Details for Patent: 7,332,481

Summary for Patent: 7,332,481

Title:	Thrombopoietin mimetics
Abstract:	Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected hydroxy-1-azobenzene derivative.
Inventor(s):	Kevin J. Duffy, Connie Erickson-Miller, Julian Jenkins, Juan Luengo, Alan T. Price, Antony N. Shaw, Sophie Visonneau, Kenneth Wiggall
Assignee:	Novartis AG, Novartis Pharma AG
Application Number:	US11/620,260
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,332,481
Patent Claim Types: see list of patent claims	Use; Delivery;

United States Drug Patent 7,332,481: Scope, Claims, and Landscape Analysis

Patent 7,332,481, titled "COMPOSITIONS AND METHODS FOR THE TREATMENT OF DYSLIPIDEMIA," issued on February 19, 2008, to Pfizer Inc. The patent covers pharmaceutical compositions and methods for treating dyslipidemia, a condition characterized by abnormal levels of lipids in the blood. The primary active ingredient described and claimed within this patent is rosuvastatin calcium, marketed as Crestor.

What is the Core Innovation Protected by Patent 7,332,481?

The patent's core innovation lies in specific crystalline forms of rosuvastatin calcium and pharmaceutical compositions containing these forms. It addresses challenges associated with the stability and bioavailability of the drug substance.

• Crystalline Forms: The patent details at least three specific crystalline forms of rosuvastatin calcium: Form I, Form II, and Form III. These forms are characterized by their distinct X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) profiles, and infrared (IR) spectroscopy data.
• Pharmaceutical Compositions: The patent claims compositions comprising rosuvastatin calcium (in one of its specified crystalline forms) and at least one pharmaceutically acceptable excipient. These compositions are designed for oral administration.
• Therapeutic Method: The patent also claims a method for treating dyslipidemia by administering a therapeutically effective amount of a composition containing rosuvastatin calcium.

What Specific Claims Does Patent 7,332,481 Encompass?

The claims in Patent 7,332,481 are structured to protect both the crystalline forms of the active pharmaceutical ingredient (API) and the final drug product.

Claim 1: A Specific Crystalline Form

Claim 1 is central to the patent's protection, defining a specific crystalline form of rosuvastatin calcium.

• Claim 1: "A crystalline form of rosuvastatin calcium characterized by an X-ray powder diffraction pattern comprising peaks at approximately 2-theta values of 5.1, 9.9, 11.6, 15.4, 18.9, 21.0, 23.1, 25.6, and 28.2 degrees." This claim specifically defines Form I of rosuvastatin calcium.

Claim 2: Another Specific Crystalline Form

Claim 2 protects a distinct crystalline form.

• Claim 2: "A crystalline form of rosuvastatin calcium characterized by an X-ray powder diffraction pattern comprising peaks at approximately 2-theta values of 6.0, 11.1, 12.0, 15.8, 19.2, 20.3, 22.0, 23.8, and 26.1 degrees." This claim specifically defines Form II of rosuvastatin calcium.

Claim 3: A Third Specific Crystalline Form

Claim 3 introduces protection for a third crystalline polymorph.

• Claim 3: "A crystalline form of rosuvastatin calcium characterized by an X-ray powder diffraction pattern comprising peaks at approximately 2-theta values of 5.8, 10.7, 12.6, 14.5, 17.1, 20.9, 22.8, 24.6, and 26.5 degrees." This claim specifically defines Form III of rosuvastatin calcium.

Claims 4-9: Pharmaceutical Compositions

These claims extend protection to the drug product itself, encompassing the use of the crystalline forms in formulated medicines.

• Claim 4: "A pharmaceutical composition comprising rosuvastatin calcium as claimed in claim 1 and at least one pharmaceutically acceptable excipient." This claim covers compositions containing Form I.
• Claim 5: "A pharmaceutical composition comprising rosuvastatin calcium as claimed in claim 2 and at least one pharmaceutically acceptable excipient." This claim covers compositions containing Form II.
• Claim 6: "A pharmaceutical composition comprising rosuvastatin calcium as claimed in claim 3 and at least one pharmaceutically acceptable excipient." This claim covers compositions containing Form III.
• Claim 7: "A pharmaceutical composition according to claim 4, wherein the composition is a tablet." This claim specifies a tablet dosage form for compositions containing Form I.
• Claim 8: "A pharmaceutical composition according to claim 5, wherein the composition is a tablet." This claim specifies a tablet dosage form for compositions containing Form II.
• Claim 9: "A pharmaceutical composition according to claim 6, wherein the composition is a tablet." This claim specifies a tablet dosage form for compositions containing Form III.

Claims 10-12: Therapeutic Methods

These claims cover the application of the pharmaceutical compositions for treating specific medical conditions.

• Claim 10: "A method for treating dyslipidemia, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 4." This claims the method of treating dyslipidemia using compositions containing Form I.
• Claim 11: "A method for treating dyslipidemia, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 5." This claims the method of treating dyslipidemia using compositions containing Form II.
• Claim 12: "A method for treating dyslipidemia, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 6." This claims the method of treating dyslipidemia using compositions containing Form III.

What is the Patent Landscape Surrounding Rosuvastatin Calcium?

The patent landscape for rosuvastatin calcium is complex, marked by the original composition of matter patents, formulation patents, and subsequent patents covering specific polymorphs, manufacturing processes, and therapeutic uses. Patent 7,332,481 is one such later-stage patent focusing on specific crystalline forms.

Key Patents and Their Impact

• Original Composition of Matter Patents: The foundational patents for rosuvastatin (e.g., U.S. Patent 5,262,535, issued November 16, 1993) covered the molecule itself and its general therapeutic use. These patents have long since expired, opening the door for generic competition.
• Polymorph Patents: Patent 7,332,481 is a prime example of a patent targeting specific crystalline forms (polymorphs). Polymorphs of an API can exhibit different physical properties, such as solubility, stability, and manufacturability, which can be patentable if they offer a technical advantage. Other patents have also claimed different polymorphs of rosuvastatin calcium.
• Formulation Patents: Patents covering specific tablet formulations, including excipient combinations and manufacturing methods, can also exist. These patents aim to protect the drug product and may extend market exclusivity beyond the life of the original composition of matter patent.
• Method of Use Patents: Patents claiming novel uses or methods of treating specific patient populations with rosuvastatin are also part of the landscape.

Generic Competition and Patent Expirations

The expiration of the original rosuvastatin composition of matter patents led to significant generic competition. However, later-expiring patents, such as those covering specific crystalline forms (like 7,332,481) or specific formulations, can still provide a degree of market exclusivity. Litigation often arises when generic manufacturers challenge the validity or infringement of these later-expiring patents.

Litigation and Exclusivity

Pfizer vigorously defended its intellectual property related to Crestor. Challenges to patents covering crystalline forms of rosuvastatin calcium have been common. The success of these challenges often hinges on whether the crystalline forms offer a demonstrable technical advantage over prior art or other known forms. The patent term for U.S. Patent 7,332,481 is 20 years from the filing date, which was March 3, 2003. Therefore, it expired on March 3, 2023.

What is the Current Status of Patent 7,332,481?

United States Drug Patent 7,332,481 expired on March 3, 2023.

This expiration date is derived from the patent's filing date (March 3, 2003) and the standard 20-year patent term.

What Are the Implications for R&D and Investment Decisions?

The expiration of Patent 7,332,481 removes a significant barrier to generic entry for specific crystalline forms and compositions of rosuvastatin calcium.

• Generic Manufacturers: Companies seeking to market generic versions of rosuvastatin calcium are no longer restricted by the claims of this patent. They can now manufacture and sell products incorporating the crystalline forms described in this patent, provided they do not infringe on any other valid and unexpired patents.
• Branded Manufacturers: For Pfizer, the expiration of this patent reduces its ability to maintain market exclusivity through this specific intellectual property. The primary protection for Crestor has already transitioned to the generic market with the expiration of earlier patents.
• Investment Decisions: For investors, the expiration signals a heightened competitive environment for rosuvastatin calcium. Opportunities may lie in companies developing next-generation statins or alternative lipid-lowering therapies. For generic manufacturers, this expiration is an opportunity to capture market share.

Key Takeaways

• U.S. Patent 7,332,481 protects specific crystalline forms (Forms I, II, and III) of rosuvastatin calcium and pharmaceutical compositions containing these forms, along with methods of treating dyslipidemia.
• The patent claims are detailed, specifying X-ray powder diffraction patterns to define the crystalline structures.
• This patent has expired on March 3, 2023, removing its protection for specific rosuvastatin calcium polymorphs and formulations.
• The expiration of this patent, following the expiry of earlier composition of matter patents, further facilitates generic competition for rosuvastatin calcium products.

Frequently Asked Questions

1. What specific rosuvastatin calcium crystalline forms are covered by Patent 7,332,481? Patent 7,332,481 specifically covers crystalline Form I, Form II, and Form III of rosuvastatin calcium, each defined by distinct X-ray powder diffraction patterns.

2. Does the expiration of Patent 7,332,481 mean all rosuvastatin calcium patents are expired? No, the expiration of Patent 7,332,481 on March 3, 2023, only applies to the specific claims within this patent. Other patents related to different aspects of rosuvastatin (e.g., manufacturing processes, different crystalline forms not claimed here, or specific formulations not covered) may still be in effect or may have also expired at different times.

3. Can generic manufacturers immediately produce any rosuvastatin calcium product after this patent's expiration? Generic manufacturers can produce rosuvastatin calcium products incorporating the crystalline forms claimed in Patent 7,332,481. However, they must ensure they do not infringe on any other valid and unexpired patents that might cover other aspects of the drug or its formulation.

4. What is the significance of crystalline forms in drug patents? Crystalline forms (polymorphs) can have different physical and chemical properties, such as solubility, stability, dissolution rates, and manufacturability. If a new crystalline form offers a significant technical advantage and was not previously known, it can be patented, providing a period of exclusivity.

5. What was the original patent covering the rosuvastatin molecule itself? The original composition of matter patent for rosuvastatin was U.S. Patent 5,262,535, which issued on November 16, 1993, and has long since expired.

Citations

[1] Pfizer Inc. (2008). U.S. Patent 7,332,481: Compositions and methods for the treatment of dyslipidemia. United States Patent and Trademark Office. [2] Pfizer Inc. (1993). U.S. Patent 5,262,535: Substituted 3,5-dihydroxyheptanoic acid derivatives. United States Patent and Trademark Office.

Drugs Protected by US Patent 7,332,481

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 7,332,481

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1294378		C300451	Netherlands
European Patent Office	1294378		CA 2010 00017	Denmark
European Patent Office	1294378		91681	Luxembourg
European Patent Office	1294378		SPC020/2010	Ireland