United States Drug Patent 5,747,447: Claim Scope, Eptifibatide Coverage, Expiration, and Patent Landscape

U.S. Patent No. 5,747,447 covered citrate-buffered, storage-stable liquid compositions of platelet aggregation inhibitor polypeptides, especially cyclic peptides corresponding to eptifibatide, marketed as Integrilin. The patent issued on May 5, 1998, and its enforceable term expired in December 2016 based on the U.S. application filing date. It does not create a current barrier to generic eptifibatide development.

The patent’s practical value was concentrated in formulation and product presentation rather than the underlying discovery of platelet aggregation inhibitors. Its strongest claims required a substantially pure inhibitor polypeptide in a liquid citrate buffer at approximately pH 5.0 to 5.5. Several dependent claims specifically identified eptifibatide and closely related analogues.

What drug and formulation does U.S. Patent 5,747,447 protect?

The principal compound identified in the claims is the cyclic peptide represented as:

Mpr-K-G-D-W-P-C-NH2

This structure corresponds to eptifibatide, a cyclic platelet glycoprotein IIb/IIIa receptor antagonist. The claim set also covers related analogues containing variations at the lysine, terminal thiol, and amino-acid positions.

The patent protects a storage-stabilized liquid formulation rather than merely the active peptide. The central formulation requirements are:

Claim element	Required limitation
Active ingredient	Substantially pure platelet aggregation inhibitor polypeptide
Physical form	Liquid solution
Buffer	Citrate buffer
pH	About 5.0 to about 5.5
Preferred pH	About 5.25
Additives	Stabilizing additives consist essentially of citrate buffer
Use	Injectable, biologically effective composition in the therapeutic claims
Product format	Sterile vial, bag, or bottle in claim 20
Stability test	Stability at about 70°C or less for at least 49 days in claims 5 and 15

The claims are directed to three legal categories:

A method of storage-stabilizing the peptide.
A storage-stable composition.
A therapeutic injectable composition and an article of manufacture containing it.

The independent claims are claims 1, 11, and 16. Claim 20 is also commercially important because it covers a sterile delivery container filled with the claimed injectable composition.

How broad are the independent claims?

Claim 1: storage-stabilization method

Claim 1 requires a method comprising:

preparing a liquid solution;
using a substantially pure platelet aggregation inhibitor polypeptide;
dissolving the polypeptide in citrate buffer;
producing a storage-stable solution;
maintaining pH from about 5.0 to about 5.5.

The claim does not require eptifibatide specifically. Its literal scope extends to the broader class of platelet aggregation inhibitor polypeptides, subject to the citrate-buffer and pH limitations.

The phrase “consisting essentially of” narrows the permitted formulation components while preserving room for ingredients that do not materially affect the claimed storage-stability characteristic. A formulation containing a conventional injectable excipient may still raise infringement issues if the additional excipient materially changes the stability mechanism or falls outside the claim’s formulation language.

Claim 11: composition claim

Claim 11 covers the product itself. It requires a storage-stable composition containing:

a substantially pure platelet aggregation inhibitor polypeptide;
a liquid solution;
a citrate buffer as the stabilizing-effective additive;
pH from approximately 5.0 to 5.5.

This claim is potentially stronger than claim 1 in a product dispute because it does not require proof of the accused manufacturer’s formulation process. Testing the marketed or manufactured product may establish the relevant composition characteristics.

Claim 16: injectable therapeutic composition

Claim 16 narrows the composition to an injectable, biologically effective amount of the polypeptide. It is directed to a therapeutic liquid product rather than a laboratory or research formulation.

Claim 16 is commercially significant because a parenteral eptifibatide product ordinarily would be evaluated against:

peptide identity;
concentration;
pH;
citrate content;
injectable presentation;
biological activity;
substantially pure active ingredient.

What specific peptide sequences are covered?

Claims 4 and 14 identify a group of cyclic peptides. The listed sequences include:

Sequence identifier	Listed peptide
SEQ ID NO: 53	Mpr-K-G-D-W(Formyl)-P-C-NH2
SEQ ID NO: 54	Mvl-K-G-D-W-P-C-NH2
SEQ ID NO: 55	Mpr-K-G-D-W-P-Pen-NH2
SEQ ID NO: 63	Mpr-(Har)-G-D-W-P-C-NH2
SEQ ID NO: 66	Mpr-(Har)-G-D-W-P-Pen-NH2
SEQ ID NO: 67	Mpr(Acetimidyl-Lys)-G-D-W-P-C-NH2
SEQ ID NO: 68	Mpr(Acetimidyl-Lys)-G-D-W-P-Pen-NH2
SEQ ID NO: 73	Mpr(Phenylimidyl-Lys)-G-D-W-P-C-NH2
SEQ ID NO: 75	Mpr(Phenylimidyl-Lys)-G-D-W-P-Pen-NH2
SEQ ID NO: 81	Mpr-Ala-(Har)-G-D-W-P-C-NH2
SEQ ID NO: 30	Mpr-K-G-D-W-P-C-NH2

The Markush language in claims 2 and 12 is substantially broader than the sequence listing. It covers peptide families with:

alternative basic lysine or homoarginine-type residues;
glycine or sarcosine;
selected neutral amino acids;
tryptophan, phenylalanine, leucine, tyrosine, or valine;
proline or modified proline;
cysteine, mercaptovaleryl, mercaptopropionyl, or penicillamine residues;
cyclic linkages between X1 and X2;
selected nonpeptide bond replacements.

The broad genus claims therefore reach beyond the commercial eptifibatide sequence, although practical enforceability would depend on written-description support, enablement, claim construction, and proof that a particular peptide falls within every claimed structural limitation.

What formulations are protected by U.S. Patent 5,747,447?

The patent’s formulation center is a citrate-buffered acidic liquid. The most commercially relevant formulation profile is:

Formulation characteristic	Claimed range or requirement
Buffer	Citrate
pH	5.0 to 5.5
Preferred pH	Approximately 5.25
Solvent	Liquid solution
Active ingredient	Substantially pure cyclic PAI polypeptide
Intended route	Injectable
Stabilizing additive	Citrate buffer, with sodium hydroxide expressly included in claim 10
Container	Sterile vial, bag, or bottle

Claims 8 and 9 cover storage at approximately -15°C to 30°C and 5°C to 30°C, respectively. Claims 5 and 15 use an accelerated-stability limitation of at least 49 days at approximately 70°C or less.

The stability claims raise an important distinction. A product need not be stored at 70°C in commercial use to fall within claims 5 or 15. The elevated-temperature condition is a testing or performance limitation. A product that satisfies the stated stability requirement may be within scope even if its commercial storage temperature is refrigerated or ambient.

What is the patent expiration date?

Event	Date
U.S. application filing	December 6, 1996
Patent issued	May 5, 1998
Expected 20-year statutory expiration	December 6, 2016
Current status	Expired

The patent’s term was governed by the post-June 8, 1995 patent-term rules, which generally provide 20 years from the earliest effective U.S. nonprovisional filing date, subject to patent-term adjustment or disclaimer. The patent is therefore no longer an enforceable exclusionary right. The USPTO patent record identifies U.S. Patent No. 5,747,447 as expired, and the FDA Orange Book cannot preserve an expired patent right after statutory expiration (U.S. Patent and Trademark Office, n.d.; FDA, 2024).

What was the Orange Book status of eptifibatide?

Eptifibatide was approved by FDA under NDA 20-697 for Integrilin, originally associated with COR Therapeutics. The product is a small synthetic cyclic peptide, not a biologic subject to the biosimilar pathway.

The relevant regulatory consequences are:

FDA approval was obtained through an NDA.
A generic competitor would ordinarily pursue an ANDA if it could demonstrate pharmaceutical equivalence and bioequivalence.
A 505(b)(2) application could be relevant for a materially different formulation, concentration, route, or clinical use.
Patent certifications under Hatch-Waxman would have been relevant while listed patents remained unexpired.
Patent expiration in 2016 removed the principal formulation-patent obstacle created by U.S. Patent 5,747,447.

The Orange Book listing, if maintained during the patent’s life, did not extend the patent beyond its statutory term. Orange Book listing and patent enforceability are separate issues. The FDA publication identifies listed patents and use codes but does not determine whether a patent claim is valid or infringed (FDA, 2024).

When did eptifibatide lose market exclusivity?

Eptifibatide lost exclusivity in stages:

Exclusivity type	Approximate status
FDA approval	1998
New chemical entity exclusivity	Expired approximately 2003
U.S. Patent No. 5,747,447	Expired December 2016
Current patent exclusivity	None from this patent
Biosimilar exclusivity	Not applicable
Generic pathway	ANDA or, in some cases, 505(b)(2)

The NCE period did not protect the product indefinitely. Once the five-year NCE period ended, an ANDA applicant could submit a Paragraph IV certification against unexpired listed patents or wait for patent expiration and submit a Paragraph III certification.

Were there Paragraph IV challenges or patent litigation?

A Paragraph IV certification would have been relevant only during the period when U.S. Patent No. 5,747,447 remained unexpired. A Paragraph IV notice could have triggered Hatch-Waxman litigation and a potential 30-month stay of FDA approval under 21 U.S.C. § 355(j)(5)(B)(iii).

The public patent record does not establish a material, currently pending infringement action involving U.S. Patent No. 5,747,447. Any historical Paragraph IV activity would need to be evaluated against the asserted patent, the accused formulation, and the date of notice. Since the patent expired in 2016, a new infringement action based solely on this patent is no longer available for post-expiration conduct.

The absence of a current enforceable patent means that present market entry risk is primarily regulatory and commercial rather than patent-litigation risk.

Which companies challenged or commercialized eptifibatide?

The principal commercial participants were:

Company	Role
COR Therapeutics	Original developer and NDA sponsor associated with Integrilin
Schering-Plough	Commercial and development partner for Integrilin
Merck	Successor commercial organization after the Schering-Plough merger
Generic manufacturers	Potential ANDA sponsors after patent expiration

Current generic availability and manufacturer participation should be assessed through FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations and the Drugs@FDA database rather than through the expired patent record. The patent itself does not identify a continuing license obligation or a surviving royalty right.

How does the patent compare with the underlying compound patent estate?

U.S. Patent No. 5,747,447 is a secondary formulation and stability patent. It should be separated from earlier patents directed to:

cyclic platelet aggregation inhibitor compounds;
peptide sequences and analogues;
methods of inhibiting platelet aggregation;
treatment of thrombotic or ischemic disorders;
peptide synthesis and purification;
pharmaceutical compositions.

The distinction matters in freedom-to-operate work. A manufacturer could avoid the claims of Patent 5,747,447 by using a non-citrate buffer or a pH outside the claimed range, but that design would not automatically avoid other patents covering eptifibatide itself, its synthesis, or its therapeutic use. Those earlier rights, however, would also generally have expired given the age of the eptifibatide patent family.

What generic entry risks remain?

The patent-specific risk is low because the patent expired. The remaining risks are:

Product-specific regulatory failure, including potency, sterility, impurities, particulate matter, and bioequivalence.
Manufacturing reproducibility for a cyclic disulfide-containing peptide.
Control of oxidation, aggregation, deamidation, and peptide-related impurities.
Patent claims in other jurisdictions with different filing dates or term adjustments.
Unexpired process, device, packaging, or formulation patents outside this patent family.
FDA exclusivity or exclusivity associated with a later-approved formulation or indication.

A generic manufacturer using citrate buffer at pH 5.0 to 5.5 could historically have faced a credible formulation-patent claim. That risk ended with expiration. A non-citrate formulation would reduce historical claim overlap but could create separate product-development and comparability issues.

Does biosimilar risk apply?

No. Eptifibatide is a synthetic cyclic peptide and is regulated as a drug rather than as a therapeutic protein biologic for purposes of the biosimilar pathway. Competitive products would generally be evaluated as generics or follow the 505(b)(2) pathway, depending on the extent of formulation and clinical differences.

The technical manufacturing risk is still substantial. The molecule contains a cyclic structure and disulfide linkage, so process controls must address:

correct ring closure;
disulfide formation;
stereochemical purity;
residual protecting groups;
peptide truncation products;
oxidation and aggregation;
final solution stability.

These are manufacturing barriers, not surviving barriers created by Patent 5,747,447.

Key Takeaways

U.S. Patent No. 5,747,447 covers citrate-buffered liquid formulations of platelet aggregation inhibitor polypeptides.
The commercial target is eptifibatide, including the sequence Mpr-K-G-D-W-P-C-NH2.
The core formulation range is approximately pH 5.0 to 5.5, with pH 5.25 preferred.
Claims cover stabilization methods, compositions, injectable therapeutic products, and sterile filled containers.
Claims 2, 3, 12, and 13 include broad Markush coverage for cyclic peptide analogues.
The patent issued May 5, 1998, and expired in December 2016.
The patent is no longer an enforceable barrier to generic eptifibatide entry.
Eptifibatide is not subject to biosimilar substitution rules because it is a synthetic peptide drug.
Current entry risk is concentrated in FDA requirements, peptide manufacturing, product quality, and any separate unexpired patent rights.
A citrate-buffered product at pH 5.0 to 5.5 would have fallen within the patent’s principal commercial scope during the patent term.

FAQs about U.S. Patent 5,747,447 and eptifibatide

Is U.S. Patent 5,747,447 still active?

No. Its statutory term expired in December 2016 based on the U.S. filing date.

Does Patent 5,747,447 cover Integrilin?

Yes. The claims expressly encompass eptifibatide-type cyclic peptides and citrate-buffered injectable liquid compositions corresponding to Integrilin.

Can a generic use citrate buffer for eptifibatide?

Yes, because the patent has expired. The manufacturer must still satisfy FDA quality, equivalence, sterility, and manufacturing requirements.

Is eptifibatide a biologic requiring a biosimilar application?

No. Eptifibatide is a synthetic cyclic peptide drug. A generic or 505(b)(2) pathway is more relevant than a biosimilar application.

Does the patent cover eptifibatide powder or lyophilized formulations?

The issued claims focus on a liquid solution. A dry powder or lyophilized product would not satisfy the liquid-solution limitations without additional facts showing reconstitution before the claimed composition or method is practiced.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs. FDA.
U.S. Patent and Trademark Office. (n.d.). Patent number 5,747,447: Storage stable platelet aggregation inhibitor polypeptide compositions. USPTO.
U.S. Patent No. 5,747,447. (1998). Storage stable platelet aggregation inhibitor polypeptide compositions. United States Patent and Trademark Office.
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	173739	⤷ Start Trial
Australia	4118293	⤷ Start Trial
Australia	679913	⤷ Start Trial
Canada	2133205	⤷ Start Trial
Canada	2573307	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,747,447

Summary for Patent: 5,747,447