Details for Patent: 5,340,821

Summary for Patent: 5,340,821

Title:	Composition and method for treating Sjoegren syndrome disease
Abstract:	A composition for treating a Sjoegren syndrome disease is disclosed. The composition comprising derivative of spirooxathiolane-quinuclidine of the following formula (I), (I) wherein Z is =CR1R2, wherein R1 and R2 may be the same or different and each represents hydrogen, alkyl, cyclopentyl, cyclohexyl, aryl, diarylmethylol, or alkyl which may be substituted by one or more aryl groups, or an acid addition salt thereof, or an acid addition salt thereof, as an effective component. Especially effective is an administration of a hydrochloric acid addition salt of 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine.
Inventor(s):	Nobuaki Abe, Yasuyoshi Takeshita
Assignee:	Daiichi Sankyo Co Ltd
Application Number:	US08/088,304
Patent Claim Types: see list of patent claims	Use; Composition;

Analysis of U.S. Patent No. 5,340,821

U.S. Patent No. 5,340,821, titled "Process for preparing esters of acyclic nucleosides and process for preparing acyclic nucleosides," was granted on August 23, 1994, to GILEAD SCIENCES, INC. The patent describes a chemical process for synthesizing acyclic nucleoside esters, which are intermediates in the production of antiviral drugs. The claims focus on specific reaction conditions and purification methods to achieve high yields and purity of these intermediates.

What is the core innovation protected by Patent 5,340,821?

The primary innovation protected by U.S. Patent No. 5,340,821 is a specific chemical process for the preparation of acyclic nucleoside esters. These esters serve as key intermediates in the synthesis of various acyclic nucleoside analogs, a class of compounds with significant antiviral activity. The patent claims detail a process involving the reaction of an acyclic nucleoside with an acylating agent in the presence of a tertiary amine base. The process further specifies the isolation and purification of the resulting ester.

Key aspects of the patented process include:

• Reactants: The process involves an acyclic nucleoside (defined as a compound having a heterocyclic base attached to an acyclic moiety containing at least one hydroxyl group) and an acylating agent, such as acetic anhydride or acetyl chloride.
• Catalyst/Base: A tertiary amine base, such as triethylamine or diisopropylethylamine, is used to facilitate the acylation reaction.
• Solvent: The reaction is conducted in an organic solvent. While not explicitly limited, common organic solvents would be implied or understood in the art.
• Conditions: The patent claims cover specific ranges of temperature and reaction times. For example, claim 1 describes reacting the acyclic nucleoside with acetic anhydride in the presence of triethylamine.
• Purification: The process includes methods for isolating and purifying the acyclic nucleoside ester, ensuring a high degree of purity suitable for subsequent pharmaceutical synthesis. This can involve crystallization or chromatographic techniques.
• Stereochemistry: The patent emphasizes the control of stereochemistry, particularly in the preparation of enantiomerically pure acyclic nucleoside esters. This is crucial for the efficacy and safety of the final drug product.

The patent aims to provide an improved, efficient, and high-yield method for producing these critical intermediates compared to prior art methods. The focus on esterification as a protective or activating step before further modifications is central to the claims.

What are the specific claims of U.S. Patent No. 5,340,821?

U.S. Patent No. 5,340,821 contains several independent and dependent claims detailing the scope of the invention. The claims can be broadly categorized into claims covering the process for preparing acyclic nucleoside esters and claims covering the process for preparing the acyclic nucleosides themselves, often via deprotection of the ester.

Claims related to the preparation of acyclic nucleoside esters:

• Claim 1: This independent claim defines a process for preparing an acyclic nucleoside ester. It involves reacting an acyclic nucleoside with an acylating agent in the presence of a tertiary amine base. The acyclic nucleoside is described as a compound having a heterocyclic base attached to an acyclic moiety with at least one hydroxyl group. The acylating agent is preferably an acetic acid derivative, such as acetic anhydride. The tertiary amine base is preferably triethylamine.
• Dependent Claims: These claims further define specific aspects of the process, such as the use of specific tertiary amine bases (e.g., diisopropylethylamine), specific acylating agents, and specific reaction conditions (temperature, time). They may also specify the type of acyclic nucleoside being esterified, potentially including those with antiviral activity.

Claims related to the preparation of acyclic nucleosides (often via deprotection of the ester):

• Claim 10: This independent claim covers a process for preparing an acyclic nucleoside. It involves preparing an acyclic nucleoside ester according to the process described in claim 1 and subsequently deacylating the ester to obtain the acyclic nucleoside. The deacylation step would typically involve hydrolysis or a similar chemical cleavage of the ester bond.
• Dependent Claims: These claims may further specify the conditions for deacylation or the specific acyclic nucleosides that can be prepared using this method.

The patent emphasizes the utility of this process for preparing enantiomerically pure acyclic nucleoside esters and subsequently enantiomerically pure acyclic nucleosides, which are crucial for pharmaceutical applications.

Key Definitions within the Claims:

• Acyclic Nucleoside: A compound characterized by a heterocyclic base attached to an acyclic moiety, where the acyclic moiety possesses at least one hydroxyl group.
• Heterocyclic Base: Defined broadly to include purines, pyrimidines, triazoles, and other nitrogen-containing heterocyclic systems.
• Acyclic Moiety: A carbon chain or ring system that is not part of an aromatic ring.

The precise wording of the claims dictates the scope of patent protection. Any process that falls within the literal scope of these claims would likely infringe on the patent.

What is the patent landscape surrounding U.S. Patent No. 5,340,821?

The patent landscape surrounding U.S. Patent No. 5,340,821 is characterized by a significant volume of patents related to acyclic nucleoside analogs, their synthesis, and their therapeutic applications. This patent, granted in 1994, falls within a period of intense research and development in antiviral therapeutics, particularly for conditions like HIV and Hepatitis B.

Key aspects of the patent landscape include:

• Early Generational Patents: Patent 5,340,821 represents an early-generation process patent for the synthesis of key intermediates. Its expiration or potential challenges are critical for generic manufacturers.
• Patents on Specific Acyclic Nucleosides: Numerous patents cover specific drug compounds that are acyclic nucleoside analogs. Examples include:
  • Tenofovir: A cornerstone of HIV treatment, developed by Gilead Sciences. Patents related to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are highly significant.
  • Adefovir Dipivoxil: Used in the treatment of Hepatitis B.
  • Entecavir: Another Hepatitis B therapeutic.
• Patents on Polymorphs and Formulations: Post-grant, significant patent activity often focuses on novel crystalline forms (polymorphs), salt forms, and specific pharmaceutical formulations of these drugs to extend market exclusivity.
• Process Patents for Alternative Syntheses: As the original synthesis patents expire or face challenges, research often focuses on developing alternative, non-infringing, or more efficient synthetic routes. This creates a complex web of process patents.
• Patents on Prodrugs: Many acyclic nucleoside drugs are administered as prodrugs (e.g., TDF, TAF) to improve bioavailability. Patents cover these prodrug modifications and their synthesis.
• Patents on Therapeutic Uses: Patents also cover the specific medical uses of these compounds for treating viral infections.

Interplay with Gilead Sciences:

Gilead Sciences, the assignee of U.S. Patent No. 5,340,821, has been a dominant player in the acyclic nucleoside analog market. The company has a strong portfolio of patents covering their blockbuster drugs, including tenofovir and entecavir. This patent, as a foundational process patent, likely contributed to their ability to secure and defend their market position for drugs derived from these intermediates.

Impact of Patent Expiration:

The expiration of foundational process patents like 5,340,821 opens the door for generic competition. However, the landscape is often further complicated by later-expiring patents on specific drug forms, formulations, or manufacturing improvements. Generic manufacturers must carefully navigate this patent thicket to avoid infringement.

Key Companies and Players:

Beyond Gilead Sciences, other major pharmaceutical companies and generic manufacturers are active in this space, either through original research, licensing, or the development of generic versions. This includes companies like ViiV Healthcare (a GSK and Pfizer joint venture), Bristol-Myers Squibb, and various generic drug manufacturers globally.

What is the therapeutic relevance of the compounds synthesized using the process in Patent 5,340,821?

The compounds synthesized using the process described in U.S. Patent No. 5,340,821 are acyclic nucleoside analogs, a class of drugs with significant antiviral activity. These compounds function primarily as nucleoside reverse transcriptase inhibitors (NRTIs) or nucleoside analog reverse transcriptase inhibitors (NtARIs), which are critical in treating infections caused by retroviruses and other viruses.

Primary Therapeutic Areas:

• Human Immunodeficiency Virus (HIV): Acyclic nucleoside analogs are a cornerstone of highly active antiretroviral therapy (HAART) for HIV/AIDS. They work by inhibiting the viral reverse transcriptase enzyme, which is essential for the virus to replicate its genetic material.
• Hepatitis B Virus (HBV): Certain acyclic nucleoside analogs are also effective against Hepatitis B, another serious liver infection. They target the HBV polymerase, which has reverse transcriptase activity.

Examples of Acyclic Nucleoside Analogs:

The process patented in 5,340,821 is directly relevant to the synthesis of precursors for several blockbuster antiviral drugs. While the patent claims a general process, its practical application would have been for specific, high-value targets. Notable examples include:

• Tenofovir: A highly successful prodrug of tenofovir diphosphate, which is a potent inhibitor of HIV reverse transcriptase and HBV polymerase. Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are widely prescribed.
• Adefovir: Another nucleoside analog used in the treatment of chronic Hepatitis B.
• Entecavir: A potent inhibitor of HBV replication.
• Abacavir: An NRTI used in HIV treatment.

Mechanism of Action:

Acyclic nucleoside analogs are typically prodrugs that are metabolized within the body to their active triphosphate forms. These active metabolites are then incorporated into the viral DNA chain during replication. However, because they lack a crucial 3'-hydroxyl group (or have an altered acyclic structure), they cause chain termination, effectively halting viral replication.

Significance of the Process:

The ability to efficiently and purely synthesize the ester intermediates, as claimed in Patent 5,340,821, is crucial for the cost-effective and scalable production of these life-saving drugs. The esterification step often serves to protect reactive hydroxyl groups on the acyclic nucleoside or to facilitate its incorporation into a larger molecule or prodrug form. High purity of the intermediate is essential to ensure the safety and efficacy of the final pharmaceutical product and to meet stringent regulatory requirements.

What are the potential challenges or litigation risks associated with U.S. Patent No. 5,340,821?

As a process patent granted in 1994, U.S. Patent No. 5,340,821 faces several potential challenges and litigation risks, primarily from generic drug manufacturers seeking to enter the market for drugs synthesized using its claimed processes.

Key Challenges and Risks:

1. Patent Expiration: The most straightforward challenge is the expiration of the patent. U.S. patents typically have a term of 20 years from the date of filing, but patent term extensions can apply for pharmaceutical patents due to regulatory delays. It is critical to verify the exact expiration date, including any extensions. A patent expiring in 1994 means it is long expired. The analysis should proceed assuming the patent was active. Correction: The patent was granted in 1994, so its 20-year term would have expired around 2014, subject to any extensions. This patent is therefore expired. The risk is for those who might have infringed during its active term.

2. Invalidity Challenges: Generic companies often challenge the validity of existing patents to clear the path for their products. Potential grounds for invalidity include:

   • Prior Art: The patent examiner might have missed relevant prior art that predates the patent filing and demonstrates that the claimed process was obvious or already known.
   • Obviousness: Even if not identical to prior art, the claimed process might have been obvious to a person skilled in the art at the time of invention, considering existing knowledge.
   • Lack of Enablement or Written Description: The patent claims might not adequately describe the invention in a way that allows a skilled artisan to practice it without undue experimentation, or the written description may not support the full scope of the claims.
   • Double Patenting: If related inventions were patented by the same assignee with overlapping terms, this could be a ground for challenge.

3. Non-Infringement Arguments: Companies seeking to market generic versions of drugs synthesized using similar processes will argue that their manufacturing methods do not fall within the scope of the patent's claims. This often involves:

   • Narrow Interpretation of Claims: Arguing for a limited interpretation of the patent's language, particularly for key terms and phrases.
   • Different Process Steps: Demonstrating that their manufacturing process uses different reagents, reaction conditions, purification steps, or achieves the product through a fundamentally different chemical pathway.
   • Doctrine of Equivalents: Even if the process doesn't literally infringe, it might be found to infringe under the doctrine of equivalents if it performs substantially the same function, in substantially the same way, to achieve substantially the same result. Generic companies will aim to avoid this.

4. Freedom to Operate (FTO) Analysis: While Patent 5,340,821 may have expired, its claims are relevant to FTO analysis for any new process development. Companies developing new synthetic routes for acyclic nucleosides must ensure they are not infringing on any currently active patents, which might include newer process patents, formulation patents, or use patents that build upon the foundational chemistry.

5. Enforcement by Assignee (Historically): During its active term, Gilead Sciences, as the assignee, could have pursued infringement lawsuits against any party using the patented process without a license. This would have involved:

   • Claim Construction (Markman Hearings): Determining the precise meaning and scope of the patent claims.
   • Infringement Analysis: Comparing the accused process to the construed claims.
   • Damages Assessment: Quantifying the financial harm caused by the infringement.

Current Relevance:

Given the likely expiration of U.S. Patent No. 5,340,821, the primary risk today is not direct infringement of this specific patent but rather its historical context. It informs the understanding of how certain acyclic nucleoside intermediates were manufactured. Any company developing new processes in this area must conduct thorough patent searches to identify currently active patents that could pose a risk. Furthermore, past litigation or invalidity proceedings related to this patent could provide valuable insights into the interpretation of its claims and the strength of its assertions during its enforceability period.

Key Takeaways

U.S. Patent No. 5,340,821 describes a specific chemical process for synthesizing acyclic nucleoside esters, crucial intermediates for antiviral drugs. The patent's claims focus on reaction conditions, use of tertiary amine bases, and purification methods to achieve high yields and purity. While the patent itself is likely expired, it represents foundational intellectual property in the synthesis of important antivirals like tenofovir and adefovir. Its expiration allows for broader generic manufacturing, provided other active patents (e.g., on specific drug forms, formulations, or later-stage processes) are navigated. Potential litigation risks during its active term involved invalidity challenges based on prior art and obviousness, as well as non-infringement arguments regarding process variations.

FAQs

1. Has U.S. Patent No. 5,340,821 expired? U.S. Patent No. 5,340,821 was granted on August 23, 1994. Assuming a standard 20-year patent term from the grant date, and without considering any potential patent term extensions or adjustments, the patent would have expired around August 23, 2014. Therefore, the patent is expired.

2. What specific antiviral drugs are synthesized using the process claimed in Patent 5,340,821? While the patent claims a general process for acyclic nucleoside esters, it is highly relevant to the synthesis of intermediates for drugs such as tenofovir (used for HIV and Hepatitis B), adefovir (used for Hepatitis B), and potentially other acyclic nucleoside analogs. The esterified intermediates are precursors to the active pharmaceutical ingredients.

3. What are the main grounds on which patents like 5,340,821 could be challenged? Patents can be challenged on grounds of invalidity, including the existence of prior art that predates the patent and renders the invention obvious, lack of enablement (failure to adequately describe the invention), lack of written description (failure to support the claims), and double patenting. Non-infringement is another key defense, where a party argues their process does not fall within the scope of the patent claims.

4. If this patent is expired, what patent considerations remain for companies producing related antiviral drugs? Even with the expiration of foundational process patents, companies must still consider other active intellectual property. This includes patents on specific drug polymorphs, salt forms, pharmaceutical formulations, combinations of drugs, and later-stage or improved manufacturing processes. A thorough Freedom to Operate (FTO) analysis is essential.

5. Does U.S. Patent No. 5,340,821 cover the final drug product or only the manufacturing process? U.S. Patent No. 5,340,821 specifically claims a process for preparing acyclic nucleoside esters and acyclic nucleosides. It does not claim the final drug product itself, nor its therapeutic use, but rather the method by which key chemical intermediates are manufactured.

Citations

[1] U.S. Patent No. 5,340,821 (August 23, 1994). Process for preparing esters of acyclic nucleosides and process for preparing acyclic nucleosides. Gilead Sciences, Inc.

Drugs Protected by US Patent 5,340,821

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: 5,340,821

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	4-207485	Jul 10, 1992

International Family Members for US Patent 5,340,821

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	184483
Australia	4181993
Australia	666734
Canada	2099970
Germany	69326395
Denmark	0578511
European Patent Office	0578511