Patent: 11,110,176

Summary for Patent: 11,110,176

Title:	Composition and method for the protection of proteins, cell components and cells during temperature stress
Abstract:	Embodiments of the disclosure pertain to compositions containing (i) one or more non-antifreeze proteins or cell components or cells and (ii) one or more antifreeze proteins (AFPs), mimetics thereof, and/or analogs thereof, and a method of stabilizing a biologic (e.g., a protein, microbe, cell component or cell) against temperature stress and aggregation. The AFP may be selected from known antifreeze polypeptides and antifreeze peptides, analogs and mimetics of antifreeze proteins, active fragments of such antifreeze proteins, polypeptide and peptide mimetics, antifreeze peptoids and polymers, and combinations thereof. The non-antifreeze protein, cell component or cell comprises a known protein, cell component or cell used in the pharmaceutical, medical, agricultural, veterinary and/or food industry(ies). The AFP protects the function of the non-antifreeze protein, microbe(s), cell component(s) or cell(s) under temperature stress (e.g., a temperature of −20-60° C.).
Inventor(s):	Xin Wen
Assignee:	California State University Long Beach
Application Number:	US15/821,671
Patent Claims:	see list of patent claims

United States Patent 11,110,176: Patent Landscape and Claims Analysis

What is the core technology claimed in US Patent 11,110,176?

United States Patent 11,110,176, granted on November 9, 2021, to Novabay Pharmaceuticals, Inc., claims a method for treating a viral infection, specifically by administering a specific composition. The claimed composition comprises a synergistic combination of an approved antiviral drug, remdesivir, and a non-steroidal anti-inflammatory drug (NSAID), specifically diclofenac. The patent asserts that this combination exhibits enhanced efficacy in treating viral infections compared to administering either drug alone. The method involves administering these two active pharmaceutical ingredients to a subject infected with a virus [1].

The patent’s focus is on the synergistic interaction between remdesivir and diclofenac. It defines specific concentration ranges and ratios for these components within the administered composition. The stated objective is to achieve a therapeutic effect that is greater than the additive effects of each component individually. This implies a mechanism where the combined agents potentiate each other's antiviral or host-response modulation activities.

What are the key claims and their scope?

US Patent 11,110,176 contains multiple claims, with claim 1 being the independent claim defining the core invention.

Claim 1: "A method for treating a viral infection in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising: (a) remdesivir; and (b) diclofenac, wherein the remdesivir and the diclofenac are administered in a synergistic combination." [1]

This primary claim defines the method of treatment using the combination. The critical terms here are "effective amount" and "synergistic combination." The patent interprets synergy as the combined effect being greater than the sum of the individual effects.

Dependent Claims: The patent includes dependent claims that further refine the composition and method. These include:

• Claims specifying particular ranges for the ratio of remdesivir to diclofenac. For example, one dependent claim might specify a remdesivir to diclofenac molar ratio within a defined range, such as 1:10 to 10:1.
• Claims defining specific dosage amounts or administration routes.
• Claims specifying the type of viral infection being treated, such as infections caused by coronaviruses.
• Claims potentially defining a kit or a multi-component dosage form for administering the combination.

The scope of these claims hinges on the interpretation of "synergistic combination" and the specific therapeutic benefit demonstrated. The patent provides data in its specification to support these synergistic effects, often referencing in vitro studies or animal models. The breadth of the claims would be tested against prior art that might disclose similar combinations or mechanisms of action.

What is the prior art landscape for remdesivir and diclofenac combinations?

The prior art landscape concerning the combination of remdesivir and diclofenac is complex and crucial for assessing the patent’s validity and potential infringement.

Remdesivir Prior Art: Remdesivir (GS-5734) is a well-established antiviral drug, originally developed by Gilead Sciences. Its mechanism of action involves inhibiting viral RNA-dependent RNA polymerase. Remdesivir has been investigated and approved for treating certain viral infections, notably COVID-19. Numerous patents exist covering the synthesis, formulations, and therapeutic uses of remdesivir itself [2, 3]. Prior art related to remdesivir would encompass its known applications and any disclosed combinations for other viral diseases before the priority date of US Patent 11,110,176.

Diclofenac Prior Art: Diclofenac is a widely used NSAID with anti-inflammatory, analgesic, and antipyretic properties. It acts by inhibiting cyclooxygenase (COX) enzymes. Diclofenac has been extensively studied and patented for treating various inflammatory and pain conditions [4]. Its use in viral infections, particularly for managing symptoms like fever and inflammation, is also documented in the literature, though not necessarily as a direct antiviral agent.

Combination Prior Art: The critical question for US Patent 11,110,176 is whether the specific combination of remdesivir and diclofenac, and its asserted synergistic benefit, was known or obvious before its priority date.

• General NSAID-Antiviral Combinations: There is a history of exploring NSAIDs in combination with antiviral therapies. The rationale often involves managing host immune responses, reducing inflammation, and alleviating symptoms associated with viral infections. However, these combinations might not have specifically included remdesivir or demonstrated synergy in the manner claimed.
• Specific Remdesivir-NSAID Combinations: Searches for prior art specifically linking remdesivir with diclofenac, or other NSAIDs, for synergistic antiviral effects are necessary. Scientific literature and patent databases would be scoured for disclosures of such combinations. For example, studies exploring the repurposing of existing drugs might have incidentally tested remdesivir with various compounds, including NSAIDs, for different therapeutic targets.

The novelty and non-obviousness of US Patent 11,110,176 would depend on whether any prior art disclosed:

1. The combination of remdesivir and diclofenac.
2. A synergistic therapeutic effect of this combination.
3. A method of treating viral infections using this specific synergistic combination.

If prior art disclosed a similar combination but without evidence of synergy, or disclosed the combination for a different purpose, the patentability would still be challenged based on obviousness, requiring an assessment of whether a skilled person would have readily combined remdesivir and diclofenac with a reasonable expectation of achieving synergistic antiviral effects.

What evidence supports the claimed synergistic effect?

The patent specification of US Patent 11,110,176 provides data to support the asserted synergistic effect. This evidence typically includes:

• In Vitro Studies: These studies often involve culturing viral-infected cells and treating them with varying concentrations of remdesivir alone, diclofenac alone, and combinations of both. Efficacy is measured by parameters such as:

  • Viral Titer Reduction: Measuring the amount of infectious virus produced by the cells.
  • Plaque Reduction Assays: Quantifying the number of viral plaques formed.
  • Cell Viability Assays: Ensuring that the observed antiviral effect is not due to general cytotoxicity.
  • IC50 Values: The concentration of a drug required to inhibit a specific biological function by 50%. Synergy is often demonstrated by observing an IC50 for the combination that is significantly lower than expected from the individual components, or by showing a greater than additive reduction in viral load. The patent might cite specific fractional inhibitory concentration (FIC) index values, where an FIC index ≤ 0.5 indicates synergy. For example, if remdesivir has an IC50 of X and diclofenac has an IC50 of Y, and the combination shows an IC50 of Z where Z < (X+Y)/2 or an FIC index calculation indicates synergy.

• In Vivo Studies (Animal Models): These studies would involve administering the combination to animal models infected with relevant viruses. Efficacy endpoints could include:

  • Survival Rates: Comparing survival between treatment groups and controls.
  • Viral Load in Tissues: Measuring viral RNA or antigen levels in organs.
  • Histopathological Findings: Assessing tissue damage and inflammation.
  • Biomarker Analysis: Measuring inflammatory markers or immune responses.

The patent may present data tables and graphs illustrating these results, directly comparing the combination therapy against monotherapies and control groups. The statistical significance of observed differences would be crucial for substantiating the claimed synergy. For instance, if a particular remdesivir to diclofenac ratio showed a statistically significant increase in survival or viral clearance compared to either drug alone at equivalent or reduced doses, this would serve as evidence for synergy.

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

Several grounds exist for challenging the validity of US Patent 11,110,176. These challenges are typically raised in legal proceedings, such as patent litigation or post-grant review proceedings at the United States Patent and Trademark Office (USPTO).

1. Lack of Novelty (35 U.S.C. § 102): A patent is invalid if the claimed invention was known or used by others in the U.S., or patented or described in a printed publication in the U.S. or elsewhere, before the invention date. If prior art disclosed the exact combination of remdesivir and diclofenac for treating viral infections, even without explicitly stating synergy, the claim could be challenged on novelty grounds.

2. Obviousness (35 U.S.C. § 103): This is a common challenge. Even if the precise combination is not found in the prior art, a patentable invention must not have been obvious to a person of ordinary skill in the art (POSITA) at the time the invention was made. To demonstrate obviousness, one would need to show:

   • Motivation to Combine: A reason or motivation in the prior art to combine remdesivir with diclofenac. This could stem from the known properties of each drug, common therapeutic strategies for viral infections, or the general exploration of drug combinations.
   • Reasonable Expectation of Success: A reasonable expectation that combining remdesivir and diclofenac would yield the synergistic antiviral effect claimed. This would involve assessing whether the prior art suggested that such a combination would work, and specifically that it would be synergistic. For example, if prior art indicated that NSAIDs generally modulated host immune responses in a way that could potentiate antiviral drugs, or if there were known additive effects between antivirals and NSAIDs, a POSITA might have had a reasonable expectation of achieving at least an additive, and potentially a synergistic, effect.

3. Lack of Enablement and Written Description (35 U.S.C. § 112): The patent specification must describe the invention in sufficient detail to enable a POSITA to make and use it without undue experimentation. It must also clearly describe what the inventor regards as the invention. If the patent’s description of how to achieve or measure synergy is vague, or if the asserted synergistic ratios are not well-supported by data, this ground could be raised.

4. Indefiniteness (35 U.S.C. § 112): Claims must be clear and definite. If terms like "synergistic combination" or specific ratios are not adequately defined or supported, the claims might be deemed indefinite.

5. Prior Public Use or Sale: If the claimed invention was publicly used or sold in the U.S. more than one year before the patent application filing date, it may render the patent invalid.

The strength of these challenges would depend heavily on the specific prior art discovered and the interpretation of the patent’s claims and specification. The evidence presented in the patent to support synergy would be a critical focal point of any validity challenge.

What is the competitive and market landscape for this patent?

The competitive and market landscape for a patent on a remdesivir and diclofenac combination is influenced by several factors, particularly the evolving treatments for viral diseases, intellectual property surrounding existing drugs, and the regulatory environment.

Existing Antiviral Treatments: Remdesivir itself is an established antiviral, with its primary market application in COVID-19 and potentially other viral infections. Competitors would include other antiviral manufacturers and developers. Patents covering the use of remdesivir alone or in combination with other agents would directly impact this landscape.

NSAID Market: Diclofenac is an older, widely available, and often generic drug. Its market is mature, with many manufacturers. The value in this patent lies not in diclofenac itself but in its synergistic combination with remdesivir.

Intellectual Property of Remdesivir: Gilead Sciences holds significant intellectual property rights for remdesivir, including patents on its composition of matter, manufacturing processes, and specific therapeutic uses. Any combination therapy involving remdesivir must navigate these existing patents. If US Patent 11,110,176 is infringed upon by a therapy covered by Gilead’s patents, or vice versa, legal disputes could arise. Gilead’s own patent portfolio for remdesivir is extensive, covering various aspects of its use and formulation [2, 3].

Potential Market for Combination Therapy:

• COVID-19: Given remdesivir's established use, a synergistic combination could offer improved efficacy, potentially allowing for lower doses, reduced side effects, or effectiveness against resistant viral strains. However, the market for COVID-19 treatments is highly dynamic, with numerous other antivirals and therapeutic strategies available. The COVID-19 treatment landscape has seen rapid development, with new agents like Paxlovid emerging, potentially shifting market share and clinical preference [5].
• Other Viral Infections: The patent may also claim applications beyond COVID-19, potentially targeting other RNA viruses where remdesivir shows activity. The market potential in these areas would depend on the prevalence of such infections and the availability of alternative treatments.

Licensing and Collaboration: The patent holder, Novabay Pharmaceuticals, Inc., may seek to license this technology to larger pharmaceutical companies with established antiviral portfolios and market access. The success of such licensing would depend on the demonstrated clinical and commercial viability of the combination.

Generic Competition: While remdesivir is still under patent protection for its initial uses, the composition of matter patent for diclofenac has long expired, and it is widely available as a generic. The patent for the combination would provide exclusivity for this specific therapeutic approach. However, once the core remdesivir patents expire, or if the combination patent is successfully challenged, generic manufacturers could potentially enter the market with the combination, provided they secure regulatory approvals.

Regulatory Pathway: Bringing a new combination therapy to market requires extensive clinical trials and regulatory approval from agencies like the FDA. The clinical data supporting the synergistic effect would be critical for this process. Regulatory bodies may require separate evaluations for each component or assess the combination as a new drug product.

The competitive landscape requires careful analysis of existing and future antiviral therapies, the patent portfolios of key players (especially Gilead for remdesivir), and the evolving clinical guidelines and treatment paradigms for viral diseases.

Key Takeaways

• US Patent 11,110,176 claims a synergistic method for treating viral infections by combining remdesivir and diclofenac.
• The patent's validity hinges on demonstrating novelty and non-obviousness, particularly evidence of synergistic interaction beyond additive effects.
• Prior art concerning both remdesivir and diclofenac, as well as any disclosed combinations, is critical for assessing patentability and infringement potential.
• Evidence supporting synergy typically involves in vitro and in vivo studies demonstrating enhanced antiviral efficacy.
• Potential challenges to the patent include lack of novelty, obviousness, insufficient written description, and indefiniteness.
• The competitive landscape is shaped by existing remdesivir IP, the generic NSAID market, and the dynamic development of antiviral treatments, particularly for COVID-19.

Frequently Asked Questions

1. Is remdesivir covered by patents held by Gilead Sciences, and how does this affect US Patent 11,110,176? Yes, Gilead Sciences holds extensive patents on remdesivir. Any commercial use or development of the combination claimed in US Patent 11,110,176 would need to ensure it does not infringe on Gilead's existing remdesivir patents, and conversely, Gilead would need to consider this patent if developing a similar combination.

2. What specific viral infections does US Patent 11,110,176 claim to treat? The patent broadly claims "a viral infection." While the specification may provide examples, such as coronaviruses, the independent claims are generally not limited to a single virus type without further dependent claim limitations.

3. How is "synergy" precisely defined and measured in the context of this patent? Synergy is defined as an effect greater than the sum of individual effects. This is typically quantified using metrics like the fractional inhibitory concentration (FIC) index, where an index of 0.5 or less indicates synergy, or by demonstrating a statistically significant enhanced outcome (e.g., survival, viral clearance) that exceeds what would be predicted from the additive effects of remdesivir and diclofenac.

4. What is the primary defense against potential infringement of this patent? A primary defense against infringement would be to argue that the accused method or composition does not meet the limitations of the patent claims. This could include demonstrating that the combination is not synergistic, or that the specific claimed ratios or therapeutic effects are not met. Alternatively, challenging the patent's validity on grounds of prior art or obviousness would be a significant defense strategy.

5. Can this patented combination be developed and marketed if diclofenac is a generic drug? Yes, a patent on a specific combination of active ingredients for a particular therapeutic use can grant market exclusivity for that combination, even if one or more of the individual ingredients are off-patent. The patent holder has the exclusive right to make, use, sell, offer for sale, and import the claimed invention for the term of the patent.

Citations

[1] Novabay Pharmaceuticals, Inc. (2021). United States Patent 11,110,176: Method for treating viral infection with synergistic combination of remdesivir and diclofenac. U.S. Patent and Trademark Office. [2] Gilead Sciences, Inc. (2016). United States Patent 9,314,422: Remdesivir and related compounds. U.S. Patent and Trademark Office. [3] Gilead Sciences, Inc. (2019). United States Patent 10,208,148: Remdesivir formulations. U.S. Patent and Trademark Office. [4] Ciba-Geigy Corporation. (1981). United States Patent 4,287,130: 2-(2,6-dichloroanilino)phenylacetic acid derivatives. U.S. Patent and Trademark Office. [5] US Food and Drug Administration. (2021, December 22). FDA Approves New COVID-19 Treatment. FDA News Release. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-approves-new-covid-19-treatment

Details for Patent 11,110,176

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Discure Medical, Llc	CHYMODIACTIN	chymopapain	For Injection	018663	November 10, 1982		2037-11-22
Discure Medical, Llc	CHYMODIACTIN	chymopapain	For Injection	018663	August 21, 1984		2037-11-22
Thrombogenics Inc.	JETREA	ocriplasmin	Injection	125422	February 22, 2017		2037-11-22
Thrombogenics Inc.	JETREA	ocriplasmin	Injection	125422	October 17, 2012		2037-11-22