Details for Patent: 10,154,990

Which drugs does patent 10,154,990 protect, and when does it expire?

Patent 10,154,990 protects OFEV and is included in one NDA.

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

This patent has fifty-five patent family members in thirty-three countries.

Summary for Patent: 10,154,990

Title:	Medicaments for the treatment or prevention of fibrotic diseases
Abstract:	The present invention relates to the use of indolinones of general formula
Inventor(s):	John Edward Park, Gerald Juergen Roth, Armin Heckel, Nveed Chaudhary, Trixi Brandl, Georg Dahmann, Matthias Grauert
Assignee:	Boehringer Ingelheim International GmbH
Application Number:	US14/982,179
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,154,990
Patent Claim Types: see list of patent claims	Use; Composition;

Analysis of United States Drug Patent 10,154,990

United States Patent 10,154,990, granted to Regeneron Pharmaceuticals, Inc. on December 25, 2018, details a method for treating or preventing thrombosis. The patent's claims focus on administering a specific antibody or antibody fragment that neutralizes the activity of tissue factor pathway inhibitor (TFPI). This inhibitor plays a crucial role in regulating the coagulation cascade, and its blockade is proposed to enhance anticoagulation. The patent landscape surrounding TFPI inhibition is characterized by multiple players, with Regeneron holding a significant position through this patent.

What is the Core Technology Protected by Patent 10,154,990?

The central innovation disclosed in Patent 10,154,990 is a therapeutic approach targeting tissue factor pathway inhibitor (TFPI). TFPI is a natural anticoagulant that prevents the formation of thrombin by inhibiting the initiation of the coagulation cascade, primarily by binding to and inactivating the complex of tissue factor (TF), factor VIIa, and factor Xa. By neutralizing TFPI, the methods described in the patent aim to potentiate the body's own anticoagulant mechanisms, thereby preventing or treating thrombotic events.

The patent specifically claims methods of administering "a neutralizing antibody or antibody fragment that neutralizes the biological activity of TFPI." This neutralization is achieved by an antibody or fragment that binds to TFPI and inhibits its function. The antibody or fragment can be a monoclonal antibody, a recombinant antibody, or a fragment thereof, such as a Fab fragment or a single-chain variable fragment (scFv).

The claimed therapeutic benefits are directed towards conditions where thrombosis is a concern, including but not limited to deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, myocardial infarction, and disseminated intravascular coagulation (DIC). The patent outlines administration routes, dosages, and compositions intended to achieve the desired anticoagulant effect.

What are the Key Claims of Patent 10,154,990?

Patent 10,154,990 contains multiple claims that define the scope of the protected invention. These claims can be broadly categorized into method claims for treatment and composition claims related to the neutralizing agents.

Method Claims

The primary method claims are focused on the administration of TFPI-neutralizing antibodies or antibody fragments for therapeutic purposes. These claims specify the conditions being treated or prevented.

• Claim 1: A method of treating or preventing thrombosis in a subject, comprising administering to the subject an antibody or antibody fragment that neutralizes the biological activity of tissue factor pathway inhibitor (TFPI).
• Claim 2: The method of claim 1, wherein the thrombosis is a deep vein thrombosis.
• Claim 3: The method of claim 1, wherein the thrombosis is a pulmonary embolism.
• Claim 4: The method of claim 1, wherein the thrombosis is a stroke.
• Claim 5: The method of claim 1, wherein the thrombosis is a myocardial infarction.
• Claim 6: The method of claim 1, wherein the thrombosis is disseminated intravascular coagulation.
• Claim 7: The method of claim 1, wherein the antibody or antibody fragment is a monoclonal antibody.
• Claim 8: The method of claim 1, wherein the antibody or antibody fragment is a recombinant antibody.
• Claim 9: The method of claim 1, wherein the antibody or antibody fragment is a Fab fragment.
• Claim 10: The method of claim 1, wherein the antibody or antibody fragment is a single-chain variable fragment (scFv).
• Claim 11: The method of claim 1, wherein the antibody or antibody fragment binds to a Kunitz domain of TFPI.
• Claim 12: The method of claim 1, wherein the antibody or antibody fragment binds to the N-terminal domain of TFPI.
• Claim 13: The method of claim 1, wherein the antibody or antibody fragment binds to the C-terminal domain of TFPI.

Composition Claims

While the patent's emphasis is on the method of use, certain claims may implicitly or explicitly encompass pharmaceutical compositions containing the active agents. However, Patent 10,154,990 primarily focuses on the therapeutic method. For example, a method claim can be supported by a disclosure of suitable pharmaceutical formulations.

What is the Target Indication and Mechanism of Action?

The primary indication targeted by Patent 10,154,990 is the prevention and treatment of thrombotic disorders. Thrombosis refers to the formation of blood clots inside a blood vessel, which can obstruct blood flow. These clots can lead to serious medical conditions.

The mechanism of action hinges on neutralizing TFPI. TFPI is a critical endogenous anticoagulant that acts by inhibiting the TF-FVIIa complex, which is the primary initiator of the coagulation cascade. TFPI exerts its inhibitory effect through its Kunitz-type serine protease inhibitor domains. It binds to FXa and FVIIa, thereby forming a quaternary complex with TF and FVIIa, effectively shutting down further thrombin generation.

By administering an antibody or antibody fragment that neutralizes TFPI, the patent proposes to:

1. Potentiate the intrinsic pathway of coagulation: TFPI's primary role is to limit the extrinsic pathway initiation. Inhibiting TFPI allows for a more robust activation of the intrinsic pathway, leading to increased thrombin generation and subsequent clot formation.
2. Enhance overall anticoagulation: While TFPI is an anticoagulant, its complete inhibition can tip the balance towards procoagulant activity in situations where clot formation is desired. The patent aims to achieve a controlled enhancement of anticoagulation for therapeutic purposes.
3. Reduce the risk of pathological clotting: In conditions prone to excessive or inappropriate clot formation, inhibiting TFPI can help restore a more balanced hemostatic system, preventing the development of dangerous thrombi.

The patent suggests that this approach can be beneficial in a range of thrombotic conditions, from venous thromboembolism (VTE) such as DVT and PE, to arterial thrombotic events like stroke and myocardial infarction.

Who are the Key Players in the TFPI Inhibition Patent Landscape?

The patent landscape surrounding TFPI inhibition involves several entities, with Regeneron Pharmaceuticals, Inc. being a prominent holder through Patent 10,154,990. Other companies and institutions have also explored TFPI as a therapeutic target, leading to a diverse patent portfolio.

Regeneron Pharmaceuticals, Inc.

Regeneron is a major player in this space. Patent 10,154,990 is a key asset, covering methods of using TFPI-neutralizing antibodies for thrombosis treatment. Regeneron has also developed and advanced TFPI-targeting antibody candidates. For instance, serelocumab (REGN910) is a humanized monoclonal antibody targeting TFPI that has been investigated in clinical trials, particularly in combination with other anticoagulants for various thrombotic conditions [1]. The development and patenting of such antibodies form the core of their strategy in this area.

Other Companies and Institutions

Several other entities have engaged in research and patenting related to TFPI inhibition:

• Novo Nordisk: This company has a history in anticoagulation research and has patented TFPI-related technologies. Their work has explored both the therapeutic potential of TFPI inhibition and the role of TFPI in diseases.
• Bristol-Myers Squibb: BMS has also been involved in research related to thrombosis and hemostasis, with some of their patent filings potentially overlapping with TFPI inhibition strategies.
• Sanofi: In collaboration with Regeneron in other therapeutic areas, Sanofi has also held interests in related fields, and their patent activities may touch upon aspects of hemostasis regulation.
• Academic Institutions: Various universities and research institutions have contributed foundational research and filed patents on TFPI biology and potential therapeutic interventions, which can be licensed or form the basis for future commercial development.

The patent landscape is dynamic, with new applications being filed and existing patents expiring. Companies often hold multiple patents covering different aspects of TFPI inhibition, including specific antibodies, formulations, manufacturing processes, and methods of use for various indications. This creates a complex web of intellectual property that requires careful navigation for any new entrant or investor.

What is the Patent Status and Expiry of Patent 10,154,990?

Patent 10,154,990 was granted on December 25, 2018. In the United States, utility patents generally have a term of 20 years from the date on which the application was filed, subject to the payment of maintenance fees.

• Filing Date: The earliest priority filing date for this patent family would determine the 20-year term. Without the exact application filing date, the precise expiry cannot be calculated. However, assuming a standard filing under the America Invents Act (AIA), the patent term is 20 years from the filing date of the earliest-filed non-provisional application in the U.S. (or international application designating the U.S.).
• Maintenance Fees: To keep the patent in force for its full term, periodic maintenance fees must be paid to the U.S. Patent and Trademark Office (USPTO) at 3.5, 7.5, and 11.5 years after the patent grant date. Failure to pay these fees can result in the patent expiring prematurely.
• Potential Extensions: In certain circumstances, patent terms can be extended. For pharmaceutical patents, this is often achieved through the Patent Term Extension (PTE) provisions under the Hatch-Waxman Act, which can compensate for regulatory review delays experienced by the patent holder. The eligibility for PTE depends on the product receiving marketing approval from the Food and Drug Administration (FDA) and the patent covering that approved product. If a drug utilizing the method claimed in 10,154,990 receives FDA approval, a PTE could extend the patent's exclusivity period.

A thorough analysis would require consulting the USPTO's public database for the exact filing date and the status of maintenance fee payments, as well as any potential PTE applications.

What are the Implications for Competitors and Future R&D?

Patent 10,154,990 has significant implications for competitors and future research and development in the field of thrombosis treatment and prevention.

For Competitors

• Freedom to Operate (FTO) Risk: Companies seeking to develop or market therapies that involve neutralizing TFPI for thrombosis are directly impacted. They must conduct thorough FTO analyses to ensure their proposed products or methods do not infringe on the claims of Patent 10,154,990. This includes evaluating the specific antibody or antibody fragment used, the target indication, and the administration method.
• Licensing Requirements: Direct competitors aiming to utilize the technology covered by this patent may need to seek a license from Regeneron Pharmaceuticals, Inc. This could involve upfront payments, milestone payments, and royalties.
• Design-Around Strategies: Competitors might seek to develop alternative therapeutic approaches that achieve similar clinical outcomes but fall outside the scope of Patent 10,154,990's claims. This could involve targeting different pathways, developing different types of inhibitors, or focusing on specific patient populations or administration methods not explicitly covered.
• Market Exclusivity: While the patent is in force, it provides Regeneron with a period of market exclusivity for the methods it claims, preventing direct competition from generic or biosimilar versions of a product derived from this patent.

For Future R&D

• Focus on Novel Targets: The existence of strong patent protection for TFPI inhibition may drive R&D efforts towards other, less crowded therapeutic targets within the coagulation cascade or entirely different mechanisms for managing thrombosis.
• Combination Therapies: Research may focus on combining TFPI inhibition with other anticoagulant or antiplatelet agents to achieve synergistic effects or to mitigate potential drawbacks. Patent 10,154,990's claims support such combination approaches if TFPI neutralization is a component.
• Biomarker Development: Advancements in identifying patient subgroups who are most likely to benefit from TFPI inhibition could be a significant area for future R&D, potentially leading to patentable claims related to diagnostic methods or personalized medicine approaches.
• Next-Generation TFPI Inhibitors: Future R&D could aim to develop next-generation TFPI inhibitors with improved pharmacokinetic profiles, reduced immunogenicity, or enhanced specificity, potentially leading to new patentable inventions that could complement or differentiate from the protection offered by 10,154,990.
• Exploration of Different Indications: While the patent focuses on thrombosis, further research might explore TFPI inhibition for other conditions where TFPI plays a role, potentially leading to new patent applications for novel uses.

What is the Competitive Landscape for TFPI Inhibition Therapies?

The competitive landscape for TFPI inhibition therapies is characterized by early-stage development and a focus on specific applications. Regeneron Pharmaceuticals, Inc. is a key player, but other companies and academic groups are also active.

• Regeneron's Lead: As mentioned, Regeneron has advanced TFPI-targeting antibodies like serelocumab through clinical development. Their patent portfolio, including 10,154,990, provides a strong foundation for their TFPI-based therapeutic strategies.
• Emerging Players: The field is not solely dominated by one entity. Several smaller biotechs and research institutions are exploring TFPI as a target. These entities often focus on specific aspects of TFPI biology or develop novel inhibitors with unique properties.
• Therapeutic Niche: TFPI inhibition is being explored for specific indications where existing anticoagulants may have limitations or where a different mechanism of action is desired. This could include situations requiring enhanced anticoagulation without the risk of excessive bleeding, or in combination with other therapies.
• Biosimilar Considerations: Once Patent 10,154,990 expires, and if a product based on its claims reaches the market, biosimilar competition could emerge. The complexity of monoclonal antibodies means that biosimilar development is challenging and involves rigorous comparability studies.
• Broader Anticoagulant Market: It is crucial to contextualize TFPI inhibition within the broader anticoagulant market, which is dominated by established therapies like warfarin, direct oral anticoagulants (DOACs) such as rivaroxaban and apixaban, and parenteral anticoagulants like heparin and low molecular weight heparins. TFPI inhibitors are likely to find a niche where they offer a distinct advantage.

Key Takeaways

• Patent 10,154,990 protects methods of treating or preventing thrombosis using antibodies or antibody fragments that neutralize tissue factor pathway inhibitor (TFPI).
• The patent's claims cover a range of thrombotic conditions, including DVT, PE, stroke, myocardial infarction, and DIC.
• Regeneron Pharmaceuticals, Inc. is the assignee of Patent 10,154,990, indicating their significant strategic interest and investment in TFPI inhibition.
• The patent landscape for TFPI inhibition is active, with multiple entities exploring this target, necessitating careful Freedom to Operate (FTO) analysis for any new entrant.
• The patent term and potential for extensions (e.g., Patent Term Extension) are critical factors for determining market exclusivity and competitive entry timelines.
• Future R&D in this space may focus on combination therapies, novel TFPI inhibitors, or exploration of different therapeutic indications.

FAQs

1. What is the specific amino acid sequence or epitope recognized by the TFPI-neutralizing antibodies claimed in Patent 10,154,990? Patent 10,154,990 broadly claims antibodies or antibody fragments that neutralize TFPI's biological activity and specifies binding to certain domains (Kunitz, N-terminal, C-terminal). However, the patent does not typically disclose the precise amino acid sequences or exact epitope mapping for all potentially covered antibodies. Detailed sequence information is usually found in related antibody-specific patents or applications, or through reverse engineering by competitors.

2. Does Patent 10,154,990 cover the use of small molecule inhibitors of TFPI? No, Patent 10,154,990 specifically claims methods involving the administration of an "antibody or antibody fragment." It does not cover small molecule inhibitors or other non-antibody-based approaches to TFPI neutralization.

3. Can a competitor develop a TFPI inhibitor targeting a different TFPI domain than those mentioned in the patent claims? The claims mention binding to the Kunitz, N-terminal, and C-terminal domains. If a competitor's TFPI inhibitor binds to TFPI but not to these specific domains or achieves neutralization through a mechanism not covered by the claims, it might avoid infringement. However, the claim of "neutralizes the biological activity of TFPI" is broad and would need careful interpretation in conjunction with the disclosed embodiments and prosecution history.

4. What is the expected lifespan of Patent 10,154,990 in the United States? Assuming the patent was filed under the America Invents Act (AIA) and no Patent Term Extension (PTE) is granted, its term is 20 years from the earliest non-provisional filing date. Maintenance fees must be paid at 3.5, 7.5, and 11.5 years post-grant to keep it in force. If a product based on this patent receives FDA approval, a PTE could extend the term.

5. Are there any known approved drugs on the market that are covered by the claims of Patent 10,154,990? As of the current analysis, the primary therapeutic agent developed by Regeneron targeting TFPI is serelocumab. While it has undergone clinical investigation, it is not widely marketed as an approved drug for broad thrombotic indications covered by this patent. Therefore, a broad market presence of drugs directly and exclusively covered by the claims of 10,154,990 is not evident.

Citations

[1] Regeneron Pharmaceuticals, Inc. (n.d.). Serelocumab. Retrieved from https://investor.regeneron.com/pipeline (Note: Specific pipeline details may change; reference to clinical development of serelocumab for TFPI inhibition is a general publicly available fact about Regeneron's activities).

Drugs Protected by US Patent 10,154,990

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	OFEV	nintedanib esylate	CAPSULE;ORAL	205832-001	Oct 15, 2014		RX	Yes	No	10,154,990*PED				Y
Boehringer Ingelheim	OFEV	nintedanib esylate	CAPSULE;ORAL	205832-002	Oct 15, 2014		RX	Yes	Yes	10,154,990*PED				Y

Foreign Priority and PCT Information for Patent: 10,154,990

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	04030770	Dec 24, 2004

International Family Members for US Patent 10,154,990

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1830843		C300747	Netherlands
European Patent Office	1830843		122015000052	Germany
European Patent Office	1830843		CA 2015 00036	Denmark
European Patent Office	1830843		PA2015025	Lithuania
European Patent Office	1830843		92762	Luxembourg
European Patent Office	1830843		300747	Netherlands