US Patent 5,164,405: Nicardipine Hydrochloride Injection Claims, Expiration, and Patent Landscape

US Patent 5,164,405 covered stable aqueous nicardipine hydrochloride compositions for parenteral use and the processes used to prepare them. Its central technical combination was nicardipine hydrochloride in water, an acidic buffer at approximately pH 3.0-4.5, and a non-chloride isotonicity agent such as sorbitol or mannitol. The patent issued on November 17, 1992, and its enforceable US term expired in November 2009 under the pre-URAA 17-year-from-issuance rule. It therefore presents no current US patent barrier to generic nicardipine injection development. [1-3]

What does US Patent 5,164,405 protect?

The patent protects both manufacturing processes and finished pharmaceutical compositions.

Claim group	Protected subject matter	Principal limitations
Claims 1-2	Manufacturing process	Water-based vehicle, buffer at pH 3.0-4.5, at least 1 mg/mL nicardipine HCl, non-chloride isotonicity agent
Claim 2	Sterilization process	Claim 1 process plus terminal autoclaving
Claims 3-5	Broad composition	Nicardipine HCl, water, acidic buffer, non-chloride isotonicity agent
Claims 6-7	Narrow composition	1-2.5 mg/mL nicardipine HCl, 48-50 mg/mL sorbitol or mannitol, 0.002-0.003 M citrate buffer
Claim 8	Specific 1 mg/mL formulation	Nicardipine HCl, sorbitol, citric acid monohydrate, sodium hydroxide, water, pH 3.5-4.5
Claim 9	Specific 2.5 mg/mL formulation	Same basic formulation as claim 8, with 2.5 mg/mL nicardipine HCl

The patent is directed to a formulation problem rather than the discovery of nicardipine itself. The specification and claims focus on maintaining a stable injectable solution during storage and terminal sterilization.

What are the key limitations of claim 1?

Claim 1 requires a process with all of the following elements:

Nicardipine hydrochloride is used as the active ingredient.
The vehicle contains at least a major proportion of water and, more specifically, is formed from an aqueous vehicle consisting essentially of water.
A physiologically acceptable buffer is dissolved in the water.
The buffer maintains the final composition at approximately pH 3.0-4.5.
Nicardipine hydrochloride is present at not less than 1 mg/mL.
A physiologically acceptable non-chloride compound renders the formulation isotonic.
The composition is suitable for parenteral administration.

The non-chloride limitation is commercially important. The claim identifies saccharides, including sorbitol, mannitol, dextrose and glucose, as well as non-saccharides such as polyethylene glycol and glycerol. A formulation using sodium chloride as the sole isotonicity agent would not satisfy the express non-chloride limitation.

The phrase "consisting essentially of water" narrows the vehicle. It allows conventional formulation excipients and processing materials that do not materially alter the claimed stability characteristics, but it creates a risk for formulations containing substantial quantities of co-solvents or nonaqueous vehicles.

How do claims 3 through 9 narrow the formulation scope?

Claim 3: broad composition claim

Claim 3 requires:

at least approximately 1 mg/mL nicardipine hydrochloride;
a non-chloride isotonicity agent;
citrate, acetate, phosphate or lactate buffer;
water as the aqueous vehicle;
suitability for parenteral administration.

The therapeutic-use language relating to cardiovascular and cerebrovascular conditions is likely less important than the physical composition limitations. A product containing the required ingredients and concentrations could fall within the claim even if its labeling uses different wording, provided the product is suitable for parenteral administration.

Claim 4: concentration range

Claim 4 recites approximately 0.5-10 mg/mL nicardipine hydrochloride. Because claim 4 depends on claim 3, which already requires at least approximately 1 mg/mL, the practical intersection is approximately 1-10 mg/mL.

This claim covers a much wider concentration range than claims 6, 8 and 9. It also specifies water for injection alone as the vehicle, excluding reliance on a separately identified organic co-solvent.

Claim 5: citrate and acetate buffers

Claim 5 narrows claim 3 to citrate or acetate buffers. Phosphate and lactate formulations remain within claim 3 but fall outside claim 5.

Claims 6 and 7: preferred formulation platform

Claim 6 requires:

1-2.5 mg/mL nicardipine hydrochloride;
sorbitol or mannitol at approximately 48.0-50.0 mg/mL;
citrate buffer at 0.002-0.003 M;
water alone as the vehicle.

Claim 7 narrows claim 6 to sorbitol. This is the principal formulation architecture reflected in claims 8 and 9.

Claims 8 and 9: commercial-strength formulations

Claim 8 covers approximately 1 mg/mL nicardipine hydrochloride with 48-50 mg/mL sorbitol, citric acid monohydrate, sodium hydroxide and water. The acid and base establish the citrate buffer and pH range.

Claim 9 covers the corresponding 2.5 mg/mL nicardipine hydrochloride formulation. These claims are highly specific and would have been most relevant to a product matching the claimed concentrations and excipient system.

Does claim 2 protect autoclave sterilization?

Yes. Claim 2 depends on claim 1 and adds terminal sterilization by autoclaving. A process must first satisfy every limitation of claim 1 and then include autoclave sterilization.

The claim does not cover every autoclaved nicardipine injection. It requires the specific acidic, buffered, non-chloride isotonic formulation defined in claim 1. An autoclaved product using a different pH, a different vehicle, a chloride isotonicity agent, or less than 1 mg/mL nicardipine hydrochloride would not literally satisfy the claim.

What technical problem did the patent address?

Nicardipine hydrochloride injectable formulations require control of stability, pH, isotonicity and sterilization compatibility. The claimed formulation uses:

acidic pH to maintain solution stability;
non-chloride osmotic agents to provide isotonicity;
water for injection as the principal vehicle;
citrate, acetate, phosphate or lactate buffering systems;
autoclaving for terminal sterilization in the process claims.

The preferred sorbitol formulation is particularly significant because it combines a defined osmotic agent concentration with a narrow citrate-buffer range and an acidic pH. A developer seeking to reproduce the historical product would likely begin with claims 8 and 9 as the closest claim benchmarks.

When did US Patent 5,164,405 expire?

Event	Date
Patent issued	November 17, 1992
Statutory term applicable to the patent	17 years from issue
Expected US expiration	November 17, 2009
Current status	Expired

The patent was issued before the transition to the 20-year term measured from the earliest effective nonprovisional filing date. Under the pre-URAA regime, the ordinary term was 17 years from grant. The USPTO identifies US 5,164,405 as an expired patent. [1, 2]

The expired status eliminates current infringement exposure based solely on this patent. It also removes the patent as a basis for a current Paragraph IV challenge or a Hatch-Waxman 30-month stay.

What is the Orange Book status of the nicardipine formulation patent?

US Patent 5,164,405 should not be treated as a currently enforceable Orange Book patent. Any historical listing associated with a nicardipine hydrochloride injection product would no longer create a live patent bar after expiration.

The relevant FDA product is nicardipine hydrochloride injection, historically marketed as Cardene I.V. The product is a conventional small-molecule injectable and is regulated through an NDA and abbreviated new drug applications, not through the biosimilar pathway. The FDA Orange Book remains the controlling source for current patent and exclusivity information associated with an approved reference product. [3, 4]

A historical Orange Book listing does not extend the statutory term of an expired patent. Nor does the FDA listing itself establish that a patent claim is valid, infringed or enforceable.

Are Paragraph IV challenges or generic entry blocked by this patent?

No. Because the patent expired in 2009, it cannot currently support:

a Paragraph IV certification directed to a live patent;
a 30-month stay of ANDA approval;
a patent-based bar to generic launch;
a new patent settlement restricting generic entry;
an injunction against a current generic manufacturer.

For a current ANDA applicant, the relevant regulatory issues are product sameness, injectable formulation requirements, bioequivalence or comparative performance requirements, manufacturing controls and any other unexpired patents listed for the reference product. US 5,164,405 itself is no longer a launch constraint.

What formulation design-arounds would have avoided the original claims?

Before expiration, a developer could have reduced literal infringement risk by changing one or more required formulation elements:

Design-around variable	Potential effect
Use sodium chloride or another chloride compound for isotonicity	Avoids the express non-chloride limitation
Use a pH outside approximately 3.0-4.5	Avoids the pH limitation, subject to product stability
Use less than 1 mg/mL nicardipine HCl	Avoids claims requiring at least 1 mg/mL
Use a nonaqueous or mixed-solvent vehicle	May avoid "consisting essentially of water"
Replace citrate, acetate, phosphate or lactate buffer	May avoid claims 3-6, depending on the full formulation
Use sorbitol or mannitol outside 48-50 mg/mL	Avoids the narrow claims 6-9
Use a different isotonic non-chloride excipient	May avoid claims 6-9 while potentially remaining within claim 3
Use aseptic filtration rather than terminal autoclaving	Avoids claim 2, but not claims 1 or 3-9

These changes would not necessarily avoid all patent claims under the doctrine of equivalents. They would, however, have been the principal claim elements available for formulation differentiation.

How strong was the patent estate for nicardipine injection?

The patent estate represented by US 5,164,405 was narrow in chemical scope but commercially relevant in formulation scope.

Strengths

It covered a complete injectable composition rather than only an isolated excipient.
It captured the preferred 1 mg/mL and 2.5 mg/mL strengths.
It claimed sorbitol and mannitol concentrations associated with isotonicity.
It included process protection for autoclave sterilization.
It covered multiple buffer families in claim 3.

Limitations

It did not cover nicardipine as a molecule.
It did not cover every injectable vehicle.
It excluded formulations using chloride-based isotonicity systems.
Its pH range was relatively narrow.
Its most commercially specific claims required narrow excipient and concentration ranges.
The patent expired more than 15 years ago.

The estate was therefore more relevant to historical product design and generic development strategy than to current enforcement.

What manufacturing and intellectual-property barriers remain?

The expired patent does not eliminate non-patent barriers. A current manufacturer still must address:

control of nicardipine hydrochloride assay and impurities;
injectable-grade excipient sourcing;
pH and osmolality control;
particulate and sterility specifications;
container-closure compatibility;
extractables and leachables;
terminal sterilization validation or aseptic processing;
stability through the proposed shelf life;
FDA current good manufacturing practice requirements;
ANDA requirements for a generic injectable product.

These barriers are regulatory and manufacturing barriers, not surviving rights under US 5,164,405.

Which companies are challenging the nicardipine injection market?

The competitive field consists primarily of generic injectable manufacturers and suppliers of nicardipine hydrochloride injection. Competition is based on FDA approval, hospital contracting, shortage status, manufacturing reliability, supply continuity and price.

The relevant competitors are not biosimilar developers. Nicardipine hydrochloride is a chemically defined small molecule, so the principal pathway is an ANDA referencing the approved injectable product. The competitive landscape also includes oral nicardipine products, but oral capsule formulations are not direct substitutes for IV nicardipine in acute-care settings.

Are there relevant licensing deals or settlements?

US Patent 5,164,405 no longer supports a commercially meaningful exclusivity settlement because its US term has expired. The public patent record for this patent does not establish a current license that would restrict generic entry.

Any historical commercial agreement involving Cardene, nicardipine hydrochloride or rights transferred among original sponsors would need to be distinguished from the patent's current legal status. A private license cannot revive an expired patent monopoly.

What litigation affects US Patent 5,164,405?

No current litigation based on this expired patent can create a present US launch block. Historical infringement or validity disputes, if any, would not extend the patent term or create new Orange Book exclusivity.

The absence of a current patent bar does not prevent litigation over another patent, trade secret, regulatory submission, product liability issue or manufacturing contract. Those matters are legally separate from US 5,164,405.

How does this patent compare with a modern injectable formulation patent?

US 5,164,405 uses a traditional composition-and-process strategy:

defined active concentration;
defined pH interval;
selected buffer systems;
selected isotonicity agents;
water-based vehicle;
optional terminal sterilization.

Modern injectable patents often claim narrower combinations involving container systems, polymorph control, impurity limits, lyophilized presentations, premixed bags, ready-to-use syringes or specific manufacturing conditions. US 5,164,405 is broader than a single exact recipe in its independent composition claim, but its term has ended and its technical scope is limited to the claimed formulation architecture.

Key Takeaways

US Patent 5,164,405 covers stable aqueous nicardipine hydrochloride injections.
Claims 1 and 2 cover preparation processes, including autoclaving under claim 2.
Claims 3-9 cover compositions using acidic buffers and non-chloride isotonicity agents.
The preferred embodiments use 1 or 2.5 mg/mL nicardipine hydrochloride, 48-50 mg/mL sorbitol, citrate buffer and water.
The patent issued on November 17, 1992.
Its US term expired in November 2009.
It is not a current Paragraph IV or Orange Book barrier.
Nicardipine injection is a small-molecule generic opportunity, not a biosimilar opportunity.
Current risk must be assessed against any other unexpired patents, FDA listings and regulatory requirements.
The principal continuing barriers are formulation reproducibility, sterile manufacturing, stability and injectable-product approval.

FAQs

Can a generic manufacturer use the sorbitol formulation claimed in US 5,164,405?

Yes, the expired patent does not prevent use of the claimed sorbitol formulation in the United States. Regulatory approval and manufacturing compliance remain necessary.

Does the patent cover nicardipine tablets or capsules?

No. The claims are directed to aqueous compositions and processes suitable for parenteral administration. They do not cover oral dosage forms as such.

Does using mannitol instead of sorbitol avoid all claims?

No. Mannitol is expressly included in the broad and intermediate claims. It would avoid the sorbitol-only limitation of claim 7 but could remain within claims 3 or 6 if the other limitations are met.

Would a nicardipine injection at 0.5 mg/mL infringe claim 3?

On the claim language provided, claim 3 requires at least approximately 1 mg/mL. A 0.5 mg/mL formulation would not literally satisfy that limitation, although claim interpretation would depend on the full patent record and applicable infringement analysis.

Does autoclaving a nicardipine injection create infringement risk today?

No risk arises from US Patent 5,164,405 because the patent is expired. Historically, autoclaving could have implicated claim 2 if the formulation also satisfied every limitation of claim 1.

References

United States Patent and Trademark Office. (1992). US Patent No. 5,164,405, stable nicardipine hydrochloride injection solutions.
United States Code, 35 U.S.C. § 154. Patent term provisions applicable to pre-URAA applications.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, Orange Book.
U.S. Food and Drug Administration. (n.d.). Nicardipine hydrochloride injection prescribing information.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Belgium	1003647	⤷ Start Trial
Canada	2011063	⤷ Start Trial
United Kingdom	2228412	⤷ Start Trial
United Kingdom	9004385	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,164,405

Summary for Patent: 5,164,405