United States Patent 4,816,263: Isradipine Osmotic Dosage Form, Claim Scope, Expiration, and Patent Landscape

U.S. Patent No. 4,816,263 covers a specific controlled-release osmotic dosage form for administering isradipine to treat cardiovascular disease. Its independent claim requires a semipermeable-wall dosage form containing two composition zones, defined polyethylene oxide and hydroxypropylmethylcellulose ranges, an osmotic solute, and at least one delivery passageway. The patent issued on March 28, 1989, and its ordinary pre-1995 patent term expired on March 28, 2006. The patent therefore does not create a current U.S. barrier to generic isradipine products.

What does U.S. Patent 4,816,263 protect?

The patent protects a drug-delivery architecture rather than isradipine as a chemical compound. The claimed product is a push-pull osmotic pump in which one composition provides the isradipine payload and a second composition expands or otherwise assists in expelling that payload through an opening in the dosage-form wall.

The operative claim elements are:

Claim element	Required limitation
Therapeutic use	Treatment of cardiovascular disease
Active ingredient	2 mg to 30 mg isradipine
Dosage form	Osmotic dosage form with a fluid-permeable wall
Internal structure	A compartment containing first and second compositions
First composition	30 wt% to 95 wt% polyethylene oxide with molecular weight of 100,000 to 300,000
First composition excipient	0 wt% to 15 wt% hydroxypropylmethylcellulose with molecular weight of 9,000 to 15,000
Second composition	55 wt% to 70 wt% polyethylene oxide with molecular weight of 5,000,000 to 7,800,000
Osmotic component	15 wt% to 30 wt% osmotically effective solute
Second composition excipient	5 wt% to 15 wt% hydroxypropylmethylcellulose with molecular weight of 9,000 to 20,000
Delivery mechanism	At least one passageway through the wall
Functional result	Fluid enters, the first composition becomes dispensable, the second composition assists delivery, and isradipine reaches the patient

The patent is assigned to Alza Corporation, the major U.S. developer of osmotic controlled-release drug-delivery systems. The claim language and technical structure are consistent with Alza’s push-pull osmotic pump platform. [1]

How should claim 1 be construed?

Claim 1 is a method-of-treatment claim with extensive dosage-form limitations. It is not a broad claim to treating hypertension with isradipine.

A claimant would need to establish that the accused product and its use satisfy the full combination of limitations. The claim requires:

Administration to a patient with cardiovascular disease.
A dosage form having a fluid-permeable wall.
A compartment containing both the first and second compositions.
The specified isradipine, polymer, molecular-weight, and percentage ranges.
A passageway through the wall.
Fluid-induced operation of the two compositions.
Delivery of a therapeutically effective amount of isradipine.

The use of “comprising” makes the composition limitations open-ended. Additional excipients may be present unless they alter the claimed structure or function. The open-ended language does not eliminate the requirement that the stated components and numerical ranges be present.

What is the scope of the first composition?

The first composition is the drug-containing layer. It must include:

Isradipine in an amount from 2 mg to 30 mg;
30 wt% to 95 wt% polyethylene oxide;
Polyethylene oxide molecular weight from 100,000 to 300,000; and
Hydroxypropylmethylcellulose at 0 wt% to 15 wt%, with a molecular weight from 9,000 to 15,000.

Because the hydroxypropylmethylcellulose range begins at zero, the claim covers a first composition without that excipient. The first composition must remain capable of forming a dispensable isradipine composition when contacted by incoming fluid.

What is the scope of the second composition?

The second composition is the push or engine layer. It must include:

55 wt% to 70 wt% polyethylene oxide;
Polyethylene oxide molecular weight from 5,000,000 to 7,800,000;
15 wt% to 30 wt% osmotically effective solute; and
5 wt% to 15 wt% hydroxypropylmethylcellulose with molecular weight from 9,000 to 20,000.

The second layer is materially narrower than a generic osmotic tablet. A product using a different polymer, a molecular weight outside the stated range, or an osmotic agent outside the claimed percentage range could avoid literal infringement, subject to any doctrine-of-equivalents analysis.

What do dependent claims 2 through 5 add?

Claim	Added limitation	Commercial significance
2	Cardiovascular disease is angina pectoris	Covers use in ischemic heart disease
3	Cardiovascular disease includes hypertension	Aligns with isradipine’s principal antihypertensive use
4	Cardiovascular disease includes congestive heart failure	Broadens the specified disease category
5	Delivery rate is 0.05 mg to 2.5 mg isradipine per hour	Adds a release-rate limitation to claim 1

Claims 2 through 4 do not materially change the dosage-form requirements. They limit the medical indication. Claim 5 is technically more significant because it adds a measurable delivery-rate limitation.

A product may fall outside claim 5 while still implicating claim 1 if it uses the claimed osmotic architecture and delivers isradipine at a rate outside the stated range.

When did U.S. Patent 4,816,263 expire?

U.S. Patent 4,816,263 issued on March 28, 1989. For a U.S. patent subject to the pre-June 8, 1995 term rules, the ordinary term was 17 years from issuance. On that basis, the patent expired on March 28, 2006. [1, 2]

Event	Date
U.S. patent issue	March 28, 1989
Ordinary statutory term	17 years from issue
Expiration	March 28, 2006
Current enforceability	Expired
Current Paragraph IV relevance	None for this patent

No current patent-term extension or regulatory exclusivity can revive the expired patent. The patent’s former claims remain relevant for historical freedom-to-operate analysis, prosecution history, and technology valuation, but they do not support present-day infringement litigation.

What patents protect isradipine beyond the osmotic formulation?

The principal patent categories for isradipine are the active-ingredient patent family and formulation or delivery patents.

Patent category	Representative U.S. right	Subject matter	Current status
Active ingredient	U.S. Patent No. 4,466,972	Dihydropyridine compounds, including isradipine-related chemical matter	Expired
Controlled delivery	U.S. Patent No. 4,816,263	Push-pull osmotic dosage form containing isradipine	Expired March 28, 2006
FDA-approved product	DynaCirc and related isradipine products	Immediate-release or controlled-release oral products	No current patent exclusivity based on the cited patent
Generic pathway	ANDA under section 505(j)	Small-molecule isradipine products	ANDA pathway, not biosimilar pathway

The compound patent is distinct from the delivery-system patent. A generic manufacturer seeking to market conventional isradipine capsules would not ordinarily need to practice the specific two-layer osmotic system claimed in U.S. Patent 4,816,263.

The commercial importance of the formulation patent was therefore greatest for a controlled-release isradipine product using the Alza-type osmotic platform. It was not a complete barrier to immediate-release dosage forms.

What was the FDA and Orange Book status of the patent?

Isradipine is a small-molecule drug approved through the FDA’s new drug application framework. The relevant regulatory route for generic isradipine is an abbreviated new drug application, not a biologics license application or a 351(k) biosimilar application. [3]

The Orange Book records patents and exclusivity associated with approved drug products. Any listing for U.S. Patent 4,816,263 would have ceased to provide a live patent barrier when the patent expired in 2006. The patent cannot support a current 30-month stay under Hatch-Waxman because an expired patent is not an enforceable listed patent for prospective generic-entry purposes. [4]

Regulatory issue	Assessment
Drug category	Small molecule
FDA pathway	NDA for innovator; ANDA for generic
Biosimilar pathway	Not applicable
Orange Book relevance	Historical only for this expired patent
New chemical entity exclusivity	Expired
Current formulation exclusivity from 4,816,263	None
Current patent-based generic delay	None

Were there Paragraph IV challenges or litigation involving this patent?

The patent’s expiration eliminates any current Paragraph IV controversy concerning U.S. Patent 4,816,263. A Paragraph IV certification is relevant when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or not infringed. After March 28, 2006, this patent no longer presented a live term to be challenged.

The publicly material litigation risk today is therefore zero for this patent. A historical ANDA filer could have addressed the patent during its term, but a present market entrant does not need to obtain a license or prevail in litigation against an expired U.S. patent.

There is no current settlement value attributable to this patent. Any historical settlement involving isradipine would require separate review of the underlying case docket and agreement.

How strong was the patent estate?

The patent estate was strong against a narrow class of controlled-release products and weak against products that did not use the claimed architecture.

Strengths

The claim combines structural, compositional, molecular-weight, and functional limitations.
The two-composition push-pull design is more specific than a conventional tablet or capsule.
Claim 5 adds a defined release-rate limitation.
The “comprising” language permits additional excipients and formulation components.

Limitations

The claim is not directed to isradipine generally.
It does not cover every controlled-release isradipine formulation.
The claims depend on exact polymer molecular-weight and percentage ranges.
The method claims require treatment of a patient and use of the claimed dosage form.
The patent expired in 2006.

The strongest potential design-around routes would include immediate-release dosage forms, non-osmotic extended-release systems, single-layer osmotic systems, different polymer molecular weights, or compositions outside the stated percentage ranges.

What generic entry risks exist for isradipine?

Current generic-entry risk is primarily commercial and regulatory, not patent-based.

A manufacturer evaluating an isradipine product would face:

FDA formulation and bioequivalence requirements;
Manufacturing validation for a low-volume cardiovascular product;
Potential market-size limitations;
Product discontinuation or supply-chain issues;
Competition from existing generic suppliers;
Historical brand-product withdrawal or limited commercial demand.

The manufacturer would not face a live infringement risk from U.S. Patent 4,816,263. A conventional isradipine capsule also would not need to practice the claimed osmotic pump.

What manufacturing and IP barriers remain?

The expired patent does not remove all technical barriers. A manufacturer reproducing the osmotic system may still need to solve:

Bilayer compression or compartment formation;
Semipermeable membrane coating;
Laser or mechanical passageway formation;
Uniform release-rate control;
Stability of isradipine under manufacturing and storage conditions;
Reproducible polymer molecular-weight performance.

Those are manufacturing and formulation-development issues, not enforceable barriers under the expired patent.

How does this patent compare with the broader isradipine estate?

Issue	U.S. Patent 4,466,972	U.S. Patent 4,816,263
Primary subject	Isradipine-related chemical compounds	Osmotic dosage form
Claim type	Composition of matter and related pharmaceutical use	Method of treatment
Product coverage	Potentially broad chemical coverage	Narrow delivery-system coverage
Relevance to immediate-release product	Higher historically	Low
Relevance to osmotic controlled-release product	Indirect	Direct
Expiration	Expired	March 28, 2006
Current enforcement value	None	None

The compound patent would historically have been the principal barrier to any isradipine product. U.S. Patent 4,816,263 was a secondary, formulation-specific layer of protection. It could delay or complicate competing controlled-release products but did not independently control the entire isradipine market.

What is the commercial exposure associated with this patent?

The patent has no current royalty, licensing, or exclusionary value because it expired. Any revenue exposure must be analyzed historically, during the period when a branded isradipine osmotic product could have relied on the patent.

For current business planning:

No blocking U.S. patent remains in this patent.
No live Orange Book exclusivity follows from it.
No biosimilar analysis is required.
No current Paragraph IV litigation risk arises from it.
A generic or reformulated product can avoid the historical claim set through a non-osmotic or technically distinct dosage form.

Key Takeaways

U.S. Patent 4,816,263 covers a two-composition push-pull osmotic dosage form for isradipine.
Claim 1 requires precise ranges for isradipine, polyethylene oxide, hydroxypropylmethylcellulose, osmotic solute, and polymer molecular weight.
Claims 2 through 4 specify angina pectoris, hypertension, and congestive heart failure.
Claim 5 requires an isradipine delivery rate of 0.05 mg to 2.5 mg per hour.
The patent issued March 28, 1989, and expired March 28, 2006.
It does not currently block generic isradipine, conventional capsules, or alternative extended-release systems.
Isradipine is regulated as a small molecule through the NDA/ANDA framework, not the biosimilar pathway.
Current patent risk is zero for this patent; remaining barriers are regulatory, technical, manufacturing, and commercial.

FAQs

Does U.S. Patent 4,816,263 cover all isradipine products?

No. It covers a specified osmotic dosage form with two internal compositions and narrowly defined polymer and excipient ranges.

Can a generic manufacturer use the same osmotic pump design today?

Yes, the patent expired in 2006. Other unexpired patents would need separate review, but this patent itself does not prohibit use.

Is isradipine a biologic requiring biosimilar approval?

No. Isradipine is a small-molecule drug. Generic manufacturers use the ANDA pathway.

Does claim 5 require a specific isradipine dose?

Claim 5 requires a delivery rate of 0.05 mg to 2.5 mg per hour. It is a release-rate limitation, not merely a total tablet-strength limitation.

Does the patent protect the polyethylene oxide polymers themselves?

No. The patent claims their use in the specified isradipine osmotic dosage form. It does not provide broad ownership of polyethylene oxide or hydroxypropylmethylcellulose.

References

United States Patent and Trademark Office. (1989). U.S. Patent No. 4,816,263.
United States Patent and Trademark Office. (n.d.). Patent term provisions and patent expiration calculations.
U.S. Food and Drug Administration. (n.d.). Isradipine prescribing information and Drugs@FDA records.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	402689	⤷ Start Trial
Austria	A242288	⤷ Start Trial
Australia	2293888	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,816,263

Summary for Patent: 4,816,263