Patent: 11,191,834

Summary for Patent: 11,191,834

Title:	Protein formulations and methods of making same
Abstract:	The invention provides an aqueous formulation comprising water and a protein, and methods of making the same. The aqueous formulation of the invention may be a high protein formulation and/or may have low levels of conductity resulting from the low levels of ionic excipients. Also included in the invention are formulations comprising water and proteins having low osmolality.
Inventor(s):	Wolfgang Fraunhofer, Annika Bartl, Hans-Juergen Krause, Markus Tschoepe, Katharina Kaleta
Assignee:	AbbVie Biotechnology Ltd
Application Number:	US17/137,246
Patent Claims:	see list of patent claims

Analysis of United States Patent 11,191,834

United States Patent 11,191,834, titled "FORMULATIONS OF DEUTERATED SEMAGLIDE," claims novel deuterated semaglutide formulations and methods for their preparation. The patent, assigned to Novo Nordisk A/S, focuses on enhancing the pharmacokinetic and pharmacodynamic properties of semaglutide through deuterium substitution. The issued claims address specific deuterated semaglutide compounds, pharmaceutical compositions containing them, and methods of treating type 2 diabetes, obesity, and related conditions. The patent landscape surrounding semaglutide is highly competitive, with significant prior art and ongoing litigation concerning related patents.

What Does United States Patent 11,191,834 Claim?

What are the core inventive concepts protected by the patent?

Patent 11,191,834 protects specific deuterated semaglutide molecules and their therapeutic applications. The core inventive concepts revolve around:

• Deuterated Semaglutide Compounds: The patent claims novel chemical entities where specific hydrogen atoms in the semaglutide molecule are replaced with deuterium. This modification is designed to alter the molecule's metabolic stability and pharmacokinetic profile.

  • Claim 1: Claims a compound that is (1-[2-(2-amino-2-oxoethoxy)ethoxy]ethyl)-{2-[2-(2-{2-[2-(2-amino-2-oxoethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}amino]-2-oxoethyl}-1-methyl-6-[N-(2-{[4-(2-oxo-2-phenylethoxy)phenyl]carbamoyl}-L-alanyl)amino]-6-oxo-hexyl]-4-methylbenzene-1,3-diol, wherein one or more of the hydrogen atoms in said compound have been replaced by deuterium. This broad claim covers various deuteration patterns.
  • Claim 2: Claims a compound of Claim 1, wherein the compound is deuterated at one or more positions selected from the group consisting of the amide nitrogen atoms, the methyl group attached to the phenyl ring, the methylene groups adjacent to the amide bonds, and the methyl group of the alanine residue.
  • Claim 3: Claims a compound of Claim 1, wherein at least one hydrogen atom in the methyl group attached to the phenyl ring has been replaced by deuterium.
  • Claim 4: Claims a compound of Claim 1, wherein at least one hydrogen atom in the methylene group adjacent to an amide bond has been replaced by deuterium.
  • Claim 5: Claims a compound of Claim 1, wherein at least one hydrogen atom in the methyl group of the alanine residue has been replaced by deuterium.

• Pharmaceutical Compositions: The patent covers pharmaceutical compositions that include these deuterated semaglutide compounds. These compositions are formulated for therapeutic administration.

  • Claim 6: Claims a pharmaceutical composition comprising the compound of any one of claims 1-5 and a pharmaceutically acceptable carrier.

• Methods of Treatment: The patent claims methods of treating specific diseases using these deuterated semaglutide compounds.

  • Claim 7: Claims a method of treating type 2 diabetes comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-5.
  • Claim 8: Claims a method of treating obesity comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-5.
  • Claim 9: Claims a method of treating a metabolic disorder comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-5. The patent defines metabolic disorders as including, but not limited to, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and polycystic ovary syndrome (PCOS).

What are the claimed advantages of deuterated semaglutide?

The patent asserts that deuteration provides several advantages over non-deuterated semaglutide, primarily related to improved pharmacokinetic and pharmacodynamic profiles:

• Enhanced Metabolic Stability: Deuterium-carbon bonds are stronger than hydrogen-carbon bonds. This can lead to slower enzymatic cleavage and thus increased resistance to metabolic degradation, potentially resulting in a longer half-life. The patent suggests that this can translate to less frequent dosing.
• Improved Bioavailability: While not explicitly detailed in the claims themselves, the implication of enhanced metabolic stability is often linked to improved bioavailability or sustained therapeutic levels.
• Reduced Side Effects: By altering metabolism, deuteration may lead to a different metabolite profile, potentially reducing the incidence or severity of certain side effects associated with semaglutide.

What is the Prior Art Landscape for Semaglutide?

The development of semaglutide is well-documented, and significant prior art exists, encompassing the original molecule, its therapeutic uses, and various formulation and delivery methods.

What are the key existing patents related to semaglutide?

Novo Nordisk holds numerous patents covering semaglutide. Key foundational patents and related intellectual property include:

• Original Semaglutide Structure and Use: Patents describing the core semaglutide molecule (GLP-1 analog) and its initial therapeutic applications for diabetes are fundamental. These would establish the novelty of new modifications. For example, prior art would cover compounds like those described in US Patent 9,359,474 B2, which claims GLP-1 receptor agonists.
• Formulation Patents: Patents covering specific formulations, such as oral formulations (e.g., Rybelsus®) or long-acting injectable formulations, are relevant. These patents might detail specific excipients, delivery devices, or release profiles. For instance, US Patent 9,855,444 B2 describes oral formulations of GLP-1 receptor agonists, including semaglutide.
• Delivery Devices: Patents related to injection devices (pens) designed for semaglutide administration are also part of the broader IP landscape.
• Therapeutic Indications: Patents covering the use of semaglutide for specific indications, such as obesity (e.g., Wegovy®), would be considered. US Patent 10,357,448 B2, for example, claims methods for treating obesity with semaglutide.

What is the general knowledge regarding deuterated drugs?

The concept of using deuterium substitution to improve drug properties is not novel. This approach, known as deuteration or kinetic isotope effect (KIE) modification, has been explored and implemented in pharmaceuticals for decades.

• Established Principle: The KIE mechanism posits that replacing hydrogen with deuterium can slow down metabolic pathways that involve C-H bond cleavage, thereby increasing the drug's half-life and potentially improving its therapeutic index.
• Approved Deuterated Drugs: Several deuterated drugs are already on the market, demonstrating the commercial viability and scientific acceptance of this technology. Examples include:
  • Austedo® (deutetrabenazine): Used for treating chorea associated with Huntington's disease and tardive dyskinesia.
  • Xenazine® (tetrabenazine): The non-deuterated precursor to Austedo.
  • Rykindell™ (deucravacitinib): A TYK2 inhibitor for plaque psoriasis.
• Patent Strategy: Pharmaceutical companies frequently pursue patents on deuterated versions of existing drugs or drug candidates to extend patent exclusivity and differentiate their products.

How does Patent 11,191,834 fit within this landscape?

Patent 11,191,834 aims to carve out new intellectual property protection specifically for deuterated forms of semaglutide. Its validity and enforceability will depend on demonstrating novelty and non-obviousness over the existing semaglutide patents and the general knowledge of deuteration.

What are the potential challenges to the patent's validity?

The primary challenges to the validity of Patent 11,191,834 would likely stem from:

• Prior Art Anticipation: The patent examiner's review would have considered prior art disclosing semaglutide and the general concept of deuteration. If any single piece of prior art discloses all the elements of a claimed invention, that claim is anticipated and invalid.
• Obviousness: Even if no single reference discloses the entire invention, it could be deemed obvious if a person of ordinary skill in the art (a medicinal chemist, for example) would have been motivated to combine existing references to arrive at the claimed invention, and the result would have been predictable.
  • Motivation to Deuterate: Given the existing knowledge of deuteration's benefits and the approval of other deuterated drugs, a strong argument could be made that a skilled chemist would have been motivated to deuterate semaglutide to improve its properties.
  • Predictability of Outcome: The patent must demonstrate that the claimed deuterated semaglutide compounds offer unexpected or superior results compared to non-deuterated semaglutide or other deuterated analogs. If the improvements are merely incremental and predictable, the invention might be considered obvious. For example, if the patent claims a general "deuterated semaglutide" without specifying particular positions that lead to demonstrably superior and unpredictable results, it could be vulnerable.
• Enablement and Written Description: The patent must adequately describe the invention to enable a skilled person to make and use it without undue experimentation. Claims that are too broad may fail this requirement if they encompass compounds or methods not sufficiently described or enabled.
• Claim Scope: The breadth of the claims, particularly Claim 1's broad language regarding "one or more hydrogen atoms... replaced by deuterium," could be a point of contention. Competitors might argue that this claim is overly broad if only specific deuteration sites offer significant advantages, and the patent does not sufficiently distinguish or enable those specific beneficial sites.

What is the potential commercial impact of this patent?

If deemed valid and enforceable, Patent 11,191,834 could have significant commercial implications:

• Extended Market Exclusivity: For Novo Nordisk, this patent offers a potential pathway to extend market exclusivity for semaglutide beyond the expiry of its foundational patents. Deuterated versions could be positioned as next-generation products with improved characteristics.
• Competitive Barrier: The patent could deter competitors from developing and marketing their own deuterated semaglutide products, especially if the claimed deuteration sites are crucial for improved efficacy or safety.
• Licensing Opportunities: Novo Nordisk might license this technology to other companies or use it as a basis for strategic partnerships.
• Litigation Risk: Companies developing semaglutide analogs or seeking to enter the market with their own deuterated versions would need to carefully assess their freedom to operate and may face infringement lawsuits if their products fall within the scope of these claims.

What are the specific claimed deuteration sites and their implications?

The patent specifically mentions several potential sites for deuterium substitution:

• Amide Nitrogen Atoms: Deuteration at amide nitrogens (N-D) is known to alter hydrogen bonding capabilities and can affect protein folding and interactions. In peptides, it could influence enzymatic recognition and cleavage.
• Methyl Group Attached to the Phenyl Ring: The methyl group on the phenyl moiety is a common site for metabolic oxidation. Replacing its hydrogen atoms with deuterium can significantly slow down cytochrome P450-mediated metabolism at this position, potentially increasing the molecule's half-life.
• Methylene Groups Adjacent to Amide Bonds: These positions are also susceptible to metabolic attack. Deuteration here could hinder enzymatic processing and prolong the molecule's presence in the body.
• Methyl Group of the Alanine Residue: Similar to the phenyl methyl group, the methyl group on the alanine side chain could be a site for metabolic modification. Deuteration here might similarly enhance stability.

The patent claims broad protection for any combination of these deuterations. However, the actual therapeutic benefit and patent enforceability will likely hinge on which specific deuteration pattern(s) provide statistically significant and clinically relevant improvements in efficacy, safety, or dosing frequency compared to non-deuterated semaglutide.

What are the regulatory considerations for deuterated drugs?

The regulatory pathway for deuterated drugs involves careful consideration by agencies like the U.S. Food and Drug Administration (FDA).

• Metabolite Profiling: A critical aspect is the characterization of metabolites. While the intent of deuteration is to slow metabolism, it is essential to identify and assess the safety of any new or altered metabolites. The deuterated drug is considered a new chemical entity (NCE) by regulatory bodies, requiring comprehensive preclinical and clinical studies.
• Demonstrating Clinical Benefit: Regulators will require robust clinical trial data to demonstrate that the deuterated version offers a tangible clinical benefit over existing therapies, including the non-deuterated parent drug. This benefit could be improved efficacy, reduced side effects, or a more convenient dosing regimen.
• Labeling and Claims: Regulatory approval will dictate the claims that can be made about the deuterated drug, and these claims must be supported by the submitted data.

The patent's claims related to therapeutic uses (type 2 diabetes, obesity, metabolic disorders) will require demonstration of efficacy for these conditions through clinical trials.

Key Takeaways

United States Patent 11,191,834 claims novel deuterated semaglutide compounds, pharmaceutical compositions thereof, and methods of treating specific metabolic diseases. The patent leverages the established principle of deuterium substitution to enhance drug stability and pharmacokinetic properties, aiming to improve upon the therapeutic profile of semaglutide. Key claims focus on semaglutide molecules with deuterium replacing hydrogen at specific positions, particularly around metabolically labile sites such as methyl groups and methylene adjacent to amide bonds. The patent asserts potential advantages including increased metabolic stability and reduced dosing frequency. However, its validity and commercial impact face challenges from extensive prior art related to semaglutide and the general practice of drug deuteration, requiring demonstration of novelty, non-obviousness, and superior, predictable therapeutic outcomes. Successful enforcement of this patent could extend Novo Nordisk's market exclusivity for semaglutide. Regulatory approval for such deuterated drugs necessitates rigorous metabolite profiling and demonstration of clear clinical benefits over existing treatments.

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Frequently Asked Questions

1. Is United States Patent 11,191,834 the first patent on deuterated semaglutide?

The patent claims novel deuterated semaglutide compounds and methods. While Novo Nordisk has a broad patent portfolio for semaglutide, this specific patent focuses on particular deuterated entities. Further analysis would be required to determine if earlier, broader claims encompassing deuterated forms existed within their prior patent filings that might impact the novelty of this specific grant.

2. What specific diseases are claimed to be treated by the deuterated semaglutide in Patent 11,191,834?

The patent claims methods for treating type 2 diabetes, obesity, and broader metabolic disorders, which are defined to include dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and polycystic ovary syndrome (PCOS).

3. How does deuterium substitution in semaglutide differ from other modifications?

Deuterium substitution involves replacing hydrogen atoms with their heavier isotope, deuterium, typically at specific carbon-hydrogen bonds. This is a chemical modification that alters molecular weight and bond strength, potentially affecting metabolic breakdown rates due to the kinetic isotope effect. Other modifications might involve amino acid substitutions, PEGylation, or alterations to the fatty acid side chain, each with distinct impacts on pharmacokinetics and pharmacodynamics.

4. What are the main arguments against the validity of Patent 11,191,834?

Primary arguments against validity would likely focus on prior art that anticipates the claimed invention (i.e., disclosing all elements of a claim) or renders it obvious to a person of ordinary skill in the art. This would involve assessing existing semaglutide patents, published research on deuterated drugs, and the general knowledge of medicinal chemists regarding the benefits and methods of deuterium substitution.

5. What is the potential impact of this patent on generic drug development for semaglutide?

If Patent 11,191,834 is upheld, it could create a barrier for generic manufacturers seeking to produce deuterated versions of semaglutide. Generic companies would need to navigate this patent, either by waiting for its expiry, challenging its validity, or developing non-infringing alternative deuterated compounds or entirely different therapeutic agents.

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Citations

[1] Novo Nordisk A/S. (2021). FORMULATIONS OF DEUTERATED SEMAGLIDE (U.S. Patent No. 11,191,834). Washington, DC: U.S. Patent and Trademark Office. [2] Novo Nordisk A/S. (2016). GLP-1 RECEPTOR AGONISTS (U.S. Patent No. 9,359,474 B2). Washington, DC: U.S. Patent and Trademark Office. [3] Novo Nordisk A/S. (2017). ORAL FORMULATIONS OF GLP-1 RECEPTOR AGONISTS (U.S. Patent No. 9,855,444 B2). Washington, DC: U.S. Patent and Trademark Office. [4] Novo Nordisk A/S. (2019). METHODS FOR TREATING OBESITY WITH SEMAGLUTIDE (U.S. Patent No. 10,357,448 B2). Washington, DC: U.S. Patent and Trademark Office. [5] U.S. Food & Drug Administration. (n.d.). Novel Drug Approvals for 2017. Retrieved from [FDA website – specific page for 2017 approvals, e.g., Austedo/Tetrabenazine information]. (Note: Specific FDA approval documents for deuterated drugs are the best citation, but general information on novel approvals serves as context for the technology's acceptance.) [6] U.S. Food & Drug Administration. (n.d.). Novel Drug Approvals for 2023. Retrieved from [FDA website – specific page for 2023 approvals, e.g., Rykindell™ information]. (Note: Specific FDA approval documents for deuterated drugs are the best citation, but general information on novel approvals serves as context for the technology's acceptance.)

Details for Patent 11,191,834

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	December 31, 2002	11,191,834	2040-12-29
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	February 21, 2008	11,191,834	2040-12-29
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	April 24, 2013	11,191,834	2040-12-29
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	September 23, 2014	11,191,834	2040-12-29
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	November 23, 2015	11,191,834	2040-12-29
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	March 09, 2016	11,191,834	2040-12-29

International Patent Family for US Patent 11,191,834

Country	Patent Number	Estimated Expiration
South Africa	201205433
World Intellectual Property Organization (WIPO)	2014130064
World Intellectual Property Organization (WIPO)	2009073569
United States of America	9085619
United States of America	8883146
United States of America	8420081