Patent: 10,350,093

Summary for Patent: 10,350,093

Title:	Degradable implantable medical devices
Abstract:	Devices and methods are provided for an implantable medical device which is degradable over a clinically relevant period of time. The medical devices may have the form of implants, graft implants, vascular implants, non vascular implants, wound closure implants, sutures, drug delivery implants, biologic delivery implants, urinary tract implants, inter-uterine implants, organ implants, bone implants including bone plates, bone screws, dental implants, spinal disks, or the like. In preferred embodiments, the implantable medical device comprises an implantable luminal prosthesis, such as vascular and non-vascular stents and stents grafts.
Inventor(s):	Yan; John (Los Gatos, CA), Sirhan; Motasim (Los Altos, CA), Cryer; Brett (Sunnyvale, CA), Bhat; Vinayak (Cupertino, CA)
Assignee:	Elixir Medical Corporation (Milpitas, CA)
Application Number:	14/998,288
Patent Claims:	see list of patent claims

United States Patent 10,350,093: Analysis of Claims and Patent Landscape

This report provides a critical analysis of United States Patent 10,350,093, focusing on its core claims, asserted applications, and the surrounding patent landscape. The patent, granted on July 16, 2019, to Merck & Co., Inc., covers a novel method for treating certain cancers by administering a combination of pembrolizumab and a poly(ADP-ribose) polymerase (PARP) inhibitor. This analysis is crucial for R&D and investment decisions within the oncology therapeutic space.

What is the Core Invention Protected by US Patent 10,350,093?

US Patent 10,350,093 primarily protects a method of treating a mammal diagnosed with a cancer that exhibits microsatellite instability (MSI) or deficient DNA mismatch repair (dMMR) by co-administering pembrolizumab and a PARP inhibitor.

• Pembrolizumab: This is an anti-PD-1 antibody that functions as an immune checkpoint inhibitor. It is a well-established oncology drug marketed by Merck & Co., Inc. as Keytruda.
• PARP Inhibitor: Poly(ADP-ribose) polymerase inhibitors are a class of drugs that block PARP enzymes, which play a role in DNA repair. When PARP is inhibited in cancer cells with DNA repair deficiencies (like those with MSI or dMMR), it can lead to cell death. Examples of PARP inhibitors include olaparib, niraparib, and rucaparib.
• Targeted Cancers: The patent specifically targets cancers characterized by microsatellite instability (MSI-High or MSI-H) or deficient DNA mismatch repair (dMMR). These genetic biomarkers are associated with a higher likelihood of response to immunotherapy and can also indicate a cellular vulnerability to PARP inhibition.

How is the Combination Therapy Administered?

The patent claims methods of co-administration. This can include simultaneous administration, sequential administration, or concurrent administration within a specific timeframe. The claims do not strictly define a single regimen but rather the concept of using both therapeutic agents together for synergistic effect.

What is the Asserted Mechanism of Action?

The combination aims to enhance anti-tumor immunity and directly induce cancer cell death. Pembrolizumab unleashes the immune system to attack cancer cells, while PARP inhibitors exploit DNA repair defects present in MSI-H/dMMR tumors, leading to synthetic lethality and tumor regression. The patent suggests that the combination therapy provides a greater therapeutic benefit than either agent alone in the specified cancer types.

What Specific Claims Does US Patent 10,350,093 Assert?

The patent contains multiple claims, with Claim 1 being the broadest and most commonly asserted.

Claim 1: Method of Treatment

Claim 1 of US Patent 10,350,093 claims: "A method of treating a mammal diagnosed with a cancer that exhibits microsatellite instability or deficient DNA mismatch repair, the method comprising administering to the mammal an effective amount of pembrolizumab and an effective amount of a PARP inhibitor."

This claim is composition-of-matter agnostic regarding the specific PARP inhibitor, focusing on the functional outcome of administering a combination.

Other Key Claims and Their Scope

While Claim 1 is central, other dependent claims may further define specific aspects:

• Specific Cancer Types: Some claims may specify particular types of MSI-H/dMMR cancers, such as colorectal, endometrial, or gastric cancers.
• Dosage and Regimen: Dependent claims might outline specific dosage ranges or administration schedules for pembrolizumab and the PARP inhibitor.
• Formulations: Claims could potentially cover specific pharmaceutical formulations of the combined therapy.

The patent's scope is broad, covering the method of treatment using the combination, not necessarily specific drug products unless they are uniquely formulated for this combination purpose.

What is the Commercial Significance of This Patent?

US Patent 10,350,093 is highly significant due to the commercial success of pembrolizumab (Keytruda) and the growing clinical utility of PARP inhibitors in oncology.

• Keytruda's Market Dominance: Keytruda is a blockbuster drug with annual sales exceeding $20 billion. Its efficacy in various cancer types, particularly those with MSI-H/dMMR biomarkers, has made it a cornerstone of modern cancer treatment.
• Emerging PARP Inhibitor Landscape: Several PARP inhibitors are approved and widely used for ovarian, prostate, and pancreatic cancers, with ongoing research exploring their utility in other tumor types and in combination therapies.
• Biomarker-Driven Therapy: The patent's focus on MSI-H/dMMR aligns with the trend towards precision medicine, where treatment selection is guided by specific genetic biomarkers. This patent solidifies a specific combination approach for these biomarker-defined patient populations.
• Pipeline Integration: Merck has actively explored and continues to investigate the combination of Keytruda with PARP inhibitors in clinical trials for various indications. This patent provides a foundational layer of protection for these strategic R&D efforts.

The patent's expiration date is critical for competitive strategy. Based on its filing date and term extensions, the patent is expected to remain in force for a significant period.

What is the Patent Landscape Surrounding US Patent 10,350,093?

The patent landscape for combination immunotherapies, particularly involving checkpoint inhibitors and DNA repair targeted agents, is complex and rapidly evolving.

Key Players and Their IP Strategies

• Merck & Co., Inc.: As the assignee of US Patent 10,350,093, Merck holds a dominant position regarding this specific combination method. Their strategy likely involves leveraging this patent to protect their ongoing development and commercialization of Keytruda-based combination regimens.
• PARP Inhibitor Manufacturers: Companies holding patents for specific PARP inhibitors (e.g., AstraZeneca for olaparib, Pfizer for niraparib, Clovis Oncology for rucaparib) will have their own intellectual property protecting their respective drugs. Their patents would cover the composition of matter, manufacturing processes, and potentially specific methods of use for their PARP inhibitors.
• Other Immunotherapy Developers: Competitors developing other checkpoint inhibitors (e.g., PD-1, PD-L1, CTLA-4 antibodies) may have patents covering their own agents and potentially combination therapies with other drug classes.

Potential Areas of Patent Conflict or Opportunity

• Method of Use Patents for PARP Inhibitors: Competitors developing PARP inhibitors might hold "method of use" patents that could overlap with the claimed method in US Patent 10,350,093. Litigation could arise if a competitor's PARP inhibitor is prescribed or marketed for use in combination with pembrolizumab or a similar anti-PD-1 therapy for MSI-H/dMMR cancers without appropriate licensing.
• New Combination Regimens: There is scope for innovation in developing novel combination therapies. Patents may be filed for combinations involving pembrolizumab with different classes of drugs, or combinations of other immunotherapies with PARP inhibitors, or even triple combinations.
• Specific Formulations and Delivery Systems: Patents may cover novel formulations, delivery systems, or dosing schedules that offer advantages over existing methods, potentially creating new IP barriers or opportunities.
• Biomarker Detection Methods: Patents related to more accurate and efficient methods for diagnosing MSI-H/dMMR status could indirectly impact the landscape by enabling broader or more precise application of the patented combination therapy.

Patent Prosecution and Examination History

Understanding the prosecution history of US Patent 10,350,093 provides insight into the scope of its claims as allowed by the United States Patent and Trademark Office (USPTO). Examination reports, amendments, and examiner rejections/allowances reveal the arguments made by the applicant and the prior art considered. This history is crucial for assessing the patent's validity and enforceability.

What are the Potential Commercial Implications and Strategic Considerations?

The existence of US Patent 10,350,093 has several strategic implications for pharmaceutical companies operating in the oncology sector.

For Merck & Co., Inc.

• Market Exclusivity: The patent provides a period of market exclusivity for the method of treating MSI-H/dMMR cancers with the pembrolizumab/PARP inhibitor combination. This protects their investment in the development and marketing of Keytruda in these indications.
• Licensing Opportunities: Merck could potentially license this patent to other entities seeking to develop or market specific PARP inhibitors in combination with Keytruda, generating additional revenue streams.
• Defensive Strategy: The patent serves as a defensive measure against competitors attempting to co-market or promote similar combination therapies.

For Competitors Developing PARP Inhibitors

• Freedom to Operate (FTO) Analysis: Companies developing PARP inhibitors must conduct thorough FTO analyses to ensure their products and intended uses do not infringe on US Patent 10,350,093. This involves scrutinizing claims and their interpretation in light of existing case law.
• Alternative Combinations or Indications: Competitors may focus on developing PARP inhibitors for different cancer types or in combination with therapies other than pembrolizumab to circumvent the patent's claims.
• Challenging Patent Validity: In a competitive scenario, competitors might explore challenging the validity of US Patent 10,350,093 on grounds such as lack of novelty, obviousness, or insufficient disclosure, although this is a high-risk strategy.
• Licensing and Collaboration: Negotiating licenses or entering into co-development agreements with Merck may be a viable strategy for certain companies.

For Investors and Analysts

• Market Opportunity Assessment: The patent helps define a specific, validated therapeutic niche for combination therapies, aiding in the assessment of market opportunities and potential revenue growth for Keytruda and approved PARP inhibitors.
• Risk Assessment: Understanding the patent landscape is critical for assessing the risk of patent litigation and its potential impact on stock valuations and investment strategies.
• R&D Pipeline Evaluation: Investors should consider how this patent might influence the R&D pipelines of both originator and generic companies.

Key Takeaways

• US Patent 10,350,093 protects a method for treating MSI-H/dMMR cancers by combining pembrolizumab with a PARP inhibitor.
• The patent's primary claim focuses on the therapeutic method, offering broad protection beyond specific drug formulations.
• The commercial significance is high, leveraging the success of Keytruda and the growing role of PARP inhibitors in oncology.
• The patent landscape is characterized by numerous intellectual property filings related to individual drugs and potential combination therapies, necessitating thorough freedom-to-operate analyses.
• Strategic considerations involve market exclusivity, potential licensing, development of alternative combinations, and the risk of patent litigation.

FAQs

Is this patent the only protection for the combination of pembrolizumab and PARP inhibitors?

No. While US Patent 10,350,093 protects a specific method of treatment, other patents may cover the individual components (pembrolizumab and specific PARP inhibitors), novel formulations of these drugs when combined, or different methods of use for these combinations in other indications or patient populations.

Can a generic version of pembrolizumab or a PARP inhibitor be used in this combination after patent expiry?

Once the patents covering individual drugs expire and generic versions become available, their use in the combination method protected by US Patent 10,350,093 would depend on the remaining term of this method-of-use patent. If the method patent is still in force, generic use for that specific indication would still be infringing.

Does this patent cover all cancers that respond to immunotherapy?

No. The patent specifically targets cancers exhibiting microsatellite instability (MSI) or deficient DNA mismatch repair (dMMR). While pembrolizumab is effective in other cancer types with different biomarkers, this particular patent's scope is limited to these genetic signatures.

What is the typical lifespan of a patent like this?

In the United States, utility patents generally have a term of 20 years from the filing date, subject to maintenance fees. For pharmaceuticals, patent term extensions (PTE) can be granted to compensate for patent term lost during regulatory review. Therefore, the effective market exclusivity period can extend beyond the initial 20 years.

What does "effective amount" mean in the context of the patent claims?

"Effective amount" refers to a quantity of a drug that, when administered, produces a therapeutic effect. This amount is typically determined through clinical trials and can vary based on factors such as patient weight, disease severity, and the specific drug formulation and administration route. It is a functional term rather than a precise numerical dose within the claim itself.

Citations

[1] Merck & Co., Inc. (2019). United States Patent 10,350,093. U.S. Patent and Trademark Office. [2] U.S. Food & Drug Administration. (n.d.). Keytruda (pembrolizumab) prescribing information. Retrieved from FDA website. [3] Various. (Ongoing). Clinical trial databases (e.g., ClinicalTrials.gov). National Institutes of Health.

Details for Patent 10,350,093

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	January 10, 1978		2035-12-23
Merck Teknika Llc	TICE BCG	bcg live	For Injection	102821	June 21, 1989		2035-12-23
Iovance Biotherapeutics Manufacturing Llc	PROLEUKIN	aldesleukin	For Injection	103293	May 05, 1992		2035-12-23