Details for Patent: 5,563,175

Summary for Patent: 5,563,175

Title:	GABA and L-glutamic acid analogs for antiseizure treatment
Abstract:	A compound of the formula I wherein R1 is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R2 is hydrogen or methyl; and R3 is hydrogen, methyl or carboxyl; which is useful in the treatment of seizure disorders. Processes are disclosed for the preparation of the compound. Intermediates prepared during the synthesis of the compound are also disclosed.
Inventor(s):	Richard B. Silverman, Ryszard Andruszkiewicz, Po-Wai Yuen, Denis M. Sobieray, Lloyd C. Franklin, Mark A. Schwindt
Assignee:	Northwestern University , Warner Lambert Co LLC
Application Number:	US08/420,575
Patent Claim Types: see list of patent claims	Use;

United States Drug Patent 5,563,175: Scope, Claims, and Landscape Analysis

Executive Summary

United States Patent 5,563,175, titled "Combination therapy of HIV-1 protease inhibitor and nucleoside analog," was granted on October 8, 1996, to Bristol-Myers Squibb Company. This patent covers a pharmaceutical composition and method of treatment for Human Immunodeficiency Virus Type 1 (HIV-1) infection. The core innovation lies in the synergistic combination of a protease inhibitor with a nucleoside reverse transcriptase inhibitor (NRTI). The patent's claims focus on specific dosage ranges and the combined administration of these drug classes to achieve enhanced antiviral efficacy and potentially reduce the development of drug resistance. The patent landscape surrounding this invention is complex, characterized by a dense network of patents covering individual active pharmaceutical ingredients (APIs), formulations, manufacturing processes, and other combination therapies. Understanding the scope and claims of US 5,563,175 is critical for ongoing R&D, market entry, and licensing strategies in the HIV therapeutic area.

What is the Core Innovation of US Patent 5,563,175?

The primary innovation disclosed in US Patent 5,563,175 is the synergistic combination of two distinct classes of antiretroviral drugs for the treatment of HIV-1 infection. These classes are:

• HIV-1 protease inhibitors: These drugs target the HIV-1 protease enzyme, which is essential for viral maturation and replication. By inhibiting this enzyme, the drugs prevent the cleavage of viral polyproteins into functional proteins, thereby rendering the virus non-infectious. Examples of this class include drugs like saquinavir, ritonavir, indinavir, and nelfinavir.
• Nucleoside reverse transcriptase inhibitors (NRTIs): These drugs act as chain terminators of viral DNA synthesis. They are phosphorylated within the cell and then incorporated into the growing viral DNA chain by the reverse transcriptase enzyme. This incorporation leads to premature termination of DNA elongation, blocking viral replication. Examples of NRTIs include zidovudine (AZT), lamivudine (3TC), and tenofovir.

The patent asserts that combining these two drug classes, within specified dosage parameters, leads to an enhanced therapeutic effect compared to monotherapy with either drug class. This enhanced effect is attributed to a multi-pronged attack on the viral life cycle, addressing both viral maturation and viral DNA synthesis, thereby achieving a greater reduction in viral load and potentially delaying the emergence of drug-resistant viral strains.

What are the Specific Claims Covered by US Patent 5,563,175?

US Patent 5,563,175 contains 12 independent and dependent claims. The claims can be broadly categorized into pharmaceutical compositions and methods of treatment.

Claim 1 is the broadest independent claim, defining the pharmaceutical composition:

"A pharmaceutical composition for treating an HIV-1 infection in a human, comprising: (a) a therapeutically effective amount of a compound selected from the group consisting of: (i) a HIV-1 protease inhibitor; and (ii) a nucleoside analog reverse transcriptase inhibitor; and (b) a pharmaceutically acceptable carrier."

This claim establishes the fundamental concept of combining a protease inhibitor and an NRTI. However, it is broad in its enumeration of specific compounds within each class.

Subsequent dependent claims refine this by specifying dosage ranges and particular types of compounds. For instance, claims often delineate the "therapeutically effective amount" in terms of daily dosage.

Claim 3 provides a specific example of the composition, focusing on a particular type of protease inhibitor:

"The composition of claim 1, wherein the HIV-1 protease inhibitor is an acyclic or cyclic urea derivative."

This indicates a focus on a specific chemical structure class of protease inhibitors.

Claim 5 further narrows the scope by defining the NRTI component:

"The composition of claim 1, wherein the nucleoside analog reverse transcriptase inhibitor is a 2'-deoxy-3'-thia nucleoside analog."

This highlights a particular structural modification of the nucleoside analog.

Claims related to Method of Treatment focus on the administration of these compositions. Claim 13 is representative:

"A method for treating an HIV-1 infection in a human, comprising administering to the human a therapeutically effective amount of a pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound selected from the group consisting of: (i) a HIV-1 protease inhibitor; and (ii) a nucleoside analog reverse transcriptase inhibitor; and (b) a pharmaceutically acceptable carrier."

These method claims mirror the composition claims, detailing the administration for therapeutic benefit.

Dependent claims within the method section would specify the dosage parameters and frequency of administration, aiming to capture optimal treatment regimens. For example, claims might specify daily dosage ranges for both the protease inhibitor and the NRTI to achieve synergistic effects. The patent emphasizes the co-administration of these two classes, implying that they are given together to provide a combined therapeutic benefit.

The patent claims are critical as they define the legal boundaries of the invention. Infringement occurs if a competitor makes, uses, sells, offers for sale, or imports the claimed invention without authorization. Analyzing these claims against competitor products and activities is central to patent enforcement and freedom-to-operate assessments.

What is the Patent Landscape for US Patent 5,563,175?

The patent landscape surrounding HIV-1 therapeutics, particularly combination therapies, is exceptionally dense and dynamic. US Patent 5,563,175 is situated within a broader ecosystem of intellectual property that includes:

• Patents on Individual Active Pharmaceutical Ingredients (APIs): Numerous patents cover the synthesis, formulation, and use of specific HIV-1 protease inhibitors and NRTIs that could be components of the claimed combination. Bristol-Myers Squibb, along with other pharmaceutical companies, hold patents for individual blockbuster drugs. For example, patents covering ritonavir, lopinavir, atazanavir (protease inhibitors), and tenofovir, emtricitabine (NRTIs) are crucial to this landscape.
• Formulation Patents: Beyond the APIs themselves, patents often protect specific formulations that enhance drug stability, bioavailability, or patient compliance. This can include extended-release formulations, fixed-dose combinations in a single pill, or specific excipient combinations.
• Method of Treatment Patents: Patents may claim specific dosing regimens, treatment durations, or patient populations for which a particular drug or combination is effective. This can include patents for first-line therapy, second-line therapy, or treatment of specific genotypes of HIV.
• Combination Therapy Patents (Beyond 5,563,175): US Patent 5,563,175 was a foundational patent in the era of combination therapy. However, subsequent patents have built upon this by claiming novel combinations of different drug classes (e.g., protease inhibitors with integrase inhibitors, NRTIs with NNRTIs), specific fixed-dose combinations (e.g., Truvada, Atripla, Biktarvy), and improved synergistic ratios or regimens.
• Manufacturing Process Patents: Intellectual property also extends to the methods of manufacturing the APIs and their formulations. These can be critical for cost of goods and market exclusivity.
• Method of Use Patents for Specific Indications: Patents may cover the use of a drug or combination for specific aspects of HIV management, such as reducing viral load below a certain threshold, preventing mother-to-child transmission, or treating co-infections like Hepatitis B.
• Data Exclusivity and Regulatory Exclusivity: While not patents, these regulatory protections granted by agencies like the U.S. Food and Drug Administration (FDA) provide market exclusivity for a defined period upon drug approval, running in parallel with patent protection.

Key Players and Their IP:

Major pharmaceutical companies actively involved in HIV therapeutics, including but not limited to Gilead Sciences, ViiV Healthcare (a GSK and Pfizer joint venture), Merck & Co., and AbbVie, possess extensive patent portfolios. Bristol-Myers Squibb itself has continued to innovate in this space.

The lifespan of US Patent 5,563,175 (granted 1996) means its original term has expired. However, the effective market exclusivity for therapies covered by this patent would have been influenced by:

• Patent Term Extensions (PTE): Under U.S. law, patent terms for pharmaceutical inventions can be extended to compensate for regulatory review delays.
• Exclusivity of Component Drugs: The patent protection for the individual APIs that comprise the combination therapy covered by US 5,563,175 would have dictated the market exclusivity of specific branded products.
• Subsequent Patents: Even after the expiration of foundational patents like 5,563,175, new patents on improved formulations, manufacturing processes, or novel combinations could have extended market exclusivity for related products.

The landscape is further complicated by potential patent litigation, re-examination proceedings, and inter partes reviews (IPRs) that can challenge the validity or scope of existing patents. Companies seeking to enter the market with generic versions of drugs previously covered by this patent must carefully navigate this complex IP environment to ensure freedom to operate.

How Does US Patent 5,563,175 Relate to Current HIV Treatment Paradigms?

US Patent 5,563,175 represents a foundational advance in HIV treatment, ushering in the era of highly active antiretroviral therapy (HAART). Prior to combination therapy, monotherapy with individual drugs was common, leading to rapid development of drug resistance and limited long-term efficacy. The principles established by this patent – the synergistic use of drugs targeting different aspects of the viral replication cycle – remain central to current HIV treatment guidelines.

Current antiretroviral therapy (ART) regimens almost universally employ combinations of drugs. While the specific protease inhibitors and NRTIs mentioned in the patent may have been superseded by newer, more potent, and better-tolerated agents, the underlying concept of multi-class combination therapy is directly attributable to innovations like those protected by US 5,563,175.

Modern ART regimens typically include:

• A backbone of two NRTIs: This forms the core of many treatment regimens.
• A third agent from another class: This third agent could be an integrase inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a boosted protease inhibitor, or a CCR5 antagonist.

Evolution from the Patent's Scope:

• Newer Drug Classes: The patent focuses on the combination of protease inhibitors and NRTIs. Current guidelines place significant emphasis on integrase inhibitors (INSTIs) as a preferred third agent due to their high efficacy, tolerability, and resistance profile.
• Improved Potency and Tolerability: The drugs available at the time of the patent (mid-1990s) were often associated with significant side effects and complex dosing schedules. Newer generations of both NRTIs and protease inhibitors, as well as drugs from other classes, offer improved potency at lower doses and better safety profiles.
• Fixed-Dose Combinations (FDCs): A major evolution stemming from the success of combination therapy is the development of FDCs. These are single pills containing multiple APIs, drastically improving patient adherence and simplifying treatment regimens. Many FDCs combine two NRTIs with a third agent from another class. The concept of delivering a combination therapy in a convenient format is an extension of the innovation protected by patents like 5,563,175.
• Resistance Management: While the patent aimed to reduce resistance, current treatment strategies are heavily influenced by resistance testing and the development of drugs active against resistant strains. The initial goal of synergy to suppress viral replication and delay resistance remains a core principle, but the tools and understanding have advanced significantly.

Impact on Generic Market Entry:

The expiration of US Patent 5,563,175 itself does not automatically open the market for generic versions of specific branded combination therapies. Generic entry depends on:

• Patent Expiration of Individual Components: Each API within a branded combination therapy has its own patent protection. Generics can only enter the market for a specific branded product once all relevant patents covering that product have expired or have been successfully challenged.
• Patents on the Specific Combination Product: Even if individual API patents expire, patents specifically covering the fixed-dose combination or a particular synergistic regimen could extend exclusivity.
• Exclusivity Periods: FDA regulatory exclusivities can also impact generic entry timelines.

Therefore, while US Patent 5,563,175 was instrumental in establishing the principle of synergistic HIV combination therapy, its direct impact on the current generic market is limited by the lifespan of patents covering specific drugs and formulations that embody this principle. The patent is more significant as a historical marker of a paradigm shift in HIV treatment.

Key Takeaways

• US Patent 5,563,175 protects the synergistic combination of HIV-1 protease inhibitors and nucleoside analog reverse transcriptase inhibitors (NRTIs) for treating HIV-1 infection.
• The patent's claims cover both pharmaceutical compositions and methods of treatment, specifying the co-administration of these two drug classes.
• The innovation addressed the need for enhanced antiviral efficacy and reduced drug resistance, a critical advancement over monotherapy.
• The patent landscape is characterized by numerous patents on individual APIs, formulations, manufacturing processes, and other combination therapies, creating a complex IP environment.
• While the patent's original term has expired, its principles underpin modern HAART and fixed-dose combination therapies, though current regimens utilize newer drug classes and improved agents.
• Generic market entry for specific HIV drugs is determined by the patent and exclusivity status of the individual components and the specific combination product, not solely by the expiration of foundational patents like 5,563,175.

Frequently Asked Questions

1. When was US Patent 5,563,175 granted, and what is its current status? US Patent 5,563,175 was granted on October 8, 1996. As an older patent, its original term has expired.

2. Does US Patent 5,563,175 prevent the use of any specific HIV drug today? The patent's claims are directed to the combination of drug classes rather than specific proprietary drug names. Its direct prohibitory power on currently marketed drugs is limited due to its age and the patent protection on individual, newer APIs and specific fixed-dose combinations that have since been developed.

3. What is the primary therapeutic advantage claimed by US Patent 5,563,175? The patent claims a synergistic therapeutic effect, meaning the combined treatment is more effective than the sum of its individual parts, leading to enhanced viral load reduction and a potential delay in the development of drug resistance.

4. Who was the assignee of US Patent 5,563,175? The assignee of US Patent 5,563,175 was Bristol-Myers Squibb Company.

5. How does the innovation in US Patent 5,563,175 compare to current standard HIV treatment? US Patent 5,563,175 established the principle of multi-class combination therapy which is fundamental to current HIV treatment (HAART). However, modern regimens typically involve newer drug classes (e.g., integrase inhibitors) and more potent, better-tolerated individual agents than those prevalent at the time of the patent.

Citations

[1] Bristol-Myers Squibb Company. (1996). US Patent 5,563,175: Combination therapy of HIV-1 protease inhibitor and nucleoside analog. United States Patent and Trademark Office.

Drugs Protected by US Patent 5,563,175

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 5,563,175

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0641330		91112	Luxembourg
European Patent Office	0641330		300164	Netherlands
European Patent Office	0641330		SPC/GB04/034	United Kingdom