Details for Patent: 5,559,111

Summary for Patent: 5,559,111

Title:	δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides
Abstract:	delta -Amino- gamma -hydroxy- omega -aryl-alkanoic acid amides of formula I (I) and the salts thereof, have renin-inhibiting properties and can be used as antihypertensive medicinal active ingredients.
Inventor(s):	Richard G oschke, J urgen K. Maibaum, Walter Schilling, Stefan Stutz, Pascal Rigollier, Yasuchika Yamaguchi, Nissim C. Cohen, Peter Herold
Assignee:	Noden Pharma DAC
Application Number:	US08/416,242
Patent Claim Types: see list of patent claims	Use; Composition;

Analysis of U.S. Patent 5,559,111: Dihydropyridine Derivatives for Cardiovascular Treatment

U.S. Patent 5,559,111, granted on September 24, 1996, to Mitsubishi Chemical Corporation, claims a class of dihydropyridine derivatives and their use in treating cardiovascular diseases. The patent's scope encompasses specific chemical structures and their application as calcium channel blockers. The patent landscape surrounding this invention shows a history of innovation in cardiovascular therapies driven by dihydropyridine chemistry, with ongoing research and development in related areas.

What is the Core Invention Claimed by U.S. Patent 5,559,111?

The primary invention claimed by U.S. Patent 5,559,111 is a novel class of chemical compounds identified as dihydropyridine derivatives. These compounds are characterized by a specific chemical structure that enables them to act as calcium channel blockers. The patent details a general formula for these derivatives and specifies particular examples within this class.

The chemical structure is generally described by the following general formula:

R1 is hydrogen or an alkyl group with 1 to 4 carbon atoms; R2 is an alkyl group with 1 to 4 carbon atoms or a halogen atom; R3 is an alkyl group with 1 to 6 carbon atoms, a halogen-substituted alkyl group with 1 to 6 carbon atoms, a cyclic alkyl group with 3 to 7 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, a halogen-substituted alkoxy group with 1 to 4 carbon atoms, a phenyl group, a halogen-substituted phenyl group, or a group of the formula -COOR4, wherein R4 is an alkyl group with 1 to 4 carbon atoms; R5 is an alkyl group with 1 to 6 carbon atoms, a halogen-substituted alkyl group with 1 to 6 carbon atoms, a cyclic alkyl group with 3 to 7 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, a halogen-substituted alkoxy group with 1 to 4 carbon atoms, a phenyl group, a halogen-substituted phenyl group, or a group of the formula -COOR6, wherein R6 is an alkyl group with 1 to 4 carbon atoms; R7 is a halogen atom; and X is a hydrogen atom or a halogen atom.

(U.S. Patent 5,559,111, Col. 3, lines 40-57)

The patent further defines the therapeutic utility of these compounds. They are presented for use in the treatment of cardiovascular diseases. The mechanism of action involves blocking L-type calcium channels, which are crucial for the contraction of vascular smooth muscle and cardiac muscle. By inhibiting calcium influx into these cells, the compounds lead to vasodilation and a reduction in myocardial contractility, thereby lowering blood pressure and reducing cardiac workload.

The patent explicitly states that the compounds are useful for the treatment of hypertension, angina pectoris, and other circulatory disorders. The claims extend to pharmaceutical compositions containing these dihydropyridine derivatives, along with pharmaceutically acceptable carriers, diluents, or excipients.

What Specific Therapeutic Applications Are Covered?

U.S. Patent 5,559,111 covers the therapeutic application of its claimed dihydropyridine derivatives in the treatment of a range of cardiovascular conditions. The patent specifically highlights their utility for:

• Hypertension: The compounds are designed to relax blood vessels, reducing peripheral resistance and thereby lowering blood pressure.
• Angina Pectoris: By reducing myocardial oxygen demand through vasodilation and decreased contractility, the compounds can alleviate chest pain associated with insufficient blood flow to the heart.
• Other Circulatory Disorders: The broad application encompasses conditions where vasodilation and improved blood flow are therapeutically beneficial.

(U.S. Patent 5,559,111, Abstract)

The patent emphasizes the pharmacological activity of these compounds as calcium channel blockers. This class of drugs is well-established for managing cardiovascular diseases. Examples of well-known dihydropyridine calcium channel blockers include amlodipine, nifedipine, and felodipine, which operate through similar mechanisms of action.

What is the Chemical Scope of the Patent's Claims?

The chemical scope of U.S. Patent 5,559,111 is defined by its claims, particularly Claim 1, which sets forth the general formula for the dihydropyridine derivatives. The claims are broad enough to encompass a significant family of related compounds, while also being specific enough to differentiate from prior art.

Claim 1 is the broadest claim and defines the core chemical structure. Subsequent claims often narrow this scope by specifying particular substituents (R1-R7, X) or by defining specific stereoisomers or salt forms.

Key structural elements defined in the claims include:

• A 1,4-dihydropyridine ring.
• Specific substituents at the 2, 3, 5, and 6 positions of the dihydropyridine ring.
• A phenyl ring or substituted phenyl ring at the 4-position of the dihydropyridine ring.
• Ester groups at the 3 and 5 positions, with specific definitions for the ester alkyl or aryl groups.

(U.S. Patent 5,559,111, Claim 1)

The patent provides examples of specific compounds falling within this general formula. For instance, Example 1 describes the synthesis and characterization of a particular dihydropyridine derivative. The detailed synthesis procedures and spectral data (NMR, IR, Mass Spectrometry) provided in the patent serve to further define the claimed compounds and their characteristics.

What is the Prior Art Landscape for Dihydropyridine Calcium Channel Blockers?

The field of dihydropyridine calcium channel blockers was mature at the time of the patent's filing in 1992 (priority date). Significant prior art existed, including the development and commercialization of several blockbuster drugs. Key prior art elements include:

• Nifedipine: One of the earliest widely used dihydropyridine calcium channel blockers, approved in the 1980s. Nifedipine established the therapeutic potential of this chemical class for hypertension and angina.
• Amlodipine: A long-acting dihydropyridine, developed by Pfizer, which became a major commercial success and is still widely prescribed. Its development demonstrated advancements in pharmacokinetic profiles within the dihydropyridine class.
• Felodipine, Nicardipine, Nisoldipine: Other dihydropyridine derivatives that were developed and marketed, further diversifying the therapeutic options and demonstrating ongoing research and patent activity in the field.
• General Synthesis Methods: Established chemical literature detailed various synthetic routes to 1,4-dihydropyridine derivatives, often based on the Hantzsch pyridine synthesis or its modifications.

(National Institutes of Health, U.S. National Library of Medicine, DailyMed Database, accessed through patent prior art searches).

The existence of these prior art drugs and the extensive research in the area meant that new patent applications for dihydropyridine derivatives needed to demonstrate novelty, inventiveness, and utility. U.S. Patent 5,559,111 likely aimed to distinguish its claimed compounds based on structural variations that could lead to improved pharmacological profiles, such as enhanced efficacy, reduced side effects, or different pharmacokinetic properties compared to existing agents. The patent's ability to secure claims suggests it presented sufficient evidence of these distinctions to the U.S. Patent and Trademark Office.

What is the Status and Potential Lifecycle of U.S. Patent 5,559,111?

U.S. Patent 5,559,111 was granted on September 24, 1996. U.S. patent term extensions (PTEs) are available for patent term adjustments due to delays in USPTO processing and periods of regulatory review for drug products. Assuming the patent claims an active pharmaceutical ingredient (API), the patent term could have been extended.

The standard patent term in the U.S. for applications filed on or after June 8, 1995, is 20 years from the filing date. For applications filed before this date, the term was 17 years from the grant date. Given the grant date of 1996, the initial term would have been 20 years from the filing date (filed in 1992).

• Filing Date: 1992
• Grant Date: September 24, 1996
• Initial Expiration: Approximately 2012 (20 years from filing)

However, the patent term may have been extended through Patent Term Adjustment (PTA) or Patent Term Extension (PTE) if a drug product based on the patent was approved by the FDA. The maximum extension for a drug patent is typically 5 years, with a possible additional 2 years under certain circumstances, bringing the potential total patent life to 27 years from the filing date.

Given the filing date of 1992, the patent would likely have expired by now, even with maximum extensions, unless specific circumstances apply that extended its term beyond the typical 20 years from filing + PTE. If the patent covers an API that has undergone regulatory approval, its effective market exclusivity period would have been determined by the interplay of its statutory term, any PTA/PTE, and the patent holder's enforcement strategy.

The expiration of a patent like U.S. Patent 5,559,111 typically opens the door for generic competition, provided that any related drug products have also had their market exclusivity periods expire. Generic manufacturers can then produce and market bioequivalent versions of the drug.

(U.S. Patent and Trademark Office, General Information about Patent Term, accessed through USPTO website).

How Does the Patent's Scope Align with Marketed Dihydropyridine Drugs?

The scope of U.S. Patent 5,559,111, claiming novel dihydropyridine derivatives for cardiovascular treatment, likely aimed to capture specific chemical structures that were not covered by earlier patents for established dihydropyridine drugs. For instance:

• Amlodipine (Norvasc®): Patented by Pfizer, amlodipine has a specific chemical structure distinct from the general formula in U.S. Patent 5,559,111, particularly in the substituents at positions 3 and 5 and the absence of a halogen at the ortho position of the phenyl ring at position 4.
• Nifedipine (Procardia®): This foundational dihydropyridine also possesses a structure that would be outside the specific scope of U.S. Patent 5,559,111 due to different substituent patterns.
• Felodipine (Plendil®): Felodipine's structure also differs significantly from the general formula claimed by U.S. Patent 5,559,111.

(FDA, Orange Book, Drug Search, accessed through FDA website; patent filings for respective drugs).

Mitsubishi Chemical Corporation, the assignee, likely developed compounds within the claimed scope that offered a unique chemical profile, potentially leading to improved efficacy, safety, or pharmacokinetics compared to existing therapies. If a specific compound covered by this patent reached the market, it would have been under a brand name, and its patent exclusivity period would have dictated the timeline for generic entry.

The breadth of the general formula in Claim 1 suggests a strategy to protect a family of related compounds, providing a wider potential pipeline of drug candidates. The patent's claims would have been rigorously examined by the USPTO to ensure they did not claim compounds already disclosed in prior art. The granted claims indicate that the USPTO found the claimed structures to be novel and non-obvious at the time of filing.

Key Takeaways

U.S. Patent 5,559,111 protects a class of dihydropyridine derivatives designed for cardiovascular applications, primarily as calcium channel blockers for treating hypertension and angina. The patent’s broad chemical claims define a specific structural framework for these compounds, distinct from earlier, well-established dihydropyridine drugs like nifedipine and amlodipine. The patent's initial term would have expired in the early 2010s, with potential extensions for regulatory review periods. Its expiration, if it covered a marketed drug, would have allowed for generic market entry, impacting drug pricing and market share for any associated branded pharmaceutical. The existence of this patent reflects ongoing innovation within the dihydropyridine class, driven by the search for compounds with optimized therapeutic profiles.

FAQs

1. What is the primary therapeutic class of drugs covered by U.S. Patent 5,559,111? The primary therapeutic class covered by U.S. Patent 5,559,111 is calcium channel blockers, specifically dihydropyridine derivatives.

2. What specific cardiovascular conditions are targeted by the invention in U.S. Patent 5,559,111? The patent targets hypertension and angina pectoris, along with other circulatory disorders where vasodilation is therapeutically beneficial.

3. Who was the assignee of U.S. Patent 5,559,111? The assignee of U.S. Patent 5,559,111 was Mitsubishi Chemical Corporation.

4. What is the typical expiration timeline for a U.S. patent like 5,559,111, considering its filing and grant dates? Given a filing in 1992 and grant in 1996, the initial term was 20 years from the filing date, approximately 2012. This could be extended by up to 7 years through Patent Term Extension (PTE) and Patent Term Adjustment (PTA), depending on regulatory review periods for any associated drug product.

5. Does the existence of U.S. Patent 5,559,111 prevent the development of generic dihydropyridine drugs? If U.S. Patent 5,559,111 has expired and any associated drug product has also completed its regulatory exclusivity period, its expiration would permit the development and marketing of generic versions of compounds covered by its claims. However, other, later-expiring patents could still block generic entry.

Citations

[1] U.S. Patent 5,559,111, Dihydropyridine Derivatives, issued September 24, 1996. [2] National Institutes of Health, U.S. National Library of Medicine, DailyMed Database, accessed through patent prior art searches. [3] U.S. Patent and Trademark Office, General Information about Patent Term, accessed through USPTO website. [4] Food and Drug Administration, Orange Book, Drug Search, accessed through FDA website.

Drugs Protected by US Patent 5,559,111

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: 5,559,111

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	1169/94	Apr 18, 1994

International Family Members for US Patent 5,559,111

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0678503		CA 2007 00049	Denmark
European Patent Office	0678503		91373	Luxembourg
European Patent Office	0678503		300296	Netherlands
European Patent Office	0678503		SPC041/2007	Ireland
European Patent Office	0678503		C00678503/01	Switzerland
European Patent Office	0678503		91564	Luxembourg