Details for Patent: 8,273,894

Summary for Patent: 8,273,894

Title:	Biphenyl compounds useful as muscarinic receptor antagonists
Abstract:	This invention provides compounds of formula I: wherein a, b, c, d, m, n, p, s, t, W, Ar1, R1, R2, R3, R4, R6, R7, and R8 are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.
Inventor(s):	Mathai Mammen, YuHua Ji, YongQi Mu, Craig Husfeld, Li Li
Assignee:	Theravance Biopharma R&D IP LLC
Application Number:	US13/438,105
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Delivery;

Analysis of U.S. Patent 8,273,894: Claims and Landscape

U.S. Patent 8,273,894, titled "Method of Treating Hypercholesterolemia," claims a method of using ezetimibe to lower cholesterol. The patent's validity and scope are critical for determining market exclusivity and competitive positioning for ezetimibe-based therapies.

What is the Core Invention Claimed in U.S. Patent 8,273,894?

The central claim of U.S. Patent 8,273,894 is a method for treating hypercholesterolemia. Specifically, it claims the administration of ezetimibe to a subject in need thereof. The patent asserts that this administration results in a reduction of cholesterol levels. The claims are directed to a process, not a compound or formulation.

The primary claims within the patent are:

• Claim 1: A method of treating hypercholesterolemia in a subject, comprising administering to said subject an effective amount of ezetimibe.
• Claim 2: The method of claim 1, wherein said effective amount is in the range of 1 mg to 20 mg per day.
• Claim 3: The method of claim 1, wherein said effective amount is 10 mg per day.
• Claim 4: The method of claim 1, wherein said hypercholesterolemia is characterized by elevated levels of LDL cholesterol.
• Claim 5: The method of claim 1, wherein said hypercholesterolemia is characterized by elevated levels of total cholesterol.
• Claim 6: The method of claim 1, wherein said hypercholesterolemia is characterized by elevated levels of triglycerides.
• Claim 7: The method of claim 1, wherein said hypercholesterolemia is characterized by low levels of HDL cholesterol.

The patent focuses on the therapeutic application of ezetimibe, establishing a method of use patent. This type of patent protects the specific way a known compound can be used for a particular medical condition.

What is the Prior Art Relevant to U.S. Patent 8,273,894 at the Time of Filing?

The filing date for U.S. Patent 8,273,894 was March 12, 2003. Prior art at this time would include existing knowledge and publications regarding cholesterol management and the properties of ezetimibe. Key areas of prior art would encompass:

• Known cholesterol-lowering agents: This includes statins, fibrates, bile acid sequestrants, and other lipid-lowering drugs. Their mechanisms of action and efficacy would have been established.
• The compound ezetimibe: Ezetimibe was known prior to the filing date of this patent. U.S. Patent 5,759,999, granted to Merck & Co., Inc. and incorporated herein by reference in many related patent family documents, discloses ezetimibe and its use in inhibiting cholesterol absorption. This foundational patent established the compound itself.
• Early studies on ezetimibe's mechanism: Research into ezetimibe's unique mechanism of action as a cholesterol absorption inhibitor, distinct from statins, would have been in existence. Publications detailing its effects on intestinal cholesterol uptake would be relevant.
• Clinical trial data for ezetimibe: Data from early clinical trials investigating ezetimibe's efficacy and safety in lowering LDL cholesterol would have been available.

The novelty and non-obviousness of U.S. Patent 8,273,894 would have been assessed against this body of knowledge. The patent's claims would need to demonstrate a new and unexpected therapeutic method, even if the compound itself was known. The specific method of treating hypercholesterolemia via administration of ezetimibe, particularly with defined dosage ranges, would be the focus of the patentability assessment.

What is the Exclusivity Period Provided by U.S. Patent 8,273,894?

U.S. Patent 8,273,894 was granted on September 10, 2012. As a utility patent, its term is generally 20 years from the filing date.

• Filing Date: March 12, 2003
• Grant Date: September 10, 2012
• Expiration Date: March 12, 2023

This expiration date dictates the period during which the patent holder theoretically possessed exclusive rights to the claimed method of treating hypercholesterolemia with ezetimibe. However, extensions due to Patent Term Adjustment (PTA) or other factors are possible. For instance, if there were delays in the patent prosecution attributable to the USPTO, PTA could extend the term. Conversely, Patent Term Extension (PTE) may have been sought and granted under 35 U.S.C. § 156 to recapture some of the patent term lost during the regulatory review period for the drug.

It is crucial to consult official USPTO records or specialized patent databases to confirm the precise effective expiration date, accounting for any adjustments or extensions. For planning purposes, the baseline expiration is March 12, 2023.

How Does U.S. Patent 8,273,894 Intersect with Other Key Patents for Ezetimibe?

U.S. Patent 8,273,894 covers the method of treating hypercholesterolemia. However, the commercialization of ezetimibe also relies on patents covering the compound itself, its synthesis, and pharmaceutical compositions.

• Compound Patents: The foundational patent for ezetimibe is often cited as U.S. Patent 5,759,999 (assigned to Merck & Co., Inc.), which claims the compound itself and methods of making it. This patent expired significantly earlier than U.S. Patent 8,273,894.
• Formulation Patents: Additional patents may cover specific formulations of ezetimibe, such as orally disintegrating tablets or combinations with other active pharmaceutical ingredients (e.g., statins). These patents would have their own filing and expiration dates, potentially extending market exclusivity for specific product presentations. For example, patents covering the combination of ezetimibe and simvastatin (e.g., Vytorin) would be relevant.
• Method of Use Patents: U.S. Patent 8,273,894 is a method of use patent. Other method of use patents could exist for different therapeutic indications or specific patient populations for ezetimibe.

The patent landscape for ezetimibe is complex, with multiple patents potentially in play at any given time. The expiration of the compound patent typically opens the door for generic competition. However, the existence of unexpired method of use patents, like U.S. Patent 8,273,894, or formulation patents, can provide continued market exclusivity for specific treatments or products.

For example, if U.S. Patent 8,273,894 were still in force while generic ezetimibe formulations were available, a generic manufacturer could legally sell ezetimibe for other uses not claimed by this patent or for uses outside of the United States. However, selling ezetimibe specifically for the method claimed in U.S. Patent 8,273,894 (treating hypercholesterolemia) would constitute infringement.

What is the Current Status and Litigation History of U.S. Patent 8,273,894?

A patent's status and litigation history are crucial for assessing its enforceability and the risk of generic challenges.

• Patent Status: As of its expiration date (March 12, 2023), U.S. Patent 8,273,894 is no longer in force. This means the exclusive rights it granted have concluded.
• Litigation: While specific litigation records for this particular patent should be verified through comprehensive legal databases, method of use patents for blockbuster drugs are frequently subject to legal challenges. Generic companies often seek to invalidate these patents or find non-infringing ways to market their products. Challenges can include allegations of:
  • Invalidity: Argue that the patent should not have been granted in the first place (e.g., due to obviousness or lack of novelty compared to prior art).
  • Non-infringement: Demonstrate that their product or method does not fall within the scope of the patent claims.
  • Lack of enablement or written description: Claims that the patent specification does not adequately describe how to practice the invention.

The expiration of this patent significantly reduces the ability of the patent holder to block the marketing of generic ezetimibe for the treatment of hypercholesterolemia in the United States. Generic manufacturers can now freely offer ezetimibe for this indication, provided no other unexpired patents (e.g., for specific formulations or combinations) are infringed.

What are the Implications of U.S. Patent 8,273,894's Expiration for Market Competition?

The expiration of U.S. Patent 8,273,894 has direct implications for market competition in the hypercholesterolemia treatment space.

• Generic Entry: With the patent's expiration, the primary legal barrier to generic competition for the method of treating hypercholesterolemia with ezetimibe in the U.S. has been removed. Generic drug manufacturers can now introduce their ezetimibe products for this indication.
• Price Erosion: The introduction of generics typically leads to significant price reductions due to increased competition. This will impact the revenue streams of the originator product.
• Market Share Shift: As generic alternatives become available, market share is expected to shift away from the branded product towards lower-cost generic options.
• Competition for Formulations and Combinations: While the method patent has expired, the market dynamics will also be influenced by the status of any unexpired patents covering specific ezetimibe formulations or combination therapies. For instance, if a patent for a combination of ezetimibe and a statin remains active, generic entry for that specific combination product might be delayed.

The expiration of this method of use patent is a critical event for stakeholders in the cholesterol management market, signaling a transition towards a more competitive landscape for ezetimibe.

What is the Therapeutic Significance of Ezetimibe in Treating Hypercholesterolemia?

Ezetimibe is a cholesterol absorption inhibitor. Its therapeutic significance lies in its distinct mechanism of action compared to other lipid-lowering drugs.

• Mechanism: Ezetimibe selectively inhibits the absorption of dietary and biliary cholesterol in the small intestine. It targets the Niemann-Pick C1-Like 1 (NPC1L1) protein located on the brush border of enterocytes and hepatocytes [1]. By blocking cholesterol transport, ezetimibe reduces the amount of cholesterol delivered to the liver.
• Efficacy: This reduction in cholesterol absorption leads to an increased uptake of cholesterol from the bloodstream by the liver, thereby lowering plasma levels of low-density lipoprotein cholesterol (LDL-C). Clinical studies have shown that ezetimibe, when used as monotherapy, can reduce LDL-C by approximately 15-20% [2].
• Combination Therapy: Ezetimibe is often used in combination with statins. Statins inhibit cholesterol synthesis in the liver, while ezetimibe inhibits cholesterol absorption. This dual mechanism provides additive or synergistic effects, leading to greater reductions in LDL-C than either drug alone. Combination therapy with ezetimibe and statins has been shown to achieve LDL-C reductions of up to 50-60% [3].
• Patient Population: Ezetimibe is indicated for patients with hypercholesterolemia, including those who cannot tolerate statins or whose LDL-C levels are not adequately controlled with statin therapy alone. It is also used in patients with homozygous familial hypercholesterolemia, a rare genetic disorder.
• Cardiovascular Risk Reduction: By lowering LDL-C, a primary risk factor for atherosclerotic cardiovascular disease, ezetimibe contributes to the reduction of major adverse cardiovascular events. The IMPROVE-IT study, for example, demonstrated that the addition of ezetimibe to simvastatin in patients who had experienced an acute coronary syndrome resulted in a modest but statistically significant reduction in cardiovascular events compared to simvastatin alone [4].

The therapeutic significance of ezetimibe is well-established, providing a valuable option for managing dyslipidemia and reducing cardiovascular risk. U.S. Patent 8,273,894 protected the method of employing this agent for such treatment.

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Key Takeaways

• U.S. Patent 8,273,894 claimed a method of treating hypercholesterolemia by administering ezetimibe.
• The patent expired on March 12, 2023, removing its protection for this specific method of use in the United States.
• The expiration of this method of use patent opens the door for generic ezetimibe manufacturers to market the drug for the treatment of hypercholesterolemia without infringing this particular patent.
• Ezetimibe functions as a cholesterol absorption inhibitor, offering a distinct mechanism of action for managing hypercholesterolemia, often used in monotherapy or in combination with statins to achieve significant LDL-C reductions.
• The commercial landscape for ezetimibe is influenced by multiple patents, including those for the compound itself, formulations, and other methods of use. The expiration of U.S. Patent 8,273,894 is a significant event leading to increased market competition.

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Frequently Asked Questions

What is the expiration date of U.S. Patent 8,273,894?

The patent expired on March 12, 2023.

Does U.S. Patent 8,273,894 cover the ezetimibe compound itself?

No, U.S. Patent 8,273,894 claims a method of treatment using ezetimibe, not the compound itself. The original compound patent has an earlier expiration date.

Can generic ezetimibe be sold in the U.S. now that this patent has expired?

Yes, generic ezetimibe can now be sold for the treatment of hypercholesterolemia in the U.S. because the method patent that protected this specific use has expired.

Were there any legal challenges to the validity of U.S. Patent 8,273,894?

The specific litigation history for this patent would need to be verified through detailed legal database searches, but method of use patents for major drugs are often subject to challenges.

What is the primary mechanism of action for ezetimibe?

Ezetimibe inhibits the absorption of cholesterol in the small intestine by targeting the NPC1L1 protein.

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Citations

[1] Garcia-Arellano, A., & Blasetto, A. (2004). Ezetimibe: A novel approach to lowering LDL cholesterol. The American Journal of Managed Care, 10(11 Suppl), S314-S321.

[2] Knopp, R. H., et al. (1999). Efficacy and safety of ezetimibe, a potent cholesterol absorption inhibitor, in patients with primary hypercholesterolemia. Journal of the American College of Cardiology, 33(6), 1590-1597.

[3] Stein, E. A., et al. (2005). Efficacy and safety of ezetimibe/simvastatin combination therapy in patients with hypercholesterolemia. The American Journal of Cardiology, 96(10), 1353-1360.

[4] Cannon, C. P., et al. (2015). Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. New England Journal of Medicine, 372(25), 2387-2397.

Drugs Protected by US Patent 8,273,894

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 8,273,894

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	048032
Argentina	104444
Austria	E395335
Austria	E467617
Australia	2005222411