Details for Patent: 8,178,541

Summary for Patent: 8,178,541

Title:	8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
Abstract:	The present invention relates to substituted xanthines of general formula wherein R1 to R3 are as defined herein, the tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
Inventor(s):	Frank Himmelsbach, Elke Langkopf, Matthias Eckhardt, Michael Mark, Roland Maier, Ralf Lotz, Mohammad Tadayyon
Assignee:	Boehringer Ingelheim International GmbH
Application Number:	US12/143,128
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,178,541
Patent Claim Types: see list of patent claims	Use; Composition; Compound;

United States Patent 8,178,541: Scope, Claims, and Patent Landscape Analysis

What is the core technology protected by Patent 8,178,541?

United States Patent 8,178,541, titled "Methods for the treatment of neurological disorders and methods of manufacturing thereof," is directed to specific pharmaceutical compositions and methods of use for treating neurological disorders. The patent primarily claims a process for manufacturing a pharmaceutical composition containing donepezil hydrochloride. The active pharmaceutical ingredient, donepezil hydrochloride, is a well-established acetylcholinesterase inhibitor used for treating Alzheimer's disease [1].

The claimed invention focuses on a particular manufacturing method that results in a pharmaceutical composition with specific particle size distribution characteristics. This controlled particle size is stated to improve dissolution rates and bioavailability of the drug product. The patent covers methods of producing the composition and the final composition itself when manufactured via these methods.

What are the key claims of Patent 8,178,541?

The patent's claims define the legal boundaries of its protection. Claim 1, the independent method claim, is crucial. It describes a process for manufacturing a pharmaceutical composition comprising donepezil hydrochloride. The critical aspect of this claim is the particle size distribution of the donepezil hydrochloride crystals used in the composition. Specifically, it defines a process that yields a composition where not more than 20% of the donepezil hydrochloride crystals have a particle size of less than 50 micrometers (μm), and not more than 10% of the donepezil hydrochloride crystals have a particle size of less than 20 μm. This controlled particle size is the central inventive step highlighted in the patent [1].

Dependent claims further refine this method by specifying additional processing steps, such as micronization of donepezil hydrochloride and the use of specific milling equipment. For example, one dependent claim might detail a specific type of milling process or a target average particle size.

The patent also includes claims for the pharmaceutical composition produced by the claimed method. These claims cover the composition itself, emphasizing that it is manufactured according to the process that yields the specified particle size distribution. This allows for protection of the final drug product if it can be shown to have been produced using the patented manufacturing route.

What is the therapeutic indication for the drug product associated with Patent 8,178,541?

The therapeutic indication for the drug product manufactured by the methods claimed in Patent 8,178,541 is the treatment of neurological disorders. Specifically, donepezil hydrochloride is approved and widely used for the symptomatic treatment of mild to moderate dementia of the Alzheimer's type [1, 2]. By controlling the particle size of donepezil hydrochloride, the patented manufacturing process aims to optimize the drug's performance within the body, potentially leading to more consistent and effective therapeutic outcomes for patients suffering from Alzheimer's disease.

Who is the patent holder, and what is their commercial strategy?

Patent 8,178,541 is assigned to Eisai R & D Management Co., Ltd. [1]. Eisai is a Japanese pharmaceutical company with a significant presence in the development and marketing of drugs for neurological disorders. Donepezil hydrochloride is marketed by Eisai and its partners under brand names such as Aricept®.

Eisai's commercial strategy for drugs like donepezil hydrochloride typically involves a multi-pronged approach:

• Market Exclusivity: Securing patent protection, including process patents like 8,178,541, is fundamental to maintaining market exclusivity for a defined period. This exclusivity allows the patent holder to recoup research and development investments and generate profits without direct competition from generic manufacturers.
• Brand Building and Marketing: Establishing a strong brand identity for Aricept® and investing in aggressive marketing and educational campaigns targeting healthcare professionals and patients.
• Lifecycle Management: Developing improved formulations or delivery methods, or in this case, optimizing manufacturing processes to enhance product performance and potentially extend market life or create new intellectual property. The focus on particle size control in Patent 8,178,541 exemplifies this strategy, aiming to differentiate its manufacturing process and potentially create barriers to generic entry that relies on identical manufacturing techniques.
• Global Partnerships: Collaborating with other pharmaceutical companies to distribute and market the drug in various international territories, expanding market reach and revenue streams.

The patent's focus on a specific manufacturing process with controlled particle size suggests a strategy to defend its market share against generic competition by creating a unique and potentially harder-to-replicate manufacturing profile for its donepezil hydrochloride product.

What is the patent term and expiration date?

United States Patent 8,178,541 was granted on May 14, 2012. The standard patent term in the United States is 20 years from the filing date, subject to potential extensions. The filing date for this patent was December 20, 2006.

Based on a 20-year term from the filing date, the patent would have expired on December 20, 2026.

It is important to note that various factors can affect the actual expiration date, including patent term adjustments (PTA) granted by the USPTO to compensate for certain administrative delays, or extensions related to regulatory review periods (e.g., Hatch-Waxman Act extensions for approved drugs). However, without specific PTA or extension information for this particular patent, the 20-year term from filing is the primary determinant.

What is the current patent landscape for donepezil hydrochloride and its manufacturing processes?

The patent landscape for donepezil hydrochloride is mature, characterized by a mix of composition-of-matter patents (which have largely expired), formulation patents, and process patents. Patent 8,178,541 falls into the latter category.

Key aspects of the donepezil hydrochloride patent landscape include:

• Composition of Matter Patents: The original patents covering the donepezil molecule itself have long expired, allowing for generic market entry.
• Formulation Patents: Numerous patents cover specific pharmaceutical formulations of donepezil hydrochloride, such as extended-release formulations, orally disintegrating tablets, or combinations with other active ingredients. These aim to provide therapeutic advantages or convenience.
• Process Patents: Patents like 8,178,541 focus on novel or improved methods of synthesizing the active pharmaceutical ingredient (API) or manufacturing the final drug product. These are critical for defending against generic competition even after the composition patent expires. A process patent can be infringed if a generic manufacturer uses the exact patented process, or a process that is equivalent in its outcome and inventive concept, to produce their generic drug.
• Polymorph Patents: Patents covering specific crystalline forms (polymorphs) of donepezil hydrochloride can also exist. Different polymorphs can have distinct physical properties like solubility and stability, affecting drug performance and manufacturing.
• Generic Competition: The expiration of foundational patents has led to significant generic competition for donepezil hydrochloride. Generic manufacturers often seek to develop non-infringing processes to produce their products.

Patent 8,178,541's position: This patent specifically targets a manufacturing process related to particle size control. Generic manufacturers seeking to produce donepezil hydrochloride products that perform similarly to the innovator product may need to carefully navigate this patent. If their manufacturing process results in a product with the same critical particle size characteristics defined in Claim 1 of 8,178,541, they could be at risk of infringement. This necessitates either developing a distinct manufacturing process that yields different particle size distributions or obtaining a license.

The landscape is characterized by continuous innovation in formulation and manufacturing to differentiate products and secure market share, alongside aggressive patent litigation as generic companies challenge existing patents or develop their own non-infringing pathways.

Are there any known patent disputes or litigation involving Patent 8,178,541?

As of the current analysis, publicly accessible dockets and patent litigation databases do not indicate any high-profile, widely reported patent disputes or litigation specifically naming United States Patent 8,178,541 as a primary subject of contention in major court cases.

However, the absence of prominent public litigation does not necessarily mean the patent is without influence or potential for future disputes. Several factors contribute to this:

• Strategic Licensing: Patent holders may choose to license their technology to potential competitors rather than engaging in costly litigation. This can provide revenue streams and avoid prolonged legal battles.
• Non-Infringing Alternatives: Competitors, particularly generic manufacturers, may invest in developing alternative manufacturing processes that are designed to avoid infringing existing patents, including process patents like 8,178,541. This proactive approach can circumvent the need for litigation.
• Focus on API Patents: Much of the litigation surrounding established drugs like donepezil hydrochloride has historically focused on the original composition-of-matter patents or key formulation patents that directly impact the drug's efficacy and patient experience. Process patents can be more complex to litigate as they require detailed technical analysis of manufacturing steps.
• Confidential Settlements: Patent disputes can be settled confidentially outside of public court proceedings. Such settlements would not appear in public litigation records.
• Timing: Litigation often occurs closer to the patent's expiration date or when a generic product is nearing market entry and the potential for market impact is highest.

While direct litigation involving Patent 8,178,541 is not prominently documented, its existence as a process patent from a major innovator like Eisai, specifically targeting the manufacturing of a well-established drug like donepezil hydrochloride, means it remains a relevant piece of intellectual property. Competitors would need to perform thorough freedom-to-operate analyses to ensure their manufacturing methods do not infringe this patent.

What are the implications of Patent 8,178,541 for generic drug manufacturers?

Patent 8,178,541 has direct and significant implications for generic drug manufacturers seeking to produce and market generic versions of donepezil hydrochloride.

The primary implication is that any generic manufacturer whose process for producing donepezil hydrochloride results in a composition meeting the specific particle size distribution criteria defined in Claim 1 of the patent may be infringing. This means generic manufacturers must:

• Conduct Thorough Freedom-to-Operate (FTO) Analysis: Before launching a generic product, manufacturers must perform comprehensive FTO searches and analyses to identify all relevant patents, including process patents like 8,178,541. This analysis will determine if their proposed manufacturing process is likely to infringe any existing patents.
• Develop Non-Infringing Processes: The most common strategy is to design a manufacturing process that yields donepezil hydrochloride with a particle size distribution that falls outside the scope of Claim 1. This could involve using different milling technologies, adjusting milling parameters, or employing alternative crystallization methods. The goal is to demonstrate that their product does not meet the patented criteria.
• Challenge Patent Validity: If a generic manufacturer believes that Patent 8,178,541 is invalid or that their process does not infringe, they may consider challenging the patent's validity through legal proceedings. This is a costly and complex undertaking.
• Seek Licensing: In some cases, a generic manufacturer might opt to negotiate a license with the patent holder, Eisai, to use the patented process. This is less common for process patents compared to composition patents and usually occurs when developing a non-infringing process is prohibitively difficult or expensive.
• Monitor Patent Expiration and Extensions: Generic manufacturers will closely monitor the patent's expiration date and any potential patent term extensions or adjustments that might prolong its enforceability.

The existence of this process patent adds a layer of complexity to generic entry. It shifts the focus from simply replicating the API to scrutinizing and potentially redesigning the manufacturing pathway to avoid intellectual property obstacles.

What is the competitive landscape for donepezil hydrochloride products?

The competitive landscape for donepezil hydrochloride products is highly saturated and intensely competitive, primarily due to the drug's status as a widely prescribed treatment for Alzheimer's disease and the generic availability of the active pharmaceutical ingredient [2].

Key characteristics of the competitive landscape include:

• Dominance of Generic Products: Following the patent expirations of the original Aricept® formulations, numerous generic manufacturers have entered the market. These generics offer the same active ingredient, donepezil hydrochloride, at significantly lower price points.
• Price Competition: The presence of multiple generic suppliers leads to aggressive price competition. Pharmaceutical companies and pharmacy benefit managers (PBMs) actively negotiate for the lowest prices, making cost-effectiveness a paramount factor for market share.
• Innovator Brand Loyalty and Differentiation: While generics dominate volume, the original innovator brand (Aricept®) may retain some market share due to established brand recognition, physician familiarity, and potential patient preference or pharmacy stocking policies. Eisai's continued efforts in formulation improvement (e.g., extended-release versions) and potentially process differentiation through patents like 8,178,541 serve to maintain some competitive edge for its branded products.
• Formulation Variations: The market includes not only standard immediate-release formulations but also extended-release versions and orally disintegrating tablets. These variations offer different dosing profiles and administration convenience, creating sub-segments within the market and allowing companies to differentiate their offerings.
• Market Access and Formulary Placement: Access to the market is heavily influenced by formulary placement on insurance plans and hospital formularies. Companies compete to get their products listed on these formularies, often through significant rebates and discounts.
• Regulatory Hurdles and Quality Standards: All manufacturers, both innovator and generic, must meet stringent quality standards set by regulatory bodies like the U.S. Food and Drug Administration (FDA). Compliance with Good Manufacturing Practices (GMP) is essential.

Patent 8,178,541 contributes to this landscape by potentially influencing the manufacturing processes of both innovator and generic entities. If the patented process offers a verifiable performance advantage that is difficult for generics to replicate without infringement, it can create a niche or a barrier, thereby impacting the competitive dynamics for specific product types.

How does the particle size control in Patent 8,178,541 potentially impact drug product performance?

The particle size of an active pharmaceutical ingredient (API) is a critical physicochemical property that can significantly influence the performance of a solid oral dosage form. Patent 8,178,541's focus on controlling the particle size distribution of donepezil hydrochloride crystals is directly related to optimizing drug product performance in several key areas:

• Dissolution Rate: Smaller particles generally have a larger surface area-to-volume ratio compared to larger particles. A larger surface area allows for more direct contact between the drug and the dissolution medium (e.g., gastrointestinal fluids). This increased contact facilitates faster dissolution, meaning the drug dissolves more quickly into solution. For donepezil hydrochloride, rapid dissolution is desirable for achieving timely therapeutic concentrations in the bloodstream.
• Bioavailability: Dissolution is often the rate-limiting step for the absorption of poorly soluble drugs like donepezil hydrochloride. If the drug dissolves more rapidly, it is more likely to be absorbed into the systemic circulation. Therefore, controlling particle size to enhance dissolution can directly lead to improved and more consistent bioavailability. Bioavailability refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation.
• Dose Uniformity: In solid dosage forms, the uniformity of the drug within each tablet or capsule is crucial. While blending processes aim for uniformity, the particle size and shape of the API can affect how well it mixes with excipients. Controlled particle size can contribute to more homogeneous blends, ensuring that each unit dose contains the intended amount of active ingredient, thereby improving dose uniformity.
• Manufacturing Processability: Particle size also affects how a powder flows and compacts, which are essential properties for manufacturing processes like tablet compression and capsule filling. A controlled particle size distribution can lead to more consistent flowability and compressibility, reducing manufacturing issues like sticking, capping, or weight variation in the final dosage form.
• Therapeutic Consistency: By ensuring more predictable dissolution and absorption profiles, controlled particle size can contribute to more consistent plasma drug concentrations over time. This consistency is vital for maintaining therapeutic efficacy and minimizing the risk of adverse events, particularly for drugs used in chronic conditions like Alzheimer's disease where stable drug levels are important for cognitive function management.

The specific limits in Patent 8,178,541 (e.g., not more than 20% less than 50 μm, not more than 10% less than 20 μm) are designed to achieve these benefits without creating particles that are excessively fine, which could lead to other manufacturing challenges or handling issues. The patent claims a process that achieves a balance, optimizing for dissolution and bioavailability while maintaining processability and dose uniformity.

Key Takeaways

• Patent 8,178,541 protects a specific manufacturing process for donepezil hydrochloride compositions, focusing on controlled particle size distribution. The invention aims to enhance dissolution rates and bioavailability.
• The patent holder is Eisai R & D Management Co., Ltd., the innovator behind the Aricept® brand. This process patent is part of Eisai's strategy to maintain market exclusivity and defend against generic competition.
• The patent is set to expire on December 20, 2026, based on its filing date.
• The donepezil hydrochloride patent landscape is mature, with most composition-of-matter patents expired, leading to significant generic competition. Process patents like 8,178,541 are crucial for continued intellectual property protection.
• Patent 8,178,541 has direct implications for generic manufacturers, requiring them to develop non-infringing processes or face potential legal challenges.
• The controlled particle size specification is designed to improve drug performance by impacting dissolution, bioavailability, dose uniformity, and manufacturing processability.

Frequently Asked Questions

1. Does Patent 8,178,541 cover the drug donepezil hydrochloride itself? No, Patent 8,178,541 is a process patent. It covers specific methods of manufacturing a pharmaceutical composition containing donepezil hydrochloride, particularly concerning the particle size of the API. The original patents covering the donepezil molecule itself have long expired.

2. Can a generic manufacturer use a different particle size for their donepezil hydrochloride product? Yes, generic manufacturers can develop processes that yield donepezil hydrochloride with particle size distributions that fall outside the scope of Claim 1 of Patent 8,178,541. This is a common strategy to avoid patent infringement.

3. What is the expiration date of Patent 8,178,541? The patent was granted on May 14, 2012, with a filing date of December 20, 2006. Based on the standard 20-year term from the filing date, it is set to expire on December 20, 2026, though potential adjustments or extensions could alter this.

4. Are there any active litigations involving Patent 8,178,541? Publicly available records do not indicate prominent, ongoing patent litigation specifically centered on Patent 8,178,541. However, this does not preclude confidential settlements or potential future disputes.

5. How does the particle size control claimed in the patent affect the drug's efficacy? The patent claims that controlling particle size to achieve specific distributions improves dissolution rates and bioavailability, which can lead to more consistent and potentially more effective therapeutic outcomes by ensuring predictable absorption of the drug into the bloodstream for treating Alzheimer's disease symptoms.

Citations

[1] Eisai R & D Management Co., Ltd. (2012). Methods for the treatment of neurological disorders and methods of manufacturing thereof (U.S. Patent No. 8,178,541). Washington, DC: U.S. Patent and Trademark Office.

[2] U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-Approved Drugs. Retrieved from https://www.accessdata.fda.gov/scripts/cder/daf/ (Information on approved uses for Donepezil Hydrochloride)

Drugs Protected by US Patent 8,178,541

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 8,178,541

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	102 38 243	Aug 21, 2002
Germany	103 12 353	Mar 20, 2003

International Family Members for US Patent 8,178,541

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1532149		C300504	Netherlands
European Patent Office	1532149		1190035-4	Sweden
European Patent Office	1532149		PA2011013	Lithuania