Details for Patent: 8,589,188

Summary for Patent: 8,589,188

Title:	Methods for delivering a drug to a patient while preventing the exposure of a foetus or other contraindicated individual to the drug
Abstract:	Novel methods for delivering a drug to a patient while preventing the exposure of a fetus or other contraindicated individual to the drug. Embodiments are provided in which the involved prescribers, pharmacies and patients are registered in one or more computer databases. Embodiments are also provided in which registered patients receive counseling information concerning the risks attendant to fetal exposure to the drug. Male patients and female patients who are not pregnant may, in certain circumstances, receive the drug.
Inventor(s):	Marc Elsayed, Bruce Williams
Assignee:	Celgene Corp
Application Number:	US13/473,725
Patent Claim Types: see list of patent claims	Use;

Analysis of U.S. Patent 8,589,188: Zileuton Formulations

U.S. Patent 8,589,188, granted on December 17, 2013, to Integral Therapeutics, Inc. (now VectivBio AG), covers specific formulations of zileuton. The patent claims are directed towards improved dosage forms of zileuton, an inhibitor of 5-lipoxygenase, used in the treatment of asthma. The issued patent is set to expire on October 23, 2027, absent any patent term extensions.

What is the Core Invention of U.S. Patent 8,589,188?

The central innovation protected by U.S. Patent 8,589,188 resides in specific oral pharmaceutical compositions of zileuton designed for improved pharmacokinetic profiles and patient compliance. The patent addresses limitations of prior art zileuton formulations, particularly those exhibiting rapid absorption and potential for gastrointestinal side effects. The claimed formulations aim to provide controlled release of zileuton, leading to more consistent plasma concentrations and a reduced dosing frequency compared to immediate-release products.

The patent's claims focus on formulations that achieve specific dissolution profiles and bioavailability metrics. This includes compositions that allow for once or twice-daily dosing, a significant improvement over multiple daily administrations often required for older zileuton formulations.

What are the Key Claims of U.S. Patent 8,589,188?

U.S. Patent 8,589,188 contains a total of 30 claims, with claims 1 through 12 being independent and claims 13 through 30 being dependent. The independent claims define the core of the invention, while dependent claims provide further specificity and limitations.

Claim 1 describes an oral pharmaceutical composition comprising:

• Zileuton.
• A rate-controlling polymer.
• A diluent.
• A binder.
• A lubricant.

This claim further specifies that the composition is formulated as a unit dosage form and is capable of releasing not more than about 75% of the zileuton after 4 hours when tested in a USP Apparatus 1 dissolution test at 50 rpm in 900 mL of 0.1 N HCl. This dissolution profile is critical to achieving the controlled release objective.

Claim 7 expands on Claim 1, specifying the composition as a tablet. It also includes a coating comprising:

• A film-forming polymer.
• A plasticizer.
• A colorant.
• A glidant.

This claim further details the controlled release mechanism, stating that the composition releases not more than about 40% of the zileuton after 4 hours and not less than about 50% of the zileuton after 8 hours in a USP Apparatus 2 dissolution test at 75 rpm in 900 mL of pH 6.8 phosphate buffer.

Claim 12 defines a method of treating an asthma patient comprising administering a unit dosage form of a pharmaceutical composition comprising zileuton and a rate-controlling polymer, wherein the administration results in a Cmax (maximum plasma concentration) of zileuton of not greater than about 6 ug/mL and a Tmax (time to reach Cmax) of at least about 2 hours. This claim directly links the formulation to a desired pharmacokinetic outcome.

Dependent claims provide further details on:

• Specific types of rate-controlling polymers (e.g., ethylcellulose, hydroxypropyl methylcellulose).
• Ranges for the amount of zileuton.
• Specific percentages of active ingredients and excipients.
• Additional excipients such as disintegrants and surfactants.
• Specific dissolution parameters for different pH conditions.

The claims are meticulously crafted to define a product with specific performance characteristics, rather than merely the active pharmaceutical ingredient itself.

What is the Patent Landscape for Zileuton Formulations?

The patent landscape for zileuton is characterized by a history of formulation development aimed at improving its therapeutic profile and market exclusivity. U.S. Patent 8,589,188 is a key patent within this landscape, representing a significant advancement in zileuton delivery systems.

Historically, zileuton was first approved by the U.S. Food and Drug Administration (FDA) in 1996 as an immediate-release formulation (Zyflo®). This formulation typically required dosing four times a day, leading to potential adherence issues.

Integral Therapeutics (and subsequently VectivBio AG) developed extended-release formulations to address these limitations. U.S. Patent 8,589,188 protects one such extended-release formulation. This patent's claims are distinct from earlier patents covering the zileuton molecule itself or basic immediate-release compositions.

Following the approval of extended-release zileuton (Zyflo® CR, marketed by Cornerstone Therapeutics, now acquired by Horizon Therapeutics), other companies have also explored and patented different zileuton formulations or manufacturing processes. This includes:

• Patents on specific polymer systems: Various rate-controlling polymers and their combinations can be patented for their ability to achieve specific drug release profiles.
• Patents on manufacturing processes: Novel methods of producing extended-release tablets or granules can be a source of patent protection.
• Patents on combination therapies: Formulations combining zileuton with other asthma medications might also be patented.
• Patents on novel polymorphic forms: While not the focus of 8,589,188, different crystalline forms of an active pharmaceutical ingredient can also be patented if they offer specific advantages.

The issued claims of 8,589,188 specifically target the performance characteristics of the formulation, such as dissolution rates and pharmacokinetic parameters. This strategy allows for protection even if the active ingredient (zileuton) itself is off-patent or covered by earlier, expired patents. Companies seeking to market generic versions of extended-release zileuton would need to navigate around these formulation patents.

What is the Exclusivity Period and Expiration Date of U.S. Patent 8,589,188?

U.S. Patent 8,589,188 has a statutory expiration date of October 23, 2027. This date is determined by the patent application filing date (October 23, 2007) plus the standard 20-year term, adjusted for any patent term extensions or adjustments.

It is important to note that patent term extensions (PTEs) are often sought for drug patents to compensate for regulatory review periods. While the patent lists an original expiration date, it is crucial to verify if any PTEs have been granted or are pending for this specific patent. PTEs can extend the patent's life for up to five years, and in exceptional circumstances, even longer.

Additionally, the patent landscape can involve other forms of exclusivity. For example, the U.S. FDA can grant its own periods of market exclusivity based on the drug's approval and the nature of the application (e.g., New Chemical Entity exclusivity, orphan drug exclusivity). However, these are distinct from patent protection.

For U.S. Patent 8,589,188, the listed expiration date provides a baseline for market exclusivity derived from the patent itself. Any entity planning to develop or market a product that infringes upon the claims of this patent must consider this expiration date and any potential extensions.

What are the Potential Infringement Pathways for Competitors?

Competitors seeking to enter the market with a zileuton formulation face several potential infringement pathways concerning U.S. Patent 8,589,188. Infringement can occur through direct, indirect, or contributory actions.

Direct Infringement: This occurs when a competitor manufactures, uses, offers to sell, or sells a zileuton formulation that embodies all the limitations of at least one of the patent's claims, without authorization. For U.S. Patent 8,589,188, direct infringement would involve producing a composition that meets the specific requirements outlined in claims 1, 7, or 12, or any other asserted claim.

Key areas for potential direct infringement include:

• Compositional Elements: Replicating the specific combination of zileuton, rate-controlling polymer, diluent, binder, and lubricant as claimed.
• Dissolution Profiles: Formulating a product that exhibits the specified dissolution rates in various media and at different time points, as defined in claims 1 and 7. This is a critical aspect of the patent.
• Pharmacokinetic Parameters: Developing a formulation that achieves the Cmax and Tmax values specified in claim 12 when administered to a patient.
• Dosage Form: Producing a unit dosage form, such as a tablet, as specified in the claims.

Indirect Infringement: This can occur through induced infringement or contributory infringement.

• Induced Infringement: Competitors might induce others (e.g., their customers or distributors) to infringe the patent. This requires demonstrating that the competitor actively encouraged or aided infringement. For instance, marketing materials could be construed as encouraging the use of a product in a manner that infringes the patent claims.
• Contributory Infringement: This occurs when a competitor sells a component that is a material part of the patented invention, knowing that the component is specially adapted for use in an infringing way and not having a substantial non-infringing use. For example, if a competitor were to supply a specific, proprietary rate-controlling polymer and guide formulators on how to use it to achieve the exact dissolution profiles claimed in patent 8,589,188, it could be deemed contributory infringement.

Navigating the Claims: Competitors must meticulously analyze the language of each claim, including all limitations and definitions. The patent's focus on specific performance characteristics (dissolution, pharmacokinetics) and precise compositions means that any deviation might avoid literal infringement. However, competitors must also consider the doctrine of equivalents, which can find infringement even if the competitor's product does not literally read on the claims, but performs substantially the same function in substantially the same way to achieve substantially the same result.

Freedom-to-Operate (FTO) Analysis: Companies intending to develop generic or biosimilar versions of extended-release zileuton must conduct a thorough Freedom-to-Operate (FTO) analysis. This involves:

1. Identifying all relevant patents, including U.S. Patent 8,589,188 and any others related to zileuton formulations, manufacturing, or use.
2. Analyzing the scope and validity of these patents.
3. Assessing whether their proposed product infringes any active patent claims.
4. Evaluating strategies to design around existing patents or challenge their validity.

The patent's emphasis on formulation and performance metrics makes it a critical barrier for generic manufacturers seeking to replicate the extended-release zileuton product's therapeutic and administrative advantages.

What is the Commercial Significance of U.S. Patent 8,589,188?

U.S. Patent 8,589,188 holds significant commercial relevance by protecting an extended-release formulation of zileuton, a drug used in the management of asthma. The commercial value of this patent stems from its ability to create a period of market exclusivity for a product with improved patient adherence and potentially reduced side effects compared to immediate-release versions.

Extended-Release Zileuton Market: The development of extended-release formulations of drugs is a common strategy to improve patient outcomes and differentiate products in the market. For zileuton, which was initially available as an immediate-release product requiring frequent dosing, an extended-release formulation offers:

• Improved Compliance: Dosing once or twice daily is more manageable for patients than four times daily, leading to better adherence to treatment regimens. This improved adherence can translate to better disease control and reduced exacerbations.
• Consistent Therapeutic Levels: Controlled release aims to maintain therapeutic drug concentrations in the bloodstream more consistently, potentially reducing peak-related side effects and ensuring efficacy throughout the dosing interval.
• Market Exclusivity and Revenue: The patent protects the specific formulation, allowing the patent holder to exclusively market and sell this improved product for the duration of the patent term, thereby capturing revenue from patients and payers who benefit from the enhanced delivery system.

Impact on Generic Competition: The existence of U.S. Patent 8,589,188 acts as a significant barrier to entry for generic manufacturers. Generic companies cannot launch a bioequivalent product that infringes upon the claims of this patent until it expires or is invalidated. The detailed claims concerning dissolution profiles and pharmacokinetic parameters require generic developers to create formulations that are demonstrably different and do not infringe, or to wait for the patent's expiration. This delay in generic competition allows the innovator company to recoup its R&D investment and generate profits.

Licensing and Acquisition Opportunities: Patents like 8,589,188 are valuable assets for pharmaceutical companies. They can be leveraged for:

• Licensing Agreements: The patent holder can license the technology to other companies, generating royalty revenue.
• Mergers and Acquisitions: The patent, and the product it protects, can be a target for acquisition by larger pharmaceutical companies looking to expand their respiratory portfolio. VectivBio AG, the current assignee, has been involved in this space.

Strategic Importance in Asthma Treatment: While zileuton is not a first-line treatment for most asthma patients, it plays a role in managing specific cases, particularly those where other therapies have been insufficient. Improvements in its delivery and patient usability, as protected by this patent, enhance its therapeutic utility and market position within its niche.

In summary, U.S. Patent 8,589,188 is commercially significant because it underpins the market exclusivity of an improved, extended-release formulation of zileuton, enhancing patient compliance and therapeutic convenience, and creating a substantial hurdle for generic competition.

Key Takeaways

• U.S. Patent 8,589,188 protects specific oral extended-release formulations of zileuton, improving patient compliance and pharmacokinetic profiles.
• The patent's claims focus on critical attributes such as dissolution rates and Cmax/Tmax values, defining a particular performance standard for zileuton compositions.
• The patent is set to expire on October 23, 2027, providing a defined period of market exclusivity.
• Competitors face direct infringement risks if their formulations meet all limitations of the patent's claims, particularly regarding dissolution and pharmacokinetic profiles.
• The commercial significance lies in enabling the exclusive marketing of an improved drug delivery system, delaying generic competition and generating revenue for the patent holder.

Frequently Asked Questions

1. What is the current status of U.S. Patent 8,589,188? U.S. Patent 8,589,188 was granted on December 17, 2013, and is currently in force. Its expiration date is October 23, 2027, barring any patent term extensions.

2. Can a generic version of extended-release zileuton be launched before October 23, 2027? Launching a generic extended-release zileuton product before October 23, 2027, would require the product to not infringe on any valid claims of U.S. Patent 8,589,188 or any other relevant patents, or for those patents to be successfully challenged. The patent's specific claims regarding formulation performance make this a complex undertaking.

3. Does U.S. Patent 8,589,188 cover the zileuton molecule itself? No, this patent is focused on specific formulations of zileuton, particularly extended-release compositions. Patents covering the zileuton molecule itself would have been filed and likely expired much earlier.

4. What are the key performance metrics claimed in U.S. Patent 8,589,188? The key performance metrics include specific dissolution profiles (e.g., not more than 75% released after 4 hours in HCl, or specific release percentages at 4 and 8 hours in phosphate buffer) and pharmacokinetic parameters (e.g., Cmax not greater than about 6 ug/mL and Tmax of at least about 2 hours).

5. What is the assignee of U.S. Patent 8,589,188? The assignee of record for U.S. Patent 8,589,188 is Integral Therapeutics, Inc. Subsequent corporate activities and acquisitions have led to VectivBio AG as the current entity associated with this patent.

Citations

[1] U.S. Patent No. 8,589,188 (filed Oct. 23, 2007).

Drugs Protected by US Patent 8,589,188

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