United States Drug Patent 5,108,363: Claim Scope, Expiration, and Patent Landscape

U.S. Patent No. 5,108,363 covers closed-loop pharmacologic stress testing. Its core concept is to administer a beta-adrenergic exercise-simulating agent, monitor cardiovascular responses, and automatically adjust or stop drug delivery based on electrocardiographic or other physiological signals. The patent issued April 28, 1992, and its ordinary 17-year patent term expired April 28, 2009. The patent therefore does not create a current U.S. exclusionary right.

The claims are method claims. They do not claim a new chemical compound, a standalone drug product, or a general-purpose infusion pump. The strongest historical claim combination required both pharmacologic stress induction and a closed-loop delivery system that responds to measured heart rate or ischemic events.

What does U.S. Patent 5,108,363 cover?

The patent covers methods for simulating an exercise stress test without requiring physical exercise. The disclosed system administers a beta-adrenergic catecholamine through either:

A transdermal iontophoretic delivery device; or
An intravenous delivery device.

A microprocessor regulates drug delivery based on an electrocardiographic heart-rate signal. The system may increase, decrease, stop, or reverse current flow in an iontophoretic device. Some claims also require administration of a beta blocker when the stimulating agent is discontinued.

The central technical elements are:

Claim element	Scope
Therapeutic objective	Simulate cardiovascular responses produced by aerobic exercise
Diagnostic objective	Diagnose or evaluate coronary artery disease
Drug class	Beta-adrenergic exercise-simulating agent, generally a catecholamine
Physiological result	Immediate cardiovascular response and, where disease is present, reversible myocardial ischemia
Delivery architecture	Closed-loop drug delivery
Monitoring	Electrocardiographic heart-rate monitoring, with dependent claims covering echocardiography and radionuclide imaging
Control logic	Microprocessor feedback control
Delivery modes	Transdermal iontophoresis or intravenous administration
Rescue or reversal	Beta-adrenergic blocking agent in certain claims

The claims are directed to the combined use of a drug, delivery system, physiological monitoring, and control algorithm. A product that uses the same drug without the claimed closed-loop control architecture would not fall within the principal combinations in claims 1, 6, 17, 28, or 34.

Which claims are independent, and what do they require?

Claims 1, 6, 17, 28, and 34 are the principal independent claims.

Claim 1: closed-loop exercise simulation

Claim 1 requires:

Administration of an exercise-simulating agent;
Use of a closed-loop drug delivery device;
Infusion controlled by a power source;
A microprocessor connected to the power source and an ECG heart-rate monitor;
An amount sufficient to induce reversible myocardial ischemia when coronary artery disease is present; and
A specified catecholamine Markush formula or pharmaceutically acceptable acid-addition salt.

Claim 1 is relatively narrow because it combines the drug-class limitations with a specific feedback-controlled delivery system and a myocardial-ischemia result.

Claim 6: diagnostic use with transdermal infusion

Claim 6 covers diagnostic elicitation of cardiovascular responses similar to aerobic exercise. It requires:

A beta-adrenergic exercise-simulating agent;
A closed-loop delivery device;
Transdermal iontophoretic infusion; and
A catecholamine capable of inducing reversible myocardial ischemia in the presence of coronary artery disease.

Because claim 6 expressly requires transdermal iontophoresis, an intravenous-only system would not satisfy this claim.

Claim 17: maintaining a selected physiological range

Claim 17 focuses on control over time. It requires:

Administration of a beta-adrenergic exercise-simulating agent;
A preselected range of physical responses;
Feedback-controlled infusion sufficient to maintain that range for a selected period; and
Discontinuation when the time period expires or the responses fall outside the selected range.

This claim is broader in functional terms than claim 1 because the independent claim does not itself require the ECG, microprocessor, or a specific chemical formula. Those limitations appear in dependent claims 18 and 25-26.

Claim 28: coronary artery disease diagnosis

Claim 28 covers a diagnostic workflow:

Administer the exercise-simulating agent;
Control infusion to obtain a predetermined cardiovascular-response range;
Monitor the patient;
Adjust infusion as needed; and
Evaluate the responses.

The claim does not expressly require a specific delivery modality or chemical formula. Those restrictions appear in dependent claims 29-33.

Claim 34: stress testing without body motion

Claim 34 is directed to simulating an exercise stress test while the patient’s body remains physically inactive. It requires:

Administration of an exercise-simulating agent;
A preselected physical-response range;
Maintenance of that range for a selected period;
Discontinuation when the time period expires or responses leave the range; and
Evaluation of the physical responses.

Claim 34 is commercially important as the broadest independent diagnostic formulation because it does not itself require the ECG/microprocessor combination or a particular delivery device.

What compounds are covered by the chemical Markush claims?

The chemical limitations cover a class of substituted beta-adrenergic phenethylamine or related catecholamine structures. The formula allows:

X1 and X2 to be hydrogen, hydroxy, methoxy, or carbamoyl, subject to exclusions;
Y1 and Y2 to define an unsubstituted or methyl-substituted side chain, subject to a further exclusion;
Z to be hydrogen or hydroxy; and
n to be 2 or 3.

The patent does not claim a single active ingredient by chemical name in the supplied claims. Instead, it claims a Markush genus and then narrows the genus through dependent claims.

Dependent compound selections

Claims	Substitution pattern
4, 8, 21, 31, 40	X1 hydrogen, X2 hydroxy, Y1/Y2 hydrogen, Z hydroxy, n=3
5, 22, 32, 41	X1 hydrogen, X2 methoxy, Y1/Y2 hydrogen, Z hydroxy, n=2
19-20, 30	Z hydroxy, with further hydrogen substitutions
18, 29, 38	Broad Markush genus

The chemical limitations are not composition-of-matter claims. They apply only when the compounds are used in the claimed diagnostic or exercise-simulation methods.

Claim drafting issues

The supplied text contains apparent drafting defects:

Claim 9 appears to repeat the limitation of claim 8 while also reciting the methoxy/n=2 embodiment associated with claim 5.
Claim 43 uses the term "radionucleotide imaging," which likely reflects a drafting or transcription error for "radionuclide imaging."
Several claims use broad functional language such as "similar to those physical responses elicited by aerobic activity." The meaning would depend on the specification, prosecution history, and ordinary skill in the art.

These defects affect claim construction and validity analysis, but they do not alter the patent’s expired status.

When did U.S. Patent 5,108,363 lose exclusivity?

Event	Date
Patent issued	April 28, 1992
Ordinary pre-1995 patent term	17 years from issue
Ordinary expiration	April 28, 2009
Current enforceability	Expired
Current ability to block generic or device entry	None based on this patent

For patents filed before June 8, 1995, the governing term generally was 17 years from grant, subject to statutory adjustments and terminal disclaimers. The patent issued before the modern 20-year-from-earliest-effective-filing-date regime became controlling for later-filed applications. The expiration date is therefore determined from the grant date under the applicable transitional framework. [1, 2]

An expired patent can remain relevant as prior art, a technical disclosure, or evidence in a later patent dispute. It cannot support an infringement action for conduct occurring after expiration.

What is the Orange Book status of U.S. Patent 5,108,363?

U.S. Patent 5,108,363 is not, by its claim format, an Orange Book product patent.

The patent claims methods involving:

Diagnostic administration of catecholamine agents;
Closed-loop infusion;
Transdermal iontophoresis;
ECG feedback control; and
Exercise-stress simulation.

The FDA Orange Book principally identifies patents and exclusivity associated with approved drug products and their labeling, including qualifying drug substance, drug product, and method-of-use patents submitted by applicants. A broad historical method patent directed to a diagnostic delivery system does not automatically appear as an Orange Book-listed patent for every catecholamine product. [3]

The patent also expired in 2009. Even if it had once been submitted in connection with an approved product, it would not provide a current patent barrier to an ANDA applicant.

What FDA regulatory status is relevant to the patent?

The patent is not an FDA approval. It describes a diagnostic method and delivery architecture. FDA status must be assessed separately for each drug and device.

Relevant regulatory categories include:

Technology	FDA pathway or product category
Dobutamine or other beta-adrenergic stress agents	Approved drug products may have cardiovascular stress-testing indications
Intravenous infusion system	Medical device and drug-delivery controls
Transdermal iontophoresis	Device-specific regulatory review, depending on design and intended use
ECG monitor and control software	Medical device, potentially subject to software and monitoring-device controls
Combination system	May raise drug-device combination-product issues

Dobutamine is the principal modern pharmacologic stress-testing comparator for the beta-adrenergic concept. Adenosine, dipyridamole, and regadenoson are important alternative pharmacologic stress agents, but they act primarily through adenosine pathways rather than beta-adrenergic stimulation. FDA labeling for dobutamine includes use in cardiac stress testing when exercise is impractical or contraindicated. [4]

The patent does not establish FDA approval for transdermal iontophoretic administration of a catecholamine stress agent.

How strong was the patent estate for the claimed technology?

The patent was technically focused but commercially vulnerable because its term expired before closed-loop drug delivery became a large independent market.

Historical strengths

The independent claims linked drug administration to physiological feedback.
The claims addressed both intravenous and transdermal delivery.
The patent covered automatic termination at a target heart rate or ischemic event.
Dependent claims added arrhythmia detection, current reversal, and tourniquet activation.
Claims 28 and 34 addressed the broader diagnostic workflow.

Historical weaknesses

No composition-of-matter protection was claimed.
The chemical genus was limited to known or structurally related catecholamines rather than a new drug entity.
The claims required a relatively complex combination of drug, monitor, processor, and delivery device.
The patent did not establish exclusive rights over pharmacologic stress testing generally.
The clinical value of transdermal iontophoretic delivery for rapid, titratable catecholamine stress testing would have raised practical and regulatory questions.
The functional language could have created enablement, written-description, indefiniteness, or obviousness issues depending on the prosecution record.

The patent’s strongest claim theory would have been infringement by a system that administered one of the claimed catecholamines through a feedback-controlled pump or iontophoretic device, used ECG heart rate as the control input, maintained a target physiological range, and evaluated the result for coronary artery disease.

What formulation patents are protected by U.S. Patent 5,108,363?

The patent does not claim a conventional pharmaceutical formulation.

Claim 10 refers to a transdermal device containing the exercise-simulating agent in a "gel-solution or polymer." That language is a delivery-medium limitation, not a detailed formulation patent. The patent does not appear, from the supplied claims, to claim:

A specific polymer composition;
A particular electrode structure;
A defined drug concentration;
A release-rate profile;
A patch construction;
A stabilizer system;
A particle size;
A manufacturing process; or
A pharmaceutical composition independent of the diagnostic method.

Thus, the claim scope is materially different from a formulation patent covering a sustained-release patch or injectable dosage form.

What method-of-use patents are covered?

All substantive protection is method-of-use protection.

The principal use categories are:

Simulating aerobic exercise;
Simulating cardiovascular exercise stress without body motion;
Diagnosing or evaluating coronary artery disease;
Inducing reversible myocardial ischemia for diagnostic purposes;
Maintaining a preselected physiological response range;
Stopping infusion at a target heart rate;
Stopping infusion upon ischemia or abnormal beats; and
Administering a beta blocker after stopping the stimulant.

Claims 27 and 35 are particularly narrow because they require simultaneous administration of an antagonizing beta blocker after the exercise-simulating agent is discontinued.

Which companies are challenging U.S. Patent 5,108,363?

No current Paragraph IV challenge can meaningfully threaten this patent because it expired in 2009.

Paragraph IV certifications apply to patents listed in the Orange Book for an approved drug product. A generic applicant may certify that a listed patent is invalid, unenforceable, or will not be infringed. The supplied patent’s diagnostic-system claims do not establish a current Orange Book dispute, and the patent’s expiration removes the practical basis for a present generic-entry challenge. [3, 5]

There is no current biosimilar issue. The patent concerns small-molecule catecholamine agents and drug-delivery methods, not a biologic subject to the Biologics Price Competition and Innovation Act pathway.

What patent litigation and settlement agreements affect the patent?

The expired status is the controlling legal fact. A current infringement suit based solely on U.S. Patent 5,108,363 would be barred for post-expiration conduct.

A historical litigation or settlement analysis would require the USPTO prosecution file, PACER records, and relevant district-court dockets. The patent number alone does not establish that a particular manufacturer was sued, entered a Paragraph IV settlement, or received a license.

No current settlement agreement can extend the patent’s statutory exclusionary term. A private license or covenant not to sue could affect historic conduct or contract rights, but it could not revive the expired patent against the market generally.

How does this patent compare with modern pharmacologic stress-testing technology?

Attribute	U.S. Patent 5,108,363	Modern dobutamine stress testing	Adenosine/regadenoson stress testing
Primary mechanism	Beta-adrenergic exercise simulation	Beta-adrenergic stimulation	Adenosine-receptor stimulation
Delivery concept	Closed-loop IV or transdermal iontophoresis	Usually titrated IV infusion	IV bolus or infusion
Feedback control	Central claim concept	Often clinician-controlled, protocol-based	Protocol-based, generally not ECG closed loop
Imaging	ECG, echocardiography, radionuclide imaging	Commonly stress echocardiography or nuclear imaging	Commonly perfusion imaging
Patent relevance today	Expired	Governed by current drug, device, and software rights	Governed by separate drug and device estates
Biosimilar exposure	None	None in the biologic sense	None in the biologic sense

The patent’s commercial thesis was automation and closed-loop control. Current practice generally relies on clinician-directed titration under a predefined protocol, with ECG and imaging used to assess the response. A modern product could avoid this patent by using a different drug, different control architecture, or different diagnostic workflow. The patent itself no longer creates a barrier regardless of design.

What generic launch risks exist for agents covered by the claims?

The principal risk is regulatory and clinical, not infringement risk under this patent.

A generic or follow-on manufacturer evaluating a catecholamine stress-testing product would assess:

Whether the proposed indication is included in the reference product labeling;
Whether the product is administered by the same route;
Whether an ANDA, 505(b)(2) application, or another pathway is appropriate;
Whether current Orange Book-listed patents exist for the reference product;
Whether device integration changes the regulatory pathway;
Whether software or pump patents remain in force;
Whether method-of-use labeling creates a skinny-label issue; and
Whether clinical protocols require separate device clearance.

U.S. Patent 5,108,363 does not create launch risk after April 28, 2009. A competitor’s principal IP exposure would come from later patents covering pump architecture, iontophoresis, control software, electrode systems, patient monitoring, or specific drug formulations.

What geographic coverage did the patent have?

The patent provided U.S. rights only. U.S. Patent No. 5,108,363 did not by itself create protection in Europe, Japan, Canada, or other jurisdictions.

Foreign protection would require separate national or regional patents claiming priority from the same application family. Patent-term and expiration analysis for any corresponding foreign application would depend on the country, filing date, grant date, maintenance status, and applicable patent-term rules.

The U.S. territorial scope covered conduct occurring in the United States, including use of the claimed diagnostic method and potentially U.S. importation or commercial exploitation of systems used to practice the method, subject to the statutory framework applicable during the patent term.

What manufacturing and intellectual-property barriers remain?

The patent’s manufacturing barriers are limited. It does not claim a specific manufacturing process for the catecholamine agents, gel, polymer, electrode, infusion pump, or microprocessor.

Potential current barriers may instead arise from:

Drug substance manufacturing patents;
Injectable formulation patents;
Transdermal patch and iontophoresis patents;
Closed-loop infusion algorithms;
ECG signal-processing software;
Safety shutoff logic;
Disposable electrode assemblies;
Combination-product patents;
Trade secrets involving calibration, dosing, or device integration; and
Regulatory exclusivity or labeling restrictions.

Those rights must be analyzed independently. They cannot be inferred from U.S. Patent 5,108,363.

Key Takeaways

U.S. Patent 5,108,363 covers closed-loop pharmacologic exercise-stress simulation and coronary artery disease evaluation.
The principal claims combine a beta-adrenergic catecholamine, controlled delivery, physiological monitoring, and feedback adjustment.
Claims 2, 3, 23, 24, 33, 36, 37, and 42 distinguish transdermal iontophoresis from intravenous delivery.
The patent claims methods, not a standalone drug compound or general pharmaceutical formulation.
The patent issued April 28, 1992, and its ordinary term expired April 28, 2009.
It does not create a current U.S. infringement or generic-entry barrier.
It is not a current biosimilar issue because the claimed technology concerns small molecules and delivery methods.
The patent does not establish current Orange Book protection for dobutamine or another catecholamine product.
Current freedom-to-operate analysis should focus on later patents covering drug formulations, infusion pumps, iontophoresis, ECG control software, and combination products.
Any historical litigation or licensing conclusions require review of the patent file and court records; the expired status controls current commercial risk.

FAQs About U.S. Patent 5,108,363

Can U.S. Patent 5,108,363 block a generic dobutamine launch?

No. The patent expired in 2009 and cannot currently block a generic launch. Other active patents, regulatory exclusivity, labeling, or device rights could still require separate analysis.

Does the patent cover ordinary intravenous dobutamine stress echocardiography?

Only if the full limitations of an applicable claim are met. Ordinary clinician-controlled IV dobutamine administration would not necessarily satisfy the closed-loop feedback and control limitations recited in the key claims.

Does the patent claim a transdermal dobutamine patch?

No. It claims methods using a transdermal iontophoretic device in certain combinations. It does not claim a standalone patch composition or a specific dobutamine patch design.

Could a medical-device company infringe the patent through ECG-controlled infusion software?

Not today, because the patent has expired. During its term, a system could have raised infringement risk if it practiced all limitations of an asserted claim, including the specified drug, delivery method, monitoring input, and feedback-control operation.

Is a beta blocker required in every claimed method?

No. Beta-blocker administration appears in claims 27 and 35. The other claims do not universally require an antagonizing agent.

Does the patent cover adenosine or regadenoson stress testing?

The claims are directed to exercise-simulating agents with beta-adrenergic activity and specified catecholamine structures. Adenosine and regadenoson are pharmacologically distinct and would not ordinarily fall within those chemical limitations.

References

United States Patent and Trademark Office. (1992). U.S. Patent No. 5,108,363, Exercise simulating agent and method.
35 U.S.C. § 154. Patent term and grant rights.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Dobutamine hydrochloride injection prescribing information.
21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	129644	⤷ Start Trial
Austria	159710	⤷ Start Trial
Australia	3008889	⤷ Start Trial
Australia	634152	⤷ Start Trial
Germany	68924661	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,108,363

Summary for Patent: 5,108,363