US Patent 8,183,226: Regadenoson Scope, Expiration, Litigation and Generic Entry Analysis

US Patent 8,183,226 covers specific clinical uses of CVT-3146, now known as regadenoson, the active ingredient in Lexiscan. Its claims are directed to rapid intravenous bolus administration at doses of at least 400 micrograms for coronary vasodilation and myocardial perfusion imaging. The patent does not broadly claim regadenoson, its chemical structure, or all pharmaceutical formulations.

The patent’s commercial relevance was strongest before generic regadenoson entered the US market. The claimed methods may still matter in litigation involving historical conduct, damages, or a product label that specifically instructs use within the claimed dosing and imaging parameters. The principal patent term is understood to have ended in 2025, subject to the USPTO’s recorded term calculation and any applicable patent-term adjustment.

What does US Patent 8,183,226 protect?

US 8,183,226 protects methods of using regadenoson for coronary vasodilation and myocardial perfusion imaging. The patent is not a composition-of-matter patent.

Patent identification

Field	Information
Patent	US 8,183,226 B2
Active ingredient	Regadenoson, formerly CVT-3146
Chemical class	Selective adenosine A2A receptor agonist
Product	Lexiscan injection
Patent type	Method-of-use
Patent holder or original assignee	CV Therapeutics, later associated with Gilead Sciences
Grant date	May 22, 2012
Claimed route	Intravenous bolus
Claimed dose threshold	At least 400 micrograms
Principal uses	Coronary vasodilation and myocardial perfusion imaging
Patent term	Public patent records associate the patent with an expiration date in 2025

The patent claims a defined clinical protocol rather than the molecule itself. A generic manufacturer can therefore face different issues depending on its proposed label, distribution instructions, and intended use.

What are the independent claims of US 8,183,226?

Claims 1 and 8 are the two independent claims.

Claim 1: coronary vasodilation

Claim 1 requires a method of producing coronary vasodilation by administering to a human:

Regadenoson, identified as CVT-3146;
By intravenous bolus;
In an amount of at least 400 micrograms.

Each limitation is material. A claim 1 infringement theory would generally require proof that the accused conduct includes the claimed drug, route, dose threshold, patient, and coronary-vasodilation purpose.

The phrase “at least 400 micrograms” creates an open-ended lower dose boundary. A 400-microgram, 500-microgram, or 600-microgram dose can fall within the literal scope of claim 1 if the remaining limitations are met. The claim does not impose an upper dose limit.

Claim 8: myocardial perfusion imaging

Claim 8 requires:

A human patient;
Intravenous bolus administration of at least 400 micrograms of regadenoson;
Administration of a radionuclide;
Examination of the myocardium for areas of insufficient blood flow after administration.

Claim 8 is narrower than claim 1 because it requires the myocardial perfusion imaging context and radionuclide administration. It can cover protocols in which regadenoson and the radionuclide are administered separately or simultaneously, as specified in dependent claims 12 and 13.

How do the dependent claims narrow the patent scope?

The dependent claims add dose, timing, patient-position, hemodynamic, and procedural limitations.

Claim	Limitation
2	Dose does not exceed about 1,000 micrograms
3	Single dose
4	No more than about 20 micrograms/kg in a supine patient
5	No more than about 10 micrograms/kg in a standing patient
6	Administration in about 20 seconds
7	Administration in about 10 seconds or less
9	Myocardial examination begins within about one minute
10	At least a 2.5-fold increase in coronary blood flow
11	The 2.5-fold increase is achieved within about one minute
12	Radionuclide and regadenoson administered separately
13	Radionuclide and regadenoson administered simultaneously
14	At least a 2.5-fold increase lasts less than about five minutes
15	At least a 2.5-fold increase lasts less than about three minutes
16	Single dose up to about 600 micrograms, independent of patient weight

Claims 2 through 7 depend from claim 1. Claims 9 through 16 depend from claim 8. A dependent claim incorporates every limitation of the claim from which it depends. For example, claim 16 still requires the claim 8 myocardial perfusion imaging framework, intravenous bolus administration, a radionuclide, and a dose of at least 400 micrograms.

What dose range does US 8,183,226 cover?

The core dose range begins at 400 micrograms.

Claim 1 covers at least 400 micrograms without an express upper limit. Claim 2 adds an upper boundary of about 1,000 micrograms. Claim 16 creates a narrower imaging protocol covering a single, weight-independent dose up to about 600 micrograms.

Dose overlap

Dose	Claim 1	Claim 2	Claim 16
200 micrograms	No	No	No
400 micrograms	Yes	Yes	Yes, if other limits are met
500 micrograms	Yes	Yes	Yes
600 micrograms	Yes	Yes	Yes
750 micrograms	Yes	Yes	No
1,000 micrograms	Yes	Yes, subject to “about” construction	No
More than 1,000 micrograms	Yes	No	No

The approved Lexiscan regimen has historically been a fixed 400-microgram intravenous injection administered as a rapid bolus, followed by saline flush. That commercial regimen sits directly within the numerical center of the patent’s independent claims and was a major reason the patent had potential Orange Book and Paragraph IV significance.

What administration methods are protected?

The patent requires intravenous bolus administration. It is not directed to oral, intramuscular, subcutaneous, transdermal, or slow intravenous infusion administration.

The claims also protect specific administration timing:

About 20 seconds under claim 6.
About 10 seconds or less under claim 7.
A single-dose protocol under claim 3.
Weight-independent dosing up to about 600 micrograms under claim 16.

The use of “about” introduces claim-construction issues. Courts commonly evaluate the term against the specification, prosecution history, technical context, and whether a skilled person would understand the claimed range. The patent does not automatically cover every administration duration or every dose near the stated number.

What myocardial perfusion imaging protocols are protected?

The imaging claims protect a protocol using regadenoson and a radionuclide to identify areas of inadequate myocardial blood flow.

Protected imaging features

The dependent claims identify several commercially relevant protocol characteristics:

Examination within approximately one minute of regadenoson administration.
A coronary blood-flow increase of at least 2.5 times baseline.
Achievement of that increase within approximately one minute.
A short duration of the hyperemic response.
Separate or simultaneous administration of the radionuclide.
A fixed dose independent of patient body weight.

The claims do not require a particular radionuclide in the text provided. A protocol using technetium-99m-based myocardial perfusion agents, for example, could potentially satisfy the radionuclide limitation if the remaining elements are present. The claims also do not require a specific imaging platform, such as SPECT, provided that the myocardial examination identifies areas of insufficient blood flow.

What is the relationship between US 8,183,226 and Lexiscan?

Lexiscan is the commercial product based on regadenoson. The FDA approved Lexiscan injection in 2008 for radionuclide myocardial perfusion imaging in adults who cannot adequately exercise.

The product’s label describes a 400-microgram intravenous injection administered as a rapid bolus, followed by saline flush. The approved dose and administration method correspond closely to the central limitations of claims 1 and 8 of US 8,183,226. [2]

This alignment made the patent more commercially significant than a use patent covering an uncommon or optional administration method. A generic applicant seeking approval for the same labeled use could face a patent certification issue if the patent remained listed and unexpired.

What was the FDA exclusivity status of regadenoson?

Regadenoson received FDA approval through an NDA for Lexiscan. Its regulatory exclusivity period was separate from patent protection.

Regulatory protection	Relevance
New drug approval	Established the approved Lexiscan indication
New chemical entity exclusivity	Applied for the statutory period following initial approval, if awarded
Method-of-use patent	Covered selected dosing and imaging protocols
Orange Book listing	Could support a Paragraph IV certification by an ANDA applicant
Pediatric exclusivity	No material pediatric extension is identified in the claim record supplied

FDA regulatory exclusivity generally expires earlier than a patent term. After regulatory exclusivity expires, an ANDA applicant may seek approval, but listed patents can still delay approval or create litigation exposure.

What was the Orange Book status of US 8,183,226?

US 8,183,226 was associated with the Lexiscan patent estate and was relevant to the Orange Book-listed patent landscape for regadenoson injection. Orange Book status must be distinguished from patent validity and enforceability.

An Orange Book listing means that the NDA holder identified the patent as claiming the approved drug or an approved method of use. It does not establish that the patent is valid, infringed, or enforceable. FDA does not adjudicate those issues through the Orange Book.

For an ANDA applicant, the practical options generally include:

Paragraph I certification if no patent is listed;
Paragraph II certification if the patent has expired;
Paragraph III certification accepting approval after patent expiration;
Paragraph IV certification asserting that the patent is invalid, unenforceable, or not infringed;
A section viii statement carving out a patented method of use, where the FDA-approved labeling permits a lawful carve-out.

The ability to use a section viii strategy depends on whether the proposed label can omit the patented method without retaining instructions that encourage the claimed use.

When does US 8,183,226 lose exclusivity?

The patent’s public term is associated with an expiration date in 2025. Patent expiration is distinct from FDA marketing exclusivity and from the date on which a court might find the patent invalid or unenforceable.

After expiration:

A generic manufacturer no longer faces prospective infringement liability for practicing the expired claims.
A Paragraph III certification can support approval after the listed expiration date.
The patent cannot block a generic launch based solely on the expired claims.
Historical infringement claims for conduct during the enforceable term may remain relevant, subject to limitations periods and litigation posture.

The patent’s term should be verified against the USPTO Patent Center record, including any patent-term adjustment, terminal disclaimer, and maintenance-fee status. The grant date itself is not the expiration date.

Which companies challenged Lexiscan patent protection?

Regadenoson has attracted generic competition because it is a small-molecule injectable with a well-defined reference product. Public market activity has included generic regadenoson approvals and launches after the principal Lexiscan patent barriers approached or reached expiration.

The relevant competitive group includes:

Astellas, the commercial owner of Lexiscan in the United States;
Original developer CV Therapeutics and its successor commercial interests;
Generic injectable manufacturers that obtained or pursued ANDA approval for regadenoson;
Contract manufacturers and specialty injectable suppliers.

A Paragraph IV filing may trigger patent litigation, but a generic launch can also occur after expiration, after a settlement, after a successful noninfringement or invalidity position, or under a label that avoids the patented use. The supplied claim set alone does not establish the identity or outcome of every ANDA challenge.

What patent litigation and settlements affect regadenoson?

The central legal issues for a generic regadenoson case would be:

Whether the proposed product label instructs a claimed use.
Whether the approved 400-microgram bolus necessarily practices the claims.
Whether the patent’s “about” dose and timing terms are definite.
Whether the claims are anticipated or obvious in light of prior adenosine agonist and myocardial perfusion imaging disclosures.
Whether the listed patent remained enforceable at the time of the proposed launch.
Whether a settlement permits an agreed launch date before patent expiration.

A method-of-use patent can be difficult to enforce against a manufacturer if the label omits the patented indication or if the claimed use is not required by the label. Under induced-infringement principles, however, detailed instructions that encourage the claimed bolus dose and imaging protocol can create exposure even where the manufacturer does not directly administer the drug.

No conclusion about a specific settlement, consent judgment, or ANDA litigation outcome follows from the claim text alone. Those matters turn on the docket, settlement terms, FDA filings, and the precise generic label.

How strong is the patent estate for regadenoson?

Strengths

The claims target the commercially relevant 400-microgram intravenous bolus.
The claims cover the primary myocardial perfusion imaging use.
The claims include rapid timing and coronary blood-flow response limitations.
The patented protocol closely corresponds to the approved Lexiscan label.
Claims 1 and 8 provide separate theories for coronary vasodilation and imaging.

Weaknesses

The patent does not claim the regadenoson molecule itself.
The claims are vulnerable to prior-art arguments concerning adenosine receptor agonists and perfusion imaging.
Several limitations use approximate terms such as “about.”
Claims 8 through 16 require additional imaging or physiological elements that may be difficult to prove from routine product use.
A label carve-out may reduce infringement risk for selected method claims.
Patent expiry removes the principal forward-looking barrier.

The estate is therefore best characterized as a clinically focused method-of-use estate rather than a broad platform estate. Its value depended heavily on the commercial label and on the timing of generic entry.

What generic entry risks exist for regadenoson?

Regadenoson has no biosimilar issue because it is a chemically synthesized small molecule, not a biologic. The relevant competitors are ANDA applicants for injectable regadenoson.

Regulatory and manufacturing barriers

Generic entry still requires:

Pharmaceutical equivalence to the reference injection;
Bioequivalence or an appropriate FDA waiver or bridging approach;
Sterile manufacturing controls;
Container-closure compatibility;
Stability data;
Injectable product quality systems;
Adequate supply of active pharmaceutical ingredient;
Labeling that addresses the cardiac stress-imaging indication.

The manufacturing barriers are meaningful but lower than those for biologics or complex drug-device combinations. Regadenoson’s short dosing regimen and fixed-dose injectable presentation reduce formulation complexity. Sterility, aseptic processing, and reliable supply are the main practical barriers.

How does US 8,183,226 compare with composition and formulation patents?

Patent category	Scope	Commercial impact
Composition patent	Regadenoson chemical structure or related compounds	Broadest protection; generally controls molecule-level entry
Formulation patent	Concentration, excipients, stability, container, or injectable presentation	Can delay or complicate substitute formulations
Method-of-use patent	Dose, route, timing, imaging, or physiological response	Depends heavily on label and actual use
Manufacturing patent	Synthesis, purification, crystallization, or sterile processing	Can raise CMC costs without blocking alternative processes
Regulatory exclusivity	FDA statutory market protection	Separate from patent validity and term

US 8,183,226 is principally in the fourth category. It does not, based on the supplied claims, prevent a competitor from making regadenoson by a different process or using a different formulation if the competitor does not practice the claimed clinical method during the enforceable term.

What is the commercial exposure from the patent?

Lexiscan became a high-value cardiovascular diagnostic product because it enabled pharmacologic stress testing in patients unable to exercise adequately. Revenue exposure was concentrated in the approved myocardial perfusion imaging market rather than in a broad therapeutic market.

The principal commercial risk from this patent was not substitution by another A2A agonist alone. It was direct generic replication of the fixed-dose, rapid-bolus Lexiscan protocol. Once patent and regulatory barriers diminished, generic competition could pressure:

US net sales;
hospital and outpatient imaging-center pricing;
payer reimbursement spreads;
distributor margins;
supply contracts;
market share for the branded product.

The patent’s narrow method claims could delay or complicate entry, but they were less durable than a composition patent covering regadenoson itself.

Key Takeaways

US 8,183,226 is a regadenoson method-of-use patent, not a composition patent.
Claim 1 covers intravenous bolus administration of at least 400 micrograms for coronary vasodilation.
Claim 8 covers regadenoson plus a radionuclide for myocardial perfusion imaging.
The 400-microgram Lexiscan regimen aligns closely with the core claim limitations.
Dependent claims add upper dose limits, rapid administration, patient position, timing, blood-flow response, and radionuclide sequencing.
The patent’s public term is associated with expiration in 2025.
Generic entry risk centered on Paragraph IV certification, label content, section viii carve-outs, and the approved 400-microgram protocol.
Regadenoson has no biosimilar pathway issue because it is a small molecule.
The remaining patent value is primarily historical, litigation-related, and relevant to conduct before expiration.

FAQs

Does US 8,183,226 cover all regadenoson products?

No. It covers specified methods of administering regadenoson. It does not broadly claim every regadenoson composition, formulation, manufacturing process, or medical use.

Can a generic regadenoson product avoid the patent by using a dose below 400 micrograms?

A dose below 400 micrograms would not satisfy the express “at least 400 micrograms” limitation. Other patents, regulatory requirements, or infringement theories could still be relevant.

Does simultaneous radionuclide administration avoid claim 8?

No. Claim 13 expressly covers simultaneous administration. Claim 12 separately covers administration of the radionuclide and regadenoson at different times.

Is a 600-microgram fixed dose within the patent?

It can be. A single, weight-independent dose up to about 600 micrograms is expressly addressed by claim 16, assuming the remaining myocardial perfusion imaging limitations are met.

Can a generic manufacturer market regadenoson after patent expiration without a license?

Patent expiration generally removes the blocking effect of the expired claims. The generic still must satisfy FDA approval requirements and comply with any unexpired patents, regulatory obligations, and applicable labeling restrictions.

References

United States Patent and Trademark Office. (2012). U.S. Patent No. 8,183,226 B2: Methods of using CVT-3146.
U.S. Food and Drug Administration. (2008). Lexiscan (regadenoson) injection prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Approved drug product labeling and regulatory exclusivity information for regadenoson injection.
U.S. Patent and Trademark Office. (2024). Patent Center: Patent term adjustment and patent status records.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2003259264	⤷ Start Trial
Canada	2492855	⤷ Start Trial
China	1671399	⤷ Start Trial
European Patent Office	1524984	⤷ Start Trial
Israel	166555	⤷ Start Trial
Japan	2005538190	⤷ Start Trial
South Korea	20050026546	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,183,226

Summary for Patent: 8,183,226