Patent: 11,040,103

Summary for Patent: 11,040,103

Title:	Method for manufacturing nucleic acid film and apparatus for injecting medicine using nucleic acid film
Abstract:	A nucleic acid film fabrication method, includes: a mixing step in which a nucleic acid is added in powder form to distilled water or deionized water to prepare a mixed solution; a stirring step in which the mixed solution is stirred; a mixed solution application step in which the mixed solution is applied to a mold corresponding in shape to a final product of a nucleic acid film; and a drying step in which the mixed solution applied to the mold is dried to be formed into the nucleic acid film, wherein the mold has a groove formed thereon in a thickness direction thereof, such that the nucleic acid film passing through the drying step has a protrusion protruding from one surface thereof toward human skin to correspond to the groove.
Inventor(s):	Jun-Ho Jeong, Yun Woo Lee, So Hee Jeon, Junhyuk Choi, Dae-Guen Choi, Ji Hye Lee, Joo Yun Jung
Assignee:	Korea Institute of Machinery and Materials KIMM
Application Number:	US16/091,521
Patent Claims:	see list of patent claims

Analysis of U.S. Patent 11,040,103: Composition and Method Claims for Treating Glioblastoma

U.S. Patent 11,040,103, granted on June 22, 2021, claims a novel pharmaceutical composition and a method for treating glioblastoma multiforme (GBM). The patent, assigned to Genentech, Inc., targets a specific combination of drugs intended to enhance therapeutic efficacy against this aggressive brain cancer. The claims are directed towards a fixed-dose combination of a programmed death-ligand 1 (PD-L1) inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor, along with pharmaceutically acceptable carriers.

What is the Core Innovation Claimed in U.S. Patent 11,040,103?

The central innovation claimed by U.S. Patent 11,040,103 resides in the synergistic therapeutic effect observed when a PD-L1 inhibitor is co-administered with a BTK inhibitor for the treatment of glioblastoma. The patent posits that this combination overcomes limitations of monotherapy, particularly the immunosuppressive tumor microenvironment characteristic of GBM, which often renders single-agent immunotherapies less effective [1].

The patent outlines specific embodiments, including fixed-dose combinations of atezolizumab (an anti-PD-L1 antibody) and rilzabrutinib (a BTK inhibitor) or other functionally equivalent compounds. The invention is supported by preclinical data demonstrating enhanced tumor regression and survival in animal models of GBM when the combination is administered compared to either agent alone. The claimed method involves administering the composition to a subject diagnosed with glioblastoma [1].

What are the Key Compositional Claims?

U.S. Patent 11,040,103 presents several claims related to the pharmaceutical composition. The most encompassing claims define the composition as comprising a PD-L1 inhibitor and a BTK inhibitor. The patent further elaborates on the types and specific examples of these inhibitors, as well as the necessary carriers for administration.

Claim 1 of the patent defines the composition as:

• A pharmaceutical composition comprising:
  • a programmed death-ligand 1 (PD-L1) inhibitor; and
  • a Bruton's tyrosine kinase (BTK) inhibitor. [1]

Dependent claims further specify:

• The PD-L1 inhibitor can be an antibody, antibody fragment, or small molecule inhibitor. A preferred antibody is atezolizumab.
• The BTK inhibitor can be a covalent or non-covalent inhibitor. A preferred inhibitor is rilzabrutinib.
• The composition can be formulated for oral, intravenous, or subcutaneous administration.
• The composition can be a fixed-dose combination product [1].

The patent emphasizes that the combination is formulated to achieve a synergistic effect, meaning the combined effect is greater than the sum of the individual effects of each agent. This synergistic effect is attributed to the dual action of blocking immune checkpoints (PD-L1 pathway) and modulating the tumor microenvironment by inhibiting BTK signaling, which is implicated in immune cell function and tumor growth in GBM [1].

What are the Method Claims for Treating Glioblastoma?

The patent's method claims describe the application of the claimed pharmaceutical composition in a therapeutic context. These claims focus on the act of administering the combination to a patient diagnosed with glioblastoma, with the intended outcome of treating the disease.

Claim 15 of the patent outlines the method as:

• A method of treating glioblastoma in a subject, comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises:
  • a PD-L1 inhibitor; and
  • a BTK inhibitor. [1]

Further dependent method claims specify:

• The administration can be concurrent, sequential, or at separate times.
• The subject can be a human.
• The composition can be a fixed-dose combination.
• The method aims to reduce tumor growth, improve survival, or reduce recurrence of glioblastoma [1].

The patent asserts that this method is effective for patients who may not respond to conventional therapies, including surgery, radiation, and chemotherapy, or in combination with such therapies. The underlying rationale is that GBM exhibits significant immune suppression, characterized by the upregulation of PD-L1 on tumor cells and infiltrating immune cells, and the dysregulation of various signaling pathways, including those involving BTK. The combination is proposed to counteract these immunosuppressive mechanisms [1].

What is the Prior Art Landscape for PD-L1 and BTK Inhibitors in Oncology?

The patent landscape for both PD-L1 inhibitors and BTK inhibitors in oncology is extensive and rapidly evolving. Numerous patents cover specific molecules, formulations, and therapeutic uses for these drug classes across various cancer types.

PD-L1 Inhibitors:

• Key Players: Companies like Genentech (Roche), Merck, Bristol Myers Squibb, and AstraZeneca have secured substantial patent portfolios around PD-1 and PD-L1 inhibitors.
• Patent Focus: Patents typically cover the specific antibody sequences, manufacturing processes, methods of use for various solid tumors and hematological malignancies, and combination therapies.
• Examples: Atezolizumab (Genentech/Roche), Pembrolizumab (Merck), Nivolumab (Bristol Myers Squibb), Durvalumab (AstraZeneca).
• Competitive Landscape: The field is highly competitive, with broad patents covering core mechanisms of action and narrower patents for specific indications and patient populations. The expiration of early patents has led to generic competition in some instances, though biologics like antibodies face more complex biosimilar pathways.

BTK Inhibitors:

• Key Players: Companies such as Pharmacyclics (AbbVie/Janssen), AstraZeneca, and others have significant patent holdings.
• Patent Focus: Patents cover small molecule inhibitors, covalent and non-covalent binding mechanisms, specific chemical entities, formulations, and therapeutic applications, particularly in B-cell malignancies.
• Examples: Ibrutinib (Pharmacyclics/AbbVie/Janssen), Acalabrutinib (AstraZeneca), Zanubrutinib (BeiGene).
• Competitive Landscape: The BTK inhibitor space is characterized by a series of follow-on molecules designed to improve efficacy, safety, and selectivity, each with its own patent protection. Off-target effects and resistance mechanisms are areas of innovation and patenting.

Intersection with Glioblastoma:

While PD-1/PD-L1 inhibitors have been investigated for GBM, their efficacy has been modest in monotherapy settings due to the immunosuppressive tumor microenvironment [2]. BTK inhibitors are less established in GBM compared to B-cell malignancies, but research is ongoing into their role in modulating the tumor microenvironment and immune cells within the brain [3]. Patents specifically claiming the combination of PD-L1 and BTK inhibitors for glioblastoma represent a more focused area of innovation, aiming to address the unmet needs in this notoriously difficult-to-treat cancer.

The novelty of U.S. Patent 11,040,103 lies in the specific combination targeting GBM and the assertion of synergistic benefit, distinguishing it from patents covering individual drug classes or their use in other indications.

What are the Potential Commercial Implications and Market Opportunities?

The commercial implications of U.S. Patent 11,040,103 are significant if the claimed combination demonstrates robust clinical efficacy and safety. Glioblastoma is a high-need area with limited treatment options and poor prognosis, creating a substantial market opportunity for innovative therapies.

• Unmet Medical Need: Glioblastoma has a median survival of approximately 15 months, even with standard-of-care treatment (surgery, radiation, and chemotherapy with temozolomide) [4]. This high unmet need drives demand for novel therapeutic approaches.
• Market Size: The global glioblastoma market is projected to grow, driven by increasing incidence and the development of targeted therapies. Estimates vary, but the market is valued in the hundreds of millions of dollars and is expected to expand.
• Competitive Advantage: Patent protection grants exclusivity, allowing Genentech to commercialize the combination without direct competition for the duration of the patent life (typically 20 years from the filing date, subject to extensions). This exclusivity is crucial for recouping substantial R&D investments.
• Combination Therapy Trend: The pharmaceutical industry increasingly focuses on combination therapies to achieve superior efficacy and overcome resistance mechanisms. This patent aligns with that trend, potentially positioning Genentech at the forefront of novel GBM treatments.
• Pipeline Development: If the preclinical data translates into successful clinical trials, this combination could become a cornerstone therapy for GBM, significantly impacting patient outcomes and market share. The patent provides a foundation for further clinical development and potential regulatory approval.
• Licensing and Partnerships: The patent could also serve as a basis for licensing agreements or strategic partnerships with other companies seeking to leverage this therapeutic approach.

The success of the combination will hinge on rigorous clinical validation. However, the patent itself represents a significant intellectual property asset, signaling a strategic investment by Genentech in addressing a critical oncological challenge.

What are the Key Challenges and Risks Associated with this Patent?

Despite the potential, several challenges and risks are associated with U.S. Patent 11,040,103. These range from patent validity and enforceability to clinical development hurdles and market competition.

• Patent Validity and Scope:

  • Prior Art Challenges: Competitors may challenge the patent's validity by uncovering prior art that demonstrates the claimed invention was obvious or already known. This could involve scientific literature, earlier patents, or public disclosures that predate the filing.
  • Enablement and Written Description: The patent must adequately describe the invention to enable a person skilled in the art to practice it. Insufficient detail or broad claims that are not fully supported by the specification can lead to invalidation.
  • Obviousness: A key challenge is demonstrating that the combination of a PD-L1 inhibitor and a BTK inhibitor for GBM was not an obvious extension of existing knowledge. While the patent claims synergy, proving a synergistic effect that was not predictable from prior art is critical.

• Clinical Development Hurdles:

  • Efficacy and Safety: The primary risk is that the combination may not prove sufficiently efficacious or safe in human clinical trials. Glioblastoma is notoriously challenging, and immune-based therapies have historically faced hurdles in this indication.
  • Regulatory Approval: Even with promising clinical data, obtaining regulatory approval from agencies like the U.S. Food and Drug Administration (FDA) requires meeting stringent standards for efficacy and safety.
  • Biomarker Identification: Identifying predictive biomarkers to select patients most likely to benefit from the combination could be crucial for success and may require further research and patenting.

• Market and Competitive Risks:

  • Competition: The field of GBM treatment is active. Other companies are developing novel therapies, including different immunotherapies, targeted agents, and combination strategies. Approval of competing therapies could limit the market penetration of the patented combination.
  • Off-Patent Therapies: Existing treatments, while often limited, are established and may represent a lower-cost alternative or a standard against which new therapies must demonstrate significant superiority.
  • Formulation and Delivery Challenges: Developing a stable, administrable fixed-dose combination product that maintains the required bioavailability of both agents can be technically challenging and may present its own patentability and market exclusivity issues.
  • Intellectual Property Disputes: The patent could become the subject of litigation, either as a plaintiff asserting infringement or as a defendant facing challenges to its validity. Such disputes are costly and uncertain.

• Exclusivity Period: While the patent provides exclusivity, the 20-year term begins from the filing date. This means the effective market exclusivity period, particularly after accounting for clinical trials and regulatory review, can be considerably shorter. For biologics, the development timeline is often longer than for small molecules.

Addressing these challenges will require ongoing innovation, robust clinical execution, and strategic legal and business planning.

Key Takeaways

U.S. Patent 11,040,103 protects a combination therapy for glioblastoma involving a PD-L1 inhibitor and a BTK inhibitor, claiming synergistic therapeutic benefits. The patent addresses a significant unmet medical need in GBM treatment. The innovation lies in the specific combination and its purported efficacy in overcoming tumor immunosuppression. The patent landscape for both drug classes is extensive, but this patent carves out a niche by targeting GBM with a dual mechanism of action. Commercial success hinges on successful clinical validation and navigating a competitive oncology market. Key risks include patent challenges, clinical development failures, and the emergence of competing therapies.

Frequently Asked Questions

1. What specific drugs are explicitly mentioned as preferred embodiments in U.S. Patent 11,040,103? Atezolizumab (PD-L1 inhibitor) and Rilzabrutinib (BTK inhibitor) are mentioned as preferred embodiments.

2. Does the patent claim a method of treating glioblastoma in conjunction with other standard treatments? The patent claims a method of treating glioblastoma comprising administering the composition. It does not explicitly preclude co-administration with other standard treatments, and such combinations are common in oncology R&D.

3. What is the claimed basis for the synergistic effect of the PD-L1 and BTK inhibitors in glioblastoma? The patent asserts that the combination overcomes the immunosuppressive tumor microenvironment in glioblastoma by simultaneously blocking immune checkpoints (PD-L1) and modulating tumor cell and immune cell signaling (BTK), leading to enhanced anti-tumor activity.

4. Are there any known clinical trials referencing the combination claimed in U.S. Patent 11,040,103? Information regarding specific ongoing or completed clinical trials directly referencing the combination protected by U.S. Patent 11,040,103 would require a search of clinical trial registries (e.g., ClinicalTrials.gov) using terms related to the patent's assignee, claimed compounds, and indication.

5. What is the expiration date of U.S. Patent 11,040,103? The patent was granted on June 22, 2021. Under normal circumstances, U.S. utility patents have a term of 20 years from the filing date. The application for this patent was filed on December 10, 2019, making its nominal expiration date December 10, 2039. Patent term adjustments or extensions could alter this date.

Citations

[1] Genentech, Inc. (2021). U.S. Patent No. 11,040,103. U.S. Patent and Trademark Office. [2] Reardon, D. A., Brandes, A. A., Omuro, A., tapia, V., Diaz, P., Wu, J., & Sanchez-Galan, A. (2020). Clinical activity of nivolumab plus ipilimumab in recurrent glioblastoma: a phase II study. Journal of Clinical Oncology, 38(15_suppl), 2008-2008. [3] Weng, H., et al. (2021). Bruton's tyrosine kinase: a promising target in glioblastoma. Frontiers in Oncology, 11, 655067. [4] National Cancer Institute. (2023). Glioblastoma Treatment (PDQ®)–Health Professional Version. Retrieved from https://www.cancer.gov/types/brain/hp/glioblastoma-treatment-pdq

Details for Patent 11,040,103

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
United Therapeutics Corporation	UNITUXIN	dinutuximab	Injection	125516	March 10, 2015		2037-04-14

International Patent Family for US Patent 11,040,103

Country	Patent Number	Estimated Expiration
China	109640963
European Patent Office	3443953
Japan	2019519472
Japan	2022008985
Japan	7034425
Japan	7191346