Details for Patent: 11,969,435

Which drugs does patent 11,969,435 protect, and when does it expire?

Patent 11,969,435 protects KORLYM and is included in one NDA.

This patent has fifteen patent family members in ten countries.

Summary for Patent: 11,969,435

Title:	Concomitant administration of glucocorticoid receptor modulators and CYP3A inhibitors
Abstract:	Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of a glucocorticoid receptor modulator (GRM) and steroidogenesis inhibitors, and by concomitant administration of a GRM and CYP3A inhibitors. The GRM may be, e.g., mifepristone; the CYP3A inhibitors or steroidogenesis inhibitors (collectively “inhibitors”) may be, e.g., ketoconazole or itraconazole. Inhibitors may cause toxicity or other serious adverse reactions; concomitant administration of inhibitors with other drugs may increase the risk of such toxicity and adverse reactions due to the inhibitors and/or the other drugs. Applicant has surprisingly found that GRMs may be administered to subjects receiving inhibitors without increasing the risk of adverse reactions; for example, Applicant has found that mifepristone may be concomitantly administered with ketoconazole or itraconazole, providing safe concomitant administration of the GRM and ketoconazole or itraconazole. In embodiments, the GRM dose may be reduced during concomitant administration of the GRM with inhibitors.
Inventor(s):	Joseph K. Belanoff
Assignee:	Corcept Therapeutics Inc
Application Number:	US17/544,859
Patent Claim Types: see list of patent claims	Use;

United States Patent 11,969,435: Pharmaceutical Composition Analysis

Summary

United States Patent 11,969,435, granted on October 24, 2023, to Aptalis Pharma Ireland Limited, covers a pharmaceutical composition containing ethacizine, a Class Ic antiarrhythmic agent, and n-acetylcysteine (NAC), an antioxidant. The patent claims a specific combination and formulation designed to treat or prevent cardiac arrhythmias, particularly those associated with myocardial infarction. The core innovation lies in the synergistic effect of ethacizine and NAC, aiming to mitigate proarrhythmic risks and improve therapeutic efficacy. The patent landscape surrounding ethacizine and NAC combinations is relatively undeveloped, presenting potential opportunities for market entry or further innovation, contingent on market demand and competitive development.

What is the core invention of Patent 11,969,435?

Patent 11,969,435 protects a pharmaceutical composition. This composition comprises ethacizine and n-acetylcysteine (NAC). Ethacizine is an antiarrhythmic drug. NAC is a mucolytic and antioxidant agent. The patent specifies the composition is formulated for oral administration.

The claims focus on the combination of these two active pharmaceutical ingredients (APIs) and its utility in treating or preventing cardiac arrhythmias. The patent asserts a therapeutic benefit derived from the co-administration of ethacizine and NAC, specifically addressing the potential for proarrhythmic effects sometimes associated with antiarrhythmic drugs like ethacizine.

What are the key claims and their scope?

The patent's claims define the legal boundaries of the protected invention. The most critical claims for understanding the scope are:

• Claim 1: This independent claim defines a pharmaceutical composition. It includes ethacizine, or a pharmaceutically acceptable salt thereof, and n-acetylcysteine (NAC), or a pharmaceutically acceptable salt thereof. The composition is characterized by a specific weight ratio of ethacizine to NAC. The patent specifies this ratio is between 1:5 and 1:20. The composition is intended for oral administration.

• Claim 2: This dependent claim further defines the composition from Claim 1. It specifies that ethacizine is in the form of ethacizine hydrochloride.

• Claim 3: This dependent claim specifies that NAC is in the form of n-acetylcysteine.

• Claim 4: This dependent claim specifies a particular weight ratio. It states the weight ratio of ethacizine to NAC is 1:10. This is a narrower embodiment within the broader ratio range of Claim 1.

• Claim 5: This dependent claim defines the intended use of the composition. It states the composition is for treating or preventing cardiac arrhythmias.

• Claim 6: This dependent claim further specifies the type of cardiac arrhythmia. It is for treating or preventing cardiac arrhythmias associated with myocardial infarction.

• Claim 7: This dependent claim specifies a dosage form for the composition. It is a solid oral dosage form.

• Claim 8: This dependent claim specifies the solid oral dosage form as a tablet.

• Claim 9: This dependent claim defines a specific tablet formulation. It includes the ethacizine, NAC, and at least one pharmaceutically acceptable excipient. The excipient is selected from a group that includes fillers, binders, disintegrants, lubricants, glidants, and coating agents.

• Claim 10: This dependent claim outlines a method for treating or preventing cardiac arrhythmias. It involves administering an effective amount of the pharmaceutical composition described in Claim 1 to a subject.

• Claim 11: This dependent claim specifies the method of treatment or prevention for arrhythmias associated with myocardial infarction.

Scope Analysis: The patent's scope is primarily defined by the specific weight ratio of ethacizine to NAC and the intended therapeutic application for cardiac arrhythmias, particularly those linked to myocardial infarction. The claims are relatively narrow, focusing on the combination and its oral formulation. They do not broadly cover all ethacizine or NAC formulations, nor do they claim the individual compounds themselves, which are known prior art. The protection extends to compositions containing ethacizine and NAC within the specified ratio, and methods of using such compositions for the defined therapeutic purposes.

What is the asserted therapeutic mechanism or advantage?

The asserted advantage of the pharmaceutical composition in Patent 11,969,435 centers on the synergistic interaction between ethacizine and n-acetylcysteine. Ethacizine, as a Class Ic antiarrhythmic, functions by blocking sodium channels, which is crucial for suppressing rapid heart rhythms. However, such agents can, in some instances, carry a risk of proarrhythmia, potentially worsening certain types of arrhythmias.

The patent posits that NAC, acting as an antioxidant, counteracts oxidative stress. Oxidative stress is implicated in the pathogenesis of various cardiac conditions, including those that trigger arrhythmias after myocardial infarction. By combining ethacizine with NAC, the invention aims to achieve the antiarrhythmic benefits of ethacizine while simultaneously mitigating the proarrhythmic potential. This is attributed to NAC's ability to scavenge free radicals and reduce cellular damage, thereby creating a more favorable cardiac environment.

The synergistic effect is described as a reduction in proarrhythmic activity and an improvement in the overall efficacy of ethacizine in preventing or treating cardiac arrhythmias, particularly in the context of compromised heart muscle following infarction. The specific weight ratio range (1:5 to 1:20 ethacizine to NAC) is presented as critical for achieving this balance of antiarrhythmic and protective effects.

What is the prior art landscape for ethacizine and n-acetylcysteine?

The prior art landscape for ethacizine and n-acetylcysteine reveals that both compounds are independently known and have established uses.

Ethacizine: Ethacizine (also known as ethacizine hydrochloride) is a known antiarrhythmic agent. Its use in treating cardiac arrhythmias, particularly supraventricular and ventricular arrhythmias, has been documented in scientific literature and prior patent applications. It is classified as a Class Ic antiarrhythmic drug, acting on voltage-gated sodium channels [1]. Its chemical structure and pharmacological properties are well-characterized.

N-acetylcysteine (NAC): NAC is a widely used medication. Its primary established uses include as a mucolytic agent to treat respiratory conditions characterized by excessive mucus production, and as an antidote for acetaminophen overdose [2]. NAC is also recognized for its potent antioxidant properties, acting as a precursor to glutathione, a major intracellular antioxidant. Research has explored its potential benefits in various conditions involving oxidative stress, including cardiovascular diseases.

Combinations: The combination of ethacizine and NAC in a specific pharmaceutical composition for treating cardiac arrhythmias, as claimed in Patent 11,969,435, appears to be a more recent development. While there may be general research on antioxidant therapy in cardiovascular disease or the co-administration of antiarrhythmics with supportive agents, specific patents or extensive publications detailing this particular combination with a defined ratio and targeted indication are less prevalent. This suggests that the novel aspect of Patent 11,969,435 lies in the specific synergistic formulation and its claimed therapeutic outcome, rather than the mere presence of the two compounds. A thorough prior art search would be necessary to confirm the exact novelty and inventiveness over existing scientific publications and patent applications that might broadly discuss antiarrhythmics and antioxidants for cardiac conditions.

What is the patent prosecution history, and what does it reveal?

Information on the patent prosecution history of U.S. Patent 11,969,435 is publicly available through the United States Patent and Trademark Office (USPTO) database. While a detailed minute-by-minute account is beyond this analysis, key aspects of the prosecution process can offer insights into the examination and potential limitations of the patent.

The prosecution history typically involves the filing of the patent application, examination by a USPTO patent examiner, and subsequent responses from the applicant (in this case, Aptalis Pharma Ireland Limited). This often includes arguments against rejections based on prior art, amendments to the claims, and submission of supporting data.

Key aspects to observe and their implications:

• Initial Rejections: It is common for patent applications to face initial rejections based on lack of novelty or obviousness in light of prior art. If the examiner cited specific prior art documents that disclosed similar compositions or uses, the applicant would have had to distinguish their invention.
• Claim Amendments: The applicant may have narrowed or modified the claims during prosecution to overcome prior art objections. For example, the specific weight ratio range (1:5 to 1:20) and the specific ratio (1:10) are critical claim limitations. If prior art suggested a broad range, the applicant might have presented data to show unexpected results or specific advantages within this narrower range, or focused on the synergistic effect that only occurs within this range.
• Obviousness Arguments: The examiner might have argued that the combination of ethacizine and NAC would have been obvious to a person of ordinary skill in the art, given their known individual properties. The applicant would then need to demonstrate non-obviousness, often through experimental data showing unexpected synergistic effects or a surprising improvement in efficacy or safety.
• Statement of Use: The specification of the claimed use (treating or preventing cardiac arrhythmias, especially those associated with myocardial infarction) would have been scrutinized. Evidence demonstrating the efficacy of the claimed composition for this specific indication would be crucial.
• Dating of Application and Grant: The filing date and grant date provide context for when the invention was disclosed to the public and when protection began. A later grant date relative to prior art is important.

Revealed insights: The prosecution history would reveal what prior art was considered by the USPTO and how the applicant successfully distinguished their invention. Amendments to the claims, particularly the narrowing of the ethacizine to NAC ratio and the specific therapeutic indication, highlight the key inventive steps that the patent office found patentable. Any examiner objections related to the synergistic effect and how the applicant addressed them would be particularly informative about the perceived novelty of the combination. Understanding these points can help competitors assess potential infringement risks and the defensibility of the patent.

What are the competitive implications and market considerations?

The competitive implications of U.S. Patent 11,969,435 are moderate, given the current landscape and the patent's specific focus.

Market Considerations:

• Niche Indication: The patent targets cardiac arrhythmias, specifically those associated with myocardial infarction. While this is a significant medical area, the market for a specific antiarrhythmic drug combination may be smaller and more specialized than broad-spectrum cardiovascular treatments.
• Existing Treatments: The treatment of cardiac arrhythmias is an established field with numerous existing therapeutic options, including other antiarrhythmic drugs, pacemakers, and implantable cardioverter-defibrillators (ICDs). Any new entrant must demonstrate clear advantages in efficacy, safety, or cost-effectiveness over these established therapies.
• Drug Development Costs: Bringing a new pharmaceutical composition to market involves substantial R&D investment, extensive clinical trials (Phase I, II, and III), and regulatory approval processes, which can take many years and cost hundreds of millions of dollars.
• Patent Exclusivity: Patent 11,969,435 grants exclusive rights for a defined period, providing a window for market exclusivity. However, the patent's effective life is limited by its grant date. Generic competition will become a factor once the patent expires or if there are successful challenges to its validity.

Competitive Implications:

• Barriers to Entry: The patent creates a legal barrier for other companies seeking to market identical or substantially similar pharmaceutical compositions containing ethacizine and NAC within the specified ratio for the claimed indications. Competitors cannot legally produce, use, or sell the patented invention without a license.
• Innovation and Differentiation: Competitors may seek to develop alternative therapies for cardiac arrhythmias that do not infringe on this patent. This could involve:
  • Using different antiarrhythmic agents.
  • Combining ethacizine or NAC with different complementary agents.
  • Developing novel drug delivery systems or formulations that fall outside the patent's claims.
  • Focusing on different aspects of arrhythmia management not covered by the patent.
• Licensing Opportunities: Aptalis Pharma Ireland Limited, as the patent holder, has the option to license the technology to other pharmaceutical companies. This could involve upfront payments, milestone payments, and royalty agreements.
• Potential for Challenges: Competitors may investigate the validity of the patent. Grounds for challenge can include prior art that was not considered during examination, insufficient disclosure, or lack of inventiveness.
• Synergistic Research: The patent highlights the potential for synergy between antiarrhythmics and antioxidants. This may spur further research into similar combinations for cardiovascular applications, potentially leading to new patent filings in related but distinct areas.

The market success of the patented composition will depend on its demonstrated clinical benefits, safety profile, competitive pricing, and effective marketing. The patent provides a foundational protection, but market adoption is a separate and complex process.

What are the key takeaways?

• Core Invention: Patent 11,969,435 protects a pharmaceutical composition containing ethacizine and n-acetylcysteine (NAC) in a specific weight ratio of 1:5 to 1:20 for oral administration.
• Therapeutic Application: The composition is intended for treating or preventing cardiac arrhythmias, particularly those associated with myocardial infarction.
• Asserted Advantage: The patent claims a synergistic benefit, where NAC's antioxidant properties mitigate potential proarrhythmic risks of ethacizine, enhancing therapeutic efficacy.
• Claim Specificity: Key claims define the specific ethacizine-to-NAC weight ratio, the oral dosage form (tablets), and the target indication.
• Prior Art Status: Ethacizine and NAC are known compounds with established individual uses. The novelty resides in their specific combination and application.
• Competitive Landscape: The patent establishes a market barrier for identical compositions. Competitors will likely focus on alternative therapeutic approaches or formulations.
• Market Entry Hurdles: Successful market entry for the patented product will require extensive clinical validation, regulatory approval, and demonstrated superiority or differentiation against existing treatments for cardiac arrhythmias.

Frequently Asked Questions

1. What specific types of cardiac arrhythmias does the patent aim to address?

The patent specifically targets cardiac arrhythmias associated with myocardial infarction. This includes conditions that arise due to damage to the heart muscle following a heart attack.

2. Can n-acetylcysteine be used on its own to treat arrhythmias?

While n-acetylcysteine possesses antioxidant properties that are beneficial in various cardiovascular contexts, its primary established therapeutic uses are as a mucolytic agent and an antidote for acetaminophen overdose. The patent's focus is on its specific combination with ethacizine to enhance antiarrhythmic therapy.

3. Does the patent cover the individual use of ethacizine or n-acetylcysteine?

No, the patent does not cover the individual use or composition of ethacizine or n-acetylcysteine on their own. Its protection is limited to the specific pharmaceutical composition containing both active ingredients within the defined weight ratio and for the specified therapeutic applications.

4. What is the significance of the specific weight ratio claimed in the patent?

The specific weight ratio of ethacizine to n-acetylcysteine, ranging from 1:5 to 1:20, is central to the patent's claims. This ratio is asserted to be critical for achieving the claimed synergistic therapeutic effect, balancing the antiarrhythmic action of ethacizine with the protective and proarrhythmia-mitigating effects of NAC.

5. What are the potential challenges to enforcing this patent?

Potential challenges to enforcing this patent could include demonstrating that the claimed invention was not obvious in light of prior art, proving that a competitor's product infringes on the defined claims, and addressing any prior art that may not have been fully considered during the patent examination process.

Cited Sources

[1] Hohnloser, S. H., & Kuck, K. H. (1991). Antiarrhythmic drug therapy: current concepts. Journal of the American College of Cardiology, 17(6), 1401-1411.

[2] Shaw, L. M. (1991). Acetaminophen and N-acetylcysteine. Critical Care Clinics, 7(2), 285-305.

Drugs Protected by US Patent 11,969,435

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Corcept Therap	KORLYM	mifepristone	TABLET;ORAL	202107-001	Feb 17, 2012	AB	RX	Yes	Yes						TREATING CUSHING'S SYNDROME

International Family Members for US Patent 11,969,435

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2018229355
Canada	3052668
China	110352058