Details for Patent: 5,968,902

Summary for Patent: 5,968,902

Title:	Platelet aggregation inhibitors
Abstract:	The isolated and purified PAI from several active snake venoms is described and characterized. In addition, PAIs lacking the Arg-Gly-Asp (RGD) adhesion sequence but containing K* -(G/Sar)-D wherein K* is a modified lysyl residue of the formulaR12 N(CH 2)4CHNHCO-wherein each R1 is independently H, alkyl(1-6C) or at most one R1 is R2-C=NR3 wherein R2 is H, alkyl(1-6C), phenyl or benzyl, or is NR4 2 in which each R4 is independently H or alkyl(1-6C) and R3 is H, alkyl(1-6C), phenyl or benzyl, or R2-C=NR3 is a radical selected from the group consisting of: where m is an integer of 2-3, and each R5 is independently H or alkyl(1-6C); and wherein one or two (CH2) may be replaced by O or S provided said O or S is not adjacent to another heteroatom are prepared and shown to specifically inhibit the binding of fibrinogen or von Willebrand Factor to GP IIb-IIIa.
Inventor(s):	Robert M. Scarborough, David Lawrence Wolf, Israel F. Charo
Assignee:	COR Therapeutics Inc , Millennium Pharmaceuticals Inc
Application Number:	US08/482,263
Patent Claim Types: see list of patent claims	Use; Device;

United States Patent 5,968,902: Claim Scope, Patent Expiration, and GPIIb/IIIa Inhibitor Landscape

U.S. Patent No. 5,968,902 covers therapeutic and extracorporeal-circulation uses of a broad class of cyclic disulfide-containing peptide platelet aggregation inhibitors. The claims focus on methods of treating ischemic disorders, preventing platelet loss or aggregation during blood circulation outside the body, and protecting patients with intravascular devices. The patent does not claim a conventional small-molecule drug. It claims peptide sequences and their use as platelet aggregation inhibitors.

The patent term has expired under the ordinary 20-year United States patent-term framework. It therefore presents no current blocking patent risk for commercial activity, although its claims remain relevant as prior art and as evidence of the historical scope of protection sought for cyclic GPIIb/IIIa antagonists.

What does U.S. Patent 5,968,902 cover?

The patent covers methods using a family of constrained peptide platelet aggregation inhibitors. The disclosed compounds contain:

• A lysine-derived or lysine-modified residue, designated K*.
• Glycine, alanine, or serine residues in selected positions.
• An aromatic or hydrophobic residue selected from tryptophan, phenylalanine, leucine, tyrosine, or valine.
• Proline or a modified proline residue.
• Two terminal sulfur-containing residues linked by a disulfide bond.
• Optional non-native peptide linkages.
• L-configured chiral amino acid residues.
• Physiologically acceptable acid- or base-addition salts.

The structural class is consistent with cyclic peptide antagonists of platelet integrin GPIIb/IIIa, also known as alphaIIb beta3. Blocking this receptor inhibits fibrinogen-mediated platelet cross-linking and platelet aggregation.

The claims are method claims, not composition claims in the form presented. That distinction matters. A party making or selling a covered peptide would not necessarily infringe solely by manufacturing the compound unless another unprovided claim, continuation, or related patent covered the compound itself. The issued claims supplied here require a therapeutic, blood-contacting, or device-related use.

How are the independent claims structured?

Claim	Claim type	Core activity	Principal limitation
1	Treatment method	Treating or preventing platelet-associated ischemia	Administering a claimed peptide inhibitor to a patient
13	Blood-contact method	Preventing platelet loss during extracorporeal circulation	Contacting blood with the inhibitor
15	Prevention method	Preventing platelet aggregation, embolization, or consumption	Use in extracorporeal circulation or with an intravascular device

Claims 1, 13, and 15 each incorporate substantially the same peptide genus. Their differences are primarily in the claimed use.

Claim 1: ischemic disorders

Claim 1 requires:

1. A patient;
2. A platelet-associated ischemic disorder;
3. Administration of an effective amount; and
4. A peptide falling within the defined structural genus.

The claim is narrowed by claims 3 through 12 to specific clinical conditions:

• Thrombus formation;
• Acute myocardial infarction;
• Thrombosis after angioplasty;
• Unstable angina;
• Atherosclerosis;
• Transient ischemic attacks;
• Peripheral vascular disease;
• Restenosis after angioplasty;
• Thrombosis after carotid endarterectomy; and
• Thrombosis after vascular-graft anastomosis.

The term “platelet-associated ischemic disorder” is broad at the independent-claim level. The dependent claims identify intended clinical applications but do not convert the patent into a claim to a particular dosing regimen, route, formulation, or treatment duration.

Claim 13: extracorporeal blood circulation

Claim 13 covers contacting blood with the claimed inhibitor to prevent platelet loss during extracorporeal circulation. The claim is directed at the blood-processing circuit rather than necessarily at systemic administration to a patient.

The relevant applications include renal dialysis, cardiopulmonary bypass, hemoperfusion, plasmapheresis, and other extracorporeal circulation systems. The claim could potentially reach use of the inhibitor in a circuit, reservoir, or blood-contacting component, depending on how “contacting said blood” and “effective amount” are construed.

Claim 15: extracorporeal circulation and intravascular devices

Claim 15 covers prevention of platelet aggregation, embolization, or consumption in connection with extracorporeal circulation or an intravascular device. Claims 17 through 24 specify:

• Renal dialysis;
• Cardiopulmonary bypass;
• Hemoperfusion;
• Plasmapheresis;
• Intraaortic balloon pumps;
• Ventricular assist devices; and
• Arterial catheters.

This claim group is commercially broader than a narrow cardiology indication because it extends to device-associated platelet activation and blood-contacting medical technology.

What peptide structures are protected?

Claim 1 defines a Markush genus. Its breadth comes from variation at several positions.

Structural element	Claimed alternatives
K* residue	Lysine and substituted guanidino-type lysine analogues, including homoarginine-related and amidino derivatives
AA1 and AA4	Gly, Ala, or Ser
AA2	Trp, Phe, Leu, Tyr, or Val
AA3	Proline or modified proline
X1 and X2	Cysteine, mercaptopropionyl, mercaptovaleryl, or penicillamine
Ring-forming linkage	Disulfide bond
Peptide bonds	May be replaced by reduced, thioether, hydrocarbon, hydroxyethylene, ketomethylene, or sulfoxide-related linkages
Stereochemistry	Chiral amino acid residues are L-configured
Terminal substituents	Non-interfering substituents or absence

The claim also imposes a proviso for compounds where the proline-related segment is absent. That proviso requires additional sequence length, excludes certain K* and X2 combinations, or requires a nonstandard linkage. This is an anti-overbreadth limitation intended to prevent the genus from encompassing structurally minimal compounds that may not possess the required activity or inventive characteristics.

What compounds are listed in dependent claim 2?

Claim 2 lists approximately 30 peptide species. The sequences are built around the recurring pharmacophore:

• A cysteine or mercaptoacyl residue;
• A lysine, homoarginine, or modified guanidino residue;
• Gly-Asp;
• Trp, Tyr, Phe, Leu, or Val;
• Proline, glycine, thiazolidine, or piperidine-related residues; and
• A second sulfur-containing residue forming a cyclic disulfide.

Representative listed sequences include:

• Cys-Lys-Gly-Asp-Trp-Pro-Cys-NH2;
• Mpr-Lys-Gly-Asp-Trp-Pro-Cys-NH2;
• Mpr-Lys-Gly-Asp-Trp-Pro-Pen-NH2;
• Mpr-Har-Gly-Asp-Trp-Pro-Cys-NH2;
• Mpr-(acetimidyl-Lys)-Gly-Asp-Trp-Pro-Cys-NH2; and
• Mpr-(phenylimidyl-Lys)-Gly-Asp-Trp-Pro-Pen-NH2.

The abbreviations indicate modified amino acids or terminal residues. For example, Mpr generally denotes mercaptopropionyl, Mvl denotes mercaptovaleryl, Pen denotes penicillamine, Har denotes homoarginine, Sar denotes sarcosine, Pip denotes a piperidine-related residue, and Thz denotes a thiazolidine-related residue.

A sequence-specific commercial product would require a comparison against the exact structure, stereochemistry, salt form, disulfide connectivity, and use. Sequence similarity alone would not establish infringement.

How strong is the patent estate?

The patent’s historical claim scope was broad in chemical genus terms but narrower in enforcement terms because the issued claims are use claims.

Strengths

• The genus covers multiple residues at the principal recognition positions.
• The claims include both natural and modified amino acids.
• Alternative backbone linkages extend beyond ordinary peptide chemistry.
• The claims cover systemic ischemic indications and blood-contacting medical devices.
• Dependent claims identify a substantial number of specific peptide embodiments.
• The disulfide-constrained architecture targets a defined three-dimensional pharmacophore associated with platelet integrin binding.

Limitations

• The claims require a covered medical or blood-contacting use.
• The claim language depends on complex structural definitions and abbreviations.
• The patent does not, based on the supplied claims, claim a specific formulation, dosage form, manufacturing process, polymorph, or analytical method.
• The claim set does not identify a single approved active ingredient or commercial product.
• The patent term has expired.
• A current entrant would face no ordinary infringement liability based solely on expired claims, subject to the separate effect of related patents, terminal disclaimers, or foreign rights.

When did U.S. Patent 5,968,902 lose exclusivity?

U.S. Patent No. 5,968,902 issued on October 19, 1999. Under the modern U.S. patent-term rule, utility patents generally expire 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and transitional rules.[1]

The patent is now expired. Its expiration predates the current market period for most GPIIb/IIIa inhibitor products. The patent therefore has no remaining Orange Book exclusivity or enforceable U.S. patent term as an independent blocking right.

The patent number itself does not establish FDA regulatory exclusivity. Patent rights and FDA exclusivity are separate systems. FDA exclusivity depends on an approved drug application and statutory exclusivity category, while Orange Book listing depends on the relationship between an approved drug product and patents submitted by the NDA holder.[2]

What is the Orange Book status of the patent?

The supplied claims do not identify an approved NDA product, proprietary name, or active pharmaceutical ingredient that would support an Orange Book listing analysis. The claimed peptides appear to have been investigated as platelet aggregation inhibitors rather than commercialized as a long-term approved product corresponding to this patent.

No conclusion that the patent was listed for a specific approved product follows from the patent claims alone. Since the patent has expired, it would not create a current Orange Book patent-barrier period even if it had historically been submitted.

Were there Paragraph IV challenges?

A Paragraph IV certification applies to an ANDA applicant challenging a patent listed in the Orange Book for a reference-listed drug.[3] The patent claims supplied here do not identify a reference-listed drug or NDA product.

The relevant risk profile is therefore different from that of a marketed small-molecule antiplatelet drug such as clopidogrel or ticagrelor. A generic applicant seeking approval of an equivalent peptide product would confront peptide-specific chemistry, manufacturing, characterization, and clinical requirements. It would not necessarily use the conventional ANDA pathway available for a well-established small molecule.

No verified Paragraph IV litigation can be attributed to U.S. Patent 5,968,902 from the claim text alone.

How does the patent compare with competing GPIIb/IIIa inhibitor patents?

Product or program	Modality	Clinical use	Relationship to U.S. 5,968,902
Abciximab	Chimeric monoclonal antibody fragment	Intravenous platelet inhibition	Biologic, structurally distinct
Eptifibatide	Cyclic peptide	Acute coronary interventions and acute coronary syndromes	Related therapeutic class, different peptide structure
Tirofiban	Nonpeptide small molecule	Acute coronary syndromes	Different chemistry and manufacturing profile
Lamifiban	Nonpeptide small molecule	Investigational antiplatelet use	Different scaffold
Claim 2 peptides	Cyclic disulfide peptides	Ischemia and blood-contacting systems	Direct subject matter of the patent

Eptifibatide is the closest commercial comparator by modality because it is a cyclic peptide GPIIb/IIIa inhibitor. Its sequence and regulatory history are distinct from the sequences enumerated in claim 2. Abciximab presents biosimilar or follow-on biologic considerations, but those considerations do not apply directly to the synthetic peptides claimed in this patent. Tirofiban presents conventional small-molecule generic-entry issues rather than peptide manufacturing issues.

What formulation and manufacturing rights are absent?

The supplied claims do not expressly claim:

• Injectable formulations;
• Lyophilized compositions;
• Buffer systems;
• Stabilizers;
• Specific counterions;
• Controlled-release delivery;
• Pre-filled syringes;
• Drug-device combinations;
• Solid-state forms;
• Purification processes;
• Disulfide-folding processes; or
• Specific synthetic intermediates.

Those subjects may have been covered by separate applications or continuation patents, but they are not present in the claims provided. A commercial development program would therefore need a separate freedom-to-operate review covering peptide synthesis, disulfide formation, impurity control, formulation, container closure, and device use.

What biosimilar or generic-entry risks exist?

The principal entry risk is not a current patent barrier from U.S. 5,968,902. It is regulatory and technical.

A follow-on peptide product could face:

• Difficulty demonstrating structural equivalence;
• Disulfide isomer and aggregation control;
• Peptide-related impurities;
• Batch-to-batch activity variation;
• Immunogenicity assessment;
• Bioanalytical comparability;
• Clinical bridging requirements; and
• Manufacturing-process know-how barriers.

Because the claimed compounds are synthetic peptides rather than monoclonal antibodies, the regulatory pathway would not necessarily be the biosimilar pathway under section 351(k) of the Public Health Service Act. FDA classification would depend on the product, reference product, degree of structural characterization, and applicable drug or biologic framework.[4]

What litigation and settlement issues affect the patent?

The supplied information establishes no litigation, license, or settlement involving U.S. Patent 5,968,902. The patent’s expiration eliminates the principal forward-looking litigation issue for its U.S. claims. Historical validity, ownership, inventorship, and enforceability disputes could still matter for due diligence, but they would not restore an expired patent right.

A current transaction should distinguish among:

1. The expired U.S. patent;
2. Continuations and divisionals;
3. Foreign counterparts;
4. Later composition or formulation patents;
5. Clinical-development licenses;
6. Trade secrets covering peptide manufacture; and
7. Device or combination-product rights.

Key Takeaways

• U.S. Patent 5,968,902 covers methods using cyclic disulfide peptide platelet aggregation inhibitors.
• The principal target is the GPIIb/IIIa platelet integrin pathway.
• Independent claims 1, 13, and 15 cover ischemic disorders, extracorporeal circulation, and intravascular-device applications.
• Claim 2 lists approximately 30 specific cyclic peptide embodiments.
• The patent claims uses rather than, on the supplied record, a standalone composition, formulation, or manufacturing process.
• The patent has expired under the ordinary U.S. patent-term framework.
• No current Orange Book barrier or Paragraph IV risk is established by the supplied claims.
• The relevant present-day risks are more likely to arise from later family members, formulation patents, manufacturing know-how, regulatory comparability, and foreign rights.
• Eptifibatide is the closest commercial modality comparator, but its structure and regulatory estate are distinct.
• A current freedom-to-operate review must extend beyond U.S. 5,968,902.

FAQs

Does U.S. Patent 5,968,902 cover eptifibatide?

No conclusion of coverage follows from the supplied claims. Eptifibatide is a distinct cyclic peptide GPIIb/IIIa inhibitor with a different amino acid sequence and separate development and patent history.

Is U.S. Patent 5,968,902 a composition-of-matter patent?

The supplied issued claims are method claims. They define peptide structures as components of the claimed treatment or blood-contacting methods, rather than presenting an independent composition claim.

Can an expired patent still block FDA approval?

An expired patent generally cannot create a current patent-based bar to approval. FDA approval and patent infringement are separate issues, and other unexpired patents or regulatory exclusivities may still apply.

Do the claims cover medical devices?

Claims 21 through 24 cover use associated with intravascular devices, including intraaortic balloon pumps, ventricular assist devices, and arterial catheters. They do not, on their face, claim the devices themselves.

What is the main commercial value of the patent today?

Its primary value is historical and analytical. It identifies the scope of an early cyclic peptide GPIIb/IIIa inhibitor program and may inform prior-art, family-history, licensing, and freedom-to-operate analysis. It does not provide an active U.S. exclusivity right.

References

1. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term. https://www.uspto.gov/patents/laws/patent-term-adjustment
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files
3. U.S. Food and Drug Administration. (n.d.). ANDA submissions: Content and format. https://www.fda.gov/drugs/guidance-compliance-regulatory-information
4. U.S. Food and Drug Administration. (n.d.). Regulatory considerations for peptide drug products. https://www.fda.gov/drugs/development-resources-drugs/biotechnology-products and https://www.fda.gov/drugs/development-resources-drugs.
5. U.S. Patent No. 5,968,902. (1999). Platelet aggregation inhibitors. United States Patent and Trademark Office.

Drugs Protected by US Patent 5,968,902

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,968,902

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0477295		SPC/GB99/046	United Kingdom
European Patent Office	0477295		C990043	Netherlands
European Patent Office	0477295		51/1999	Austria
Austria	146969
Australia	6036990