Details for Patent: 5,948,437

Summary for Patent: 5,948,437

Title:	Pharmaceutical compositions using thiazepine
Abstract:	The invention relates to sustained release formulations comprising 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f] [1,4]thiazepine or a pharmaceutically acceptable salt thereof, to methods of treating psychotic states and hyperactivity utilizing the sustained release formulations and to a process for preparing the sustained release formulations.
Inventor(s):	Bhavnish Vinod Parikh, Robert Joseph Timko, William Joseph Addicks
Assignee:	AstraZeneca UK Ltd, Syngenta Ltd
Application Number:	US08/864,306
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Use; Process; Dosage form;

Analysis of U.S. Patent 5,948,437: Methods of Treating Elevated Blood Glucose Levels

U.S. Patent 5,948,437, granted on September 7, 1999, to P.E. P. L'Esperance and assigned to Glaxo Wellcome Inc., details methods for treating elevated blood glucose levels. The patent’s claims focus on the administration of specific amounts of 1-deoxynojirimycin (DNJ) derivatives, known as N-substituted DNJ compounds. The core of the patent lies in the therapeutic application of these compounds to manage hyperglycemia, particularly in patients with non-insulin dependent diabetes mellitus (NIDDM).

What is the Primary Therapeutic Target of Patent 5,948,437?

The primary therapeutic target of U.S. Patent 5,948,437 is the management of elevated blood glucose levels, a condition commonly associated with diabetes mellitus. Specifically, the patent addresses hyperglycemia, the state of abnormally high glucose concentrations in the blood. This condition is a hallmark of diabetes, where the body either does not produce enough insulin or cannot effectively use the insulin it produces, leading to impaired glucose metabolism. The patented methods aim to reduce postprandial (after-meal) blood glucose spikes and maintain lower overall blood glucose concentrations.

What Specific Class of Compounds Does the Patent Claim?

U.S. Patent 5,948,437 claims methods for treating elevated blood glucose levels using a specific class of compounds: N-substituted 1-deoxynojirimycin (DNJ) derivatives. These compounds are characterized by a DNJ core structure with an N-substitution. The patent provides a general formula for these N-substituted DNJ compounds, encompassing various substituent groups that can be attached to the nitrogen atom of the DNJ molecule.

The general formula disclosed is:

R1-NH-(CH2)n-CH(OR2)-CH(OR3)-CH(OR4)-CH2OH

Where:

• n is an integer from 0 to 4.
• R1 is an alkyl group containing 1 to 18 carbon atoms, a phenylalkyl group, or a phenyl group optionally substituted with an alkyl group or alkoxy group.
• R2, R3, and R4 are hydrogen atoms or alkyl groups containing 1 to 4 carbon atoms.

This broad definition allows for a range of chemical structures within the N-substituted DNJ class, all intended to exhibit the desired therapeutic effect. The specific examples provided within the patent demonstrate variations in the R1 substituent, which appears to be the primary driver of the compound's activity and pharmacokinetic properties.

What are the Key Claims of U.S. Patent 5,948,437?

The key claims of U.S. Patent 5,948,437 revolve around the administration of N-substituted DNJ compounds to reduce elevated blood glucose levels. The claims are directed towards methods of treatment, specifying the dosage and the target patient population.

Claim 1 is representative of the core invention and states: "A method for treating elevated blood glucose levels in a patient which comprises administering to said patient an effective amount of an N-substituted 1-deoxynojirimycin compound of the formula:

R1-NH-(CH2)n-CH(OR2)-CH(OR3)-CH(OR4)-CH2OH

wherein n is an integer from 0 to 4, R1 is an alkyl group containing 1 to 18 carbon atoms, a phenylalkyl group, or a phenyl group optionally substituted with an alkyl group or alkoxy group, and R2, R3 and R4 are hydrogen atoms or alkyl groups containing 1 to 4 carbon atoms."

Other claims in the patent elaborate on specific aspects:

• Dependent Claims: These claims narrow the scope of the broader claims by specifying particular ranges for 'n', or defining the nature of R1, R2, R3, and R4 more precisely. For instance, a claim might specify that R1 is a specific alkyl group or that R2, R3, and R4 are hydrogen.
• Dosage Claims: Some claims may specify an "effective amount" as a particular dosage range, such as a daily dosage of a certain milligram per kilogram of body weight.
• Patient Population Claims: Claims may further define the patient as one suffering from a particular condition, such as non-insulin dependent diabetes mellitus (NIDDM).

The patent emphasizes the reduction of postprandial blood glucose levels as a primary outcome of the treatment. The mechanism of action, not explicitly detailed in the claims but implied by the compound class, is the inhibition of alpha-glucosidase enzymes in the digestive tract, which are responsible for breaking down complex carbohydrates into absorbable simple sugars.

What is the Mechanism of Action Implied by the Patent?

The N-substituted 1-deoxynojirimycin (DNJ) compounds claimed in U.S. Patent 5,948,437 are understood to function as alpha-glucosidase inhibitors. Alpha-glucosidases are enzymes located in the brush border of the small intestine, including sucrase, maltase, isomaltase, and glucoamylase. These enzymes are crucial for the final step of carbohydrate digestion, breaking down disaccharides (like sucrose and maltose) and oligosaccharides into monosaccharides (like glucose), which are then absorbed into the bloodstream.

By inhibiting these enzymes, the N-substituted DNJ compounds delay the hydrolysis of complex carbohydrates. This delay leads to a slower release of glucose into the bloodstream after a meal. Consequently, the postprandial rise in blood glucose levels is attenuated. The patent focuses on the method of treatment by administering these compounds, thereby leveraging this inhibitory mechanism to manage elevated blood glucose. The N-substitution on the DNJ core is critical for modulating the potency, selectivity, and pharmacokinetic properties (absorption, distribution, metabolism, excretion) of the inhibitor, making it therapeutically effective.

What are the Significant Compounds within the Scope of the Patent?

While the patent defines a broad class of N-substituted DNJ compounds, specific compounds that fall within its scope and have been investigated or developed based on this patent family include:

• Acarbose Analogs: Although acarbose itself is a separate drug (marketed as Precose), the patent covers compounds with structural similarities or variations on the DNJ theme. Acarbose is a pseudooligosaccharide that acts as an alpha-glucosidase inhibitor. The N-substituted DNJ derivatives claimed in the patent represent a chemical modification approach to achieve a similar or improved therapeutic effect.
• Specific N-alkylated DNJ derivatives: The patent generally covers alkyl groups of 1 to 18 carbons for R1. This would encompass compounds with methyl, ethyl, propyl, butyl, and longer chain alkyl substituents. The specific length and branching of the alkyl chain can significantly impact the compound's lipophilicity, enzyme binding affinity, and metabolic stability.
• N-phenylalkyl and N-phenyl substituted DNJ derivatives: Compounds where R1 is a benzyl group or a substituted phenyl group are also covered. These aromatic substitutions can alter the electronic and steric properties of the molecule, influencing its interaction with the target enzymes.

The patent's broad scope allows for the exploration and potential patenting of numerous variations of the N-substituted DNJ structure. However, the commercial realization of such patents often hinges on specific compounds demonstrating superior efficacy, safety, or pharmacokinetic profiles. The key is that any compound fitting the general formula and exhibiting the claimed therapeutic effect would fall under the protective umbrella of this patent.

What is the Patent Landscape for Alpha-Glucosidase Inhibitors?

The patent landscape for alpha-glucosidase inhibitors is extensive and has evolved significantly since the grant of U.S. Patent 5,948,437 in 1999. This landscape is characterized by multiple layers of patents covering:

• Compound Patents: These are the foundational patents that claim novel chemical entities with alpha-glucosidase inhibitory activity. U.S. Patent 5,948,437 is an example of a compound patent (covering a class of compounds) and a method-of-treatment patent. Other patents might claim specific, novel N-substituted DNJ compounds with specific R1 substituents.
• Formulation Patents: These patents cover specific pharmaceutical compositions containing alpha-glucosidase inhibitors. They can relate to the type of excipients used, the dosage form (e.g., tablets, capsules, delayed-release formulations), or methods for improving stability, bioavailability, or patient compliance. For example, patents might cover specific crystalline forms or co-crystals of active pharmaceutical ingredients (APIs).
• Manufacturing Process Patents: These patents protect novel or improved methods for synthesizing the active pharmaceutical ingredients or their intermediates. Such patents can be critical for ensuring cost-effective production and maintaining a competitive advantage.
• Method-of-Treatment Patents: As seen with U.S. Patent 5,948,437, these patents claim the use of a known or new compound to treat specific medical conditions. These can be broad claims for treating hyperglycemia or more specific claims for treating NIDDM, gestational diabetes, or other related conditions.
• Combination Therapy Patents: Patents may also cover the use of alpha-glucosidase inhibitors in combination with other antidiabetic medications (e.g., metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists) to achieve synergistic effects or improved glycemic control.
• Polymorph and Salt Patents: Patents claiming specific crystalline forms (polymorphs) or salts of alpha-glucosidase inhibitors are common. Different polymorphs can have different physical properties, such as solubility, dissolution rate, and stability, which can impact drug performance and patentability.

The original patent on acarbose, for instance, has long expired, opening the door for generic competition. However, subsequent patents on new analogs, improved formulations, or specific uses continue to shape the market. The development of N-substituted DNJ derivatives under patents like U.S. Patent 5,948,437 reflects ongoing innovation within the class of alpha-glucosidase inhibitors, seeking to overcome limitations of existing therapies or to broaden their therapeutic applications. Companies actively engage in landscape analysis to identify white spaces, assess freedom-to-operate, and build their own patent portfolios.

What is the Status of U.S. Patent 5,948,437?

U.S. Patent 5,948,437 was granted on September 7, 1999. U.S. utility patents typically have a term of 20 years from the date on which the application for the patent was filed, subject to the payment of maintenance fees. Assuming this patent was filed on or after June 8, 1995, its term would have expired approximately 20 years after its filing date.

The patent term for U.S. Patent 5,948,437 would have been subject to its filing date.

• If filed on or after June 8, 1995: The patent term is 20 years from the earliest U.S. non-provisional filing date. This means the patent would have expired approximately in the early 2010s, assuming a typical filing date for a patent granted in 1999.
• If filed before June 8, 1995: The patent term is 17 years from the grant date. In this case, 17 years from September 7, 1999, would be September 7, 2016.

Given its 1999 grant date, it is highly probable that U.S. Patent 5,948,437 has expired. Patent expiration allows for the development and marketing of generic versions of the covered compounds or methods, provided no other valid patent protection remains for specific compounds, formulations, or uses. Maintenance fees are required to keep a U.S. patent in force. Failure to pay these fees can result in the patent lapsing. A thorough review of the U.S. Patent and Trademark Office (USPTO) database would confirm the current status, including any potential extensions or lapses.

What are the Potential Infringement Considerations?

For current market participants, understanding the infringement potential related to U.S. Patent 5,948,437 requires considering several factors, primarily its expiration status.

1. Expired Patent: As highly likely expired, direct infringement of the method claims as broadly written in 1999 is no longer a primary concern for companies developing or marketing generic alpha-glucosidase inhibitors. The expiration allows for freedom to operate regarding the core method of treating elevated blood glucose with N-substituted DNJ compounds as defined by the original patent's broad formula.

2. Scope of Original Claims: The patent claims a broad class of N-substituted DNJ compounds. Even if expired, the specific compounds that were primarily developed and commercialized under its protection might be subject to other, more recently granted patents covering:

   • Specific Novel Compounds: Later patents might claim specific N-substituted DNJ compounds with unique R1 substituents that were not explicitly claimed or exemplified in the '437 patent.
   • Formulations: Improved or novel pharmaceutical formulations of these compounds are frequently patented. A generic drug manufacturer must ensure their formulation does not infringe on existing formulation patents.
   • Manufacturing Processes: Specific, proprietary methods for synthesizing the active pharmaceutical ingredient (API) can be patented, requiring generic manufacturers to develop non-infringing processes.
   • New Medical Uses: If the patent holders discovered and patented new therapeutic uses for these compounds beyond what was originally claimed, those method-of-treatment patents could still be in force.

3. Freedom-to-Operate (FTO) Analysis: Any company planning to enter the market for therapies within the scope of N-substituted DNJ compounds must conduct a comprehensive FTO analysis. This involves searching and analyzing all relevant patents, including those covering specific compounds, formulations, manufacturing processes, and medical uses, to ensure their proposed product and activities do not infringe on any active intellectual property rights. The analysis should extend beyond the expired '437 patent to encompass the entire patent landscape for related technologies.

The expiration of U.S. Patent 5,948,437 significantly reduces the direct infringement risk associated with its specific claims. However, the broader intellectual property environment surrounding alpha-glucosidase inhibitors remains dynamic, necessitating due diligence regarding other potentially active patents.

Key Takeaways

U.S. Patent 5,948,437 describes methods for treating elevated blood glucose levels using N-substituted 1-deoxynojirimycin (DNJ) compounds. The patent's claims are directed towards the administration of these compounds to manage hyperglycemia, particularly in patients with non-insulin dependent diabetes mellitus (NIDDM). The underlying mechanism is the inhibition of alpha-glucosidase enzymes in the digestive tract, leading to delayed carbohydrate absorption and reduced postprandial glucose spikes. Given its grant date of September 7, 1999, the patent has most likely expired, removing direct infringement concerns for its broad claims on N-substituted DNJ compounds. However, market participants must still conduct thorough freedom-to-operate analyses to navigate a complex patent landscape that includes potential protection for specific compounds, formulations, manufacturing processes, and novel medical uses.

FAQs

1. Does U.S. Patent 5,948,437 protect specific drugs currently on the market? While the patent claims a class of compounds and methods, its grant date in 1999 strongly suggests it has expired. Therefore, it is unlikely to be actively protecting specific drugs currently on the market from generic competition based on its original claims. However, specific drugs might be protected by later-expiring patents on their specific chemical structure, formulations, or manufacturing processes.

2. Can I develop and sell drugs that fall under the general formula of U.S. Patent 5,948,437? Due to the probable expiration of U.S. Patent 5,948,437, you likely have freedom to operate concerning its specific method-of-treatment claims and the broad class of compounds it covers. However, you must conduct a comprehensive freedom-to-operate analysis to ensure your product does not infringe on any other valid and active patents related to specific compounds within that class, their formulations, manufacturing, or novel uses.

3. What is the primary therapeutic benefit of the compounds claimed in U.S. Patent 5,948,437? The primary therapeutic benefit is the reduction of elevated blood glucose levels, particularly postprandial hyperglycemia, by inhibiting alpha-glucosidase enzymes in the small intestine. This mechanism slows down the digestion and absorption of carbohydrates, leading to more stable blood glucose concentrations.

4. Are there any known side effects associated with the types of compounds claimed in this patent? Alpha-glucosidase inhibitors, as a class, commonly cause gastrointestinal side effects, including flatulence, diarrhea, and abdominal discomfort. These are often dose-dependent and related to the increased fermentation of undigested carbohydrates in the colon. Specific side effect profiles would vary depending on the exact N-substituted DNJ compound and its pharmacokinetic properties.

5. Did Glaxo Wellcome Inc. commercialize any drugs based on U.S. Patent 5,948,437? U.S. Patent 5,948,437 was assigned to Glaxo Wellcome Inc. (now GlaxoSmithKline). While the patent covers a class of compounds, determining if a specific commercialized drug directly resulted from this patent requires examining the development history and patent portfolios associated with that drug. GlaxoSmithKline has historically been involved in various diabetes-related drug development.

Citations

[1] L'Esperance, P. E. P. (1999). Method for treating elevated blood glucose levels. U.S. Patent 5,948,437. Retrieved from USPTO Patent Full-Text and Image Database.

Drugs Protected by US Patent 5,948,437

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate