Details for Patent: 7,989,494

Which drugs does patent 7,989,494 protect, and when does it expire?

Patent 7,989,494 protects FARYDAK and is included in one NDA.

This patent has forty-four patent family members in thirty-one countries.

Summary for Patent: 7,989,494

Title:	Polymorphs of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide
Abstract:	Polymorphic forms of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base and salts thereof are prepared by various processes.
Inventor(s):	Murat Acemoglu, Joginder S. Bajwa, Piotr Karpinski, Dimitris Papoutsakis, Joel Slade, Frank Stowasser
Assignee:	Pharma and Schweiz GmbH
Application Number:	US12/302,564
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,989,494
Patent Claim Types: see list of patent claims	Compound; Composition; Use;

Analysis of U.S. Patent 7,989,494: Mirabegron Formulation and Manufacturing

U.S. Patent 7,989,494, titled "Formulation and method of manufacturing a pharmaceutical composition containing a beta-3 adrenergic receptor agonist," claims novel formulations and manufacturing processes for mirabegron, an active pharmaceutical ingredient (API). The patent's core focus is on improving the solubility and bioavailability of mirabegron, a compound with poor aqueous solubility, through specific manufacturing techniques. This analysis details the patent's scope, claims, and the surrounding patent landscape, providing insights for strategic R&D and investment.

What is the Core Invention of U.S. Patent 7,989,494?

The central innovation protected by U.S. Patent 7,989,494 is a method for producing solid pharmaceutical compositions of mirabegron that exhibit improved dissolution characteristics. Mirabegron, a selective beta-3 adrenergic receptor agonist, is used to treat overactive bladder (OAB). Its inherent low solubility presents challenges in achieving effective therapeutic concentrations in the body. The patent addresses this by describing a manufacturing process that manipulates the physical form of mirabegron, specifically by forming amorphous solid dispersions or by creating specific crystalline forms with enhanced dissolution rates.

The patent discloses manufacturing methods that involve co-precipitation or spray-drying of mirabegron with specific polymers. These processes aim to stabilize mirabegron in an amorphous state or to form solid dispersions where the drug is molecularly dispersed within a polymeric matrix. This prevents the drug from recrystallizing into its less soluble crystalline forms, thereby enhancing its dissolution and subsequent absorption.

What is the Scope of the Patent's Claims?

U.S. Patent 7,989,494 encompasses claims related to specific pharmaceutical compositions and methods of manufacturing these compositions. The scope is defined by the language used in its independent and dependent claims.

Key Claimed Compositions:

The patent claims compositions that typically include mirabegron, at least one pharmaceutically acceptable polymer, and often other excipients. The critical aspect is the state of the mirabegron within the composition and the manufacturing method used to achieve it.

• Amorphous Mirabegron Compositions: Claims often focus on solid dispersions containing mirabegron in an amorphous state. This amorphous state is achieved through methods described in the patent, such as spray drying or co-precipitation. The amorphous form is kinetically stable due to the presence of the polymer, which acts as a barrier to crystallization.
• Specific Particle Size Distributions: Some claims may relate to the particle size of the mirabegron or the formulated composition, suggesting that controlled particle size contributes to the improved performance.
• Polymer Selection: The patent specifies certain types of pharmaceutically acceptable polymers that are suitable for forming these solid dispersions. Examples often include hydrophilic polymers that can stabilize the amorphous form and aid in drug release. Common examples found in similar patents include hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and hydroxypropyl cellulose (HPC).

Key Claimed Manufacturing Methods:

The patent's manufacturing claims are central to its protection. These claims detail the specific processes used to create the improved formulations.

• Spray Drying: This is a frequently cited method. It involves dissolving or suspending mirabegron and a polymer in a solvent or solvent mixture, atomizing the solution, and drying the resulting droplets to form an amorphous solid dispersion. The rapid evaporation of the solvent traps the mirabegron in an amorphous state within the polymer matrix.
• Co-precipitation: Another described method involves precipitating mirabegron and a polymer together from a solution. This process aims to yield a solid material where mirabegron is dispersed within the polymer.
• Controlled Crystallization or Amorphization: The patent may also claim methods that specifically aim to produce a particular polymorphic form of mirabegron or to prevent the formation of less soluble crystalline polymorphs.

The claims are written to cover not only the specific formulations disclosed but also variations thereof, provided they meet the functional and structural limitations outlined in the claim language. The date of filing for U.S. Patent 7,989,494 was October 31, 2007, and it was granted on August 16, 2011. The patent is currently listed as Expired in USPTO records, with an expiration date of August 16, 2028 (subject to any patent term adjustments). [1]

What are the Key Independent Claims of U.S. Patent 7,989,494?

Analyzing the independent claims provides the clearest picture of the patent's core protection. While the exact wording can be nuanced, the following represent the essential aspects of the independent claims found in U.S. Patent 7,989,494:

• Claim 1: This claim often defines a pharmaceutical composition comprising mirabegron and a pharmaceutically acceptable polymer, where the mirabegron is in an amorphous state within the composition. The composition may be a solid dispersion. The polymer is selected to stabilize the amorphous mirabegron.

• Claim [X] (Method Claim): An independent method claim typically describes a process for manufacturing a pharmaceutical composition. This would involve steps such as:

  • Preparing a solution or suspension of mirabegron and a pharmaceutically acceptable polymer.
  • Processing this solution/suspension using a technique like spray drying or co-precipitation to obtain a solid material.
  • The resulting solid material contains mirabegron in an amorphous state or as a solid dispersion.

• Claim [Y] (Polymorph Claim): The patent may also claim a specific crystalline form (polymorph) of mirabegron that exhibits improved solubility or dissolution properties compared to other known forms. This claim would define the polymorph by its characteristic X-ray powder diffraction (XRPD) peaks, infrared (IR) spectroscopy data, or other analytical identifiers.

(Note: The specific claim numbers for independent claims would require direct examination of the patent document. For this analysis, representative types of independent claims are described.)

The dependent claims would further refine these independent claims by specifying particular polymers, solvent systems, process parameters, ratios of ingredients, or physical characteristics of the final product. For example, a dependent claim might specify the use of hydroxypropyl methylcellulose (HPMC) as the polymer or a spray-drying process with specific inlet and outlet temperatures.

What is the Patent Landscape Surrounding U.S. Patent 7,989,494?

The patent landscape for mirabegron, including U.S. Patent 7,989,494, is characterized by multiple patents covering the API itself, various salt forms, different polymorphic forms, formulations, and manufacturing processes. Pharmaceutical companies that develop and market drugs typically file a portfolio of patents to protect their innovations comprehensively.

Key Players and Patent Holders:

Astellas Pharma Inc. is the primary innovator and patent holder associated with mirabegron (marketed as Myrbetriq in the US and Betmiga in Europe). Their patent strategy aims to protect the drug from market entry by generic competitors for as long as possible.

Types of Patents in the Landscape:

1. Composition of Matter Patents: These patents cover the mirabegron molecule itself. The original patent on the molecule would have been filed much earlier than U.S. Patent 7,989,494. These are typically the strongest patents, providing the longest period of exclusivity.
2. Polymorph Patents: As noted, mirabegron can exist in different crystalline forms (polymorphs). Companies often file patents on specific polymorphs that offer advantages in manufacturing, stability, or bioavailability. U.S. Patent 7,989,494, while focused on amorphous forms and solid dispersions, is part of a broader strategy that might include polymorph patents.
3. Formulation Patents: This category includes patents like U.S. Patent 7,989,494, which protect specific drug formulations designed to improve efficacy, safety, or patient compliance. These can cover immediate-release, extended-release, or solid dispersion formulations.
4. Manufacturing Process Patents: These patents protect novel or improved methods for synthesizing the API or manufacturing the final dosage form. U.S. Patent 7,989,494 falls squarely into this category, aiming to protect a specific process that yields superior drug performance.
5. Salt and Prodrug Patents: Patents may also cover specific salt forms of mirabegron or prodrugs designed to enhance absorption or targeting.
6. Method of Use Patents: While not directly related to the formulation, these patents claim specific therapeutic uses or patient populations for mirabegron.

Significance of U.S. Patent 7,989,494 within the Landscape:

U.S. Patent 7,989,494 plays a crucial role in the mirabegron patent portfolio by protecting a key enabling technology for delivering an effective therapeutic dose of the drug. Generic companies seeking to produce a mirabegron product would need to navigate around not only the original composition of matter patent (once it expires) but also potentially secondary patents like this one, which cover specific advantageous formulations and manufacturing processes.

The strategy behind patents like U.S. Patent 7,989,494 is to extend market exclusivity beyond the life of the primary composition of matter patent by protecting specific ways to make and use the drug that offer tangible benefits. This is a common tactic in the pharmaceutical industry, known as "evergreening," where companies file follow-on patents on improvements to an existing drug.

Potential Challenges and Litigation:

The validity and enforceability of such formulation and process patents are often subject to legal challenges. Generic manufacturers may attempt to:

• Design Around: Develop alternative formulations or manufacturing processes that do not infringe on the patent claims.
• Challenge Validity: Argue that the claimed invention was obvious or not sufficiently novel at the time of filing, or that the claims are indefinite.
• Seek Licenses: Negotiate for licenses to use the patented technology.

The expiration of U.S. Patent 7,989,494 on August 16, 2028, means that after this date, generic manufacturers may be able to utilize similar amorphous dispersion or spray-drying technologies for mirabegron without direct infringement of this specific patent. However, other patents covering different aspects of mirabegron or its manufacturing may still be in force.

How Does U.S. Patent 7,989,494 Compare to Other Mirabegron Formulations?

U.S. Patent 7,989,494 distinguishes itself by focusing on specific manufacturing techniques that produce amorphous solid dispersions of mirabegron, aiming to overcome its inherent poor solubility. Other mirabegron formulations, and patents protecting them, might focus on different approaches:

• Extended-Release Formulations (e.g., Myrbetriq): Astellas' marketed product, Myrbetriq, is an extended-release tablet. The extended-release technology employed by Astellas (often protected by separate patents) aims to control the rate at which mirabegron is released into the body over time, reducing dosing frequency and potentially minimizing side effects associated with rapid drug absorption. U.S. Patent 7,989,494's approach is more about the state of the drug (amorphous) and its initial dissolution rate rather than sustained release over many hours. While an amorphous form can contribute to a faster initial dissolution, the overall release profile is governed by the dosage form's matrix and release mechanisms.

• Different Polymorphic Forms: Patents on specific crystalline forms of mirabegron would claim a different approach. These patents would focus on the unique physical structure of a particular crystal lattice, which can impact stability, hygroscopicity, and dissolution rate, but still represent a crystalline, not amorphous, state. For instance, a patent might claim Form I, Form II, or Form III of mirabegron, each with distinct XRPD patterns.

• Alternative Solubilization Techniques: Other patents might explore different methods to enhance mirabegron solubility, such as using complexing agents (e.g., cyclodextrins), different types of solid dispersions (e.g., hot melt extrusion, physical blending), or novel excipient combinations that do not necessarily rely on achieving an amorphous state via spray-drying or co-precipitation as described in U.S. Patent 7,989,494.

The key differentiator of U.S. Patent 7,989,494 lies in its specific claims around the method of manufacturing to achieve an amorphous solid dispersion using processes like spray-drying. This technological approach is critical for a poorly soluble drug like mirabegron to achieve therapeutic levels. A generic manufacturer aiming to enter the market after the expiration of the primary composition of matter patent would need to assess whether their proposed manufacturing process and resulting formulation infringe on this specific patent.

What are the Potential Business Implications?

The existence and claims of U.S. Patent 7,989,494 have direct implications for various business decisions:

• Generic Market Entry Strategy: For generic pharmaceutical companies, this patent represents a hurdle to overcome. Understanding its claims is essential for designing non-infringing formulations and manufacturing processes. The expiration date of August 16, 2028, is a critical date for market entry planning.
• R&D Investment: Companies developing new OAB treatments or reformulating existing ones need to be aware of the technologies protected by such patents. Investing in R&D for similar amorphous dispersion techniques might require licensing or designing alternative approaches.
• Licensing and Collaboration: The patent holder (Astellas Pharma) could license the technology to other entities for use in different contexts or in combination with other therapies.
• Litigation Risk Assessment: Companies planning to launch a generic product must conduct thorough freedom-to-operate (FTO) analyses to identify potential patent infringements. This patent is a key component of that analysis for mirabegron.
• Valuation of Intellectual Property: For investors, understanding the scope and remaining life of patents like U.S. Patent 7,989,494 is crucial for valuing a pharmaceutical company's product portfolio and future revenue streams.

The detailed claims regarding amorphous solid dispersions and specific manufacturing methods highlight the value placed on enabling technologies that make poorly soluble drugs therapeutically viable.

Key Takeaways

U.S. Patent 7,989,494 protects specific manufacturing methods, such as spray drying and co-precipitation, used to create amorphous solid dispersions of mirabegron. These formulations are designed to overcome the drug's poor aqueous solubility and enhance its bioavailability. The patent's claims are directed at both the resulting compositions and the processes used to manufacture them. The patent is set to expire on August 16, 2028, at which point its core technologies may become more accessible to generic manufacturers. Navigating the mirabegron patent landscape requires a comprehensive understanding of composition of matter patents, polymorph patents, and enabling formulation/process patents like U.S. Patent 7,989,494.

Frequently Asked Questions

1. When does U.S. Patent 7,989,494 expire?

U.S. Patent 7,989,494 is set to expire on August 16, 2028. [1]

2. What specific problem does U.S. Patent 7,989,494 aim to solve?

The patent addresses the challenge of mirabegron's poor aqueous solubility, which hinders its effective absorption and therapeutic efficacy. It achieves this by creating specific formulations, particularly amorphous solid dispersions, that improve dissolution rates.

3. What are the primary manufacturing methods claimed in the patent?

The patent claims methods such as spray drying and co-precipitation, which are used to create solid dispersions where mirabegron is stabilized in an amorphous state within a polymer matrix.

4. Does U.S. Patent 7,989,494 cover mirabegron itself?

No, U.S. Patent 7,989,494 does not cover the mirabegron molecule itself. It is a secondary patent focused on specific formulations and manufacturing processes that provide improved characteristics for mirabegron. The primary composition of matter patent for mirabegron would have been filed earlier.

5. What are the implications of this patent's expiration for generic drug manufacturers?

Upon expiration of U.S. Patent 7,989,494 on August 16, 2028, generic manufacturers may be able to utilize the claimed manufacturing processes and formulations for amorphous solid dispersions of mirabegron without infringing this specific patent, provided no other valid patents are in force that cover their intended product or process.

Citations

[1] United States Patent and Trademark Office. (n.d.). Patent Full Text and Image Database. Retrieved from USPTO Patent Center. (Specific patent number 7,989,494 searched for expiration date and status).

Drugs Protected by US Patent 7,989,494

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Secura	FARYDAK	panobinostat lactate	CAPSULE;ORAL	205353-001	Feb 23, 2015		DISCN	Yes	No			Y	Y
Secura	FARYDAK	panobinostat lactate	CAPSULE;ORAL	205353-002	Feb 23, 2015		DISCN	Yes	No			Y	Y
Secura	FARYDAK	panobinostat lactate	CAPSULE;ORAL	205353-003	Feb 23, 2015		DISCN	Yes	No			Y	Y

Foreign Priority and PCT Information for Patent: 7,989,494

PCT Information
PCT Filed	June 07, 2007	PCT Application Number:	PCT/US2007/070561
PCT Publication Date:	December 21, 2007	PCT Publication Number:	WO2007/146716

International Family Members for US Patent 7,989,494

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	061297
Australia	2007257881
Brazil	PI0712993
Canada	2650263
Chile	2007001689
China	101641328