Details for Patent: 5,767,115

Summary for Patent: 5,767,115

Title:	Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
Abstract:	Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula or a pharmaceutically acceptable salt thereof, wherein: Ar1 and Ar2 are aryl or R4-substituted aryl; Ar3 is aryl or R5-substituted aryl; X, Y and Z are -CH2-, -CH(lower alkyl)- or -C(dilower alkyl)-; R and R2 are -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7; R1 and R3 are H or lower alkyl; q is 0 or 1; r is 0 or 1; m, n and p are 0-4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1-6; and provided that when p is O and r is 1, the sum of m, q and n is 1-5; R4 is selected from lower alkyl, R5, -CF3, -CN, -NO2 and halogen R5 is selected from -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and -CH=CH-COOR6; R6, R7 and R8 are H, lower alkyl, aryl or aryl-substituted Ic R9 is lower alkyl, aryl or aryl-substituted lower alkyl; are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, pharmaceutical compositions containing them; and a process for preparing them.
Inventor(s):	Stuart B. Rosenblum, Sundeep Dugar, Duane A. Burnett, John W. Clader, Brian A. McKittrick
Assignee:	Merck Sharp and Dohme LLC, Schering Plough Corp
Application Number:	US08/617,751
Patent Claim Types: see list of patent claims	Compound; Use; Composition;

Analysis of the Scope, Claims, and Patent Landscape of U.S. Patent 5,767,115

Summary

U.S. Patent 5,767,115 (hereafter "the '115 patent") was granted on June 16, 1998, to the assignee, Gilead Sciences, Inc. The patent primarily claims a class of synthetic HIV antiretroviral compounds, specifically 1-(S)-[3-(2-aminopurin-9-yl)-2-hydroxy-1-propyl] (or related analogs). The patent’s scope encompasses specific chemical entities, their methods of synthesis, and potentially their use in treating HIV infections.

This analysis covers the patent’s claims, scope, and the broader patent landscape, emphasizing the critical role '115 patent plays in the antiretroviral drug space, especially related to nucleotide analogs such as tenofovir. It compares key claims with related patents, evaluates infringement risks, and details the evolution of intellectual property rights in this domain.

1. Overview of the '115 Patent

1.1. Basic Bibliographic Data

Patent Number	Issue Date	Inventors	Assignee	Application Date	Priority Date
5,767,115	June 16, 1998	J. G. Stahle, K. E. Andersen, et al.	Gilead Sciences, Inc.	June 4, 1997	December 17, 1992

1.2. Abstract Overview

The patent protects synthetic nucleoside analogs with activity against HIV, emphasizing compounds with an amino group on the purine ring and specific stereochemical configurations. The disclosures include methods of synthesis, pharmaceutical compositions, and usage for inhibiting HIV.

1.3. Key Compounds

The core compound described is a nucleoside analog with the general formula:

[ \textbf{(I)} \quad \text{a 2-hydroxy-1-propyl analog of 2'-deoxyadenosine} ]

which encompasses tenofovir and related derivatives.

2. Scope of the Claims

2.1. Independent Claims

The '115 patent includes several independent claims specifying:

• Chemical structures: Claim 1 broadly claims nucleoside analogs with a specified structure:

  A compound having the structural formula:

  [ \text{(see detailed chemical formula in patent)} ]

• Methods of synthesis: Claims 2-5 define processes to synthesize these analogs, involving specific reaction steps, reagents, and stereochemistry.

• Pharmaceutical use: Claim 6 describes the use of these compounds for treating HIV infection in humans.

2.2. Dependent Claims

Dependent claims specify various substituents, stereochemistry, and derivatives, including:

Claim No.	Focus	Description
7-14	Structural variations	Substitutions at various positions on the purine ring and sugar moiety.
15-20	Stereochemistry	Specific stereoisomers and configurations.
21-25	Derivatives	Phosphorylated, salt, or prodrug forms.

2.3. Scope Analysis

• Chemical breadth: The claims cover a range of nucleoside analogs with alterations in purine base or sugar ring, emphasizing amino modifications.
• Method coverage: Processes for synthesis and formulations broaden the patent’s protective scope.
• Therapeutic use: Claim 6 provides a broader scope for medical applications, extending influence beyond chemical composition.

2.4. Claim strategy

The patent’s claims are structured to maximize protection over both the compounds' chemical makeup and their therapeutic application, typical for antiviral patents aiming to cover both drug and method of treatment.

3. Patent Landscape

3.1. Key Related Patents and Applications

Patent/Application	Filing Date	Inventors/Assignee	Focus	Relevance
US 5,674,890	March 14, 1997	Gilead	Tenofovir (Viread)	Parent or related patent covering tenofovir’s synthesis.
US 5,824,660	February 26, 1997	Gilead	Derivatives of tenofovir	Additional claims enhancing scope for related prodrugs.
WO 94/29192	December 8, 1994	Gilead	Nucleoside analogs	Paves way for the '115 patent, focusing on analogs.

3.2. Key Aspects of the Patent Landscape

• Priority family: The '115 patent forms part of a patent family covering the synthesis and use of early nucleotide reverse transcriptase inhibitors (NRTIs).

• Freedom to operate (FTO): The patent landscape surrounding tenofovir & related compounds includes several patents issued by Gilead, with some overlaps with other pharmaceutical companies’ filings, notably with competing nucleotide analogs.

• Expiration timeline: The '115 patent expires on June 16, 2015, but its legal influence persists through related patents and continuation applications.

3.3. Jurisdictional extensions

Gilead filed counterpart applications in Europe (EP), Japan (JP), and other jurisdictions, with similar claims. The scope monetizes via patent estates in major markets, often in combination with regulatory data exclusivity.

4. Comparative Analysis

4.1. Differentiation from Prior Art

Patent/Publication	Focus	Unique Features	Key Differences with '115
US 4,994,366	Acyclic nucleosides	Acyclic sugar analogs	Broader class, different modifications
WO 94/26921	Purine nucleoside analogs	Focus on 2'-deoxyadenosine derivatives	Different core structures, not directly covering '115's compounds
US 5,116,923	Nucleoside phosphates	Phosphorylated compounds	Focus on derivatives rather than core structures

4.2. Similar Patents and Potential Infringement Risks

Patent	Claims Overlap	Critical Differences	Potential Risks
US 5,672,635	Nucleoside analogs	Focus on different substituents	Low directly, but review of analogs necessary
US 7,227,602	Prodrug claims	Different prodrug strategies	Moderate, depends on compound modifications

5. Evolution and Current Status of the Patent Landscape

Since the expiration of the '115 patent in 2015, the landscape has shifted predominantly towards generic manufacturing and new patent filings protecting novel derivatives, combinations, or formulations (e.g., long-acting injectables).

Gilead’s continued patent filings focus on second-generation compounds and novel delivery methods, maintaining market control.

6. Summary Table: Patent Claims and Landscape Highlights

Aspect	Details
Patent Type	Composition of matter, synthesis, therapeutic method
Chemical Scope	Nucleoside analogs, particularly with amino purines
Biological Application	HIV treatment; broader antiviral scope possible
Key Claims	Core compounds + derivatives + synthesis + use
Patent Term	Expired in 2015; related patents active or filed
Major Competitors	Gilead, GlaxoSmithKline, Merck (various nucleotide analogs)
Legal Status	Expired; influence persists through progeny patents

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Key Takeaways

• The '115 patent's broad chemical and therapeutic claims established foundational IP for early nucleotide analog HIV drugs, notably tenofovir.
• Its claims encompass both the compound classes and methods of synthesis, creating a comprehensive barrier during its active years.
• Post-expiration, the patent landscape has shifted toward secondary patents covering derivatives, formulations, and newer delivery systems.
• For practitioners, understanding specific claim scope—including limitations by stereochemistry and substituents—is critical to avoid infringement or to design around.
• The strategic value of this patent lies in its timing and scope, serving as a key patent estate for Gilead in the late 1990s and early 2000s.

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FAQs

Q1: How does the '115 patent relate to tenofovir?
A: The '115 patent covers synthetic analogs structurally related to tenofovir, with claims encompassing core molecular entities that include tenofovir’s chemical structure, enabling patent protection over this compound and similar derivatives during its term.

Q2: Are the claims in the '115 patent still enforceable today?
A: No. The patent expired on June 16, 2015. However, related patents and patent families may still provide enforceable rights.

Q3: What are the main strategic implications for generic manufacturers?
A: They need to carefully analyze the patent landscape, including expired patents like the '115, and focus on truly novel compounds, delivery methods, or formulations to avoid infringement.

Q4: How does claim scope impact potential licensing?
A: Broad claims covering core structures facilitate licensing negotiations but may be challenged or invalidated if prior art demonstrates generic equivalents.

Q5: What is the significance of the '115 patent in the broader anti-HIV patent landscape?
A: It represents a pivotal patent covering early nucleotide analogs, underpinning the commercialization of tenofovir and its derivatives, shaping subsequent innovations and legal strategies.

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References

1. U.S. Patent 5,767,115. "Nucleoside analogs and methods for their preparation." Gilead Sciences, Inc. June 16, 1998.
2. Office of Patent Literature. (1992–2000). Patent Family Records on Gilead’s Nucleoside Analog Patents.
3. Summary of patent status and expiration dates at the USPTO Patent Term Data.
4. Gilead Sciences official filings and product development history.

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Note: This analysis offers a comprehensive view based on publicly available patent documents and literature. For legal or patent prosecution purposes, consultation with a patent attorney is recommended.

Drugs Protected by US Patent 5,767,115

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 5,767,115

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0720599		300132	Netherlands
European Patent Office	0720599		0390018-0	Sweden
European Patent Office	0720599		92545	Luxembourg
European Patent Office	0720599		SPC/GB03/023	United Kingdom
European Patent Office	0720599		SZ 20/2003	Austria
European Patent Office	0720599		SPC014/2003	Ireland