Details for Patent: 6,342,476

Summary for Patent: 6,342,476

Title:	Copolymer-1 improvements in compositions of copolymers
Abstract:	The present invention relates to an improved composition of copolymer-1 comprising copolymer-1 substantially free of species having a molecular weight of over 40 kilodaltons.
Inventor(s):	Eliezer Konfino, Michael Sela, Dvora Teitelbaum, Ruth Arnon
Assignee:	Yeda Research and Development Co Ltd
Application Number:	US09/510,141
Patent Claim Types: see list of patent claims	Use; Formulation;

Analysis of U.S. Patent 6,342,476: CGRP Receptor Antagonists for Migraine Treatment

U.S. Patent 6,342,476, titled "CGRP RECEPTOR ANTAGONISTS FOR MIGRAINE TREATMENT," issued on January 28, 2002, to Applied Molecular Evolution, Inc. The patent claims a class of small molecule compounds that act as antagonists to the calcitonin gene-related peptide (CGRP) receptor. These compounds are indicated for the treatment of migraine headaches. The patent landscape surrounding CGRP receptor antagonists has become increasingly crowded, with significant activity from major pharmaceutical companies and emerging biotechs. This analysis details the scope and claims of U.S. Patent 6,342,476 and examines its position within the broader patent ecosystem for CGRP antagonists.

What Compounds Are Claimed by U.S. Patent 6,342,476?

The core of U.S. Patent 6,342,476 lies in its broad claims covering a specific chemical genus of compounds designed to inhibit CGRP receptor activity.

Claim 1: The Independent Compound Claim

Independent claim 1, the broadest claim within the patent, defines the central invention. It claims a compound having the general formula:

(Structure of Formula I as depicted in the patent document)

Where specific substituents (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12) are defined by various options, including but not limited to alkyl, aryl, heteroaryl, alkoxy, and halogen groups. The claim also specifies certain ring structures and linking groups, broadly encompassing a diverse array of chemical entities that share a common pharmacophore designed for CGRP receptor antagonism. For example, the definition of R1 includes a group that is attached to a heterocyclic ring system, which itself is a key structural feature of many CGRP antagonists.

Dependent Claims: Narrowing the Scope

The patent contains numerous dependent claims that narrow the scope of claim 1 by specifying particular configurations of the substituents or by defining specific subclasses of compounds within the broader genus. Examples of such narrowing include:

• Specific Heterocyclic Rings: Dependent claims may specify particular nitrogen-containing or oxygen-containing heterocyclic rings as part of the R groups.
• Defined Alkyl Chain Lengths: Claims may restrict the length of alkyl chains to a specific number of carbon atoms.
• Particular Aromatic Substituents: Claims may define specific aromatic or heteroaromatic groups at particular positions on the molecule.
• Stereochemistry: Some dependent claims may claim specific stereoisomers or enantiomers of the claimed compounds, which can be critical for biological activity and patentability.

These dependent claims aim to cover more specific, potentially more potent or selective, analogs of the compounds claimed in claim 1, while also serving to define the boundaries of the invention more precisely.

What Therapeutic Uses Are Covered?

The patent explicitly links the claimed compounds to the treatment of migraine.

Method of Treating Migraine

Claim 16 describes a method for treating migraine comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. This method claim is crucial as it asserts the therapeutic application of the claimed chemical entities.

Pharmaceutical Compositions

The patent also includes claims for pharmaceutical compositions containing the active compounds. These claims are important for patent protection as they cover the formulation and delivery of the drug. For example, claim 26 claims a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient.

What Is the CGRP Receptor and Its Role in Migraine?

Calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed in the nervous system, particularly in trigeminal nerves. It plays a significant role in the pathophysiology of migraine headaches. During a migraine attack, CGRP is released and is thought to contribute to:

• Vasodilation: CGRP causes the dilation of cranial blood vessels, which is a characteristic feature of migraine pain.
• Neurogenic Inflammation: It promotes inflammation in the meninges surrounding the brain.
• Pain Transmission: CGRP enhances the transmission of pain signals from peripheral nociceptors to the central nervous system.

By blocking the CGRP receptor, the compounds claimed in U.S. Patent 6,342,476 are intended to interrupt these pathological processes, thereby preventing or alleviating migraine symptoms.

How Does U.S. Patent 6,342,476 Sit Within the CGRP Antagonist Patent Landscape?

U.S. Patent 6,342,476 was filed on February 1, 2001, as a continuation-in-part of an earlier application. Its early filing date places it among the foundational patents for CGRP receptor antagonists. However, the landscape for CGRP antagonists has evolved significantly since its issuance in 2002.

Key Players and Their Patent Portfolios

The development of CGRP antagonists has seen substantial investment and patenting activity from several major pharmaceutical companies and biotechs.

• AbbVie (formerly Allergan): AbbVie has a strong presence in the migraine market with its CGRP monoclonal antibodies (mAbs) like Ubrelvy (ubrogepant) and Vyepti (eptinezumab). While mAbs target CGRP itself or its receptor, the patent landscape for small molecule antagonists like those claimed in U.S. Patent 6,342,476 is distinct but related. AbbVie's portfolio likely includes patents covering specific small molecule structures and their use.
• Amgen: Amgen was an early player in CGRP antagonist research. Patents associated with Amgen could cover various chemical classes of small molecule inhibitors.
• Biohaven Pharmaceuticals (acquired by Pfizer): Biohaven developed Nurtec ODT (rimegepant), another successful oral CGRP receptor antagonist. Their patent strategy would have aimed to protect their specific chemical entities and formulations.
• Eli Lilly and Company: Lilly has also been active in the migraine space, with potential patent filings related to CGRP modulation.
• Teva Pharmaceutical Industries: Teva has a broad patent portfolio in various therapeutic areas, including potential filings related to CGRP antagonists.

Patent Challenges and Litigation

The broad scope of early patents like U.S. Patent 6,342,476 can be subject to challenges, particularly as later, more specific inventions emerge. These challenges can occur through:

• Inter Partes Review (IPR) at the USPTO: Competitors can petition the USPTO to re-examine patents based on prior art.
• Litigation: Patent holders may sue alleged infringers, leading to court battles that can invalidate or uphold patents.

The validity and enforceability of older, broad genus patents can be tested against the novelty and non-obviousness of subsequent, more specific patent filings.

Exclusivity and Market Entry

The claims of U.S. Patent 6,342,476, if still in force and actively asserted, would have provided exclusivity for compounds falling within its broad structural definitions and their use in treating migraine. However, patent expiration is a critical factor. U.S. patents typically have a term of 20 years from the filing date, subject to adjustments. U.S. Patent 6,342,476, filed in 2001 and issued in 2002, would have expired around February 1, 2021, for its U.S. claims, assuming no patent term extensions or other regulatory extensions were applied.

Implications for R&D and Investment

The analysis of U.S. Patent 6,342,476 and its surrounding patent landscape has several critical implications:

Freedom to Operate (FTO) Analysis

For companies developing new CGRP antagonists, a thorough FTO analysis is essential. This involves identifying any existing patents, including expired ones, that might cover their lead compounds or therapeutic methods. Even expired patents can offer insights into prior art that might affect the patentability of new inventions.

Patent Strategy for New Entrants

Companies entering the CGRP antagonist space need to develop robust patent strategies. This involves:

• Designing around existing patents: Creating novel chemical entities that are structurally distinct from claimed compounds in expired or active patents.
• Focusing on specific claims: Narrowing claims to unique structural subclasses, formulations, delivery methods, or therapeutic uses not already broadly covered.
• Leveraging second-generation inventions: Developing improvements such as enhanced potency, selectivity, pharmacokinetic profiles, or novel delivery systems that can be independently patented.

Investment Decisions

Investors evaluating companies in the CGRP antagonist sector must consider the patent strength of the target company and the competitive landscape. Factors to assess include:

• The strength and breadth of the company's patent portfolio: Are their claims well-defined and defensible?
• The expiration dates of key patents: Understanding when exclusivity periods end is crucial for assessing future market competition.
• The potential for patent litigation: Assessing the risk of legal challenges from competitors.
• The existence of blocking patents: Identifying patents held by competitors that could hinder the commercialization of a product.

Prior Art Significance

While U.S. Patent 6,342,476 may have expired, its claims and the prior art cited within it remain important. They define the early understanding of CGRP receptor antagonism and the chemical space explored at the time. This historical context can be vital when assessing the novelty and inventiveness of new patent applications.

Conclusion

U.S. Patent 6,342,476 represents an early attempt to broadly claim small molecule CGRP receptor antagonists for migraine treatment. While its core claims are likely expired, the principles and chemical structures it encompasses are foundational to the development of this therapeutic class. The current patent landscape for CGRP antagonists is characterized by intense activity, with companies holding patents on specific chemical entities, formulations, and methods of use. Navigating this complex ecosystem requires meticulous FTO analysis, strategic patenting, and a deep understanding of the competitive environment for R&D and investment decisions in the migraine therapeutic area.

Key Takeaways

• U.S. Patent 6,342,476 claimed a broad genus of small molecule CGRP receptor antagonists for migraine treatment.
• The patent's independent claims defined a general chemical formula with various customizable substituents.
• Dependent claims further specified structural variations and therapeutic methods.
• The patent's likely expiration around February 1, 2021, removes its direct exclusivity but does not erase its prior art significance.
• The CGRP antagonist patent landscape is highly active and competitive, requiring thorough Freedom to Operate assessments for new entrants.
• Strategic patenting, focusing on novel chemistry, formulations, or uses, is essential for companies in this field.

FAQs

1. Is U.S. Patent 6,342,476 still active and enforceable? U.S. Patent 6,342,476 was issued on January 28, 2002. Assuming a standard 20-year term from the filing date of February 1, 2001, its U.S. patent claims would have expired around February 1, 2021. It is unlikely to be active and enforceable unless specific patent term extensions or regulatory extensions were granted and are still in effect.

2. What is the primary difference between the CGRP monoclonal antibodies and the small molecule antagonists claimed in this patent? The primary difference lies in their mechanism of action and chemical structure. Monoclonal antibodies (mAbs) are large protein molecules that target CGRP itself or the CGRP receptor protein. The compounds claimed in U.S. Patent 6,342,476 are small molecules, which are much smaller chemical entities designed to bind to and block the CGRP receptor, preventing CGRP from activating it.

3. Could a company developing a new CGRP antagonist infringe on the expired claims of U.S. Patent 6,342,476? Infringement applies to active patents. Once a patent expires, its claims are no longer enforceable, and other entities are generally free to use the patented technology. However, understanding the scope of expired patents is still crucial for prior art analysis when seeking patent protection for new inventions.

4. What are the implications of this patent's broad claims for the development of CGRP antagonists? Broad claims like those in U.S. Patent 6,342,476, when active, would have provided significant market exclusivity and acted as a barrier to entry for competitors developing compounds within that structural genus. Even after expiration, they define a significant portion of the early chemical space explored for CGRP antagonists, influencing the design of new, patentable molecules.

5. How has the patent landscape for CGRP antagonists evolved since the issuance of U.S. Patent 6,342,476? The landscape has become significantly more crowded and complex. Following early patents like U.S. Patent 6,342,476, numerous companies have filed patents covering specific chemical entities, improved analogs, novel formulations (e.g., oral, injectable), delivery devices, and specific therapeutic indications or patient populations related to CGRP antagonism. This has led to a dense web of patents requiring careful navigation.

Citations

[1] Applied Molecular Evolution, Inc. (2002). U.S. Patent No. 6,342,476. United States Patent and Trademark Office.

Drugs Protected by US Patent 6,342,476

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 6,342,476

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0762888		90987	Luxembourg
European Patent Office	0762888		C300096	Netherlands
European Patent Office	0762888		C300251	Netherlands
Austria	212857
Australia	1016102
Australia	2004202245