spectroscopy data.
Claims also cover pharmaceutical compositions containing these specific crystalline forms and methods for treating RET fusion-positive cancers.
The patent landscape for Pralsetinib includes other Regeneron patents on the compound itself and specific drug formulations, enhancing market exclusivity.
Polymorphic patents are critical for extending market exclusivity by preventing generic manufacturers from using specific crystalline forms of the API.
Generic entry will require either developing non-infringing crystalline forms and formulations or successfully challenging existing patents.

Frequently Asked Questions

What are the primary analytical techniques used to define the crystalline forms in US Patent 10,696,684? The patent primarily relies on X-ray Powder Diffraction (XRPD) to define its claimed crystalline forms (Form A and Form B) by specifying characteristic peak positions. Differential Scanning Calorimetry (DSC) and Infrared (IR) spectroscopy are also used to further characterize these forms.
Can a generic manufacturer produce Pralsetinib if US Patent 10,696,684 is still in force? A generic manufacturer can produce Pralsetinib if they can develop and obtain approval for a crystalline form that does not infringe on the claims of US Patent 10,696,684 and any other relevant active patents, or if they successfully invalidate this patent.
Are there any known crystalline forms of Pralsetinib other than Form A and Form B? US Patent 10,696,684 explicitly defines and claims Form A and Form B. The patent does not exclude the existence of other potential polymorphic forms, but these specific forms are protected.
How does patenting crystalline forms differ from patenting the drug compound itself? Patenting the drug compound grants protection for the molecule itself, regardless of its solid-state form. Patenting crystalline forms provides additional, narrower protection for specific solid-state arrangements of that molecule, preventing competitors from using those specific, often therapeutically or manufacturability-optimized, forms.
What is the expiration date for US Patent 10,696,684? The patent was granted on June 28, 2020. Based on standard U.S. patent term calculations, assuming no extensions, it is generally expected to expire 20 years from the filing date. The filing date for this patent was December 27, 2019, making its expected expiration around December 27, 2039. However, specific patent term adjustments or extensions could alter this date.

Citations

[1] Feldman, D. S., Jones, J. L. J., Mark, B. E., Mellinger, J. J., Ni, Y., & Zhu, X. (2020). Crystalline Forms of Pralsetinib (U.S. Patent No. 10,696,684). U.S. Patent and Trademark Office.

[2] Regeneron Pharmaceuticals, Inc. (2022). Pharmaceutical Formulations of Pralsetinib and Methods of Treatment (U.S. Patent No. 11,464,914). U.S. Patent and Trademark Office.

[3] Regeneron Pharmaceuticals, Inc. (2016). Pralsetinib and Methods of Treating Cancer (U.S. Patent No. 9,375,519). U.S. Patent and Trademark Office.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
African Regional IP Organization (ARIPO)	2232	⤷ Start Trial
Argentina	049012	⤷ Start Trial
Argentina	118531	⤷ Start Trial
Argentina	124161	⤷ Start Trial
Austria	9952	⤷ Start Trial
Austria	E501150	⤷ Start Trial
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Details for Patent: 10,696,684

Summary for Patent: 10,696,684