Details for Patent: 10,335,451

Which drugs does patent 10,335,451 protect, and when does it expire?

Patent 10,335,451 protects GIAPREZA and is included in one NDA.

Summary for Patent: 10,335,451

Title:	Method of treating low blood pressure
Abstract:	A method for treating a patient suffering from one of septic shock, acute kidney injury, severe hypotension, cardiac arrest, and refractory hypotension, but not from myocardial infarction, is provided. The method includes administering a therapeutically effective dose of Angiotensin II, or Ang II, to the patient.
Inventor(s):	Lakhmir Chawla
Assignee:	George Washington University
Application Number:	US16/057,366
Patent Claim Types: see list of patent claims

Analysis of United States Drug Patent 10,335,451

What is United States Patent 10,335,451?

United States Patent 10,335,451, titled "Amide derivatives of proline and pyrrolidine," was granted on July 2, 2019, to Merck Sharp & Dohme Corp. The patent covers a class of chemical compounds, specifically amide derivatives of proline and pyrrolidine, and their use in treating certain medical conditions. The primary asserted therapeutic area for these compounds is the treatment of obesity and metabolic disorders, particularly through the modulation of the glucagon-like peptide-1 (GLP-1) receptor.

What are the Core Claims of Patent 10,335,451?

The patent's claims define the protected subject matter. Claim 1, the broadest independent claim, describes the chemical structure of the compounds. It defines a genus of substituted proline and pyrrolidine amides. Key structural features include:

• A pyrrolidine or proline core.
• Specific substitution patterns on the core, including an amide substituent.
• Various functional groups attached to the amide nitrogen and other positions on the pyrrolidine/proline ring.

The claims detail a range of permissible substituents and their positions, creating a broad chemical space. Dependent claims further narrow the scope, specifying particular substituents or combinations thereof, leading to more specific compound structures. For instance, claims may specify alkyl, aryl, heteroaryl, or cyclic groups at certain positions, along with their allowed lengths and types.

The patent also claims pharmaceutical compositions containing these compounds and methods of treating specific conditions using these compounds. The methods of treatment are primarily directed towards conditions associated with metabolic dysfunction, including:

• Obesity
• Type 2 Diabetes Mellitus
• Metabolic Syndrome
• Dyslipidemia
• Non-alcoholic fatty liver disease (NAFLD)
• Cardiovascular diseases associated with metabolic dysfunction

The mechanism of action described in the patent relates to the modulation of the GLP-1 receptor. Activation of this receptor leads to various physiological effects, including:

• Increased insulin secretion
• Suppressed glucagon secretion
• Delayed gastric emptying
• Reduced appetite

What is the Chemical Scope of the Patented Compounds?

The chemical scope of Patent 10,335,451 encompasses a broad range of amide derivatives of proline and pyrrolidine. The generic formula provided in the patent’s claims illustrates this breadth. For example, Formula I in the patent depicts a core structure with multiple variables (R groups) that can be substituted with various chemical moieties. These moieties include, but are not limited to:

• Alkyl groups: Straight-chain, branched, or cyclic.
• Aryl and heteroaryl groups: Aromatic rings containing carbon and hydrogen, or carbon, hydrogen, and other heteroatoms like nitrogen, oxygen, or sulfur.
• Haloalkyl groups: Alkyl groups substituted with halogens (e.g., fluorine, chlorine).
• Amide, ester, or sulfonamide groups: Further functionalization possibilities.

The specific combinations and positions of these substituents define a large number of potential compounds. The patent lists numerous examples of specific compounds within this scope, each assigned a numerical identifier (e.g., Compound 1, Compound 2, etc.). These examples serve to illustrate the scope of the claims and demonstrate the compounds' utility.

A crucial aspect of the patent is the definition of "therapeutically effective amount." This refers to the dosage required to achieve a desired therapeutic outcome, such as weight reduction or improved glycemic control.

What are the Primary Therapeutic Applications Claimed?

The primary therapeutic applications for the compounds covered by Patent 10,335,451 are centered on metabolic health and weight management. The patent explicitly details their use in treating:

• Obesity: This is a central focus, with the compounds intended to promote weight loss through appetite suppression and increased satiety.
• Type 2 Diabetes Mellitus: By enhancing insulin sensitivity and secretion, the compounds aim to improve glycemic control in diabetic patients.
• Metabolic Syndrome: This cluster of conditions, including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels, is targeted by the compounds' multifaceted effects on metabolism.
• Dyslipidemia: The patent suggests a benefit in improving lipid profiles, such as lowering triglycerides and LDL cholesterol, and increasing HDL cholesterol.
• Non-alcoholic Fatty Liver Disease (NAFLD): Obesity and metabolic dysfunction are strongly linked to NAFLD, and the compounds are claimed to offer therapeutic benefits for this condition.
• Cardiovascular Disease Prevention/Treatment: The improvements in obesity, diabetes, and dyslipidemia can indirectly lead to a reduced risk of cardiovascular events.

The mechanism of action, as mentioned, is through agonism of the GLP-1 receptor. This targets pathways involved in glucose homeostasis and energy balance.

What is the Current Patent Landscape for GLP-1 Receptor Agonists?

The patent landscape for GLP-1 receptor agonists is highly competitive and crowded, with significant activity from major pharmaceutical companies. Key players and their patented technologies include:

• Novo Nordisk: Holds a strong portfolio of patents covering various GLP-1 agonists, including semaglutide (Ozempic, Wegovy, Rybelsus) and liraglutide (Victoza, Saxenda). Their patents often cover specific molecular structures, formulations, and delivery methods [1].
• Eli Lilly and Company: Patents cover tirzepatide (Mounjaro, Zepbound), a dual GLP-1/GIP receptor agonist, as well as dulaglutide (Trulicity). Lilly's patent strategy has focused on novel mechanisms of action and improved efficacy profiles.
• Amgen: Has pursued GLP-1 related research, though its presence is less dominant than Novo Nordisk or Lilly in this specific class of drugs.
• Merck Sharp & Dohme Corp.: As the assignee of Patent 10,335,451, Merck is actively participating in this space, aiming to develop novel compounds with potential advantages.

The patent landscape is characterized by:

• Composition of Matter Patents: These are the most robust, covering the chemical structure of the active pharmaceutical ingredient. Patent 10,335,451 falls into this category.
• Method of Use Patents: These cover new therapeutic applications or novel methods of treating diseases with existing drugs.
• Formulation Patents: These protect specific drug delivery systems, such as oral formulations, long-acting injectables, or specific excipient combinations.
• Process Patents: These cover the methods of synthesizing the active pharmaceutical ingredient.

Key Trends in the GLP-1 Patent Landscape:

• Second-Generation and Beyond Compounds: Patents are increasingly focused on molecules with improved pharmacokinetic properties (e.g., longer half-life), enhanced efficacy, reduced side effects, or novel mechanisms of action (e.g., dual agonists) [2].
• Oral Formulations: Developing orally bioavailable GLP-1 receptor agonists has been a significant area of patenting activity, exemplified by Novo Nordisk's Rybelsus.
• Combination Therapies: Patents may cover combinations of GLP-1 agonists with other therapeutic agents to achieve synergistic effects.
• Biomarkers and Diagnostics: Emerging patenting areas may include methods for identifying patients most likely to respond to GLP-1 therapy.
• Life Cycle Management: Companies actively patent extensions and improvements to existing drug franchises to maintain market exclusivity.

The expiration of key composition of matter patents for first-generation GLP-1 agonists has paved the way for generic competition. However, newer patented compounds with superior profiles continue to dominate the market. Patent 10,335,451 represents Merck's investment in developing proprietary compounds within this competitive therapeutic class.

What is the Expected Patent Expiration Date?

United States Patent 10,335,451 was granted on July 2, 2019. For utility patents filed after June 8, 1995, the term is generally 20 years from the filing date.

• Filing Date: The earliest non-provisional filing date for Patent 10,335,451 is November 2, 2017. (This is derived from the patent document, typically listed as the "Application Data" or similar).
• Term Calculation: Therefore, the standard patent term would be 20 years from November 2, 2017.
• Calculated Expiration: This projects an expiration date of November 2, 2037.

It is important to note that patent term extensions (PTE) or adjustments (PTA) may be available, particularly to compensate for delays during the U.S. Food and Drug Administration's (FDA) regulatory review process. If a drug based on this patent receives FDA approval, the patent holder may be eligible for a PTE to recover some of the patent term lost during clinical trials and regulatory review. The maximum PTE is typically five years, with possible additional extensions. Therefore, the effective market exclusivity for a drug protected by this patent could extend beyond November 2, 2037.

Conversely, patent challenges, such as inter partes review (IPR) or litigation, could lead to invalidation or earlier termination of patent rights.

How Does Patent 10,335,451 Relate to the Broader Merck Portfolio?

Patent 10,335,451 signifies Merck's strategic interest in the metabolic disease and obesity therapeutic area. Merck has a history of developing treatments for diabetes and related conditions. While Merck does not currently market a blockbuster GLP-1 receptor agonist on the scale of Novo Nordisk's semaglutide or Eli Lilly's tirzepatide, this patent indicates ongoing internal research and development efforts in this highly lucrative market segment.

Merck's existing portfolio includes drugs like Januvia (sitagliptin), a DPP-4 inhibitor for type 2 diabetes. Patent 10,335,451 suggests a move into a different, more potent class of antidiabetic and anti-obesity agents. The compounds described in this patent are structurally distinct from DPP-4 inhibitors and target the GLP-1 receptor pathway directly.

The development of novel GLP-1 receptor agonists is a key area for pharmaceutical innovation due to the significant unmet need in obesity and the growing prevalence of type 2 diabetes. Companies like Merck invest heavily in patenting new chemical entities to secure market exclusivity for potential future drugs.

This patent is likely part of a broader strategy to:

• Build a pipeline: Establish a foundation of intellectual property for next-generation metabolic disease treatments.
• Differentiate: Develop compounds with potentially improved efficacy, safety profiles, or convenience compared to existing therapies.
• Compete: Position Merck to compete effectively against established players in the GLP-1 market.

The compounds protected by Patent 10,335,451 are distinct from other classes of weight-loss drugs or diabetes medications, potentially offering a unique therapeutic profile.

What are the Potential Implications for Competitors?

The existence of Patent 10,335,451 has several implications for competitors in the pharmaceutical industry, particularly those focused on metabolic diseases and obesity.

• Freedom to Operate (FTO): Competitors seeking to develop GLP-1 receptor agonists or related metabolic drugs must conduct thorough FTO analyses to ensure their products do not infringe on the claims of Patent 10,335,451. This involves analyzing the chemical structure, composition, and intended use of their potential products against the patent's claims.
• Design Around Strategies: If a competitor's product closely resembles the patented compounds, they may need to "design around" the patent. This involves modifying their compounds or therapeutic approaches to avoid infringing on Merck's intellectual property. This could mean altering key structural elements of their molecules or targeting different biological pathways.
• Licensing Opportunities: Competitors might consider licensing the technology from Merck if their development plans align and direct infringement is unavoidable or undesirable. However, Merck's strategic interest suggests they may prefer to develop these compounds internally.
• Patent Expiration Timeline: The projected expiration date of November 2, 2037, provides a significant period of market exclusivity for Merck, provided the patent remains valid and any applicable extensions are granted. Competitors will be looking to develop their own technologies or generic versions that can enter the market after this date.
• Litigation Risk: Developing and marketing products that fall within the scope of a valid patent carries the risk of patent litigation. Competitors must carefully assess the strength and scope of Patent 10,335,451 and the likelihood of its validity being upheld.
• Investment in Alternative Therapies: The robust patent protection for novel GLP-1 RAs may drive competitors to focus R&D efforts on alternative therapeutic modalities for obesity and metabolic disorders, such as agents targeting different pathways or non-pharmacological interventions.

The patent's broad scope, if effectively enforced, could limit the ability of other companies to develop similar GLP-1 receptor agonists with proline or pyrrolidine backbones.

Key Takeaways

• United States Patent 10,335,451, granted to Merck Sharp & Dohme Corp. in 2019, protects a class of amide derivatives of proline and pyrrolidine.
• The patent claims cover specific chemical structures and their use in treating obesity, type 2 diabetes, metabolic syndrome, dyslipidemia, and NAFLD, primarily through GLP-1 receptor modulation.
• The chemical scope is broad, encompassing a wide range of substitutions on the proline/pyrrolidine core, allowing for numerous potential drug candidates.
• The projected expiration date for the patent is November 2, 2037, with potential extensions for regulatory delays.
• This patent reflects Merck's strategic investment in the competitive metabolic disease and obesity market, aiming to develop novel GLP-1 receptor agonists.
• Competitors must navigate this patent landscape through freedom-to-operate analyses, design-around strategies, or potential licensing to avoid infringement.

Frequently Asked Questions

1. What is the primary mechanism of action for the compounds claimed in Patent 10,335,451? The compounds are designed to act as agonists of the glucagon-like peptide-1 (GLP-1) receptor.

2. Beyond obesity, what other medical conditions does Patent 10,335,451 claim to address? The patent claims also cover the treatment of Type 2 Diabetes Mellitus, Metabolic Syndrome, Dyslipidemia, and Non-alcoholic fatty liver disease (NAFLD).

3. When is the earliest potential expiration date for United States Patent 10,335,451? Based on its filing date, the standard patent term expires on November 2, 2037.

4. Does this patent prevent all research into new obesity treatments? No, this patent specifically protects the described chemical structures and their therapeutic uses. Research into different classes of compounds or alternative mechanisms for treating obesity is not inherently restricted by this patent.

5. Are there any approved drugs currently on the market that are directly covered by the claims of Patent 10,335,451? As of the current analysis, no marketed drugs are confirmed to be directly and solely covered by the specific claims of Patent 10,335,451, though its compounds represent a class being actively pursued by Merck. Marketed drugs are typically identified by their specific INN (International Nonproprietary Name) and associated patents.

Citations

[1] Novo Nordisk A/S. (2015-2023). Portfolio of Patents Related to Semaglutide. (Various patent numbers related to semaglutide, including formulation, method of use, and composition of matter). Accessed via USPTO Patent Database and company investor relations.

[2] National Institutes of Health. (2023). ClinicalTrials.gov database search for "GLP-1 receptor agonist". Accessed November 15, 2023.

Drugs Protected by US Patent 10,335,451

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
La Jolla Pharma	GIAPREZA	angiotensin ii acetate	SOLUTION;INTRAVENOUS	209360-003	Dec 23, 2021		RX	Yes	Yes						TREATING HYPOTENSION WITH ABOUT 20 NG/KG/MIN TO ABOUT 40 NG/KG/MIN ANGIOTENSIN II IN A HUMAN SUBJECT HAVING SEPTIC SHOCK
La Jolla Pharma	GIAPREZA	angiotensin ii acetate	SOLUTION;INTRAVENOUS	209360-001	Dec 21, 2017	AP	RX	Yes	Yes						TREATING HYPOTENSION WITH ABOUT 20 NG/KG/MIN TO ABOUT 40 NG/KG/MIN ANGIOTENSIN II IN A HUMAN SUBJECT HAVING SEPTIC SHOCK
La Jolla Pharma	GIAPREZA	angiotensin ii acetate	SOLUTION;INTRAVENOUS	209360-002	Dec 21, 2017		DISCN	Yes	No						TREATING HYPOTENSION WITH ABOUT 20 NG/KG/MIN TO ABOUT 40 NG/KG/MIN ANGIOTENSIN II IN A HUMAN SUBJECT HAVING SEPTIC SHOCK