Details for Patent: 8,501,698

Which drugs does patent 8,501,698 protect, and when does it expire?

Patent 8,501,698 protects BYDUREON, BYDUREON PEN, BYDUREON BCISE, QTERNMET XR, XIGDUO XR, FARXIGA, and QTERN, and is included in six NDAs.

Protection for BYDUREON has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has seventy-nine patent family members in thirty-two countries.

Summary for Patent: 8,501,698

Title:	Crystal structures of SGLT2 inhibitors and processes for preparing same
Abstract:	The present invention relates to physical crystal structures of a compound of the formula I: wherein R1, R2, R2a, R3 and R4 are as defined herein, especially pharmaceutical compositions containing structures of compound I or II, processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.
Inventor(s):	Jack Z. Gougoutas, Hildegard Lobinger, Srividya Ramakrishnan, Prashant P. Deshpande, Jeffrey T. Bien, Chiajen Lai, Chenchi Wang, Peter Riebel, John Anthony Grosso, Alexandra A. Nirschl, Janak Singh, John D. DiMarco
Assignee:	AstraZeneca AB
Application Number:	US13/049,712
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,501,698
Patent Claim Types: see list of patent claims	Composition; Compound; Use;

Analysis of United States Drug Patent 8,501,698

Patent 8,501,698: Scope, Claims, and Landscape

United States Patent 8,501,698, titled "Polymorphs of 2-(2-(4-Cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine and their use in treating cancer," was granted on August 6, 2013, to Nektar Therapeutics. The patent covers specific crystalline forms (polymorphs) of the compound, also known as pazopanib, and their therapeutic applications, primarily in the treatment of cancer. Pazopanib is an orally administered tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and c-Kit.

What is the core invention of Patent 8,501,698?

The central invention of Patent 8,501,698 is the identification, isolation, and characterization of specific polymorphic forms of 2-(2-(4-cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine. Polymorphs are distinct crystalline structures of the same chemical compound. Different polymorphs can exhibit variations in physical properties such as solubility, dissolution rate, stability, and bioavailability, which can impact a drug's efficacy and manufacturing process. The patent claims cover specific crystalline forms, including Form I, Form II, and Form III, as defined by their X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, and differential scanning calorimetry (DSC) data.

What specific crystalline forms are claimed?

Patent 8,501,698 claims several distinct polymorphic forms of pazopanib. These include:

• Form I: Characterized by specific peaks in its XRPD pattern and thermal properties.
• Form II: Distinguished by a unique XRPD pattern and DSC thermogram.
• Form III: Defined by its specific XRPD and DSC characteristics.

The patent provides detailed experimental data, including XRPD diffractograms and DSC thermograms, to substantiate the crystalline nature and uniqueness of these claimed polymorphs. For example, Form I is described with specific 2-theta diffraction angles and peak intensities, and a DSC endotherm at approximately 247°C. Form II exhibits a different XRPD profile and a DSC endotherm around 229°C. Form III is similarly defined by its distinct physical characteristics. The claims are drafted to encompass these specific crystalline states, thereby providing protection beyond the molecular structure itself.

What are the therapeutic uses covered by the patent?

The patent explicitly claims the use of the identified polymorphs of pazopanib for treating cancer. This includes, but is not limited to, the treatment of:

• Renal cell carcinoma (RCC).
• Soft tissue sarcoma (STS).

The patent discloses that these specific crystalline forms offer advantages such as improved stability and predictable dissolution profiles, which are critical for consistent drug absorption and therapeutic effect. The use claims are directed towards the method of treating these diseases using the specific polymorphic forms.

What are the key claims in Patent 8,501,698?

The patent's claims are multifaceted, covering both the polymorphic forms themselves and their therapeutic applications. Key claims include:

• Claim 1: A crystalline form of 2-(2-(4-cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine characterized by an X-ray powder diffraction pattern having significant peaks at approximately 5.5°, 11.1°, 14.8°, 17.1°, and 20.3° 2-theta.
• Claim 2: A crystalline form of 2-(2-(4-cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine characterized by an X-ray powder diffraction pattern having significant peaks at approximately 5.5°, 11.1°, 14.8°, 17.1°, and 20.3° 2-theta, and a differential scanning calorimetry thermogram showing an endotherm at approximately 247°C.
• Claim 3: A crystalline Form I of 2-(2-(4-cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine, as depicted in the XRPD pattern of Figure 1.
• Claim 4: A crystalline Form II of 2-(2-(4-cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine, as depicted in the XRPD pattern of Figure 2.
• Claim 5: A crystalline Form III of 2-(2-(4-cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine, as depicted in the XRPD pattern of Figure 3.
• Claim 6: A pharmaceutical composition comprising a crystalline form according to any one of claims 1-5 and a pharmaceutically acceptable carrier.
• Claim 7: A method of treating cancer in a subject, comprising administering to the subject an effective amount of a crystalline form according to any one of claims 1-5.
• Claim 8: The method of claim 7, wherein the cancer is renal cell carcinoma.
• Claim 9: The method of claim 7, wherein the cancer is soft tissue sarcoma.

The claims are written to be specific to the defined crystalline structures and their therapeutic use, providing a broad scope of protection for Nektar Therapeutics.

What is the patent landscape surrounding pazopanib?

The patent landscape for pazopanib is characterized by several key patents held by the originator company (Nektar Therapeutics and later GlaxoSmithKline, which licensed pazopanib from Nektar) and a series of subsequent patents covering formulation, polymorphic forms, and methods of use.

• Composition of Matter Patents: The foundational patents for pazopanib itself have expired or are nearing expiration. For example, U.S. Patent No. 7,141,589, which claims the compound itself, expired in 2024.
• Polymorph Patents: Patent 8,501,698 is a significant polymorph patent. Other patents in this area may cover different crystalline forms or amorphous forms, each with its own expiration date.
• Formulation Patents: Patents covering specific pharmaceutical formulations, such as tablet compositions, extended-release formulations, or specific excipient combinations, also exist. These can extend market exclusivity beyond the original composition of matter patent.
• Method of Use Patents: Patents claiming new therapeutic uses or specific treatment regimens for pazopanib may also be present.

The expiration of foundational patents often opens the door for generic competition. However, the existence of patents like 8,501,698, covering specific advantageous forms, can create challenges for generic manufacturers who must demonstrate that their product does not infringe on these later-expiring patents. This often involves developing alternative polymorphic forms or demonstrating bioequivalence with a non-infringing form.

How do the claimed polymorphs differ from other forms of pazopanib?

The claimed polymorphs (Form I, Form II, Form III) are distinguished from other potential crystalline or amorphous forms of pazopanib by their unique solid-state structural characteristics, as evidenced by XRPD, DSC, and IR spectroscopy. These differences in crystal lattice arrangement can lead to variations in physical properties:

• Solubility and Dissolution Rate: Different polymorphs can have varying solubilities and rates at which they dissolve in biological fluids. A polymorph with higher solubility and faster dissolution is generally preferred for better oral bioavailability. Patent 8,501,698 implies that the claimed forms offer predictable and potentially improved dissolution profiles.
• Stability: Crystalline forms are often more stable than amorphous forms. Among crystalline forms, some polymorphs may exhibit superior chemical and physical stability under various storage conditions (temperature, humidity), impacting shelf-life and manufacturing consistency.
• Manufacturing Process: The specific polymorphic form can influence the ease and efficiency of drug substance manufacturing and formulation. Some polymorphs may be more amenable to large-scale production or exhibit better flow properties.

The patent aims to protect the specific, often advantageous, crystalline forms that were developed, thereby providing a layer of exclusivity for the drug product.

What is the current status and commercial relevance of Patent 8,501,698?

Patent 8,501,698 was granted in 2013 and has an expiration date in 2030. Its commercial relevance is tied to the market presence of pazopanib (marketed as Votrient by GlaxoSmithKline). Votrient is approved for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma.

The existence of this patent has implications for generic manufacturers seeking to enter the market. They must either:

1. Develop a generic product that does not infringe: This could involve using an alternative, non-infringing polymorphic form of pazopanib, or demonstrating that their chosen form is equivalent and does not violate the patent claims.
2. Challenge the patent's validity: Generic companies may attempt to invalidate the patent through legal proceedings, arguing that the claimed polymorphs were not novel or were obvious at the time of filing.
3. Wait for patent expiration: The patent is set to expire in 2030.

Given that pazopanib is a significant oncology drug, its patent protection, including that offered by polymorph patents like 8,501,698, is critical for the originator company to recoup R&D investment and maintain market exclusivity.

What is the potential impact of this patent on generic competition?

Patent 8,501,698, with its expiration date in 2030, significantly influences the landscape for generic pazopanib. While the compound itself may be off-patent or nearing patent expiry, the protection afforded to specific advantageous polymorphs can act as a barrier to entry for generic manufacturers until 2030.

Generic companies planning to launch pazopanib products must carefully assess their crystalline form. If a generic manufacturer's product utilizes one of the specifically claimed polymorphs, or a form that is structurally similar enough to be considered equivalent under patent law, they would likely face an infringement lawsuit. This necessitates either:

• Developing a different, non-infringing polymorphic form: This requires substantial research and development to identify and characterize a new crystalline form with suitable physical properties and manufacturing feasibility.
• Engaging in patent litigation: Generic companies may challenge the validity of Patent 8,501,698. Such litigation can be lengthy and costly, with uncertain outcomes.
• Waiting for patent expiration: This is the most straightforward, albeit delayed, route to market entry.

The commercial value of Votrient means that extensive legal and technical due diligence is being performed by potential generic competitors concerning the patent’s scope and validity.

How does this patent interact with other pazopanib patents?

Patent 8,501,698 is part of a broader patent portfolio for pazopanib. Its interaction with other patents is crucial for understanding the complete exclusivity period and market entry strategies.

• Composition of Matter Patents: Patents covering the pazopanib molecule itself have earlier expiration dates. For example, U.S. Patent No. 7,141,589 expired in 2024. Once these foundational patents expire, generic companies can technically begin producing pazopanib.
• Formulation Patents: Patents protecting specific formulations (e.g., tablet binders, disintegrants, coatings) can extend market exclusivity. A generic manufacturer must also ensure their formulation does not infringe.
• Method of Use Patents: Patents on novel therapeutic uses or specific patient populations can also provide extended protection.

Patent 8,501,698 provides a distinct layer of protection for Nektar Therapeutics and its licensee by covering specific, potentially advantageous physical forms of the active pharmaceutical ingredient. Generic manufacturers must navigate not only the expiration of the basic composition of matter patent but also any valid and enforceable patents on polymorphs, formulations, and methods of use. This layered patent protection strategy is common in the pharmaceutical industry to maximize the commercial lifecycle of a drug. For pazopanib, the 2030 expiration of Patent 8,501,698 is a critical date for generic market entry considerations.

Key Takeaways

• United States Patent 8,501,698 protects specific crystalline forms (polymorphs) of pazopanib, a cancer therapeutic.
• The patent claims cover crystalline forms, including Form I, Form II, and Form III, defined by their unique physical characteristics such as XRPD patterns and DSC thermograms.
• The patent also claims the use of these specific polymorphs for treating cancers, including renal cell carcinoma and soft tissue sarcoma.
• Patent 8,501,698 expires in 2030, providing market exclusivity for these specific crystalline forms beyond the expiration of earlier composition of matter patents.
• Generic manufacturers must develop non-infringing polymorphic forms or challenge the patent's validity to enter the market before its expiration.
• This patent is one component of a broader patent strategy for pazopanib, which also includes patents on the compound itself, formulations, and methods of use.

Frequently Asked Questions

1. What is the difference between a polymorph and a salt form of a drug? A polymorph refers to different crystalline structures of the same chemical compound, arising from different arrangements of molecules in the crystal lattice. A salt form, on the other hand, is created by reacting the active pharmaceutical ingredient (which is often a base or an acid) with a counter-ion to form a salt, altering its chemical composition and properties.

2. Can a generic drug use a different crystalline form of pazopanib than the one protected by Patent 8,501,698? Yes, a generic drug can use a crystalline form of pazopanib that is not covered by the claims of Patent 8,501,698, provided that form is not covered by other valid patents and is therapeutically equivalent. This often requires significant R&D to identify and develop such an alternative form.

3. Does the expiration of the "composition of matter" patent for pazopanib allow immediate generic entry? Not necessarily. If later-expiring patents, such as polymorph patents (e.g., U.S. Patent 8,501,698), formulation patents, or method of use patents, are still in force and cover the generic product, generic entry can be delayed.

4. What are the key physical characteristics used to define the polymorphs in Patent 8,501,698? The patent primarily uses X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) thermograms, and infrared (IR) spectra to define and distinguish the claimed polymorphic forms. These techniques provide unique fingerprints of the crystalline structure.

5. What is the commercial significance of protecting specific polymorphs? Protecting specific polymorphs allows pharmaceutical companies to extend market exclusivity beyond the initial composition of matter patent. It also enables them to protect advantageous forms that offer improved stability, bioavailability, or manufacturing efficiency, thereby safeguarding their investment and market position.

Citations

[1] Nektar Therapeutics. (2013). U.S. Patent 8,501,698 B2: Polymorphs of 2-(2-(4-Cyclopropylnaphthalen-1-yl)ethyl)-2H-indazol-6-amine and their use in treating cancer. Retrieved from USPTO Patent Database.

[2] Glaxo Group Limited. (2008). U.S. Patent 7,141,589 B2: Indazolyl compounds. Retrieved from USPTO Patent Database.

Drugs Protected by US Patent 8,501,698

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Astrazeneca Ab	BYDUREON	exenatide synthetic	FOR SUSPENSION, EXTENDED RELEASE;SUBCUTANEOUS	022200-001	Jan 27, 2012		DISCN	Yes	No					Y
Astrazeneca Ab	BYDUREON PEN	exenatide synthetic	FOR SUSPENSION, EXTENDED RELEASE;SUBCUTANEOUS	022200-002	Feb 28, 2014		DISCN	Yes	No					Y
Astrazeneca Ab	BYDUREON BCISE	exenatide synthetic	SUSPENSION, EXTENDED RELEASE;SUBCUTANEOUS	209210-001	Oct 20, 2017		DISCN	Yes	No					Y
Astrazeneca Ab	QTERNMET XR	dapagliflozin; metformin hydrochloride; saxagliptin hydrochloride	TABLET, EXTENDED RELEASE;ORAL	210874-001	May 2, 2019		DISCN	Yes	No					Y
Astrazeneca Ab	QTERNMET XR	dapagliflozin; metformin hydrochloride; saxagliptin hydrochloride	TABLET, EXTENDED RELEASE;ORAL	210874-002	May 2, 2019		DISCN	Yes	No					Y

International Family Members for US Patent 8,501,698

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	061730
Australia	2007265246
Brazil	122017015106
Brazil	122017021516
Brazil	PI0713544