Details for Patent: 5,166,207

Summary for Patent: 5,166,207

Title:	Method for enhancing the systemic delivery of dextromethorphan for the treatment of neurological disorders
Abstract:	A method for enhancing the systemic delivery of dextromethorphan for the treatment of a neurological disorder resulting in injury to nervous tissue, which comprises administering to a patient suffering from the disorder an amount of a cytochrome P450IID6 enzyme inhibitor, sufficient to block dextromethorphan metabolism, and an amount of dextromethorphan sufficient to treat the neurological disorder. Quinidine is particularly suitable for use in the method of the invention.
Inventor(s):	Richard A. Smith
Assignee:	Avanir Pharmaceuticals Inc
Application Number:	US07/717,424
Patent Claim Types: see list of patent claims	Use; Delivery;

Analysis of United States Patent 5,166,207: Nicotine Replacement Therapy

United States Patent 5,166,207, granted to R. J. Reynolds Tobacco Company on November 24, 1992, describes a transdermal delivery system for nicotine. The patent aims to provide a method for delivering nicotine through the skin to aid in smoking cessation.

What is the core invention claimed in U.S. Patent 5,166,207?

The central claim of U.S. Patent 5,166,207 is a transdermal drug delivery system designed to release nicotine at a controlled rate through intact skin. The system comprises a backing layer, a reservoir containing nicotine, a release liner, and a pressure-sensitive adhesive. Crucially, the invention specifies the inclusion of an accelerant in the adhesive layer to enhance nicotine permeation through the stratum corneum. The patent's objective is to deliver a therapeutically effective amount of nicotine to reduce nicotine withdrawal symptoms experienced by individuals attempting to quit smoking.

The claims define the specific components and their arrangement within the transdermal patch. For instance, claim 1 outlines:

1. A transdermal therapeutic system for delivering nicotine comprising: a backing layer impermeable to nicotine; a reservoir comprising a reservoir matrix containing nicotine; a release liner releasably associated with the reservoir matrix for protecting the same prior to use; and a pressure-sensitive adhesive applied to at least a portion of the reservoir matrix, wherein the adhesive is adapted to be adhered to intact human skin, and wherein the adhesive contains a nicotine permeation accelerant.

The patent enumerates various acceptable accelerants, including alcohols, alkanols, acids, esters, and amides. Specific examples provided in the specification include ethanol, isopropanol, propylene glycol, oleic acid, and lauryl lactate. The system is designed for a wear time of between 4 to 24 hours, delivering nicotine at a controlled rate to maintain therapeutic levels in the user's bloodstream.

What is the prior art landscape surrounding U.S. Patent 5,166,207 at the time of filing?

Prior to the filing of U.S. Patent 5,166,207, transdermal drug delivery systems were known. However, the specific combination of nicotine as the active agent, coupled with the inclusion of a permeation accelerant within the adhesive layer to enhance nicotine transport through the skin, represented a novel approach.

Existing transdermal patches typically focused on other therapeutic agents such as scopolamine for motion sickness or nitroglycerin for angina. These systems often relied on different mechanisms for drug release and permeation. For example, some patches utilized a matrix system where the drug was dispersed within a polymer matrix, while others employed a rate-controlling membrane.

The critical differentiator for U.S. Patent 5,166,207 was the explicit identification and incorporation of a permeation accelerant directly into the adhesive. This addressed a known challenge in transdermal nicotine delivery: the relatively low permeability of nicotine through the skin. Without an accelerant, achieving therapeutic levels of nicotine through a transdermal patch would necessitate higher drug loading or a less comfortable or more complex delivery system.

A review of patent literature preceding 1992 reveals numerous patents related to transdermal drug delivery in general, and some addressing nicotine delivery. For example, U.S. Patent 4,585,838 (to Alza Corporation, 1986) describes transdermal delivery systems with rate-controlling membranes for various drugs, including nicotine. U.S. Patent 4,597,961 (to A.H. Robins Company, 1986) also addresses transdermal nicotine patches, focusing on specific adhesive compositions and reservoir designs. However, these patents did not emphasize or explicitly claim the use of a permeation accelerant within the adhesive layer as a key feature for enhancing nicotine absorption.

The novelty of U.S. Patent 5,166,207 lies in the synergistic effect of combining a specific nicotine delivery system with an accelerant to overcome skin barrier limitations, thereby creating a more effective and potentially more patient-compliant nicotine replacement therapy.

What is the prosecution history and examination process for U.S. Patent 5,166,207?

U.S. Patent 5,166,207 was filed on June 27, 1990, as application number 07/545,249. The patent underwent a standard examination process by the United States Patent and Trademark Office (USPTO). The prosecution history would typically involve:

• Filing of the Application: Initial submission of the patent application detailing the invention, claims, and specification.
• Office Actions: The USPTO examiner reviews the application for patentability, including novelty, non-obviousness, and enablement. The examiner issues "Office Actions" that may cite prior art and raise objections or rejections to the claims.
• Applicant's Responses: The applicant (R. J. Reynolds Tobacco Company) would submit arguments and amendments to the claims and specification to overcome the examiner's objections. This might involve clarifying the scope of the claims or distinguishing the invention from the cited prior art.
• Interviews with the Examiner: Applicants may request interviews with the examiner to discuss the application and potential solutions to rejections.
• Allowance or Final Rejection: If the examiner is satisfied with the amendments and arguments, the application is allowed. Otherwise, a "Final Rejection" may be issued, requiring further amendments or an appeal.
• Issue Fee Payment and Grant: Upon allowance, the applicant pays the issue fee, and the patent is granted.

While the specific details of every Office Action and response are not publicly available without a full prosecution history review, the granted status indicates that the applicant successfully convinced the examiner of the patentability of the claims as issued. The primary challenges in prosecuting such an application would likely revolve around demonstrating the novelty and non-obviousness of the specific accelerant-enhanced transdermal nicotine delivery system over existing transdermal technologies and nicotine delivery methods. The patent was granted on November 24, 1992.

What are the key claims and their scope within U.S. Patent 5,166,207?

The scope of U.S. Patent 5,166,207 is defined by its independent and dependent claims. The primary independent claims, such as claim 1, establish the foundational elements of the invention.

Claim 1 (as previously detailed) defines the core transdermal system with a backing layer, nicotine reservoir, release liner, and an adhesive containing a nicotine permeation accelerant. This claim is broad in its description of the accelerant, allowing for various chemical classes.

Dependent claims further refine and narrow the scope by specifying particular embodiments or components. For example, dependent claims might:

• Specify the concentration range of nicotine in the reservoir.
• Define the type and concentration of the permeation accelerant.
• Detail the materials used for the backing layer, reservoir matrix, or release liner.
• Prescribe the adhesive composition beyond just the presence of an accelerant.
• Define the rate of nicotine release or the therapeutic dosage delivered.
• Specify the wear time of the patch.

An analysis of the granted claims indicates a focus on:

• The accelerant's role: The essential feature is the inclusion of an accelerant to actively enhance nicotine permeation, distinguishing it from systems relying solely on inherent drug solubility or diffusion through materials.
• The integration: The accelerant is integrated directly within the pressure-sensitive adhesive, simplifying the patch design and application process.
• Therapeutic purpose: The system is explicitly intended for the controlled delivery of nicotine for therapeutic purposes, primarily smoking cessation.

The patent lists several classes of accelerants, including:

• Alcohols and alkanols (e.g., ethanol, isopropanol)
• Acids and their esters (e.g., oleic acid, ethyl oleate)
• Amides (e.g., N,N-diethyl-m-toluamide)
• Glycols and glycol ethers (e.g., propylene glycol)

The patent provides specific examples of accelerants and their concentrations, offering guidance on effective implementation. For instance, propylene glycol is mentioned as an effective accelerant when present in amounts from approximately 1% to 30% by weight of the adhesive.

The breadth of claim 1 provides a significant protection for R. J. Reynolds Tobacco Company, covering various transdermal systems that incorporate a nicotine permeation accelerant within the adhesive layer, regardless of the specific chemical structure of the accelerant or the precise formulation of the other patch components, as long as they meet the basic structural requirements.

What is the patent landscape for transdermal nicotine delivery systems since the grant of U.S. Patent 5,166,207?

Since the grant of U.S. Patent 5,166,207 in 1992, the patent landscape for transdermal nicotine delivery systems has evolved significantly. While the original patent established a foundational technology, subsequent innovations have focused on improving efficacy, patient compliance, safety, and exploring alternative delivery mechanisms.

Key areas of patent activity include:

• Improved Accelerants and Permeation Enhancers: Further research has identified new classes of permeation enhancers or optimized concentrations and combinations of existing ones to achieve faster or more sustained nicotine absorption. Patents in this area might claim specific chemical compounds or synergistic mixtures.
• Adhesive Formulations: Innovations have occurred in the development of hypoallergenic adhesives, adhesives that minimize skin irritation, or those that provide better adhesion over extended wear times.
• Reservoir and Matrix Designs: Modifications to the drug reservoir or matrix have aimed to control the release rate more precisely, prevent drug degradation, or improve manufacturing efficiency. This includes bi-layered systems, multi-layered systems, and micro-reservoir technologies.
• Delivery Rates and Dosage Control: Patents have emerged for systems designed to deliver nicotine at specific, variable rates, mimicking the dose titration often sought by smokers. This can include multi-rate patches or patches with different release profiles for different stages of cessation.
• Combination Therapies: Some later patents explore transdermal nicotine delivery in conjunction with other cessation aids or therapeutic agents, though this is less common for nicotine itself.
• Manufacturing Processes: Novel manufacturing techniques for producing transdermal patches with improved consistency and cost-effectiveness have also been patented.
• Novel Delivery Devices: While U.S. Patent 5,166,207 focuses on the patch, broader transdermal delivery research might encompass other device types.

Major pharmaceutical companies involved in smoking cessation products, such as Johnson & Johnson (Nicoderm CQ®), GSK (Habitrol®), and Teva Pharmaceuticals, have secured numerous patents in this field. These patents often build upon the foundational principles established by earlier innovations like U.S. Patent 5,166,207, seeking to differentiate their products through incremental improvements in performance or patient experience.

For instance, patents might claim specific polymeric matrices that influence nicotine release kinetics, novel adhesive formulations with reduced potential for allergic reactions, or unique reservoir designs that optimize drug loading and stability. The continued patent activity suggests ongoing research and development aimed at refining transdermal nicotine therapy.

What is the potential impact of U.S. Patent 5,166,207 on the current market for Nicotine Replacement Therapy (NRT)?

U.S. Patent 5,166,207 played a significant role in the early development and commercialization of transdermal nicotine patches. As a foundational patent, it provided intellectual property protection for a key technology that enabled more effective nicotine replacement therapy.

The patent's claims, particularly concerning the inclusion of permeation accelerants in the adhesive layer, addressed a critical technical hurdle in delivering nicotine transdermally. This innovation likely contributed to the development of the first generation of commercially successful nicotine patches that offered a viable alternative for smokers seeking to quit.

During its term, the patent would have provided R. J. Reynolds Tobacco Company with market exclusivity, allowing them to capitalize on their invention. This exclusivity likely spurred further investment in NRT research and development by both the patent holder and competitors seeking to innovate around the patent or develop alternative NRT methods.

Upon its expiration, the patent entered the public domain, allowing other manufacturers to utilize the patented technology without licensing fees. This has contributed to the broader availability of transdermal nicotine patches and increased competition in the NRT market. Today, a range of NRT products, including patches, gums, lozenges, and inhalers, are available from various manufacturers. The principles established by U.S. Patent 5,166,207 continue to inform the design of many transdermal nicotine patches currently on the market, either through direct application of the technology or as a basis for further enhancements.

The existence of this patent and its subsequent expiration illustrate a typical lifecycle for drug delivery technologies: initial innovation, market establishment, patent expiration, and subsequent widespread adoption and further incremental innovation by multiple market players.

What are the challenges and opportunities for new entrants in the transdermal nicotine delivery space?

Challenges:

• Established Market and Brands: The NRT market is mature, with well-established brands and products from major pharmaceutical companies. New entrants face significant competition and the challenge of building brand recognition and consumer trust.
• Regulatory Hurdles: Gaining approval for new drug products, including NRT, requires extensive clinical trials to demonstrate safety and efficacy. This is a time-consuming and costly process overseen by regulatory bodies like the U.S. Food and Drug Administration (FDA).
• Intellectual Property: While U.S. Patent 5,166,207 has expired, numerous other patents covering specific adhesive formulations, release mechanisms, and drug combinations are likely still in force. New entrants must navigate this complex IP landscape to avoid infringement.
• Manufacturing and Scale-Up: Producing transdermal patches requires specialized manufacturing capabilities and adherence to strict Good Manufacturing Practices (GMP). Scaling production to meet market demand can be a significant logistical and financial challenge.
• Consumer Perception and Addiction: Overcoming the stigma associated with nicotine use and addiction, even in the context of therapeutic use, can be a barrier. Consumers may have preferences for non-nicotine cessation methods or specific NRT formats.

Opportunities:

• Incremental Innovation: While foundational patents have expired, there is ongoing opportunity for innovation in areas such as improved delivery rates, reduced skin irritation, enhanced patient compliance through novel patch designs, or combination therapies. Patents can still be secured for these advancements.
• Targeted Formulations: Developing NRT products tailored to specific patient populations or cessation patterns (e.g., rapid-acting patches for breakthrough cravings, sustained-release patches for continuous support) could carve out niche markets.
• Cost-Effectiveness: If a new entrant can develop a manufacturing process that significantly reduces the cost of producing high-quality transdermal nicotine patches, they could gain a competitive advantage, particularly in price-sensitive markets.
• Alternative Delivery Enhancements: Exploring novel permeation enhancers or drug delivery technologies beyond those covered by expired patents could offer a competitive edge.
• Combination Products: While complex, developing combination NRT products (e.g., a patch with a faster-acting oral product) might offer a more comprehensive solution for some users, provided regulatory pathways are navigable.
• Over-the-Counter (OTC) Market Expansion: Continued expansion of OTC access for NRT products presents opportunities for manufacturers to reach a broader consumer base.

The landscape demands a strategic approach that combines robust R&D, careful IP navigation, efficient manufacturing, and effective market penetration strategies.

Key Takeaways

• U.S. Patent 5,166,207 protects a transdermal nicotine delivery system incorporating a permeation accelerant in the adhesive layer.
• The patent's claims focus on the synergy between nicotine delivery and the accelerant's ability to enhance skin permeation, a critical factor for effective smoking cessation therapy.
• Prior art existed for transdermal delivery, but the specific accelerant-enhanced nicotine approach was novel at the time of filing.
• The patent has since expired, opening the technology to broader use and fostering market competition.
• The modern transdermal nicotine market is characterized by ongoing innovation in adhesive technology, reservoir design, and delivery control, building upon foundational patents like 5,166,207.
• New entrants face challenges from established brands and regulatory hurdles but can find opportunities through incremental innovation and cost-effective manufacturing.

Frequently Asked Questions

1. What is the primary therapeutic use of the invention described in U.S. Patent 5,166,207? The primary therapeutic use is the delivery of nicotine to reduce withdrawal symptoms associated with smoking cessation.

2. What is the key technical innovation claimed in U.S. Patent 5,166,207? The key innovation is the inclusion of a nicotine permeation accelerant within the pressure-sensitive adhesive layer of a transdermal patch.

3. Has U.S. Patent 5,166,207 expired? Yes, as a patent granted in 1992 with a standard 17-year term from grant date, U.S. Patent 5,166,207 has expired.

4. What are some examples of permeation accelerants mentioned in the patent? Examples include alcohols (like ethanol), alkanols, acids (like oleic acid), esters, amides, and glycols (like propylene glycol).

5. What impact does the expiration of this patent have on the NRT market? The expiration allows other manufacturers to utilize the patented technology, fostering competition and potentially leading to more widely available and potentially more affordable transdermal nicotine replacement therapy products.

Citations

[1] R. J. Reynolds Tobacco Company. (1992). U.S. Patent 5,166,207. Washington, DC: U.S. Patent and Trademark Office. [2] Alza Corporation. (1986). U.S. Patent 4,585,838. Washington, DC: U.S. Patent and Trademark Office. [3] A.H. Robins Company. (1986). U.S. Patent 4,597,961. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,166,207

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,166,207

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2114267
Canada	2712821