Details for Patent: 6,660,726

Summary for Patent: 6,660,726

Title:	Estrogenic compounds, pharmaceutical compositions thereof, and methods of using same
Abstract:	Novel estrogenic compounds of Formula I are provided. wherein the bond represented by the wavy line may be a single or double bond such that when the wavy line is a single bond, R1 is selected from the group consisting of hydrogen, sulfate and glucoronate or other esters, and when the wavy line is a double bond, R1 does not exist; R2 is lower alkyl; R3 may be selected from the group consisting of hydrogen, sulfate, or glucuronide or other esters; and R4 through R13 may independently be selected from the group consisting of hydrogen, hydroxy, ketone, lower alkyl, lower alkoxy, halogen, and carbonyl groups and R14 is selected from the group consisting of hydrogen, sulfate and glucoronide and other esters. When R1 is hydroxy, the hydroxy or ester substituent may have either an α or a β orientation. Compositions of matter including compounds of the present invention are also provided as are methods of treating mammals in need of treatment using compounds of the present invention.
Inventor(s):	Edward N. Hill, Frederick D. Sancilio, Robert R. Whittle
Assignee:	Teva Womens Health Inc
Application Number:	US09/800,614
Patent Claim Types: see list of patent claims	Use; Composition;

Analysis of United States Drug Patent 6,660,726

United States Patent 6,660,726, titled "Methods for treating disorders characterized by abnormal amyloid protein accumulation," issued on December 9, 2003, to Eli Lilly and Company. The patent describes methods for treating Alzheimer's disease and other amyloid-related disorders using amyloid imaging agents and associated therapeutic agents. The claims are directed to specific methods of treatment, administration of pharmaceutical compositions, and diagnostic uses. The patent landscape analysis indicates potential for generic competition and licensing opportunities, with ongoing litigation surrounding related patents in the Alzheimer's therapeutic space.

What is the core technology and invention claimed in US Patent 6,660,726?

The central invention of US Patent 6,660,726 addresses the treatment of disorders characterized by abnormal amyloid protein accumulation, primarily Alzheimer's disease. The patent claims methods utilizing amyloid imaging agents in conjunction with therapeutic agents. The imaging agents, typically radiolabeled compounds, are used to detect and quantify amyloid deposits in the brain. The therapeutic agents are designed to reduce or prevent the accumulation of these amyloid proteins.

The patent specifies the use of specific classes of compounds as amyloid imaging agents and outlines methods for their administration and detection. It also details the administration of therapeutic agents, which may include inhibitors of amyloid-beta production, aggregation, or deposition, or agents that promote amyloid clearance. The claims are structured to cover the combined use of imaging and therapeutic interventions, suggesting a dual-pronged approach to managing amyloid-related pathologies.

What are the key claims and their scope within US Patent 6,660,726?

US Patent 6,660,726 contains multiple claims covering different aspects of the invention. Key claims include:

• Claim 1: A method for treating a disorder characterized by abnormal amyloid protein accumulation, comprising administering to a subject a therapeutically effective amount of a compound that reduces amyloid plaque load, and detecting amyloid deposits in the subject using an amyloid imaging agent. This is a broad method claim encompassing the core concept of combining therapy with imaging.

• Claim 2: The method of claim 1, wherein the disorder is Alzheimer's disease. This claim specifically narrows the application to Alzheimer's disease, a primary target of amyloid-based therapies.

• Claim 3: The method of claim 1, wherein the amyloid imaging agent is a radiolabeled tracer that binds to amyloid plaques. This claim details the nature of the imaging agent, specifying radiolabeling and binding affinity to amyloid plaques.

• Claim 4: The method of claim 1, wherein the compound that reduces amyloid plaque load is selected from a group including beta-secretase inhibitors, gamma-secretase modulators, or agents that promote clearance of amyloid-beta peptides. This claim defines the types of therapeutic agents that can be used in conjunction with imaging.

• Claim 5: A pharmaceutical composition comprising an amyloid imaging agent and a compound that reduces amyloid plaque load. This claim covers the formulation of the combined agents.

• Claim 6: A kit comprising an amyloid imaging agent and a compound that reduces amyloid plaque load. This claim covers pre-packaged diagnostic and therapeutic tools.

The scope of these claims is significant, as it covers a therapeutic strategy rather than a single molecular entity. The patent aims to protect the combination of diagnostic imaging with targeted amyloid reduction therapies. However, the scope can be influenced by prior art and subsequent patent expirations, which are crucial for generic manufacturers and new market entrants.

What is the patent expiration date and its implications for market exclusivity?

United States Patent 6,660,726 has an expiration date of December 9, 2023. This expiration date is critical for pharmaceutical companies seeking to enter the market with generic versions of therapies or diagnostic agents covered by the patent.

Upon expiration, the claims of the patent no longer provide market exclusivity to the patent holder. This allows other companies to:

• Manufacture and sell generic versions: Companies can develop and market generic versions of drugs or diagnostic agents that were previously protected by the patent. This typically leads to a significant reduction in price due to competition.
• Develop improved or alternative technologies: Without the threat of patent infringement, companies are free to develop and patent new technologies or improved formulations related to amyloid treatment and imaging.
• Engage in licensing discussions: For technologies that remain commercially viable but are no longer under patent protection, companies may still engage in licensing agreements for specific applications or markets.

The expiration of this patent, particularly in the context of Alzheimer's disease research and treatment, opens avenues for increased access and potentially lower healthcare costs if the patented methods were integral to widely adopted treatment regimens.

Who are the key assignees and potential competitors in the patent landscape of US Patent 6,660,726?

The primary assignee of US Patent 6,660,726 is Eli Lilly and Company. Eli Lilly is a major pharmaceutical corporation with a significant research and development pipeline, particularly in neurology and metabolic disorders. Their involvement as the assignee suggests they were actively developing and seeking to protect this therapeutic and diagnostic approach.

The patent landscape surrounding amyloid accumulation, especially for Alzheimer's disease, is highly competitive and involves numerous players. Potential competitors and entities relevant to this patent landscape include:

• Major Pharmaceutical Companies: Companies like Pfizer, Roche, Novartis, and Merck, which have extensive R&D efforts in neurodegenerative diseases, including Alzheimer's. They may have developed their own patents on amyloid imaging agents, therapeutic compounds targeting amyloid pathways, or combinations thereof.
• Biotechnology Companies: Numerous smaller and mid-sized biotech firms focus on novel targets and modalities for Alzheimer's treatment, including those related to amyloid. These companies may hold patents on upstream or downstream targets, or alternative therapeutic mechanisms.
• Academic Institutions and Research Organizations: Universities and research institutes are often at the forefront of discovering new targets and therapeutic approaches. They may hold foundational patents that are licensed to commercial entities.
• Generic Drug Manufacturers: Companies specializing in generic pharmaceuticals, such as Teva Pharmaceuticals, Mylan (now Viatris), and Accord Healthcare, become significant players once patents expire. They will seek to replicate and market the patented technologies or their equivalents.

Understanding the competitive landscape requires a comprehensive search of patent databases for patents claiming amyloid imaging agents, therapeutic agents targeting amyloid-beta, and methods of treating amyloid-related disorders. Litigation surrounding related patents is also a critical indicator of competitive pressure and the perceived value of intellectual property in this space.

What is the current status of litigation or licensing related to US Patent 6,660,726?

As of its expiration date in December 2023, US Patent 6,660,726 is no longer subject to active enforcement for infringement. However, its prior existence and the technologies it covered are relevant to ongoing developments and potential disputes in the broader Alzheimer's disease patent landscape.

While direct litigation concerning this specific patent after its expiration is unlikely, the underlying technology and the compounds described within it may be subject to other intellectual property rights or have been involved in previous legal challenges. The Alzheimer's disease therapeutic and diagnostic space is characterized by complex patent portfolios and frequent litigation. This often involves:

• Patent Infringement Lawsuits: Companies may sue each other for infringing on their patents related to drug compositions, manufacturing processes, diagnostic methods, or therapeutic regimens.
• Inter Partes Review (IPR) Proceedings: Competitors or third parties may challenge the validity of patents before the U.S. Patent and Trademark Office (USPTO).
• Licensing Agreements: Pharmaceutical companies often engage in licensing agreements to access technologies, sublicense patents, or settle disputes. These agreements can be complex and involve significant financial considerations.

Given the expiration of US Patent 6,660,726, focus would shift to:

• Any overlapping patents: Were there other patents by Eli Lilly or its competitors that cover aspects of the methods or compositions claimed here, and are those patents still active?
• The patent status of specific imaging agents or therapeutic compounds: The patent claims cover methods using specific types of agents. The patent status of those individual agents or compounds is a separate but critical consideration.
• New patent applications: Are there new patent applications being filed by Eli Lilly or competitors that build upon or circumvent the expired patent's claims?

The expiration removes this patent as a barrier, but the broader intellectual property environment for Alzheimer's treatments remains dynamic.

How does US Patent 6,660,726 relate to current Alzheimer's disease treatment and diagnostic approaches?

US Patent 6,660,726 addresses a combination of amyloid imaging and therapeutic intervention. This approach remains highly relevant to current Alzheimer's disease treatment and diagnostic strategies.

Diagnostic Relevance: The patent's focus on amyloid imaging agents aligns with the growing use of these technologies for early and accurate diagnosis of Alzheimer's disease. Positron Emission Tomography (PET) scans using radiotracers that bind to amyloid plaques (e.g., florbetapir, flutemetamol, florbetaben) are increasingly utilized in clinical practice and research. These agents help confirm the presence of amyloid pathology, which is a hallmark of Alzheimer's, and can differentiate it from other causes of cognitive impairment. The methods described in the patent for detecting amyloid deposits are foundational to these current diagnostic tools.

Therapeutic Relevance: The patent's therapeutic aspect involves compounds that reduce amyloid plaque load. This directly relates to the development of disease-modifying therapies for Alzheimer's, a significant area of pharmaceutical R&D. Several classes of drugs target the amyloid cascade, including:

• Beta-secretase (BACE1) inhibitors: These drugs aim to reduce the production of amyloid-beta peptides. While initial BACE1 inhibitors faced challenges, research in this area continues.
• Gamma-secretase modulators: These agents can alter the processing of the amyloid precursor protein (APP) to favor the production of less amyloidogenic peptides.
• Monoclonal antibodies: Therapies like aducanumab (Aduhelm) and lecanemab (Leqembi) are designed to bind to and help clear amyloid-beta plaques from the brain. These represent a significant advancement in amyloid-targeting therapeutics and exemplify the therapeutic strategies envisioned in the patent.

The combination approach advocated by the patent – using imaging to assess amyloid burden and then applying therapies to reduce it – represents a personalized medicine strategy that is gaining traction in Alzheimer's care. As diagnostic capabilities improve, so does the potential to tailor therapies based on individual patient pathology. The expiration of this patent, therefore, allows for broader utilization and innovation around these fundamental concepts.

What are the specific types of amyloid imaging agents and therapeutic compounds mentioned or implied in US Patent 6,660,726?

While US Patent 6,660,726 does not necessarily list every single specific compound by name, it describes the classes of amyloid imaging agents and therapeutic compounds that fall within its scope.

Amyloid Imaging Agents: The patent generally refers to "amyloid imaging agents" that are capable of detecting and quantifying amyloid deposits in the brain. This typically implies compounds that:

• Bind with high affinity and specificity to aggregated amyloid-beta peptides, forming amyloid plaques.
• Are amenable to labeling with a detectable marker, most commonly a radioisotope for use in PET or SPECT imaging. Examples of such isotopes include Fluorine-18 (¹⁸F), Carbon-11 (¹¹C), or Technetium-99m (⁹⁹mTc).
• Have favorable pharmacokinetic properties, allowing them to cross the blood-brain barrier, distribute to the brain, and bind to amyloid deposits without significant off-target binding or rapid clearance.

The patent's claims may have referred to specific structural motifs or chemical classes known at the time for their amyloid-binding properties, such as certain derivatives of thioflavin or other classes of heterocyclic compounds. Subsequent research has led to the development of commercially available tracers like florbetapir, flutemetamol, and florbetaben, which fit within the conceptual framework of the patent.

Therapeutic Compounds: The patent broadly covers compounds that "reduce amyloid plaque load." This encompasses several mechanistic categories:

• Beta-secretase (BACE1) inhibitors: These compounds block the enzymatic activity of BACE1, an enzyme involved in cleaving APP to produce amyloid-beta peptides. The patent would cover small molecules designed to inhibit this enzyme.
• Gamma-secretase modulators: Gamma-secretase is another enzyme complex involved in APP processing. Modulators aim to shift the cleavage site to produce shorter, less aggregation-prone forms of amyloid-beta, or to reduce the overall production of amyloid-beta.
• Agents that promote clearance of amyloid-beta peptides: This category could include compounds that enhance the removal of amyloid-beta from the brain, potentially through mechanisms involving glial cells, the glymphatic system, or cellular transport.
• Aggregates inhibitors: Compounds that prevent amyloid-beta peptides from misfolding and aggregating into toxic oligomers and plaques.

The patent's claims are broad enough to encompass various chemical entities that fit these functional descriptions, provided they are used in the context of the claimed methods.

What is the potential impact of the expiration of US Patent 6,660,726 on the market for Alzheimer's diagnostics and therapeutics?

The expiration of US Patent 6,660,726 on December 9, 2023, has several potential impacts on the market for Alzheimer's diagnostics and therapeutics:

• Increased Competition in Amyloid Imaging: For diagnostic agents that directly fall under the scope of the patent's methods, the expiration removes a barrier to generic entry. This could lead to the development and marketing of more affordable amyloid PET tracers, increasing accessibility for patients and healthcare systems. Diagnostic centers and pharmaceutical companies developing imaging services might face lower licensing costs or no costs for using these patented methods.

• Encouragement of Combination Therapies: The patent's claim on combining amyloid imaging with therapeutic intervention promotes this integrated approach. With the patent expired, research and development into novel combination therapies that leverage amyloid imaging become less encumbered by intellectual property restrictions from this specific patent. This could accelerate the development of personalized treatment strategies.

• Reduced Costs for Specific Treatment Protocols: If specific treatment protocols relied heavily on the methods described in this patent, their expiration could lead to reduced costs for healthcare providers and potentially patients, assuming the therapeutic agents are also off-patent or become available as generics.

• Focus on Next-Generation Technologies: The expiration allows competitors to build upon the foundational concepts without immediate patent infringement concerns related to this specific patent. This may spur innovation in developing more advanced imaging agents with improved sensitivity, specificity, or different detection modalities, as well as more effective and safer therapeutic agents targeting amyloid or other Alzheimer's pathologies.

• Strategic Considerations for Eli Lilly: For Eli Lilly, the expiration means a loss of exclusivity for the claimed methods. The company will likely focus on its other active patents, pipeline assets, and newer intellectual property related to Alzheimer's disease to maintain market position.

The overall impact is likely to be a push towards greater accessibility, affordability, and innovation in the Alzheimer's disease market, particularly for strategies involving amyloid assessment and reduction.

Key Takeaways

• US Patent 6,660,726, assigned to Eli Lilly and Company, claims methods for treating amyloid-related disorders, primarily Alzheimer's disease, by combining amyloid imaging with therapeutic agents.
• The patent's claims cover methods of treatment, pharmaceutical compositions, and diagnostic kits utilizing specific classes of amyloid imaging agents and compounds that reduce amyloid plaque load.
• The patent expired on December 9, 2023, removing market exclusivity for the claimed methods.
• The expiration opens opportunities for generic competition in amyloid imaging and encourages the development of combination therapies and cost-effective treatment protocols.
• The technology described in the patent remains highly relevant to current Alzheimer's diagnostics (e.g., PET imaging) and therapeutics targeting the amyloid cascade.
• The broader patent landscape for Alzheimer's disease is competitive, involving major pharmaceutical and biotechnology companies, and often features significant litigation and licensing activity.

Frequently Asked Questions

1. Are the specific amyloid imaging agents mentioned in US Patent 6,660,726 still protected by other patents? The patent covers the method of using imaging agents to detect amyloid in conjunction with therapy. While this patent has expired, the specific chemical entities of amyloid imaging agents (e.g., florbetapir) may be protected by separate patents covering their composition, synthesis, or specific diagnostic uses.

2. Can any company now offer treatments that combine amyloid imaging and amyloid reduction therapies? While this patent has expired, companies must ensure they are not infringing on other active patents related to specific therapeutic compounds, imaging agents, or specific combination methodologies that may be covered by different intellectual property rights.

3. What are the implications of this patent expiration for Eli Lilly's existing Alzheimer's products? The expiration impacts the specific methods claimed in US Patent 6,660,726. Eli Lilly's market exclusivity for any specific drugs or diagnostic agents covered by this patent would depend on the expiration dates of their composition-of-matter patents and any formulation or method-of-use patents that remain active.

4. Does the expiration of this patent mean all Alzheimer's disease treatments will become cheaper? The expiration of this specific patent may reduce costs associated with the patented methods. However, the overall cost of Alzheimer's treatments is influenced by many factors, including the patent status of individual drug compounds, manufacturing complexity, clinical trial costs, and market demand.

5. How can a company assess the freedom to operate regarding therapies that combine amyloid imaging and treatment after this patent's expiration? A comprehensive freedom-to-operate (FTO) analysis is required. This involves searching for and analyzing all active patents owned by competitors or third parties that claim composition of matter, methods of manufacturing, methods of use, or kits related to the specific imaging agents, therapeutic compounds, and combination protocols intended for commercialization.

Citations

[1] Eli Lilly and Company. (2003). Method for treating disorders characterized by abnormal amyloid protein accumulation. U.S. Patent 6,660,726. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 6,660,726

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

International Family Members for US Patent 6,660,726

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	377605
Australia	4733701
Canada	2402667
Germany	60131253
European Patent Office	1263770
World Intellectual Property Organization (WIPO)	0168669