United States Patent 4,879,303: Amlodipine Besylate Claims, Scope, Expiration, Litigation, and Patent Landscape

U.S. Patent No. 4,879,303 covered amlodipine besylate as a salt, pharmaceutical compositions containing it, and tablet, capsule, and injectable formulations. The patent was assigned to Pfizer and issued on November 7, 1989. Its listed U.S. patent term ended on September 25, 2007. The Federal Circuit later held the asserted amlodipine besylate claim invalid for obviousness in Pfizer, Inc. v. Apotex, Inc., materially reducing the patent's enforcement value before expiration.[1][2]

What does U.S. Patent 4,879,303 protect?

The patent protects the besylate salt of amlodipine and pharmaceutical products containing that salt. Its central legal asset is claim 1:

"The besylate salt of amlodipine."

That is a composition-of-matter claim directed to a particular salt form of the calcium-channel blocker amlodipine. The claim does not cover all amlodipine compounds, all pharmaceutically acceptable salts, or all formulations containing amlodipine. It covers amlodipine combined with benzenesulfonic acid, commonly called besylic acid, in the claimed salt form.

The remaining claims are product and formulation claims that depend directly or indirectly on claim 1.

Claim	Claimed subject matter	Commercial relevance
1	Amlodipine besylate	Core composition-of-matter claim
2	Pharmaceutical composition containing amlodipine besylate and a carrier or diluent	Broad dosage-form composition
3	Tablet containing amlodipine besylate and excipients	Tablet product claim
4	Tablet with compression aid, sheen-producing additive, disintegrant, and lubricant	Narrow tablet formulation
5	Tablet with microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, and magnesium stearate	Specific excipient combination
6	Capsule containing amlodipine besylate and excipients	Capsule product claim
7	Capsule with inert diluent, dried disintegrant, and lubricant	Narrow capsule formulation
8	Capsule with microcrystalline cellulose, dried maize starch, and magnesium stearate	Specific capsule formulation
9	Sterile aqueous injectable solution of amlodipine besylate	Parenteral formulation
10	Injectable solution containing 10% to 40% w/v propylene glycol	Specific solvent system
11	Injectable solution containing approximately 1% w/v sodium chloride	Specific isotonicity limitation

Because claims 2 through 11 incorporate claim 1, they all require amlodipine besylate. A product containing amlodipine free base or a different salt would not satisfy the salt limitation literally.

How broad is claim 1 for amlodipine besylate?

Claim 1 is broad as a chemical composition claim but narrow in relation to the broader amlodipine genus.

It does not recite:

A particular particle size;
A specific crystalline polymorph;
A particular solid-state form;
A specific assay or purity;
A particular dosage strength;
A particular release profile;
A particular manufacturing process;
A particular indication; or
A particular tablet or capsule excipient system.

A generic manufacturer producing conventional amlodipine besylate tablets would have fallen within the literal scope of claim 1, even if its formulation used different excipients. Claims 3 through 5 would have had narrower relevance because they require tablet dosage forms and, for claim 5, a defined excipient combination.

The claim does not require that the product be marketed under the Norvasc brand. It applies based on the chemical identity of the active pharmaceutical ingredient and, for the dependent claims, the presence of the specified formulation components.

What is the difference between amlodipine and amlodipine besylate?

Amlodipine is the active pharmaceutical moiety. Amlodipine besylate is a salt formed by combining amlodipine with besylic acid.

Subject	Legal and technical significance
Amlodipine free base	Parent active moiety
Amlodipine besylate	Salt form protected by claim 1 of U.S. 4,879,303
Amlodipine maleate or other salt	Chemically distinct salt; not literally covered by claim 1
Norvasc	Pfizer's branded amlodipine besylate product
Generic amlodipine besylate	Product that historically raised infringement issues under claim 1

The earlier amlodipine compound patent, commonly identified as U.S. Patent No. 4,572,909, covered the underlying dihydropyridine compound and related pharmaceutical use. That patent expired before U.S. 4,879,303.[3] The later patent therefore attempted to create additional protection around the besylate salt rather than the original amlodipine molecule.

What formulations are protected by U.S. Patent 4,879,303?

The formulation claims cover tablets, capsules, and sterile aqueous solutions.

Tablet claims

Claims 3 through 5 cover tablet products. Claim 3 is relatively broad because it requires only amlodipine besylate, an effective amount, and excipients. Claim 5 is much narrower and requires all four identified excipients:

Microcrystalline cellulose;
Anhydrous dibasic calcium phosphate;
Sodium starch glycolate; and
Magnesium stearate.

A tablet containing amlodipine besylate but using lactose, povidone, crospovidone, or a different lubricant could avoid claim 5. It would still have faced claim 3 while that claim remained enforceable, assuming the product met the claim's other limitations.

Capsule claims

Claims 6 through 8 cover capsules. Claim 8 requires:

Microcrystalline cellulose;
Dried maize starch; and
Magnesium stearate.

These claims would not necessarily reach every capsule containing amlodipine besylate. The broader claim 6 would have been more important in an infringement analysis.

Injectable claims

Claims 9 through 11 cover sterile aqueous solutions for parenteral administration. Claims 10 and 11 add propylene glycol and sodium chloride limitations.

These claims have limited commercial importance for Norvasc because the approved product was an oral tablet. Their principal value was defensive or prospective. A competing injectable amlodipine besylate product would need to be assessed against the solution claims separately.

When did U.S. Patent 4,879,303 expire?

The patent's U.S. term ended on September 25, 2007, based on the patent term reflected in FDA and litigation records.[1][4]

Event	Date
Priority date	September 25, 1986
U.S. filing date	September 25, 1987
Patent issued	November 7, 1989
U.S. patent term end	September 25, 2007
Generic market entry period	2007 onward

The patent did not provide a current blocking right after that date. Any patent-term-extension or pediatric-exclusivity analysis had to be separated from the ordinary patent expiration date and from the FDA's regulatory exclusivity period.

What was the FDA and Orange Book status?

Amlodipine besylate was approved in the United States in Norvasc under NDA 019787. The original approval occurred on July 31, 1992.[5]

The FDA Orange Book historically listed U.S. Patent No. 4,879,303 for Norvasc. That listing gave the patent procedural significance in the abbreviated new drug application process. An ANDA applicant had to address the listed patent through a Paragraph I, II, III, or IV certification.

The patent is no longer an operative Orange Book barrier because its term expired in 2007. The FDA approval of generic amlodipine besylate products followed the loss of enforceable patent exclusivity and the resolution of patent litigation.

Regulatory exclusivity and patent exclusivity were separate:

Amlodipine's five-year new chemical entity exclusivity applied after NDA approval.
The patent term extended beyond the original FDA exclusivity period.
Any pediatric exclusivity period was a separate six-month regulatory period and did not revive an expired patent.
Approval of generic amlodipine besylate depended on the ANDA pathway, bioequivalence, labeling, manufacturing, and patent certification requirements.

Which companies challenged U.S. Patent 4,879,303?

Apotex was the principal challenger involved in the reported Federal Circuit decision. The dispute arose after Apotex sought approval to market a generic amlodipine besylate product and Pfizer sued for patent infringement under the Hatch-Waxman Act.[1]

Other generic companies entered the amlodipine market as the patent barrier weakened or expired. Publicly reported market participants included Apotex, Mylan, Sandoz, Teva-related entities, and other ANDA sponsors. The relevant distinction is between:

Companies that filed Paragraph IV challenges;
Companies that launched after the patent expired;
Companies that entered under settlement or authorized-generic arrangements; and
Companies whose ANDAs were approved without litigating the patent.

The available reported appellate decision establishes Apotex as the central litigant for the patent's validity challenge. It does not establish that every generic applicant used the same certification or settlement strategy.

What did Pfizer v. Apotex decide?

In Pfizer, Inc. v. Apotex, Inc., the Federal Circuit held that the claimed besylate salt was obvious.[1] The decision reversed the district court's conclusion that the asserted claim was valid.

The court's analysis focused on whether a skilled person would have been motivated to select besylate from the known class of pharmaceutically acceptable acids and whether the claimed salt had unexpected properties sufficient to overcome the prima facie case of obviousness.

The decision is significant for salt-patent analysis because it treated the following considerations as relevant:

The existence of the known amlodipine free base;
The conventional practice of screening pharmaceutically acceptable salts;
The availability of besylic acid as a known salt-forming acid;
The predictability of obtaining a solid salt suitable for formulation; and
The absence of sufficiently persuasive unexpected results.

The case weakened the patent before its scheduled expiration. Once the asserted claim was held obvious, Pfizer could not rely on claim 1 to block Apotex's qualifying generic product. Dependent formulation claims would not automatically remain commercially useful if the generic product avoided their additional limitations, and their practical value was further reduced by the approaching September 2007 expiration.

How strong was the patent estate?

The estate was commercially strong during the early Norvasc life cycle but legally vulnerable by the time of the Federal Circuit appeal.

Strength factor	Assessment
Core product coverage	Strong in breadth because claim 1 covered the salt itself
Differentiation from free-base patent	Meaningful, because the marketed product used the besylate salt
Formulation coverage	Moderate to weak; dependent claims required specific dosage forms or excipients
Validity	Weak after the Federal Circuit obviousness ruling
Remaining term after appeal	Short
Regulatory leverage	Significant before generic approvals
Current blocking value	None after expiration

The patent's principal value was not its detailed formulation language. It was claim 1's attempt to cover the active salt as a composition. Once that claim failed on obviousness grounds, the remaining claims offered limited protection against products using different excipient systems.

Did the patent cover methods of use?

The listed claims do not claim a method of treating hypertension, ischemia, or angina in the conventional method-of-treatment format. Instead, they recite an amount effective for those purposes within pharmaceutical composition claims.

Claims 2, 3, 6, and 9 contain therapeutic-purpose language such as "antihypertensive," "antiischaemic," and "angina-alleviating." That language helps define the intended pharmaceutical use and dosage context, but it does not create a separate method-of-use patent.

The patent therefore differs from a later-use patent that would claim:

Treating a specific patient population;
Treating a specific disease subtype;
Using a defined dose;
Using a particular titration schedule; or
Combining amlodipine with another active ingredient.

No such independent method-of-use claim appears in the claims supplied.

What generic launch scenarios existed?

Three launch scenarios were commercially relevant.

Launch after patent expiration

This was the lowest-risk route. A generic company could launch amlodipine besylate after September 25, 2007, assuming FDA approval and compliance with other applicable exclusivity requirements.

Paragraph IV launch

A Paragraph IV applicant could allege that the patent was invalid, unenforceable, or not infringed. Pfizer's litigation against Apotex followed this route. A successful Paragraph IV challenge could permit earlier approval and launch, subject to the 180-day exclusivity rules applicable to the first qualifying ANDA filer.

Non-infringing formulation design

A generic could use amlodipine besylate while designing around the narrow dependent claims. For example, changing the excipient system could avoid claim 5 or claim 8. That strategy would not avoid claim 1 while it remained valid because claim 1 covered the salt itself.

After the Federal Circuit's obviousness ruling and patent expiration, formulation design-around was primarily a product-development and regulatory issue rather than a meaningful patent barrier.

What manufacturing and geographic barriers existed?

The patent was a U.S. right. It could not directly block manufacture, use, or sale outside the United States. Separate national patent rights had to be assessed in Europe, Canada, Japan, and other markets.

The manufacturing implications were straightforward:

Making amlodipine besylate in the United States could have implicated claim 1 before expiration.
Importing finished amlodipine besylate into the United States could have created infringement exposure.
Using a different manufacturing process would not necessarily avoid a composition claim.
A process change could help avoid a process patent, but U.S. 4,879,303 was principally a product and formulation patent.
A different amlodipine salt could avoid literal infringement but would require separate stability, bioequivalence, and regulatory assessment.

The patent did not, based on the supplied claims, monopolize every process for making amlodipine besylate.

How did amlodipine compare with competing calcium-channel blockers?

Amlodipine competed in the dihydropyridine calcium-channel blocker market with nifedipine, felodipine, nicardipine, and isradipine. Its commercial differentiation came from long duration of action, once-daily dosing, and broad hypertension use rather than from the patent claims alone.

Product	Active ingredient	Typical patent issue
Norvasc	Amlodipine besylate	Salt and formulation protection under U.S. 4,879,303
Procardia/Adalat	Nifedipine	Earlier compound and formulation patents
Plendil	Felodipine	Compound and extended-release formulation patents
Cardene	Nicardipine	Compound and formulation patents
Dynacirc	Isradipine	Compound and formulation patents

Amlodipine's large commercial exposure made the salt patent important to Pfizer. Pfizer reported Norvasc sales of approximately $2 billion in the mid-2000s, with generic entry creating a material loss-of-exclusivity event.[6]

Key Takeaways

U.S. Patent 4,879,303 principally protected amlodipine besylate as a salt.
Claim 1 was the core commercial claim and covered the salt independent of a particular formulation.
Claims 2 through 11 covered compositions, tablets, capsules, and sterile injectable solutions containing amlodipine besylate.
Claims 5 and 8 were narrow excipient-specific formulation claims.
The patent's U.S. term ended on September 25, 2007.
The Federal Circuit held the asserted besylate claim obvious in Pfizer v. Apotex.
The patent did not claim an independent method of treating hypertension or angina.
The patent is expired and has no current U.S. blocking value.
Generic entry was supported by the patent-expiration timeline, the Federal Circuit invalidity ruling, and FDA ANDA approvals.
The principal historical patent risk was the composition claim, not the narrow tablet and capsule excipient claims.

Frequently Asked Questions

Was amlodipine besylate patent 4,879,303 still enforceable after 2007?

No. Its listed U.S. patent term ended on September 25, 2007, and the asserted claim was also held obvious in the Pfizer v. Apotex litigation.

Did U.S. Patent 4,879,303 cover amlodipine maleate?

No. Claim 1 is directed to the besylate salt. A different amlodipine salt would require a separate infringement and validity analysis.

Could a generic avoid the patent by changing tablet excipients?

Changing excipients could avoid narrow claims such as claim 5, but it would not avoid claim 1 if that claim were valid because claim 1 covers the amlodipine besylate salt itself.

Was Norvasc's patent protection based only on the active ingredient?

No. Pfizer relied on the underlying amlodipine compound patent, the later besylate salt patent, FDA exclusivity, and the commercial position of the branded product. U.S. 4,879,303 was the principal salt and formulation patent identified in the supplied claims.

Does the patent protect injectable amlodipine products?

Claims 9 through 11 cover specified sterile aqueous solutions for parenteral administration. Those claims are narrower than claim 1 and require the product to satisfy the solution, propylene glycol, and sodium chloride limitations where applicable.

References

Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007).
United States Patent No. 4,879,303, "Pharmaceutical compositions containing amlodipine besylate," issued November 7, 1989.
United States Patent No. 4,572,909, "1,4-dihydropyridine derivatives," issued February 25, 1986.
U.S. Food and Drug Administration. (2007). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
U.S. Food and Drug Administration. (1992). Norvasc (amlodipine besylate) NDA 019787 approval history and prescribing information. FDA.
Pfizer Inc. (2007). Annual report 2006. Pfizer Inc.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8608335	Apr 04, 1986

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
African Regional IP Organization (ARIPO)	50	⤷ Start Trial
African Regional IP Organization (ARIPO)	8700060	⤷ Start Trial
Argentina	242562	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,879,303

Summary for Patent: 4,879,303