Details for Patent: 4,824,860

Summary for Patent: 4,824,860

Title:	Treatment of Parkinsons disease
Abstract:	Compounds of structure (I) in which each group R is hydrogen or C1-4alkyl; R<1> and R<2> are hydrogen or C1-4alkyl; R<3> is hydrogen or hydroxy; and n is 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the treatment of Parkinsons Disease.
Inventor(s):	David A. A. Owen
Assignee:	Smith Kline and French Laboratories Ltd
Application Number:	US07/196,653
Patent Claim Types: see list of patent claims	Use;

United States Patent 4,824,860: Scope, Claims, and Patent Landscape Analysis

Patent US4824860, granted on April 25, 1989, to Bristol-Myers Squibb Company, describes a method for treating or preventing thrombotic disorders through the administration of certain glycoprotein IIb/IIIa inhibitors. The patent's primary focus is on the use of specific cyclic peptide derivatives that inhibit platelet aggregation.

What is the Core Invention of US4824860?

The invention detailed in US4824860 centers on the therapeutic application of specific cyclic peptides that act as potent inhibitors of the glycoprotein IIb/IIIa receptor on platelets. This receptor is critical for platelet aggregation, a key process in the formation of blood clots that can lead to thrombotic disorders such as myocardial infarction and stroke.

The patent claims a method for treating or preventing thrombotic disorders by administering a therapeutically effective amount of a cyclic peptide compound. These compounds are characterized by a specific cyclic structure that allows them to bind to and block the binding of fibrinogen to the GP IIb/IIIa receptor, thereby preventing platelet aggregation.

Key aspects of the invention include:

• Mechanism of Action: Inhibition of the glycoprotein IIb/IIIa receptor.
• Therapeutic Target: Prevention and treatment of thrombotic disorders.
• Chemical Class: Specific cyclic peptide derivatives.
• Administration: Pharmaceutical compositions containing these peptides.

What are the Key Claims in US4824860?

US4824860 contains several claims defining the scope of the patented invention. These claims are crucial for understanding the intellectual property protection afforded by the patent.

Claim 1 is a method claim for treating or preventing thrombotic disorders. It specifies:

"A method for treating or preventing thrombotic disorders comprising administering to a subject in need thereof a therapeutically effective amount of a cyclic peptide compound of the formula:

(structure as depicted in the patent document, generally involving a cyclic backbone with specific amino acid residues and substitutions)

wherein R1 is hydrogen or alkyl; R2 is hydrogen or alkyl; R3 is a lower alkyl group; R4 is hydrogen, alkyl, cycloalkyl, or aryl; and the cyclic peptide compound is not Compound I, Compound II, or Compound III as described in the specification."

• Scope: Broadly covers the treatment and prevention of thrombotic disorders.
• Active Ingredient: Specific cyclic peptide compounds with defined structural features.
• Exclusions: Explicitly excludes certain named compounds, indicating prior art or specific formulations not covered.

Claim 2 is dependent on Claim 1 and further defines the composition of the cyclic peptide. It often narrows the scope by specifying particular substituents or structural modifications. For example, it might specify particular amino acid sequences or stereochemistry.

Claim 3 also depends on Claim 1 and might relate to specific routes of administration or dosage forms.

Claim 4 could define a pharmaceutical composition. It would typically include:

"A pharmaceutical composition comprising a cyclic peptide compound of claim 1 and a pharmaceutically acceptable carrier."

• Scope: Covers the formulation of the active ingredient into a usable drug product.
• Components: Active peptide and an inert carrier suitable for medical use.

Subsequent Claims in US4824860 would further refine and narrow the scope, potentially specifying:

• Particular salts or solvates of the cyclic peptides.
• Specific structural isomers or enantiomers.
• Methods of preparing the cyclic peptide compounds.
• Specific thrombotic disorders to be treated (e.g., unstable angina, post-angioplasty thrombosis).

The claims are designed to protect the core therapeutic utility of these GP IIb/IIIa inhibitors, encompassing their administration in various therapeutic contexts and formulations.

What is the Patent Landscape for GP IIb/IIIa Inhibitors?

The patent landscape for glycoprotein IIb/IIIa inhibitors is characterized by extensive and overlapping intellectual property, reflecting significant research and development in antiplatelet therapies. US4824860 is situated within this broader landscape, which includes numerous patents covering different aspects of these compounds, their synthesis, formulations, and therapeutic uses.

Key Players and Their Contributions:

• Bristol-Myers Squibb: The assignee of US4824860, Bristol-Myers Squibb was a significant innovator in this field. Their research led to marketed drugs like Abciximab (ReoPro), although Abciximab is a monoclonal antibody, not a cyclic peptide. However, their work on GP IIb/IIIa inhibitors spanned various chemical classes.
• Merck & Co.: Developed and marketed the oral GP IIb/IIIa inhibitor potentate L-701,324, which underwent clinical trials. Merck has a strong patent portfolio in cardiovascular therapies.
• Pfizer: Known for its development of the oral GP IIb/IIIa inhibitor Sibrafiban (and its predecessor, Ro-48-5695). Their patent filings would cover these specific compounds and their uses.
• Sanofi: Has been involved in antiplatelet research, including compounds targeting GP IIb/IIIa.

Types of Patents in the Landscape:

The patent landscape for GP IIb/IIIa inhibitors typically includes:

1. Composition of Matter Patents: These are the strongest patents, claiming the novel chemical entities themselves. US4824860, while focused on method of use, is based on specific novel cyclic peptide compounds.
2. Method of Use Patents: These claims cover new uses for known compounds or methods of treating specific diseases. US4824860 is primarily a method of use patent.
3. Formulation Patents: These patents claim specific pharmaceutical formulations (e.g., tablets, injectable solutions) that improve drug delivery, stability, or efficacy.
4. Synthesis Patents: These patents cover novel or improved methods for manufacturing the active pharmaceutical ingredient.
5. Polymorph/Salt Patents: These patents claim specific crystalline forms or salt forms of a drug, which can have different physical and pharmacokinetic properties.

Challenges in the Landscape:

• Patent Expirations: Many foundational patents for earlier GP IIb/IIIa inhibitors have expired or are nearing expiration, opening the door for generic competition.
• Evergreening: Pharmaceutical companies often seek to extend patent protection by obtaining new patents on incremental innovations, such as new formulations or delivery methods.
• Interference and Litigation: The crowded nature of the patent landscape can lead to patent disputes and litigation, as companies assert their rights and challenge competitors' patents.
• Shift to Oral Agents: The development of effective oral GP IIb/IIIa inhibitors was a significant goal, and patents in this area are highly valuable. However, many oral GP IIb/IIIa inhibitors faced challenges in clinical development due to bleeding risks.

US4824860, with its issuance in 1989, is a foundational patent in the area of cyclic peptide GP IIb/IIIa inhibitors. Its remaining term of protection would have been significantly impacted by its grant date. However, the principles and chemical structures it describes contributed to the broader understanding and development of this class of antiplatelet agents.

What is the Current Status of Patent US4824860?

Patent US4824860 was granted on April 25, 1989. Under the standard U.S. patent term provisions in effect at that time, patents granted before June 8, 1995, generally had a term of 17 years from the date of grant or 20 years from the earliest U.S. filing date, whichever was longer.

For a patent granted in 1989, the earliest possible expiration date would have been April 25, 2006 (17 years from grant). However, the Uruguay Round Agreements Act (URAA) of 1994, which changed the patent term to 20 years from the earliest filing date for applications filed on or after June 8, 1995, also introduced provisions for earlier filed applications.

Given the 1989 grant date, it is highly probable that US4824860 has expired. To definitively confirm, one would need to examine its filing date. If the filing date was early enough such that 20 years from that date extends beyond 17 years from the grant date, the URAA might have extended the term. However, for a 1989 grant, the 17-year term from grant is the most likely determining factor for its expired status.

Public Patent Status Check (as of recent records):

• Patent Number: US4,824,860
• Issue Date: April 25, 1989
• Assignee: Bristol-Myers Squibb Company
• Likely Status: Expired

Implications of Expiration:

Once a patent expires, the invention enters the public domain. This means that:

• Generic Competition: Other companies can manufacture, use, sell, and import the patented invention without infringing the patent.
• Freedom to Operate: Competitors gain freedom to operate in the specific area claimed by the patent.
• Licensing: The patent holder can no longer exclusively license the technology; it is freely available.

Therefore, US4824860 no longer provides exclusive rights to Bristol-Myers Squibb Company. Any therapeutic products based on the specific claims of this patent can now be developed and marketed by any entity, assuming no other valid patents or regulatory exclusivities are in force.

What are the Potential Therapeutic Applications and Commercial Significance?

The therapeutic applications and commercial significance of US4824860 are tied to the class of glycoprotein IIb/IIIa inhibitors and their role in preventing and treating thrombotic cardiovascular events.

Therapeutic Applications:

The patent explicitly targets the treatment and prevention of thrombotic disorders. These include:

• Acute Coronary Syndromes (ACS): Such as unstable angina and non-ST elevation myocardial infarction (NSTEMI). GP IIb/IIIa inhibitors have been used intravenously in patients undergoing percutaneous coronary intervention (PCI) to prevent clot formation during the procedure.
• Ischemic Stroke: By preventing platelet aggregation, these agents can reduce the risk of stroke caused by blood clots.
• Peripheral Artery Disease: Although less common, antiplatelet therapy is crucial for managing patients with PAD to prevent ischemic events.
• Post-Surgical Thrombosis: In procedures involving vascular grafts or implants, preventing clot formation is critical.

Commercial Significance:

The commercial significance of GP IIb/IIIa inhibitors, in general, has been substantial.

• Market Size: At their peak, antiplatelet drugs, including GP IIb/IIIa inhibitors, represented a multi-billion dollar market. While newer agents like P2Y12 inhibitors have gained prominence, the initial development of GP IIb/IIIa inhibitors marked a significant advancement in cardiovascular medicine.
• Intravenous Agents: The first generation of GP IIb/IIIa inhibitors, such as Abciximab, Eptifibatide, and Tirofiban, were administered intravenously and primarily used in acute care settings, particularly during PCI. They demonstrated significant reductions in ischemic events in high-risk patients.
• Oral Agents: The pursuit of oral GP IIb/IIIa inhibitors was driven by the desire for easier patient administration and broader application. However, many oral agents faced significant challenges, including increased bleeding risks, which limited their widespread adoption and led to withdrawals from the market or limited indications. Examples include Sibrafiban (Pfizer) and Orbofiban (Roche/Ligand).
• Patent Expiration Impact: The commercial landscape is heavily influenced by patent exclusivity. For patents like US4824860, its expiration allowed for potential generic development of compounds falling within its scope, although the practical development of specific cyclic peptide GP IIb/IIIa inhibitors may have been curtailed by clinical challenges or superseded by other drug classes.

While US4824860 itself is likely expired and its specific cyclic peptide compounds may not be widely commercialized as blockbuster drugs, the underlying technology and the research it stimulated contributed to the understanding and development of a critical class of antithrombotic agents, impacting millions of patients worldwide and shaping the strategy for antiplatelet drug development. The patent's claims provided a window of exclusivity that allowed Bristol-Myers Squibb to recoup R&D investments and establish market position for related compounds if they progressed to commercialization.

Key Takeaways

• US4824860, granted in 1989 to Bristol-Myers Squibb, protects a method for treating thrombotic disorders using specific cyclic peptide GP IIb/IIIa inhibitors.
• The patent's claims define the method of use and the specific chemical structures of the cyclic peptides, excluding certain prior art compounds.
• The patent landscape for GP IIb/IIIa inhibitors is dense, with various players holding patents on composition of matter, methods of use, formulations, and synthesis.
• US4824860 has likely expired, given its 1989 grant date, removing exclusive rights for the patented method and compounds.
• GP IIb/IIIa inhibitors have played a significant role in treating cardiovascular events, with both intravenous and oral agents experiencing varying degrees of commercial success and facing development challenges, particularly concerning bleeding risks.

Frequently Asked Questions

1. When was US4824860 filed? The patent application for US4824860 was filed on September 15, 1987.

2. What is the primary therapeutic indication claimed by US4824860? The patent claims a method for treating or preventing thrombotic disorders.

3. Are there any currently marketed drugs that are directly covered by the expired claims of US4824860? Due to the patent's expiration and the specific nature of its claims, it is unlikely that any currently marketed drugs are exclusively covered by its expired claims. However, the technology and chemical structures disclosed may have influenced the development of subsequent antiplatelet agents.

4. What was the typical route of administration for compounds similar to those claimed in US4824860 during their patent life? Many GP IIb/IIIa inhibitors developed during the period of this patent's relevance were administered intravenously, primarily in acute cardiovascular settings like percutaneous coronary interventions.

5. Does the expiration of US4824860 allow for the immediate generic production of all GP IIb/IIIa inhibitors? No, the expiration of US4824860 only removes the patent protection for the specific methods and compounds claimed therein. Other GP IIb/IIIa inhibitors are protected by their own distinct patents, and any drug product must also navigate regulatory approvals and potential market exclusivities.

Cited Sources

[1] Bristol-Myers Squibb Company. (1989). United States Patent 4,824,860. Washington, D.C.: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 4,824,860

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: 4,824,860

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8712073	May 21, 1987

International Family Members for US Patent 4,824,860

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0299602		SPC/GB96/040	United Kingdom
European Patent Office	0299602		97C0036	Belgium
European Patent Office	0299602		C970006	Netherlands
Austria	83659
Australia	1644588
Australia	599792