United States Patent 7,846,961: Perindopril Arginine Alpha-Crystal Claims, Scope, Expiration and Patent Landscape
U.S. Patent No. 7,846,961 protects a specific alpha-crystalline form of the L-arginine salt of perindopril, a solvent-mediated process for producing that form, pharmaceutical compositions containing it, and its use in treating hypertension and heart failure. The patent is primarily a solid-state and manufacturing patent, not a broad patent on perindopril or ACE inhibition.
The central enforceable asset is claim 1, which defines the product through powder X-ray diffraction peaks at approximately 4.5°, 7.9° and 13.5° 2θ. Claims 2 and 3 provide narrower diffraction-based versions. Claims 4 and 5 cover selected crystallization processes. Claims 6 through 9 extend protection to formulations and therapeutic use.
What does U.S. Patent 7,846,961 protect?
The patent protects four related subject-matter categories:
| Claim group |
Protected subject matter |
Primary infringement issue |
| Claims 1-3 |
Alpha-crystalline L-arginine salt of perindopril |
Whether the accused material is the claimed polymorph |
| Claims 4-5 |
Preparation process using aqueous dissolution and mixed solvents |
Whether the accused process uses the claimed solvent combinations |
| Claims 6-8 |
Pharmaceutical compositions, including compositions with indapamide |
Whether the composition contains the claimed crystalline salt |
| Claim 9 |
Treatment of arterial hypertension and heart failure |
Whether the claimed compound is administered for the claimed conditions |
The patent does not claim:
- Perindopril generally;
- Perindopril erbumine;
- Every salt of perindopril;
- Every crystalline form of perindopril arginine;
- A particular tablet, capsule or dosage strength;
- A broad antihypertensive method independent of the alpha-crystalline form.
The scope therefore turns on the identity of the solid form and, for process claims, the exact manufacturing route.
What is the key product claim in Patent 7,846,961?
Claim 1 covers:
An alpha-crystalline form of the L-arginine salt of perindopril exhibiting essentially the PXRD peaks at 4.5°, 7.9° and 13.5° 2θ.
This is a product-by-form claim. It does not require a particular manufacturing process. A product can infringe claim 1 even if it was made by a process different from the process recited in claim 4, provided the resulting material has the claimed structural characteristics.
The claim has three material limitations:
- The active must be perindopril.
- The counterion must be L-arginine.
- The material must be the alpha-crystalline form identified by the specified PXRD pattern.
The phrase “essentially” gives the claim some tolerance for experimental variation, peak intensity differences and additional minor peaks. It does not eliminate the need to show that the accused material has the defining diffraction pattern.
How do claims 1, 2 and 3 differ?
Claims 2 and 3 are narrower dependent claims.
| Claim |
PXRD requirement |
Practical significance |
| Claim 1 |
4.5°, 7.9° and 13.5° |
Broadest product-form claim |
| Claim 2 |
Claim 1 plus 17.5° and 20.6° |
Requires five identified peaks |
| Claim 3 |
Detailed PXRD profile with 17 listed lines and relative intensities |
Most specific crystallographic definition |
Claim 3 lists diffraction lines at approximately 4.52°, 7.94°, 12.152°, 13.480°, 14.029°, 14.948°, 15.873°, 17.531°, 18.787°, 19.579°, 20.635°, 22.616°, 23.367°, 23.807°, 24.434°, 27.148° and 28.214° 2θ.
The detailed intensity table strengthens identification of the claimed form but can also create a narrower infringement target. Minor differences caused by instrument calibration, sample preparation, crystallinity, preferred orientation or impurity content may become material in a claim-construction dispute.
What formulations are protected by Patent 7,846,961?
Claim 6 covers a pharmaceutical composition containing the claimed alpha-crystalline perindopril arginine with one or more pharmaceutically acceptable, inert, non-toxic carriers.
The claim is composition-focused. It does not require a particular excipient, dosage form or route of administration. It can potentially reach tablets, capsules or other oral dosage forms if the claimed crystalline salt is present.
Claim 7 adds a diuretic. Claim 8 narrows that combination to indapamide. The indapamide limitation is commercially relevant because it corresponds to the fixed-dose antihypertensive combination marketed with perindopril arginine in products such as Prestalia.
The formulation claims do not independently protect:
- A formulation containing only perindopril erbumine;
- A formulation containing a different perindopril arginine polymorph;
- A formulation in which the active is present only as an amorphous solid;
- A formulation that uses the same excipients but excludes the claimed alpha form.
Does the patent cover the manufacturing process?
Yes. Claim 4 covers a process in which perindopril is dissolved in water with L-arginine, followed by addition of:
- An apolar solvent selected from methylcyclohexane, cyclohexane and toluene; and
- A polar solvent selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N-methyl-2-pyrrolidinone.
The resulting crystals are filtered, washed and dried.
Claim 5 is narrower. It requires methylcyclohexane as the apolar solvent and dimethyl sulfoxide as the polar solvent.
| Process element |
Claim 4 |
Claim 5 |
| Initial medium |
Water with perindopril and L-arginine |
Same |
| Apolar solvent |
Methylcyclohexane, cyclohexane or toluene |
Methylcyclohexane |
| Polar solvent |
DMSO, DMF, DMAc or NMP |
Dimethyl sulfoxide |
| Recovery |
Filtration, washing and drying |
Same |
A manufacturer can avoid literal infringement of claims 4 and 5 by using a different crystallization route, such as a different solvent system, antisolvent, temperature profile or isolation sequence. That alternative process would not necessarily avoid claims 1 through 3 if it produces the claimed alpha form.
How strong is the product-form patent claim?
The product claims have meaningful commercial value because they can cover the active solid form regardless of the manufacturing route. Their strength depends on four technical questions:
- Whether the claimed alpha form is distinguishable from other perindopril arginine forms;
- Whether the three-peak definition in claim 1 is sufficiently reproducible;
- Whether the accused product actually contains the alpha form;
- Whether the claimed form was novel and non-obvious over earlier perindopril salt and polymorph disclosures.
Claim construction and proof
An infringement case would likely require:
- PXRD testing of the accused active pharmaceutical ingredient or finished product;
- Comparison against the reference pattern;
- Analysis of peak position tolerances;
- Potential supporting tests such as differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy or solid-state NMR;
- Evidence addressing mixtures of polymorphs or conversion during formulation.
A product containing a mixture of the alpha form and another form may still raise infringement issues if the alpha form is present in the accused material. The result would depend on the claim language, the evidentiary record and any applicable prosecution-history limitations.
Validity pressure points
The principal validity issues are likely to be:
- Anticipation by an earlier disclosure of the same alpha form;
- Obviousness based on known perindopril arginine salts and routine polymorph screening;
- Inherent anticipation through prior crystallization processes;
- Indefiniteness or written-description arguments concerning “essentially” and PXRD tolerances;
- Enablement of the full solvent alternatives in claim 4.
A prior-art reference that discloses perindopril arginine without identifying the claimed alpha form would not necessarily anticipate claims 1 through 3. A reference that discloses the same PXRD peaks, or necessarily produces the same form, would present a stronger anticipation case.
When did U.S. Patent 7,846,961 expire?
The patent was granted on December 7, 2010. Its earliest priority date is reported as December 19, 2003. The ordinary patent-term endpoint is December 19, 2024, subject to any patent-term adjustment, terminal disclaimer or other term calculation reflected in USPTO records.
| Event |
Date |
| Earliest priority |
December 19, 2003 |
| U.S. grant |
December 7, 2010 |
| Ordinary 20-year term endpoint |
December 19, 2024 |
| Post-expiration position |
Claims generally no longer enforceable after expiration |
The key commercial consequence is that the patent is no longer a normal forward-looking U.S. launch barrier after its expiration date. It may still matter for historical Paragraph IV litigation, damages analysis, past sales, license interpretation and foreign counterparties with different expiration dates.
What is the Orange Book status of Patent 7,846,961?
The patent is relevant to FDA-approved perindopril arginine products, particularly fixed-dose perindopril arginine and amlodipine products. Orange Book significance depends on the specific reference-listed drug and the patent-listing history maintained by FDA.
The regulatory distinction is important:
- Perindopril erbumine products are not automatically covered by a patent directed to perindopril arginine.
- A product containing perindopril arginine may implicate the patent if its active ingredient is the claimed alpha-crystalline form.
- A generic applicant must address listed patents for the relevant reference product, not every patent relating to the broader perindopril molecule.
An ANDA applicant could address a listed patent through Paragraph IV certification, arguing that the patent is invalid, unenforceable or will not be infringed. A Paragraph IV notice can trigger Hatch-Waxman litigation and a 30-month stay of approval under the conditions specified in the Federal Food, Drug, and Cosmetic Act. The stay does not extend an expired patent term.
Which companies could challenge the patent?
Potential challengers are manufacturers seeking approval for:
- Perindopril arginine tablets;
- Perindopril arginine and amlodipine fixed-dose combinations;
- Products using the same alpha-crystalline active;
- Products using a non-infringing alternative polymorph.
The relevant challenger set includes generic drug companies with cardiovascular portfolios and contract manufacturers supplying ANDA sponsors. Publicly identifying a definitive challenger requires linking an ANDA, Paragraph IV notice or patent litigation docket to the specific listed patent.
A generic applicant may pursue one of three technical strategies:
| Strategy |
Patent exposure |
| Use the claimed alpha form |
High exposure to claims 1-3 and potentially claims 6-9 |
| Use a different crystalline form |
Lower product-claim exposure, but requires robust polymorph characterization |
| Use an amorphous or alternative solid form |
Potentially avoids product claims, subject to stability and bioequivalence requirements |
What patent litigation and settlement issues matter?
A Paragraph IV case involving this patent would likely focus on whether the proposed product contains the patented alpha form. The technical record would be central. FDA approval alone would not resolve the patent question.
Key litigation questions include:
- Whether the ANDA specification identifies the solid form;
- Whether the generic’s manufacturing process uses the claimed solvent system;
- Whether the product converts to the alpha form during storage;
- Whether the generic composition falls within claims 6 through 8;
- Whether a treatment-use claim can be asserted against the proposed label;
- Whether the patent was listed for the exact reference product at issue.
Settlement terms could include a licensed entry date, a covenant not to sue, a manufacturing restriction, a polymorph specification or a conversion date tied to patent expiration. Hatch-Waxman settlements may also raise Federal Trade Commission review issues, particularly where the branded company provides value in exchange for delayed generic entry. The claims supplied here do not establish the terms or existence of any particular settlement.
How does this patent compare with broader perindopril patents?
Patent 7,846,961 occupies a later and narrower position in the perindopril lifecycle.
| Patent category |
Typical scope |
Relevance to 7,846,961 |
| Base compound patent |
Perindopril molecule |
Generally expired earlier |
| Salt patent |
Perindopril arginine or another salt |
Broader than the crystalline-form claims |
| Polymorph patent |
Defined crystalline form |
Core category of 7,846,961 |
| Process patent |
Crystallization or isolation method |
Claims 4-5 |
| Formulation patent |
Dosage form or excipient system |
Claims 6-8 are comparatively broad but form-dependent |
| Method-of-use patent |
Hypertension or heart failure treatment |
Claim 9, subject to form and label issues |
The patent is strongest against a competitor using the same alpha-crystalline perindopril arginine material. It is weaker against a competitor that can develop, characterize and manufacture a different solid form without conversion to the patented form.
Does the patent create biosimilar risk?
No. Perindopril arginine is a small-molecule active pharmaceutical ingredient. The relevant FDA pathway is an ANDA, not a biosimilar application under the Public Health Service Act.
The principal regulatory risks are:
- Paragraph IV patent certification;
- Solid-form characterization;
- Pharmaceutical equivalence;
- Bioequivalence;
- Stability;
- Product-by-process and manufacturing documentation;
- Labeling and method-of-use restrictions.
The absence of biosimilar risk does not eliminate manufacturing barriers. A competing manufacturer must still establish a reproducible, stable and regulatory-compliant form of perindopril arginine.
What geographic coverage does the patent provide?
U.S. Patent 7,846,961 provides rights only in the United States. Foreign protection depends on national or regional counterparts derived from the same patent family.
A global freedom-to-operate review should separately examine:
- European Patent Office counterparts;
- United Kingdom, France, Germany, Italy and Spain;
- Canada;
- Japan;
- China;
- India;
- Australia;
- Countries where Servier marketed perindopril arginine.
Expiration dates can differ because of national filing dates, patent-term adjustments, supplementary protection certificates and local prosecution history. A U.S. expiration does not establish the status of foreign family members.
What manufacturing and intellectual-property barriers remain after expiration?
After U.S. expiration, the patent no longer blocks commercial manufacture based solely on its claims. Technical barriers remain:
- Reproducing a consistent solid form;
- Avoiding unwanted polymorphic conversion;
- Controlling water content and residual solvents;
- Establishing stability through shelf life;
- Demonstrating bioequivalence;
- Maintaining adequate supply-chain controls;
- Avoiding other unexpired formulation or combination patents.
The most important post-expiration distinction is between patent clearance and development feasibility. A company may be free to make perindopril arginine but still need to solve form-control and regulatory comparability problems.
Key Takeaways
- U.S. Patent 7,846,961 is a polymorph patent covering alpha-crystalline perindopril L-arginine.
- Claims 1 through 3 are the core product claims and depend on PXRD identification.
- Claims 4 and 5 cover specific water, apolar-solvent and polar-solvent crystallization routes.
- Claims 6 through 8 cover pharmaceutical compositions, including indapamide combinations.
- Claim 9 covers treatment of hypertension and heart failure using the claimed crystalline compound.
- The patent does not broadly cover all perindopril, all perindopril salts or all perindopril arginine forms.
- The ordinary U.S. patent-term endpoint is December 19, 2024.
- The competitive pathway is an ANDA with potential Paragraph IV certification, not a biosimilar application.
- The principal technical challenge for a generic manufacturer is proving that its active ingredient is a different solid form or otherwise avoiding the claimed alpha form.
- Any remaining U.S. commercial barrier must be assessed against other Orange Book-listed patents for the relevant reference product.
FAQs About U.S. Patent 7,846,961
Is perindopril erbumine covered by Patent 7,846,961?
Generally, no. The claims are directed to the L-arginine salt of perindopril, not perindopril erbumine.
Can a generic use a different polymorph of perindopril arginine?
Potentially. A different polymorph may avoid claims 1 through 3, but the manufacturer must confirm that the material does not convert into the claimed alpha form during processing, storage or administration.
Does claim 4 cover every process that produces alpha-crystalline perindopril arginine?
No. Claim 4 is limited to the specified aqueous and mixed-solvent process elements. Claims 1 through 3 are product claims and may apply regardless of the manufacturing process.
Is an indapamide combination independently blocked by the patent?
Only if the composition contains the claimed alpha-crystalline perindopril arginine and satisfies the applicable composition claim. Indapamide alone is not the protected subject matter.
Can a company launch after December 19, 2024?
The expiration of this patent removes its forward-looking U.S. barrier, but launch requires review of other unexpired patents, FDA requirements, exclusivity, labeling restrictions and any applicable litigation or settlement obligations.
References
- U.S. Patent and Trademark Office. (2010). U.S. Patent No. 7,846,961, crystalline form of perindopril arginine, process for its preparation and pharmaceutical compositions containing it.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, Orange Book.
- U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application submissions and Paragraph IV patent certifications.
- United States Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417.
- U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation guidance.
