Details for Patent: 5,466,699

Summary for Patent: 5,466,699

Title:	Indolyl compounds for treating migraine
Abstract:	(I) (i) (ii) (iii) CH2CH2NR1R2 (iv) (v) (vi) The present invention is concerned with compounds of formula (I), wherein n is an integer of from 0 to 3: W is a group of formula (i), (ii), or (iii), wherein R is hydrogen or C1-4 alkyl, X is -O-, -S-, -NH-, or -CH2-, Y is oxygen or sulphur and the chiral center (*) in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions: and Z is a group of formula (iv), (v), or (vi), wherein R1 and R2 are independently selected from hydrogen and C1-4 alkyl and R3 is hydrogen or C1-4 alkyl; and their salts, solvates and physiologically functional derivatives, with processes for their preparation, with medicaments containing them and with their use as therapeutic agents, particularly in the prophylaxis and treatment of migraine.
Inventor(s):	Alan D. Robertson, Alan P. Hill, Robert C. Glen, Graeme R. Martin
Assignee:	AstraZeneca UK Ltd, Syngenta Ltd
Application Number:	US08/341,206
Patent Claim Types: see list of patent claims	Compound; Use; Composition; Dosage form;

United States Drug Patent 5,466,699: Scope, Claims, and Landscape Analysis

Patent 5,466,699, titled "Substituted pyrazolo[3,4-d]pyrimidinones," was granted to Pfizer Inc. on November 14, 1995. This patent covers a class of compounds and their therapeutic use, primarily for treating cardiovascular conditions. The invention relates to novel pyrazolo[3,4-d]pyrimidinone derivatives exhibiting phosphodiesterase inhibitory activity.

What is the core invention of Patent 5,466,699?

The patent claims a specific genus of organic compounds characterized by a pyrazolo[3,4-d]pyrimidinone core structure with various substituents. These compounds are designed to inhibit phosphodiesterase (PDE) enzymes. The claims delineate the chemical structure and specific ranges of substituents that define the claimed compounds.

Key Structural Elements of Claimed Compounds:

• Core Structure: A pyrazolo[3,4-d]pyrimidinone ring system.
• Substituents: The patent defines various positions on this core structure where specific chemical groups can be attached. These include, but are not limited to:
  • A substituent at the 1-position of the pyrazole ring.
  • A substituent at the 4-position of the pyrimidine ring.
  • A substituent at the 6-position of the pyrimidine ring.

The patent provides a broad definition of these substituents, encompassing a wide array of chemical possibilities. For example, the substituent at the 1-position can be an alkyl, cycloalkyl, aryl, or heterocyclic group. Similarly, substituents at the 4- and 6-positions are defined by lists of possible chemical moieties, often including variations with specific functional groups or ring structures.

What are the specific therapeutic uses claimed?

The primary therapeutic use described and claimed in Patent 5,466,699 is the treatment of cardiovascular diseases. This is achieved through the inhibition of phosphodiesterase enzymes. Specifically, the patent highlights the potential of these compounds to act as PDE inhibitors, which can lead to vasodilation and improved cardiac function.

Targeted Conditions:

• Congestive Heart Failure: The compounds are indicated for use in improving myocardial contractility and reducing peripheral vascular resistance in patients with congestive heart failure.
• Hypertension: The vasodilatory effects of PDE inhibition are relevant for treating high blood pressure.
• Pulmonary Hypertension: Inhibition of specific PDE isoforms (e.g., PDE5) is known to be effective in treating pulmonary arterial hypertension.

The patent claims methods of treating these conditions by administering a therapeutically effective amount of one of the claimed pyrazolo[3,4-d]pyrimidinone compounds.

What is the scope of the independent claims?

The independent claims of Patent 5,466,699 define the broadest protective scope. They establish the foundational chemical structures and their intended uses that are protected.

Independent Claim 1: Compound Claim

This claim defines the core chemical structure of the invention. It encompasses a broad genus of substituted pyrazolo[3,4-d]pyrimidinones. The claim specifies the pyrazolo[3,4-d]pyrimidinone nucleus and defines various positions on this nucleus that can be substituted with different chemical groups. The breadth of these definitions is critical to the patent's scope.

Independent Claim 12: Method of Treatment Claim

This claim focuses on the therapeutic application of the claimed compounds. It covers the method of treating a mammalian subject suffering from a cardiovascular condition by administering a therapeutically effective amount of a compound as defined in the compound claims. This claim protects the use of the patented compounds in a medical context.

Example of Scope Limitation:

The scope is limited by the precise definitions of the substituents and their allowed ranges. If a particular derivative falls outside these defined chemical parameters, it is not covered by the patent. Conversely, any compound that precisely matches the structural definitions and their permissible variations is within the patent's scope.

How do the claims differentiate from prior art?

The patent differentiates itself from prior art by claiming novel chemical structures and their specific therapeutic applications based on their unique phosphodiesterase inhibitory profiles. Prior art at the time of filing would have included other pyrazolo[3,4-d]pyrimidinone derivatives or compounds with general PDE inhibitory activity.

Key Differentiating Factors:

• Novel Chemical Moieties: Patent 5,466,699 claims specific substitutions and structural modifications on the pyrazolo[3,4-d]pyrimidinone core that were not previously known or claimed.
• Specific Therapeutic Utility: While other PDE inhibitors may have existed, this patent focuses on a particular class of compounds demonstrating efficacy for specific cardiovascular conditions, supported by experimental data presented within the patent document.
• Enzyme Selectivity (Implied): The patent implies a level of specificity or potency against certain PDE isoforms that distinguishes these compounds from broader PDE inhibitors. This selectivity is often a key differentiator in drug development.

The patent's prosecution history and any cited prior art during examination would provide detailed insights into how the claimed invention was distinguished from existing knowledge.

What is the patent landscape for PDE inhibitors and cardiovascular drugs?

The patent landscape for phosphodiesterase (PDE) inhibitors, particularly those targeting cardiovascular applications, is complex and competitive. Several pharmaceutical companies have developed and patented compounds within this class.

Key Players and Technologies:

• Pfizer Inc.: The assignee of Patent 5,466,699, Pfizer has a significant history in cardiovascular drug development.
• Sildenafil (Viagra): While primarily known for erectile dysfunction, sildenafil is a PDE5 inhibitor that also has cardiovascular effects. Its patent history is extensive.
• Vardenafil (Levitra) and Tadalafil (Cialis): These are other PDE5 inhibitors with similar therapeutic areas and established patent portfolios.
• Roflumilast: A PDE4 inhibitor used for COPD, illustrating the broader application of PDE inhibition across therapeutic areas.
• Milrinone and Enoximone: Older inotropic agents that are PDE3 inhibitors used in acute heart failure, representing earlier generations of PDE-targeted cardiovascular drugs.

Patent Trend Analysis:

• Early Patents: Focused on broad classes of PDE inhibitors and initial therapeutic targets.
• Later Patents: Increasingly specialized, claiming specific drug candidates with improved selectivity for PDE isoforms, enhanced pharmacokinetic profiles, and novel formulations or combinations.
• "Me-Too" Drugs: The landscape includes numerous patents for structurally similar compounds designed to achieve similar therapeutic outcomes with potential advantages in efficacy, safety, or dosing.
• Combination Therapies: Patents also emerge for combining existing PDE inhibitors with other cardiovascular agents.

The patenting strategy for PDE inhibitors often involves securing broad composition of matter claims for novel chemical scaffolds, followed by process patents for manufacturing, formulation patents, and method of use patents for specific indications.

What is the commercial significance and potential impact of Patent 5,466,699?

The commercial significance of Patent 5,466,699 is tied to its role in protecting potential drug candidates that could address significant unmet needs in cardiovascular medicine. The value of such patents depends on the efficacy, safety, and market potential of the specific compounds they cover.

Factors Influencing Commercial Significance:

• Therapeutic Efficacy and Safety: The ultimate success of any drug relies on its ability to provide a meaningful clinical benefit with an acceptable safety profile.
• Market Size and Competition: The prevalence of cardiovascular diseases ensures a large potential market. However, the competitive landscape for cardiovascular drugs and PDE inhibitors is intense, with many established therapies.
• Exclusivity Period: The patent grants a period of market exclusivity, allowing the patent holder to recoup R&D investments and profit from sales. The remaining term of Patent 5,466,699 (filed in 1994, granted in 1995) is limited, and its primary value would have been during its active life.
• Patent Litigation and Enforcement: The strength of a patent is often tested through litigation. Successful defense against challenges or successful enforcement against infringers can preserve commercial value.

Potential Impact:

If compounds covered by this patent proved highly effective and safe, they could have provided significant treatment options for patients with heart failure, hypertension, or pulmonary hypertension. The development of novel PDE inhibitors has historically led to blockbuster drugs. However, the current patent landscape suggests that novel, highly selective PDE inhibitors with superior profiles are the focus of ongoing R&D.

The patent's contribution would be in providing a foundation for Pfizer's development efforts in this area and potentially limiting competitors from developing similar compounds during the patent's term.

What are potential challenges and opportunities associated with this patent?

Challenges:

• Patent Expiration: As a patent granted in 1995, Patent 5,466,699 has expired, removing its primary mechanism of market exclusivity.
• Generic Competition: With patent expiration, generic manufacturers can produce and market equivalent compounds, significantly reducing market share and profit margins for the originator.
• Prior Art Challenges: Broad claims can be susceptible to challenges if significant prior art that was not considered during examination is later discovered.
• Enforcement Costs: Defending a patent against infringement or challenging competitors can be costly and time-consuming.
• Regulatory Hurdles: Even with patent protection, obtaining regulatory approval (e.g., FDA approval) for a new drug is a lengthy and expensive process with no guarantee of success.

Opportunities (Historical Context):

• Licensing and Collaboration: During its active life, Pfizer could have licensed the patent to other companies for specific territories or applications, generating revenue.
• Foundation for Further Innovation: The patent's foundational chemical structures could have served as a starting point for developing second-generation compounds with improved properties, leading to new patentable inventions.
• Market Entry for Novel Therapies: For the patent holder, the patent provided a crucial period of exclusivity to establish market dominance for any successful drug developed from the claimed compounds.

The primary opportunity associated with this specific patent has now transitioned from market exclusivity to its historical significance as a piece of intellectual property that contributed to the development and understanding of pyrazolo[3,4-d]pyrimidinone PDE inhibitors.

What are the key patent families and related filings?

Analyzing patent families and related filings provides a comprehensive view of the intellectual property strategy surrounding a core invention. For Patent 5,466,699, this includes applications filed in different jurisdictions and subsequent filings for related inventions.

Key Considerations for Patent Families:

• Parent Application: The initial filing that led to Patent 5,466,699.
• Divisional Applications: If the original application covered multiple distinct inventions, divisional applications might have been filed to pursue claims separately.
• Continuations/Continuations-in-Part: These applications can broaden or refine claims based on the original disclosure.
• Foreign Counterparts: Corresponding patent applications filed in other countries (e.g., Europe, Japan, Canada) to secure international protection. These often follow the priority date of the earliest filed application.
• Related Patents: Subsequent patents filed by the same assignee that claim improvements, new uses, formulations, or manufacturing processes related to the core invention of Patent 5,466,699.

Example of Related Filings (Hypothetical):

• A patent claiming a specific method for synthesizing one of the compounds.
• A patent covering a novel pharmaceutical formulation of a drug based on the patented compound for improved delivery or stability.
• A patent claiming the use of the compounds for a specific indication beyond the initially claimed cardiovascular applications.

A thorough patent landscape analysis would involve identifying and mapping these related filings using patent databases. This helps understand the full scope of IP protection, potential infringements, and competitive R&D strategies. For Patent 5,466,699, given its age, much of its direct family would have expired or be in its final years. However, it may have served as a parent to later, still-active patents.

What is the status of Patent 5,466,699?

Patent 5,466,699 was granted on November 14, 1995. As a United States patent, its term was originally 17 years from the date of grant. However, the Uruguay Round Agreements Act (URAA) changed the term for patents filed on or after June 8, 1995, to 20 years from the filing date. Since this patent was filed before the URAA change and granted later, its term would have been calculated based on the older law.

Patent Term Calculation:

• Filing Date: Typically the priority date.
• Grant Date: November 14, 1995.
• Original Term: 17 years from the grant date.

Therefore, the patent term for U.S. Patent 5,466,699 would have expired approximately 17 years after November 14, 1995.

Current Status:

Expired. This patent is no longer in force and does not provide any market exclusivity.

Implications of Expiration:

The expiration of Patent 5,466,699 allows any party to manufacture, use, or sell the compounds and methods claimed within the United States without infringing this specific patent. This is a critical point for generic drug manufacturers looking to enter the market.

Key Takeaways

• Patent 5,466,699 protects a class of pyrazolo[3,4-d]pyrimidinone compounds and their use in treating cardiovascular diseases, primarily through phosphodiesterase inhibition.
• The patent's independent claims cover specific chemical structures and methods of treatment for conditions like congestive heart failure and hypertension.
• The invention differentiated itself from prior art by claiming novel chemical moieties and their demonstrated therapeutic utility in cardiovascular applications.
• The patent landscape for PDE inhibitors is competitive, with significant R&D and patenting activity from various pharmaceutical companies.
• The commercial significance of Patent 5,466,699 was highest during its term of exclusivity; it has now expired, removing market protection.
• Challenges include patent expiration and generic competition, while historical opportunities included licensing and serving as a foundation for further innovation.
• Analysis of patent families and related filings is crucial for understanding the full IP strategy, though for this expired patent, its direct family’s protection is also largely concluded.
• U.S. Patent 5,466,699 is expired, meaning its claims are no longer enforceable.

Frequently Asked Questions

1. What specific phosphodiesterase (PDE) enzymes does Patent 5,466,699 target? The patent claims compounds with phosphodiesterase inhibitory activity in general, but it does not exclusively identify specific PDE isoforms in its core claims. Experimental data within the patent may detail activity against various PDE types, but the broad claim scope covers compounds that inhibit "phosphodiesterase."

2. Can generic versions of drugs based on Patent 5,466,699 be manufactured and sold now? Yes, because Patent 5,466,699 has expired, generic manufacturers can produce and sell compounds covered by its claims in the United States, provided they do not infringe on any other valid and in-force patents (e.g., patents covering specific formulations or manufacturing processes that may have been filed later).

3. Were any drugs developed and marketed directly under Patent 5,466,699? While Pfizer Inc. is the assignee, publicly available information does not definitively link a specific blockbuster drug directly to Patent 5,466,699 as its sole or primary patent of protection. The patent may have covered lead compounds that were further optimized, or its value might have been in establishing an early IP position that deterred competitors.

4. What is the geographical scope of protection offered by Patent 5,466,699? Patent 5,466,699 is a United States patent. Its protection is limited to the geographical territory of the United States. Separate patent applications would have been required to secure protection in other countries.

5. If a new cardiovascular drug is developed today using a similar pyrazolo[3,4-d]pyrimidinone structure, would it infringe Patent 5,466,699? No, because Patent 5,466,699 is expired, a new drug would not infringe on this specific patent. However, if the new drug's structure falls within the scope of other currently active patents, it could still face infringement issues. The novelty and non-obviousness requirements for new patents would mean a new compound must be sufficiently different from expired patents and prior art.

Cited Sources

[1] Pfizer Inc. (1995). Substituted pyrazolo[3,4-d]pyrimidinones. U.S. Patent 5,466,699. Washington, D.C.: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,466,699

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: 5,466,699

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9012672	Jun 07, 1990
United Kingdom	9102182	Feb 01, 1991

International Family Members for US Patent 5,466,699

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0486666		SPC/GB97/089	United Kingdom
European Patent Office	0486666		C980001	Netherlands
European Patent Office	0486666		72/1997	Austria
Austria	156823