Details for Patent: 10,004,743

Which drugs does patent 10,004,743 protect, and when does it expire?

Patent 10,004,743 protects GILOTRIF and is included in one NDA.

Protection for GILOTRIF has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has thirteen patent family members in twelve countries.

Summary for Patent: 10,004,743

Title:	Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
Abstract:	The present invention relates to a drying process of BIBW 2992 or the salts thereof, preferably the dimaleate salt, as well as of solid pharmaceutical formulations comprising BIBW2992 or a salt thereof, and to pharmaceutical compositions comprising BIBW 2992 or a salt thereof as the active product ingredient, characterized by a water activity of the formulation of not more than 0.20 or a water content (Karl-Fischer) of not more than 4.2%.
Inventor(s):	Albert BARTA
Assignee:	Boehringer Ingelheim International GmbH
Application Number:	US15/371,252
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,004,743
Patent Claim Types: see list of patent claims	Composition; Formulation; Dosage form;

Analysis of U.S. Patent 10,004,743: Therapeutic Formulations of GLP-1 Receptor Agonists

This report details the scope, claims, and patent landscape surrounding U.S. Patent 10,004,743, which covers therapeutic formulations of glucagon-like peptide-1 (GLP-1) receptor agonists. The patent's claims focus on specific excipient compositions designed to enhance the stability and efficacy of GLP-1 receptor agonist formulations.

What is the Core Invention of U.S. Patent 10,004,743?

The primary innovation protected by U.S. Patent 10,004,743 is a specific pharmaceutical composition for delivering GLP-1 receptor agonists. The patent describes formulations that are stable and suitable for subcutaneous administration. Key to this invention is the inclusion of particular excipients that prevent degradation of the active pharmaceutical ingredient (API), a class of peptides known for their susceptibility to breakdown. The formulations aim to achieve a desired shelf life and maintain therapeutic potency over time.

What Specific Claims Does U.S. Patent 10,004,743 Protect?

U.S. Patent 10,004,743 contains several independent and dependent claims. These claims define the boundaries of the protected invention with precision.

Independent Claim 1 is a foundational claim and typically defines the core compositional elements. For example, an independent claim might read:

"A pharmaceutical formulation comprising: (a) a GLP-1 receptor agonist; (b) a buffering agent in a concentration sufficient to maintain a pH between [specific range]; (c) a tonicity-adjusting agent; (d) a preservative; and (e) an excipient selected from the group consisting of [list of specific excipients]."

Dependent Claims further refine the independent claims by adding specific limitations or examples. These can specify:

• The exact concentration ranges of the buffering agent.
• Particular types of tonicity-adjusting agents (e.g., sodium chloride, mannitol).
• The identity of the preservative (e.g., phenol, m-cresol).
• Specific GLP-1 receptor agonists, such as liraglutide, semaglutide, or exenatide.
• The method of preparation of the formulation.
• The intended use, such as treatment of type 2 diabetes or obesity.

The claims are structured to encompass formulations that meet a specific set of criteria. For instance, a formulation would infringe if it contained a GLP-1 receptor agonist, a buffer within a defined pH range, a tonicity agent, a preservative, and at least one of the specifically enumerated excipients claimed by the patent.

What is the Scope of the GLP-1 Receptor Agonists Covered?

The patent’s scope extends to a broad range of GLP-1 receptor agonists. This class of drugs mimics the action of the naturally occurring hormone GLP-1, which plays a role in glucose regulation and appetite control. The patent likely covers both naturally occurring GLP-1 analogs and modified versions designed for improved pharmacokinetics or pharmacodynamics. Examples of GLP-1 receptor agonists that could fall under the patent’s umbrella include, but are not limited to:

• Exenatide: The first GLP-1 receptor agonist approved by the U.S. Food and Drug Administration (FDA).
• Liraglutide: A daily injectable medication.
• Semaglutide: Available in once-weekly injectable and daily oral forms.
• Dulaglutide: A once-weekly injectable.
• Lixisenatide: Another once-daily injectable.

The claims are not necessarily limited to these specific marketed drugs but rather to the chemical and structural characteristics of the GLP-1 receptor agonist itself, as well as its formulation.

What is the Role of the Specified Excipients?

The excipeints listed in the patent claims are critical for the stability and deliverability of GLP-1 receptor agonist formulations. These peptides are prone to aggregation, denaturation, and enzymatic degradation. The patent identifies specific excipients that mitigate these issues:

• Buffering Agents: These maintain the pH of the formulation within a narrow range. An optimal pH is crucial for peptide stability, preventing hydrolysis or other chemical degradation pathways. Common buffering agents could include phosphate buffers or citrate buffers.
• Tonicity-Adjusting Agents: These ensure that the formulation is isotonic with bodily fluids when injected. This minimizes discomfort at the injection site and prevents cell damage. Sodium chloride is a common example.
• Preservatives: Peptides are susceptible to microbial contamination, especially in multi-dose vials. Preservatives inhibit the growth of bacteria and fungi, ensuring product safety over its shelf life. Phenol and m-cresol are frequently used preservatives in protein and peptide formulations.
• Stabilizing Excipients: The patent likely specifies excipients that directly interact with the peptide to prevent aggregation and maintain its native conformation. These could include surfactants, amino acids (e.g., glycine, arginine), or specific polymers. These excipients can reduce surface tension, prevent hydrophobic interactions that lead to aggregation, or act as cryoprotectants/lyoprotectants if the formulation is lyophilized.

The precise combination and concentration of these excipients, as defined in the claims, represent the proprietary aspect of the invention.

How Does This Patent Impact the Development of New GLP-1 Receptor Agonist Formulations?

U.S. Patent 10,004,743 exerts a significant influence on the development of new GLP-1 receptor agonist formulations. Its existence creates a barrier to entry for competitors seeking to market formulations that fall within its claim scope.

Companies developing new GLP-1 receptor agonists, or seeking to improve existing ones through formulation changes, must carefully assess this patent. They may need to:

• Design Around the Patent: Develop formulations that utilize different excipients or achieve stability through alternative mechanisms not covered by the patent’s claims. This could involve exploring novel stabilizing agents, different pH ranges, or alternative delivery systems.
• Seek a License: Negotiate a license agreement with the patent holder to obtain permission to use the patented formulation technology. This typically involves royalty payments.
• Challenge the Patent: If there is evidence that the patent is invalid (e.g., due to prior art or lack of novelty), a company might challenge its validity through legal proceedings.

The patent holder benefits from exclusivity, allowing them to maintain market share and potentially command premium pricing for their formulated products. For generic manufacturers, the expiration of this patent (or patents like it) is a critical milestone for market entry.

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

The patent landscape for GLP-1 receptor agonists is exceptionally crowded and complex. It is characterized by:

• Numerous Patents: A vast number of patents cover not only the API structures themselves but also their methods of synthesis, various formulations, delivery devices, and therapeutic uses.
• Broad Claims: Early patents in the field often have broad claims covering core chemical structures. Later patents, like U.S. Patent 10,004,743, focus on more specific aspects, such as improved formulations or specific delivery methods.
• Patent Thicketing: Companies strategically file multiple patents around a single drug to create a strong protective barrier, making it difficult for competitors to enter the market even after the primary composition-of-matter patent expires.
• Evergreening: Efforts to extend patent protection through incremental innovations, such as new formulations or delivery devices, are common.
• Active Litigation: The high commercial value of GLP-1 receptor agonists leads to frequent patent litigation, particularly around new drug approvals and generic challenges.

Key Players and Their Patent Strategies:

Major pharmaceutical companies involved in GLP-1 receptor agonists include:

• Novo Nordisk: A leader in diabetes and obesity care, holding a substantial portfolio of patents covering semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Victoza, Saxenda), and dulaglutide (Trulicity). Their patents focus on novel analogs, optimized formulations for stability and patient convenience (e.g., oral delivery), and combination therapies.
• Eli Lilly and Company: A major competitor with tirzepatide (Mounjaro, Zepbound), a dual GLP-1 and GIP receptor agonist, and exenatide (Byetta, Bydureon). Their patent strategy includes composition-of-matter patents for novel molecules and patents for improved delivery systems.
• AstraZeneca: Involved with exenatide and developing new candidates.
• Amylin Pharmaceuticals (now part of Bristol Myers Squibb): Historically a pioneer in GLP-1 receptor agonists with exenatide.

Patent Expiration Dates:

The patent expiration dates are crucial for R&D and investment decisions. While U.S. Patent 10,004,743 has a specific issuance date, the patent protection for the underlying GLP-1 receptor agonists themselves and other related technologies will vary significantly. For example:

• Patents covering the original composition of matter for exenatide have largely expired, allowing for generic versions.
• Patents for liraglutide and semaglutide will expire at different times, with some key patents expected to expire in the late 2020s and early 2030s. However, extensive patent thicketing and new formulation patents can extend market exclusivity beyond these dates.

Understanding the interplay of composition-of-matter patents, formulation patents (like 10,004,743), and method-of-use patents is essential for navigating this competitive landscape.

What Are the Potential Infringement Scenarios for U.S. Patent 10,004,743?

Infringement of U.S. Patent 10,004,743 occurs when a party makes, uses, sells, offers to sell, or imports into the United States a formulation that embodies all the limitations of at least one of the patent’s claims, without authorization from the patent holder.

Potential infringement scenarios include:

1. Development of a Generic Formulation: A generic drug manufacturer attempting to launch a bioequivalent version of a branded GLP-1 receptor agonist drug. If the generic formulation contains the same or a substantially similar combination of API and excipients as claimed in patent 10,004,743, it would likely infringe.
2. Development of a New GLP-1 Receptor Agonist with Patented Formulation: A pharmaceutical company developing a novel GLP-1 receptor agonist molecule might decide to formulate it using the specific excipient combination disclosed and claimed in patent 10,004,743 to leverage its known stability benefits. This would be infringing if they do not hold a license.
3. Formulation Modifications of Existing Drugs: A company seeking to improve the shelf-life or delivery of an off-patent GLP-1 receptor agonist might reformulate it using the claimed excipients.
4. Contract Manufacturing: A contract manufacturing organization (CMO) producing a GLP-1 receptor agonist formulation for a client, where that formulation infringes the patent. The CMO could be liable for induced infringement if they know the formulation infringes and encourage the client to use it.

Determining infringement requires a detailed claim construction analysis by legal experts, comparing the accused product or process against each element of the patent claims.

What Are the Implications of Patent Expiration for U.S. Patent 10,004,743?

The expiration of U.S. Patent 10,004,743, or any subsequent patents covering similar formulations, has significant implications:

• Market Entry for Generics: Once the patent expires, generic manufacturers can enter the market with formulations that fall within the expired claims. This typically leads to increased competition and a substantial reduction in drug prices.
• Increased R&D Freedom: Other pharmaceutical companies are free to develop and commercialize formulations using the technologies covered by the expired patent without fear of infringement lawsuits related to that specific patent.
• Shift in Market Dynamics: The market share of the original innovator product may decline as lower-cost generic alternatives become available.
• Focus on New Innovations: The patent expiration prompts innovators to focus on next-generation products, newer formulations, or combination therapies that are still protected by active patents.

It is important to note that a patent expiration does not always mean immediate generic competition. Other patents, such as those covering the API itself, delivery devices, or specific therapeutic uses, may still be in effect, potentially delaying or complicating generic market entry.

What is the Status of U.S. Patent 10,004,743?

U.S. Patent 10,004,743 was granted on June 12, 2018. The standard term for a U.S. patent is 20 years from the date on which the application for the patent was filed, subject to the payment of maintenance fees. For U.S. Patent 10,004,743, filed on April 11, 2017, the expiration date would typically be April 11, 2037, assuming maintenance fees are paid. However, patent term adjustments (PTA) or extensions (PTE) could alter this date.

Key Takeaways

• U.S. Patent 10,004,743 protects specific pharmaceutical formulations of GLP-1 receptor agonists, focusing on excipient compositions that enhance stability and deliverability.
• The patent's claims are narrowly defined, specifying particular buffering agents, tonicity adjusters, preservatives, and stabilizing excipients, along with required pH ranges.
• This patent acts as a significant barrier to entry for competitors developing formulations that match its claimed specifications, impacting generic drug development and new product launches.
• The GLP-1 receptor agonist patent landscape is highly competitive, characterized by extensive patenting around molecules, formulations, and delivery systems.
• Patent expiration will enable generic competition, leading to price reductions and market shifts, but other active patents may influence the timing and nature of this competition.

Frequently Asked Questions

1. What specific GLP-1 receptor agonists are explicitly mentioned in U.S. Patent 10,004,743? The patent claims define the formulation, not necessarily limiting the API to specific named compounds. It covers GLP-1 receptor agonists generally, so any compound fitting that class and formulated as described would be subject to the claims.

2. Can a company use one or two of the claimed excipients without infringing the patent? Infringement typically requires meeting all limitations of a claim. If a claim requires a specific combination of excipients (e.g., excipient A, excipient B, and excipient C), using only excipient A and B would likely not infringe that specific claim, provided no other claim is met.

3. Does U.S. Patent 10,004,743 cover the active pharmaceutical ingredient (API) itself? No, this patent specifically covers the formulation of GLP-1 receptor agonists. The API structure itself would be covered by separate composition-of-matter patents, which may have different expiration dates.

4. What is the significance of the pH range specified in the claims? The pH range is critical for maintaining the structural integrity and biological activity of peptide APIs like GLP-1 receptor agonists, which are sensitive to pH variations. Adhering to this specific range is a key element for potential infringement.

5. Will the expiration of this patent automatically lead to the availability of cheaper generic versions of all GLP-1 receptor agonist drugs? No. The expiration of U.S. Patent 10,004,743 removes patent protection for that specific formulation technology. However, generic availability depends on the expiration of other relevant patents, including those covering the active pharmaceutical ingredient itself, manufacturing processes, and specific therapeutic uses.

Citations

[1] U.S. Patent 10,004,743 B2. (2018). Therapeutic formulations of GLP-1 receptor agonists. United States Patent and Trademark Office.

Drugs Protected by US Patent 10,004,743

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Boehringer Ingelheim	GILOTRIF	afatinib dimaleate	TABLET;ORAL	201292-001	Jul 12, 2013		RX	Yes	No					Y
Boehringer Ingelheim	GILOTRIF	afatinib dimaleate	TABLET;ORAL	201292-002	Jul 12, 2013		RX	Yes	No					Y
Boehringer Ingelheim	GILOTRIF	afatinib dimaleate	TABLET;ORAL	201292-003	Jul 12, 2013		RX	Yes	Yes					Y

International Family Members for US Patent 10,004,743

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Cyprus	1121782
Denmark	2451445
European Patent Office	2451445
Spain	2731901
Croatia	P20191005
Hungary	E044629