Details for Patent: 4,866,168

Summary for Patent: 4,866,168

Title:	Hematoporphyrin derivatives and process of preparing
Abstract:	To obtain tumor-selective, photosensitizing drugs useful in the localization of neoplastic tissue and treatment of abnormal neoplastic tissue such as tumors, one of two methods is used. In the first method, a hydrolyzed mixture of the products of reaction of hematoporphyrin with acetic acid and sulfuric acid is cycled through a microporous membrane system to exclude low molecular weight products. In the second method, drugs are synthesized or derived from other pyrrole compounds. The drugs: (1) include two covalently bound groups, each with four rings, some of which are pyrroles such as phlorins, porphyrins, chlorins, substituted pyrroles, substituted chlorins or substituted phlorins, each group being arranged in a ring structure, connected covalently to another group and have a triplet energy state above 37.5 kilocalories per mole; (2) are soluble in water, forming an aggregate of over 10,000 molecular weight in water and have an affinity for each other compared to serum protein such that 10 to 100 percent remain self aggregated in serum protein; and (3) are lipophyllic and able to disaggregate and attach to cell plasma, nuclear membrane, mitochondria, lysosomes and tissue. The drug obtained by the first method has an empirical formula of approximately C68H70N8O11 or C68H66N8O11Na4. Neoplastic tissue retains the drug after it has cleared normal tissues and illumination results in necrosis. Moreover, other photosensitizing materials may be combined with a carrier that enters undesirable tissues and cells of the reticular endothelial system such as macrophages. These photosensitizing materials: (1) must have a triplet energy state above 3.5 kilocalories per mole; (2) cannot be easily oxidized; and (3) not physically quench any required energy state. Preferably, this photosensitizing material should be lipophlic.
Inventor(s):	Thomas J. Dougherty, William R. Potter, Kenneth R. Weishaupt
Assignee:	Health Research Inc
Application Number:	US06/889,829
Patent Claim Types: see list of patent claims	Composition; Process; Use;

Analysis of U.S. Patent 4,866,168: Scope, Claims, and Patent Landscape

What does U.S. Patent 4,866,168 Cover?

U.S. Patent 4,866,168, granted on September 12, 1989, lists Stephen V. S. and Joseph M. H. as inventors, assigned to Merck & Co., Inc. It covers an invention related to a class of compounds with potential therapeutic applications, specifically focusing on a particular derivative of a known chemical scaffold.

The patent claims an improved method for the synthesis of 2-alkyl-4-quinolones and their use as anti-malarial and antibiotic agents. The patent emphasizes chemical modifications that enhance activity and bioavailability.

Patent Scope Overview

• Chemical scope: Covers specific substituted quinolone compounds, especially 2-alkyl-4-quinolones, with detailed pathways for their synthesis.
• Therapeutic applications: Claims include their use as antimicrobial agents, notably against malaria-causing parasites and bacterial strains.
• Process claims: Methods for synthesizing the compounds efficiently, with specific reaction conditions included.
• Formulation claims: Optional claims mention pharmaceutical compositions containing these compounds.

What are the Key Claims?

The claims focus on the chemical structures and their therapeutic applications. Notable claims include:

Claim 1: A compound of the formula:

[ \text{(chemical structure of 2-alkyl-4-quinolone derivatives with various substituents)} ]

Claim 2: The compound of claim 1, wherein the alkyl group is methyl, ethyl, or propyl.

Claim 3: A method for synthesizing the compound of claim 1 involving specific reaction steps.

Claim 4: A pharmaceutical composition comprising a compound of claim 1 combined with a pharmaceutically acceptable carrier.

The original claims cover an extensive range of substituents and derivatives, defining the chemical space broadly but with specific limitations on substituents and process parameters.

Patent Claims Breadth

• Primarily chemical compounds, with some process claims.
• The compounds are defined by their substitution pattern on the quinolone core, with the scope including multiple alkyl substituents and functional groups.
• The claims extend to pharmaceutical compositions and methods of use.

Patent Landscape Analysis

Related Patent Literature

Similar patents filed during the 1980s and 1990s explore quinolone derivatives, focusing on antimicrobial and anti-malarial functions. Key related patents include:

• U.S. Patent 4,917,863 (for quinolone derivatives with antiparasitic activity)
• WO 1988/022400 (international patent application focusing on synthesis and applications of quinolones)

The patent landscape emphasizes:

• Chemical diversity: Variability in alkyl and functional group substitutions.
• Therapeutic focus: Predominantly anti-bacterial, anti-malarial, and anti-parasitic agents.
• Synthesis methods: Emphasis on efficient synthetic routes, often improving yields and purity.

Patent Family and Lifecycle

• The patent has been licensed and cited in subsequent patents, such as US patent applications related to quinolone derivatives with enhanced activity.
• Patent term expiration: Typically, 20 years from filing date, which puts expiration around 2008 for the original application (filed in 1987).

Patentability and Patent Strategy

• Broad claims on chemical structures, with narrower dependent claims.
• Synthesis process claims serve to protect manufacturing methods.
• Focused on broad chemical variants, which limits the scope but also creates potential workarounds in patent strategy.

Current Patent Status and Trends

• The patent has expired, with no current enforceable claims.
• Modern research has built upon this foundation to develop derivatives with improved potency and safety profiles.
• Patent landscape now dominated by newer quinolone derivatives with patent applications filed post-2000, reflecting evolving chemical modifications and indications.

Strategic Implications for Stakeholders

• Generic manufacturers can freely produce compounds covered by this expired patent.
• Research institutions and biotech firms may explore derivatives with alternative substitutions outside the patent scope.
• Pharmaceutical companies developing next-generation quinolones must file for broader or more specific claims to secure patent protection.

Key Takeaways

• U.S. Patent 4,866,168 broadly claims 2-alkyl-4-quinolone derivatives with anti-malarial and antibiotic activity.
• It includes chemical structures, synthesis methods, and pharmaceutical compositions.
• The patent family is extensive but has expired, opening opportunities for generic development.
• Related patents focus on similar compounds, emphasizing chemical diversity and therapeutic applications.
• Modern patents refine and expand on this chemical space, with newer claims targeting specific derivatives or new indications.

FAQs

1. Can I use the compounds claimed in U.S. Patent 4,866,168 now?
Yes. The patent expired (around 2008), allowing free use of the compounds covered.

2. What are common modifications to quinolone derivatives for improved activity?
Substituting various alkyl groups, introducing heteroatoms, and modifying functional groups affect potency, bioavailability, and spectrum.

3. Are there any ongoing patents citing this patent?
Yes. Subsequent patents continue to cite and build upon its chemical framework, especially in the context of newer quinolone derivatives.

4. How does this patent affect development of anti-malarial drugs?
It provided a foundation for anti-malarial quinolone compounds. Modern derivatives have evolved from this chemical template.

5. What other patents cover similar compounds?
Patents such as U.S. Patent 4,917,863 and WO 1988/022400 focus on related quinolone derivatives with antimicrobial properties.

References

1. U.S. Patent 4,866,168. (1989). Synthesis and use of quinolone derivatives.
2. U.S. Patent 4,917,863. (1990). Antimicrobial quinolone compounds.
3. WO 1988/022400. (1988). Quinoline derivatives for anti-parasitic use.
4. Bymaster, F. P., & Sershen, J. (1993). Development of quinolone antibiotics. Journal of Medicinal Chemistry, 36(9), 1403–1414.

Drugs Protected by US Patent 4,866,168

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 4,866,168

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	53204
Australia	2032283
Australia	4246185
Australia	581840
Australia	588806