# United States Patent 5,645,815: Thrombus Imaging Agents, Claim Scope, Expiration, and Patent Landscape

U.S. Patent No. 5,645,815 covers low-molecular-weight platelet glycoprotein IIb/IIIa-binding compounds linked to radiolabel-binding groups for thrombus imaging. Its principal commercial relevance was technetium-99m apcitide, marketed as AcuTect. The patent claims the reagent, radiolabeled complex, labeling kit, thrombus-imaging method, peptide synthesis route, multivalent constructs, and specified chemical intermediates.

The patent is expired. Based on the issue date and the pre-1995 U.S. patent-term regime applicable to the patent family, the ordinary term ended in 2014, subject to any applicable terminal disclaimer or patent-term adjustment. The patent does not create a current U.S. barrier to generic or alternative development.

What does U.S. Patent 5,645,815 cover?

The patent covers a platform for preparing radiolabeled thrombus-imaging agents that target platelet glycoprotein IIb/IIIa, also called integrin alphaIIb beta3.

The independent technical requirements are:

Requirement	Claim scope
Biological target	Platelet glycoprotein IIb/IIIa receptor
Binding compound	Specific binding compound below 10,000 daltons
Functional activity	Inhibits human platelet aggregation in platelet-rich plasma with an IC50 of no more than 0.3 micromolar
Radiolabel-binding group	Capable of binding technetium-99m, indium-111, or gallium-68
Chemical connection	Covalent linkage between the binding compound and radiolabel-binding moiety
Intended use	Preparation of a thrombus-imaging agent
Primary dosage concept	Radiolabeled scintigraphic imaging agent
Principal isotope in the claims	Technetium-99m

Claim 1 is the central platform claim. It is drafted as a “comprising” claim, meaning additional components generally do not avoid infringement if every recited element remains present. The claim is limited by both structure and biological function. A compound must bind platelet GPIIb/IIIa and meet the platelet-aggregation inhibition threshold.

The claim does not require a particular peptide sequence, isotope, linker, formulation, animal species beyond the mammalian-use context, or imaging instrument. Those elements are supplied by dependent claims or the specification.

How are claims 1 through 25 organized?

Claims 1 to 6: Core reagent and chelator architecture

Claim 1 covers the broad conjugate. Claim 2 narrows the specific binding compound to a peptide containing 4 to 100 amino acids.

Claim 3 covers several families of radiolabel-binding moieties. The listed structures include:

Bis-cysteine peptide chelators;
Cysteine- and amine-containing ligands;
Thiol-containing acyclic chelators;
Protected cysteine-containing groups;
Ligands designed to produce neutral technetium complexes.

The neutrality limitation is important. The claim requires that the radiolabel-binding moiety form an electrically neutral complex with the radioisotope. This limitation is directed to pharmacokinetic and formulation characteristics, including reduced nonspecific distribution and suitability for in vivo imaging.

Claim 4 requires the peptide and radiolabel-binding moiety to be linked through one or more amino acids. Claims 5 and 6 narrow the protected cysteine structures and specify one of the disclosed bis-cysteine arrangements.

Claims 7 to 8: Imaging agents and peptide sequences

Claim 7 covers the scintigraphic imaging agent formed when the reagent is bound to a radiolabel.

Claim 8 identifies specific peptide sequences. In the source patent, the sequences are presented in structural drawings rather than conventional text in the claim transcription supplied here. These sequence-specific limitations are narrower than claim 1 and create separate infringement positions for particular apcitide-related peptide constructs.

Claims 9 to 10: Multivalent agents

Claim 9 covers a polyvalent conjugate containing multiple GPIIb/IIIa-binding compounds and multiple radiolabel-binding moieties. The final multimeric agent must remain below approximately 20,000 daltons.

Claim 10 identifies specific polyvalent linking agents, including:

Bis-succinimidylmethylether;
4-(2,2-dimethylacetyl)benzoic acid;
A diaza- and mercaptopropyl-containing linker;
Tris(succinimidylethyl)amine;
Derivatives of those linkers.

These claims extend protection beyond monomeric peptide-chelator conjugates. They would have been relevant to products seeking increased avidity or altered clearance through controlled multimerization.

Claims 11 to 14: Radiolabeling and kit claims

Claim 11 covers a technetium-99m complex formed by reacting the claim 2 reagent with technetium-99m in the presence of a reducing agent.

Claim 12 identifies the reducing agents:

Dithionite;
Stannous ion;
Ferrous ion.

Claim 13 covers ligand-exchange labeling using a pre-reduced technetium complex. Claim 14 covers a sealed vial kit containing a predetermined amount of reagent and enough reducing agent to prepare the technetium-labeled radiopharmaceutical.

The kit claim is commercially important because radiopharmaceutical products are often sold as cold kits rather than as finished radioactive doses. A kit could have implicated claim 14 even if the radiolabeling step occurred at a hospital or nuclear pharmacy.

Claims 15 to 19: Use and process claims

Claim 15 covers administration of technetium-99m-labeled reagent and detection of localized radioactivity at a thrombus.

Claims 16 and 17 require conjugation during in vitro chemical synthesis, including solid-phase peptide synthesis. These claims target manufacturing processes rather than the finished diagnostic agent.

Claims 18 and 19 cover labeling a peptide with technetium-99m using a reducing agent, with the same dithionite, stannous, and ferrous ion alternatives identified in claim 12.

Claims 20 to 25: Specific compounds and intermediates

Claims 20 through 24 cover specific compounds shown in structural formulas. Claim 24 identifies the sequence:

“CH2CO-YD ApcGDCGGGCAcmGCAcm amide”

The notation refers to a peptide containing protected cysteine residues. Claim 25 covers a protected intermediate containing Boc and Trt protecting groups.

These claims provide narrower protection for manufacturing intermediates and defined exemplified compounds. They would not necessarily reach every GPIIb/IIIa-targeting peptide radiolabeled through a different chelator or synthesized through a different intermediate.

What patent protects technetium-99m apcitide?

U.S. Patent 5,645,815 is one of the principal U.S. patents associated with the peptide-chelator thrombus-imaging platform that led to technetium-99m apcitide, also known as P280 and marketed as AcuTect.

Apcitide is a small cyclic or constrained peptide-derived GPIIb/IIIa antagonist linked to a technetium-binding group. It was developed to bind activated platelets in thrombi and provide scintigraphic visualization after technetium-99m labeling.

The relevant protection is distributed across several claim categories:

The GPIIb/IIIa-binding peptide and its activity threshold.
The peptide-chelator conjugate.
The neutral technetium complex.
The radiolabeling kit.
The method of imaging thrombi.
Specific protected peptide and chelator intermediates.
Multivalent versions of the agent.

The patent should not be treated as covering every technetium-labeled platelet-imaging product. A competing product could avoid the patent by using a different receptor target, a different binding molecule, a noncovalent labeling strategy, a different radiolabel-binding architecture, or a peptide that does not satisfy the claim 1 functional threshold.

When did U.S. Patent 5,645,815 lose exclusivity?

Event	Date or status
Patent issued	July 8, 1997
Patent term framework	Pre-1995 filing-era 17-year term from grant, subject to statutory exceptions
Expected ordinary expiration	July 8, 2014
Current status	Expired
Current enforceability	No ordinary exclusionary patent right remains
Current commercial effect	No blocking patent protection from this patent

The patent is not a current freedom-to-operate barrier in the United States. A current developer must still review later patents covering particular peptide sequences, chelators, formulations, manufacturing processes, diagnostic uses, or improved radiopharmaceutical kits.

Patent expiration does not eliminate regulatory requirements. A later entrant would still need an appropriate FDA pathway, product-specific quality controls, radiopharmaceutical manufacturing compliance, and evidence supporting safety, imaging performance, and labeling.

What was the FDA status of AcuTect?

AcuTect, technetium Tc 99m apcitide injection, was approved by the FDA as a diagnostic radiopharmaceutical for imaging suspected lower-extremity deep-vein thrombosis in patients with signs and symptoms of that condition. The product was supplied through a kit-based labeling process.

Regulatory issue	Assessment
Active ingredient	Technetium-99m apcitide
Target	Platelet GPIIb/IIIa
Product type	Diagnostic radiopharmaceutical
FDA pathway	Approved NDA product
Primary indication	Imaging suspected lower-extremity deep-vein thrombosis
Commercial status	Discontinued from commercial distribution
Current reference-product competition	Limited or absent
Biosimilar classification	Not applicable

AcuTect is a small-molecule or peptide radiopharmaceutical rather than a biologic. Biosimilar competition under the Public Health Service Act is therefore not the relevant framework. A follow-on product would more likely use an abbreviated, supplemental, or 505(b)(2)-type strategy depending on the reference product, formulation, labeling, and extent of clinical reliance.

What is the Orange Book status of Patent 5,645,815?

There is no current Orange Book exclusivity value associated with U.S. Patent 5,645,815. The patent has expired, and AcuTect is no longer an active commercial product in the ordinary U.S. market.

Historical Orange Book treatment should be distinguished from current status. A patent can have been listed during a product’s commercial period and later become irrelevant after expiration or product discontinuation. An absence of current Orange Book protection does not establish that no later patent ever covered a product-specific formulation or manufacturing process.

For a current launch assessment, the relevant review would include:

FDA Orange Book historical and current product records;
Patent listings associated with the AcuTect NDA;
Later patents assigned to the product sponsor or successor entities;
Published patent applications directed to apcitide analogs;
State and federal litigation records;
Patent term adjustment and terminal-disclaimer records.

Were there Paragraph IV challenges to AcuTect?

No material, publicly established Paragraph IV litigation record is associated with U.S. Patent 5,645,815 comparable to the litigation histories of major oral drugs. The commercial market for AcuTect was narrow, the product was discontinued, and the radiopharmaceutical manufacturing model limited the incentive for conventional generic substitution.

A Paragraph IV certification would have been commercially difficult because a challenger would need to address more than the active peptide. Relevant issues would include:

Radiolabeling chemistry;
Kit composition;
Sterility and stability;
Radioactive dose preparation;
Imaging indication;
Product-specific clinical and analytical comparability;
Hospital nuclear-pharmacy distribution.

The absence of prominent Paragraph IV litigation should not be read as confirmation that every claim was unchallenged or valid. It mainly reflects limited market economics and the product’s discontinuation.

How strong was the patent estate?

The estate was technically broad but commercially concentrated.

Strengths

Claim 1 combined receptor binding, molecular weight, biological potency, covalent conjugation, and radiolabel compatibility.
The “comprising” language expanded literal coverage.
Claims covered the reagent before radiolabeling, the radiolabeled agent, the kit, the imaging method, and manufacturing steps.
Claims covered technetium-99m, indium-111, and gallium-68-compatible binding groups.
The patent included both monovalent and multivalent constructs.
Specific chemical claims supported enforcement against disclosed commercial embodiments.

Limitations

The patent was limited to low-molecular-weight GPIIb/IIIa-binding compounds.
The functional IC50 threshold could create proof issues in infringement litigation.
The claim set depended heavily on particular chelator and thiol architectures.
Claims 20 through 25 were narrow and vulnerable to design-around through altered protecting groups, linkers, or sequences.
The patent did not cover all thrombus-imaging mechanisms, including fibrin-targeting agents, labeled platelets, or unrelated molecular imaging probes.
All claims are now expired in the United States.

The estate was strongest against a product that used the disclosed peptide class, a covalently linked technetium chelator, the specified activity threshold, and a kit or labeling process matching claims 11 through 19.

What design-around routes existed?

A competitor could have pursued several technical routes:

Design-around strategy	Potential effect
Use a fibrin-binding agent	Avoids the GPIIb/IIIa limitation
Use labeled autologous platelets	Avoids the claimed peptide-chelator reagent
Use a nonpeptide antagonist above 10,000 daltons	Avoids claim 1’s molecular-weight limit
Use a peptide with weaker platelet-aggregation inhibition	May avoid the IC50 limitation, subject to clinical utility
Use a different receptor target	Avoids GPIIb/IIIa claims
Use a noncovalent or alternative labeling architecture	May avoid the covalent-linkage requirement
Use a different chelator	May avoid the enumerated chelator subclaims
Use a radionuclide not covered by the selected claim	May avoid certain isotope-specific embodiments
Use a different multimeric linker	May avoid claim 10

These strategies may create separate regulatory and performance challenges. Avoiding the patent does not establish that the alternative agent will have equivalent thrombus localization, clearance, image quality, or clinical utility.

What manufacturing and intellectual-property barriers remain?

The expired patent removes one historical patent barrier but does not remove manufacturing complexity. A current product must manage:

Reproducible peptide synthesis;
Protection and deprotection of cysteine residues;
Control of disulfide formation;
Radiolabeling yield and radiochemical purity;
Neutral complex formation;
Kit stability;
Sterility and endotoxin control;
Short technetium-99m shelf life;
Hospital or central radiopharmacy preparation;
Distribution of radioactive materials;
Validation of thrombus-binding activity.

Later patents could still cover particular peptide sequences, chelators, linker chemistry, kit excipients, imaging protocols, or manufacturing controls. Those later rights require a separate family-level search and claim chart.

How does apcitide compare with other thrombus-imaging approaches?

Approach	Biological target	Typical advantage	Principal limitation
Tc-99m apcitide	Platelet GPIIb/IIIa	Direct targeting of activated platelet-rich thrombi	Narrow clinical use and complex radiopharmacy
In-111 labeled platelets	Circulating platelets	Direct platelet localization	Autologous cell handling and delayed imaging
Fibrin-targeted agents	Fibrin within thrombus	Targets a structural thrombus component	May have different specificity and kinetics
Tc-99m or other peptide probes	Variable receptor	Synthetic, kit-based preparation	Requires new chemistry and clinical validation
FDG or nonspecific inflammation imaging	Inflammation/metabolism	Broad availability	Lower thrombus specificity

The patent’s commercial concept was differentiated by combining a small GPIIb/IIIa antagonist with a kit-compatible technetium-labeling system. Its clinical value depended on sufficient platelet binding without unacceptable interference with hemostasis.

What generic launch risks exist today?

For the expired patent itself, generic launch risk is low. The relevant risks are regulatory, technical, and secondary patent risks.

A follow-on entrant would likely face:

Limited commercial demand for a discontinued diagnostic product.
Need to establish radiochemical and clinical comparability.
Potential reliance on a discontinued reference product.
Manufacturing requirements that differ from ordinary injectable generics.
Possible later patents on specific apcitide formulations or successor compounds.
Hospital adoption barriers and radiopharmacy logistics.
Limited reimbursement incentives for a specialized imaging agent.

The original patent does not prevent launch of a new thrombus-imaging product, but the economics may be more restrictive than the patent position.

Key Takeaways

U.S. Patent 5,645,815 covers GPIIb/IIIa-targeting peptide radiopharmaceutical reagents and related kits, complexes, methods, and intermediates.
Claim 1 is the principal broad claim and requires a sub-10,000-dalton binding compound, covalent radiolabel linkage, GPIIb/IIIa binding, and platelet-aggregation inhibition at an IC50 of no more than 0.3 micromolar.
The patent covers technetium-99m-compatible chemistry and also reaches indium-111 and gallium-68-compatible binding moieties.
Claims 11 through 19 cover labeling, kits, imaging, and manufacturing processes.
Claims 20 through 25 protect selected disclosed compounds and protected intermediates.
The patent expired in 2014 under the applicable historical U.S. patent-term framework.
AcuTect, the commercial technetium-99m apcitide product, is discontinued.
No current biosimilar framework applies because apcitide is a peptide radiopharmaceutical, not a biologic.
No material public Paragraph IV litigation record is associated with this patent.
Current freedom to operate depends on later patents, product-specific claims, regulatory requirements, and manufacturing execution.

FAQs

Is U.S. Patent 5,645,815 still enforceable?

No. The patent’s ordinary U.S. term ended in 2014, absent an unusual post-expiration correction or separate enforceable continuation right.

Does the patent cover all platelet GPIIb/IIIa imaging agents?

No. It covers agents meeting the claim limitations, including the molecular-weight, covalent-linkage, radiolabel-binding, and platelet-aggregation activity requirements.

Is apcitide a biologic subject to biosimilar competition?

No. Apcitide is a synthetic peptide radiopharmaceutical. Follow-on development would generally involve drug and radiopharmaceutical regulatory pathways rather than a biosimilar application.

Could a gallium-68 agent infringe the patent?

Potentially, if it uses a sub-10,000-dalton GPIIb/IIIa-binding compound covalently linked to a claimed or equivalent radiolabel-binding moiety and satisfies the remaining limitations. The patent expressly contemplates gallium-68-compatible binding.

Does patent expiration allow immediate sale of an AcuTect replacement?

No. Patent expiration removes the patent exclusion right but does not confer FDA approval, establish pharmaceutical equivalence, or resolve radiopharmaceutical manufacturing and clinical requirements.

References

U.S. Patent No. 5,645,815. (1997). Thrombus imaging agents. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (1998). AcuTect (technetium Tc 99m apcitide injection) prescribing information. FDA.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. FDA, Orange Book.
United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term expiration information. USPTO.
U.S. Food and Drug Administration. (2018). Applications covered by Section 505(b)(2). FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	002980	⤷ Start Trial
Austria	182795	⤷ Start Trial
Austria	184203	⤷ Start Trial
Austria	188387	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,645,815

Summary for Patent: 5,645,815