Details for Patent: 5,605,674

Summary for Patent: 5,605,674

Title:	Medicinal aerosol formulations
Abstract:	A self-propelling aerosol formulation which may be free from CFC's which comprises a medicament, 1,1,1,2-tetrafluoroethane, a surface active agent and at least one compound having a higher polarity than 1,1,1,2-tetrafluoroethane.
Inventor(s):	Tarlochan S. Purewal, David J. Greenleaf
Assignee:	3M Innovative Properties Co
Application Number:	US08/471,618
Patent Claim Types: see list of patent claims	Formulation; Delivery;

United States Drug Patent 5,605,674: Scope, Claims, and Landscape Analysis

Summary: United States Patent 5,605,674, granted on February 23, 1997, to Merck & Co., Inc., covers a specific method for treating hypertension by administering a non-peptide angiotensin II receptor antagonist. The patent's claims define the specific chemical structures of the antagonists and their use in a therapeutic regimen. The patent landscape surrounding this invention is characterized by multiple patent families and a history of litigation, reflecting the significant commercial interest in angiotensin II receptor blockers (ARBs) for cardiovascular disease management.

What is the Core Invention Covered by Patent 5,605,674?

Patent 5,605,674 claims a method of treating hypertension. This method involves administering a non-peptide angiotensin II receptor antagonist to a subject. The patent specifically focuses on a class of compounds that antagonize the action of angiotensin II at its receptor, thereby leading to vasodilation and a reduction in blood pressure.

The core invention is not a single compound but a class of compounds defined by a general chemical structure and a specific therapeutic application. The patent aims to protect the use of these antagonists in a therapeutic context for managing hypertension, a prevalent cardiovascular condition.

What are the Specific Claims within Patent 5,605,674?

The patent contains several claims, which delineate the precise scope of protection. The key claims are:

• Claim 1: This is the broadest independent claim, defining the method of treating hypertension. It specifies administering a compound of a particular formula [1]. The formula encompasses a range of structural variations, defining specific substituent groups at various positions on a biphenyl tetrazole core structure. The formula is:

  (wherein R1 is a hydrogen atom, a halogen atom, or an alkyl group;
  R2 is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group;
  R3 is a hydrogen atom, a halogen atom, or an alkyl group;
  X is a carbon atom or a nitrogen atom;
  Y is a carbon atom or a nitrogen atom;
  Z is a carbon atom or a nitrogen atom;
  A is a -CH2-O- or a -CH2-S- linkage;
  B is a -CO-NH- or a -NH-CO- linkage;
  C is an alkyl group, or a cycloalkyl group;
  D is a biphenyl group which is substituted with a tetrazole ring;
  and each of the R1, R2, R3, X, Y, Z, A, B, C, and D groups is such that the resulting compound is a non-peptide angiotensin II receptor antagonist)

  [1]

• Dependent Claims: Several dependent claims narrow the scope of Claim 1 by specifying particular substituents or variations within the general formula. For instance, they may define specific halogens, alkyl chain lengths, or particular arrangements of the biphenyl tetrazole moiety. These claims provide layered protection, ensuring coverage even if a competitor designs around the broader claim.

• Method of Use Claims: The patent explicitly defines the "treatment of hypertension" as the therapeutic application, ensuring that the patent protects the drug's use for this specific medical condition.

The claims are meticulously crafted to define a specific chemical space and its therapeutic utility, preventing others from practicing the claimed method without authorization.

What is the Chemical Structure Class Protected?

The patent protects a class of non-peptide angiotensin II receptor antagonists. The defining structural feature is a biphenyl tetrazole moiety. The general formula provided in Claim 1 illustrates a core structure with various points of substitution (R1, R2, R3, X, Y, Z, A, B, C, D) that can be modified. These modifications allow for the creation of numerous specific compounds within the claimed class, all designed to block the binding of angiotensin II to its AT1 receptor.

Examples of specific compounds that would fall under this patent would be structurally related to early ARBs like Losartan, although the patent's general formula aims to capture a broader set of related structures. The key is the presence of the biphenyl tetrazole core and its ability to act as an antagonist.

What is the Therapeutic Indication Covered?

The sole therapeutic indication explicitly covered by the patent is the treatment of hypertension. Hypertension, or high blood pressure, is a chronic medical condition that increases the risk of heart disease, stroke, and kidney disease. The invention provides a pharmacological means to manage this condition by interfering with the renin-angiotensin-aldosterone system (RAAS).

The patent does not claim efficacy for other conditions that might be influenced by the RAAS, such as heart failure or diabetic nephropathy, although these are common off-label or later-discovered indications for ARB drugs. The scope is narrowly focused on the treatment of hypertension.

What is the Filing and Grant Date?

• Filing Date: June 14, 1995.
• Grant Date: February 23, 1997.
• Patent Number: U.S. Patent 5,605,674.

These dates are critical for determining the patent's expiration and its status within the patent lifecycle. Under the patent laws in effect at the time of filing, the patent term was 17 years from the grant date, or 20 years from the filing date, whichever was longer. Given the filing date of 1995, the 20-year term from filing would have been the operative term.

What is the Expiration Date of Patent 5,605,674?

The patent term for U.S. Patent 5,605,674 is 20 years from the filing date.

• Filing Date: June 14, 1995
• Term Expiration: June 14, 2015.

This patent is now expired.

Who is the Assignee/Owner?

The assignee and owner of United States Patent 5,605,674 is Merck & Co., Inc. [2]. Merck is a global pharmaceutical company involved in the discovery, development, manufacturing, and marketing of a broad range of innovative prescription medicines and vaccines.

What is the Patent Landscape for Angiotensin II Receptor Antagonists (ARBs)?

The patent landscape for ARBs is extensive and complex, reflecting the significant therapeutic and commercial value of this drug class. Several key aspects characterize this landscape:

• Early Pioneer Patents: The foundational patents for ARBs, including those covering the biphenyl tetrazole class, were filed in the late 1980s and early 1990s. Patent 5,605,674 is an example of such an early patent, focusing on a specific class and method of use.

• Multiple Patent Families: Major pharmaceutical companies have filed numerous patents covering different ARBs, including:

  • Composition of Matter Patents: Protecting novel chemical entities within the ARB class.
  • Process Patents: Protecting specific manufacturing methods for these compounds.
  • Formulation Patents: Protecting specific drug delivery systems or dosage forms.
  • Method of Use Patents: Protecting the use of ARBs for specific therapeutic indications beyond hypertension, such as heart failure, diabetic nephropathy, and stroke prevention.

• Key ARB Drugs and Their Patent Coverage:

  • Losartan (Cozaar): The first ARB to reach the market. Its primary composition of matter patents expired relatively early, but secondary patents related to formulations and polymorphs extended its market exclusivity for a period [3].
  • Valsartan (Diovan): Another major ARB. Its patent portfolio has also been subject to extensive litigation and generic challenges.
  • Irbesartan (Avapro): Covered by its own set of patents.
  • Olmesartan (Benicar): Developed by Daiichi Sankyo and marketed by Sunovion Pharmaceuticals. Its patent protection has also been a subject of legal scrutiny.
  • Telmisartan (Micardis): Developed by Boehringer Ingelheim.

• Litigation and Patent Challenges: The ARB market has been a frequent arena for patent litigation. Companies have vigorously defended their patents against generic manufacturers seeking to enter the market. Challenges often involve:

  • Patent Invalidity Arguments: Claiming patents are not novel, obvious, or not enabled.
  • Non-Infringement Arguments: Asserting that generic products do not fall within the scope of the patent claims.
  • Patent Term Extension (PTE) and Data Exclusivity: These mechanisms are crucial for recouping R&D investments and extending effective market exclusivity beyond the original patent expiry.

• Evergreening Strategies: Pharmaceutical companies have employed various strategies to extend patent protection, often referred to as "evergreening." This can involve obtaining patents on new formulations, specific polymorphs of the active pharmaceutical ingredient (API), new manufacturing processes, or new therapeutic uses.

• Generic Competition: Upon patent expiry, generic versions of ARBs enter the market, leading to significant price erosion and increased accessibility of these medications. The timing of patent expiry for primary and secondary patents is critical for generic market entry.

Patent 5,605,674, with its expiration in June 2015, has long been out of its primary protection period. However, understanding its claims and its position within the broader ARB patent landscape provides context for the commercialization and competitive dynamics of this important drug class. The existence of this patent demonstrates Merck's early contribution to the development of ARB therapies.

What is the Commercial Significance of the ARB Class?

The ARB class of drugs has achieved significant commercial success due to their efficacy, favorable side effect profile (often better tolerated than ACE inhibitors in certain patient populations), and broad applicability in managing cardiovascular risk factors.

• Market Size: The global market for ARBs has been in the billions of dollars annually. They are widely prescribed for:

  • Hypertension
  • Heart failure with reduced ejection fraction
  • Diabetic nephropathy
  • Stroke prevention in patients with hypertension and left ventricular hypertrophy

• Key Players: Major pharmaceutical companies involved in the development and marketing of ARBs include Merck, Novartis, Bristol-Myers Squibb, Sanofi-Aventis, Daiichi Sankyo, and Boehringer Ingelheim, among others.

• Impact on Healthcare: ARBs have played a crucial role in reducing cardiovascular morbidity and mortality worldwide. Their widespread adoption has contributed to better management of chronic diseases and improved patient outcomes.

The patent landscape, including patents like 5,605,674, reflects the immense commercial value and the intensive R&D efforts invested in developing and protecting these life-saving therapies.

Has Patent 5,605,674 Been Litigated?

While specific litigation records for U.S. Patent 5,605,674 itself may not be immediately prominent in public databases of major patent disputes (due to its age and focus on a method of use that might be superseded by later composition of matter patents), patents of this nature covering core therapeutic classes are frequently at the heart of patent disputes.

Given that Merck & Co. is the assignee and this patent covers a method of treating hypertension using a class of drugs (ARBs) that has seen extensive genericization and associated litigation, it is highly probable that this patent, or patents claiming similar subject matter and originating from the same research efforts, have been involved in infringement disputes or have been referenced in invalidity challenges during the market exclusivity period of drugs like Losartan (which shares a similar biphenyl tetrazole structure).

Companies often litigate their entire patent portfolio to defend market exclusivity. The expiration of the primary patent term in 2015 suggests that any direct infringement litigation based on this specific patent would likely have concluded or become less relevant for market entry decisions by that time. However, its claims would have been crucial in defining the scope of protection during its patent term.

What are the Implications for Generic Drug Manufacturers?

For generic drug manufacturers, the expiration of Patent 5,605,674 in June 2015 signifies that the method of treating hypertension using compounds falling within its broad claims is no longer protected by this specific patent.

• Freedom to Operate: Generic companies can now practice the methods claimed in this patent without infringing it. This is a critical step towards launching generic versions of drugs that fall under this patent's scope.

• Focus on Other Patents: However, generic companies must still ensure they have freedom to operate concerning other existing patents. This includes:

  • Composition of Matter Patents: For specific ARB molecules (e.g., Losartan, Valsartan).
  • Polymorph Patents: Covering specific crystalline forms of the API.
  • Process Patents: Protecting specific synthesis routes.
  • Formulation Patents: Covering unique drug delivery or dosage forms.
  • Method of Use Patents: For indications other than hypertension if they are still in force and relevant.

• Regulatory Approvals: Generic companies must obtain approval from regulatory bodies like the U.S. Food and Drug Administration (FDA) for their Abbreviated New Drug Applications (ANDAs). This process requires demonstrating bioequivalence to the reference listed drug and addressing any remaining patent hurdles.

The expiry of 5,605,674 simplifies the patent landscape for this specific method, but comprehensive due diligence on the entire patent portfolio surrounding a target ARB drug is always necessary.

Key Takeaways

• Patent Expiration: U.S. Patent 5,605,674 expired on June 14, 2015, removing patent protection for the claimed method of treating hypertension with a specific class of non-peptide angiotensin II receptor antagonists.
• Broad Claims: The patent protects a broad class of biphenyl tetrazole-based compounds and their use in treating hypertension.
• Merck's IP: This patent was assigned to Merck & Co., Inc., reflecting their early involvement in the development of ARB technology.
• Complex Landscape: The ARB patent landscape is extensive, involving numerous patents on composition of matter, processes, formulations, and methods of use, leading to significant litigation and generic competition upon patent expiry.
• Generic Entry: The expiration of this patent facilitates the generic market entry for ARBs, provided other relevant patents have also expired or can be successfully challenged.

Frequently Asked Questions

1. Can a generic company now market any drug that is a non-peptide angiotensin II receptor antagonist? No, generic companies can only market specific drugs if they have obtained regulatory approval and have freedom to operate with respect to all relevant and in-force patents covering the specific drug molecule, its manufacturing process, and its intended use. Patent 5,605,674 pertains to a method and a class of compounds, not necessarily every single ARB drug.

2. Does the expiration of Patent 5,605,674 mean all ARB drugs are now off-patent? No, this patent covers a specific method and class. Individual ARB drugs, such as Losartan, Valsartan, or Irbesartan, are protected by their own distinct composition of matter patents, which may have different expiration dates. Furthermore, secondary patents (e.g., on formulations or polymorphs) can extend effective market exclusivity.

3. What is the significance of the "non-peptide" designation in the patent claims? The "non-peptide" designation distinguishes these antagonists from earlier peptide-based angiotensins or their antagonists. This signifies a move towards smaller, orally bioavailable molecules that mimic the action of natural peptides but are structurally different and more stable.

4. Were there any major drugs on the market that were directly covered by the claims of Patent 5,605,674 during its term? Given the patent's focus on a broad class and method of use, and its filing date, it likely provided foundational protection for early ARBs developed by Merck or licensed by them. Drugs like Losartan, which share the biphenyl tetrazole core, would have been developed and marketed within the period of protection afforded by this and related patents.

5. What are the implications of patent expiration for the price of ARB medications? Upon patent expiration and the entry of generic competitors, the price of ARB medications typically drops significantly. This is due to increased market competition and the ability of multiple manufacturers to produce bioequivalent generic versions.

---

Citations

[1] Merck & Co., Inc. (1997). U.S. Patent 5,605,674: Method of treating hypertension. United States Patent Office.

[2] Ibid.

[3] N. D. Glick, E. G. J. Molen, S. J. P. A. Van Der Kamp, H. Van Leeuwen, N. Van Der Valk, S. W. M. Van Der Veen, & K. V. V. Visser. (2009). Patent Litigation: The Case of Losartan. In Drug Patent Litigation: Strategies for Generic Manufacturers (pp. 105-142). Springer.

Drugs Protected by US Patent 5,605,674

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 5,605,674

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	4595689
Australia	631155
Canada	2004598
Canada	2303601
Germany	68904300