US Patent 5,648,333: Icatibant Bradykinin Antagonist Claims, Scope, Expiration, and Patent Landscape

US Patent No. 5,648,333 covers a broad family of synthetic bradykinin B2-receptor antagonists, including the icatibant peptide sequence used in Firazyr. Its strongest commercial claim is claim 14, which specifically covers icatibant and its physiologically tolerable salts. The patent also claims related peptide genera, D-Phe analogues, pharmaceutical compositions, and therapeutic methods for bradykinin-mediated conditions, including hereditary angioedema and asthma.

The patent issued on July 15, 1997, from a Hoechst-originated peptide program. Its 20-year US patent term expired in 2014, subject to any applicable patent-term adjustment or terminal disclaimer. The patent therefore does not currently block generic or follow-on development on its own. Its historical importance is substantial because it contains direct claims to icatibant, but its present value is primarily prior-art, freedom-to-operate, and patent-landscape value rather than enforceable exclusivity.

What drug and technology does US Patent 5,648,333 protect?

US 5,648,333 protects peptide antagonists of bradykinin, a vasoactive peptide involved in vascular permeability, inflammation, pain, bronchoconstriction, hypotension, and angioedema.

The core architecture is represented by formula I:

A-B-C-E-F-K-P-G-M-F'-I

The claimed molecules are synthetic peptides containing:

Element	Technical role in the claimed structure
A	N-terminal hydrogen, alkyl, acyl, sulfonyl, amino-acid-derived or related substituent
B	Basic amino acid, principally Arg, Lys, Orn, 2,4-diaminobutyroyl or homoarginine
C	Proline-derived peptide segment, often Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly
E	Aromatic amino acid, including Phe, substituted Phe, Tyr, O-methyltyrosine or thienylalanine
F	Variable neutral, acidic or basic amino acid, or a direct bond
K	Optional aminocarbonyl spacer, or a direct bond
P	D-Tic in claims 1-14; D-Phe in claims 15-24
G	Proline-related constrained heterocycle, including Oic, Aoc, Tic and related ring systems
M	Variable amino acid or direct bond
F'	Usually Arg or Lys in the narrower claims
I	Hydroxyl, amino or ethylamino C-terminus

The structure is designed to reproduce key spatial and charge characteristics of bradykinin while preventing productive receptor activation. The D-amino-acid and constrained heterocyclic residues increase resistance to enzymatic degradation and impose a receptor-binding conformation.

Which claims specifically cover icatibant?

Claim 14 is the principal direct composition-of-matter claim for icatibant.

Icatibant is:

H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH

The claim covers that peptide and physiologically tolerable salts. Firazyr is marketed as icatibant acetate, a subcutaneous injection for acute attacks of hereditary angioedema.

The claim structure is narrowed through a series of dependent claims:

Claim	Scope relevant to icatibant
1	Broad peptide genus with variable termini, amino acids, spacers and heterocycles
2	Narrows B, C, E, F, F', K and M to defined amino-acid classes
3	Narrows F' primarily to Arg or Lys and limits G' ring systems
4	Defines a narrower Arg/Orn/Lys series with Phe-related aromatic residues
5	Defines peptides using D- or L-H-Arg, H-Lys or H-Orn at A and Pro-derived C segments
6	Similar genus with Ser or direct-bond F and defined K relationship
7	Cys-containing alternatives
8-9	Specific heterocyclic G radicals
10	Defines D-Arg or hydrogen at A, Arg-related B, Pro/Hyp segments, Phe or Thia, Ser, D-Tic, Oic/Aoc/Tic and Arg
11	Further narrows the sequence to Thia/Ser and Aoc or Oic
12	Lists ten specific peptide sequences, including icatibant
13	Lists three narrower species
14	Directly claims icatibant

Claims 12 and 13 also include icatibant-related analogues. Claim 14 is the cleanest sequence-specific protection because it does not depend on a longer list of alternatives.

How broad are the independent peptide claims?

The broadest protection is claim 1. It is a Markush claim covering a large number of peptide permutations rather than one commercial molecule.

Its breadth comes from four sources:

Multiple N-terminal groups under A.
Multiple basic amino acids and side-chain substitutions under B.
Broad classes of aromatic, aliphatic and heterocyclic residues at E, F, P, G, M and F'.
Both D-Tic and related constrained heterocyclic systems.

The claim is technically broad but structurally dense. A potential infringer would need to practice every required limitation. A peptide that omits the required P segment, changes the configuration of a critical residue, uses a materially different central sequence, or falls outside the specified heterocyclic definitions may avoid literal infringement.

The dependent claims materially improve enforcement clarity by reducing the number of permitted alternatives. Claims 10-14 are commercially more important than claim 1 because they identify discrete bradykinin-antagonist sequences and the icatibant structure.

What does claim 15 add to the patent?

Claims 15-24 create a second peptide genus. The principal distinction is that P is D-phenylalanine rather than D-Tic.

Claim 15 therefore covers:

A-B-C-E-F-K-D-Phe-G-M-F'-I

where G is a larger heterocyclic bicyclic or tricyclic radical. Claims 16-20 narrow the permitted amino acids and ring systems. Claims 21-24 list specific D-Phe-containing compounds.

Examples include:

H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Phe-Oic-Arg-OH
H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Phe-Oic-Arg-OH
H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-(p-Cl)Phe-Oic-Arg-OH
H-D-Arg-Arg-Pro-Hyp-Gly-Tbg-Ser-D-Tic-Oic-Arg-OH

These compounds are distinct from icatibant because the protected sequence incorporates D-Phe in the P position, while icatibant contains D-Tic. Claims 15-24 expand the patent beyond the commercial icatibant species and may be relevant to historical analogues, research compounds and sequence-based prior-art analysis.

What therapeutic uses are claimed?

Claims 25-33 cover methods and pharmaceutical compositions directed to bradykinin-mediated pathological conditions.

The listed conditions include:

Wounds and burns
Rashes, erythema and edema
Angina
Arthritis
Asthma
Allergies and rhinitis
Shock and low blood pressure
Inflammation
Pain and pruritus
Changed sperm motility
Tonsillitis in claims 31-33

Claims 25 and 28 cover treatment methods using the broad peptide genera of claims 1 and 15. Claims 26 and 29 specifically recite asthma treatment. Claims 31-33 are directed to the compound of claim 24.

The method claims are narrower than the composition claims because they require administration for a listed bradykinin-related condition. They do not restore exclusivity to the expired composition claims. Their practical value depends on enforceability, disclosure support, claim construction and whether the relevant treatment indication was separately protected by a later unexpired patent.

What is the commercial relevance to Firazyr and hereditary angioedema?

Icatibant is the active pharmaceutical ingredient in Firazyr. The FDA approved Firazyr in 2011 for acute attacks of hereditary angioedema in adults. The product is administered by subcutaneous injection and acts as a selective bradykinin B2-receptor antagonist. FDA labeling identifies icatibant acetate as the active ingredient and describes the product as a prefilled syringe containing 30 mg of icatibant acetate solution. [2]

US 5,648,333 is important because claim 14 directly names the icatibant sequence. The patent, however, predates the commercial product by more than a decade and expired before the modern generic-entry period for icatibant.

The product’s commercial protection depended on more than this patent. Relevant layers can include:

Protection layer	Relevance
Peptide composition claims	Directly cover icatibant and analogues
Formulation claims	May cover injectable composition, pH, stabilizers or concentration
Manufacturing claims	May cover synthesis, purification or salt formation
Regulatory exclusivity	Separate from patent term
Method-of-use claims	May cover hereditary angioedema or other indications
Trade secrets	May protect manufacturing controls and process parameters
Device or packaging rights	May cover prefilled-syringe presentation

When did US Patent 5,648,333 lose exclusivity?

The patent issued July 15, 1997. Under the post-1995 US patent-term regime, the baseline term is 20 years from the earliest effective nonprovisional US filing date, subject to patent-term adjustment, terminal disclaimers and statutory exceptions. The patent expired in 2014 based on the underlying family chronology. [1]

The practical timeline is:

Event	Date or period
Priority and peptide research filings	Early-to-mid 1990s
US patent application	Mid-1990s
Grant of US 5,648,333	July 15, 1997
Baseline patent term	Approximately 20 years from the earliest effective US nonprovisional filing
Patent expiry	2014
Firazyr FDA approval	2011
Current composition-of-matter status	Expired
Current commercial question	Whether later formulation, process, method or device patents remain relevant

Patent expiry does not invalidate the underlying technical disclosure. It places the claimed subject matter into the public domain, subject to separate rights in later patent families.

What is the Orange Book status of US 5,648,333?

US 5,648,333 is not an enforceable current Orange Book barrier because it expired in 2014. Historical listing status must be distinguished from current patent enforceability. FDA Orange Book listings identify patents submitted by an NDA holder for an approved product, but an Orange Book listing does not extend an expired patent or establish infringement. [3]

For icatibant, the relevant regulatory analysis should separate:

The expired sequence patent represented by US 5,648,333.
Any later-listed formulation or manufacturing patents.
Any pediatric exclusivity or other regulatory exclusivity.
The approval pathway used by an icatibant applicant.
The applicant’s Paragraph IV certifications and litigation position.

A generic applicant can challenge listed patents through an Abbreviated New Drug Application. A Paragraph IV certification alleges that a listed patent is invalid, unenforceable or not infringed. If the NDA holder sues within the statutory period, FDA approval may be subject to a 30-month stay under the Hatch-Waxman framework, subject to statutory exceptions and later court action. [4]

Which companies challenged icatibant exclusivity?

The main commercial competition has involved generic and alternative icatibant development rather than biosimilar competition. Icatibant is a synthetic peptide, not a biologic produced through a biologics license application. Biosimilar rules under the Public Health Service Act are therefore generally not the primary pathway. The relevant competitor category is generic or hybrid peptide-drug development.

Known commercial participants have included:

Shire, which commercialized Firazyr after acquiring or licensing rights associated with icatibant.
Takeda, which later acquired Shire and its hereditary-angioedema portfolio.
Generic drug developers pursuing icatibant acetate injection.
Specialty manufacturers evaluating peptide synthesis, sterile filling and injectable-product requirements.

A definitive list of Paragraph IV filers and litigation outcomes requires review of FDA patent-listing records, ANDA litigation dockets and district-court filings. The expired status of US 5,648,333 means that any later dispute would more likely concern separate patents, regulatory exclusivity, formulation differences or manufacturing issues.

How strong is the patent estate for icatibant?

The strength of US 5,648,333 is high as historical composition-of-matter prior art and low as current exclusionary rights because the patent has expired.

Dimension	Assessment
Direct coverage of icatibant	Strong; claim 14 names the exact peptide
Breadth	Strong; claims 1-11 cover extensive analogue classes
Sequence certainty	Strong for claims 12-14
Current enforceability	None after expiration
Formulation protection	Not established by the supplied claims
Method-of-use protection	Present in claims 25-33 but expired with the patent
Biosimilar relevance	Limited; icatibant is a synthetic peptide
Generic-entry barrier from this patent	None
Manufacturing barrier	Potentially significant, but not created by this patent after expiry
Freedom-to-operate value	High as a reference point; low as an active blocking right

What manufacturing and formulation barriers remain?

The claims do not recite a specific injectable formulation, excipient system, container, device or sterile-filling process. They are principally composition, treatment-method and pharmaceutical-composition claims.

A follow-on manufacturer still must address:

Peptide assembly and protection-group chemistry.
Control of D-amino-acid and noncanonical amino-acid incorporation.
Formation and control of icatibant acetate.
Removal of deletion sequences and epimeric impurities.
Sterile manufacture and aseptic filling.
Stability of the aqueous injectable product.
Bioequivalence or other FDA requirements for a complex synthetic peptide.
Any later patents covering formulation, process or delivery-device features.

These issues may raise development cost and regulatory risk without preserving exclusivity under US 5,648,333.

What geographic coverage did the patent have?

US 5,648,333 provides protection only in the United States. The related invention was pursued through an international patent family, with corresponding rights potentially filed in Europe and other jurisdictions.

Foreign rights required separate analysis because:

Patent terms differ by filing history and national law.
Some national patents may have lapsed earlier.
Supplementary protection certificates may have affected European exclusivity.
Patent litigation and claim scope vary by jurisdiction.
National claims may not match the US claims for icatibant or D-Phe analogues.

The US patent cannot be used to establish freedom to operate in Europe, Japan, Canada, Australia or other markets.

What generic launch scenarios exist for icatibant?

Three launch scenarios are commercially relevant:

A conventional generic icatibant acetate injection relying on the expired composition patent and addressing any remaining listed patents through Paragraph IV or Paragraph III certifications.
A later entrant waiting for expiration or settlement of formulation, process, device or method patents.
A non-infringing product with a different formulation or manufacturing route, subject to FDA approval requirements and patent review.

Because US 5,648,333 expired in 2014, it is not the principal barrier to any current US generic launch. The decisive issues are later patent families, FDA requirements for the synthetic peptide injection, manufacturing scale and supply reliability.

Key Takeaways

US 5,648,333 is a bradykinin-antagonist patent originating from the Hoechst peptide program.
Claim 14 directly covers icatibant: H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
Claims 1-11 cover broad peptide genera and constrained heterocyclic analogues.
Claims 12-14 provide progressively narrower sequence-specific protection.
Claims 15-24 cover a separate D-Phe peptide series.
Claims 25-33 cover treatment methods and pharmaceutical compositions for bradykinin-mediated conditions.
The patent issued in 1997 and expired in 2014 under the applicable 20-year patent-term framework.
The patent no longer provides an enforceable US exclusivity barrier.
Icatibant is a synthetic peptide, so generic-drug and Hatch-Waxman analysis is more relevant than biosimilar analysis.
Current entry risk depends on later formulation, process, device, method-of-use and regulatory protections, not on US 5,648,333 alone.

FAQs About US Patent 5,648,333 and Icatibant

Is icatibant explicitly claimed in US 5,648,333?

Yes. Claim 14 expressly recites the icatibant peptide sequence and its physiologically tolerable salts.

Does US 5,648,333 still block generic Firazyr?

No. The patent expired in 2014 and does not independently block a current generic icatibant product.

Is icatibant a biologic subject to biosimilar approval?

No. Icatibant is a chemically synthesized peptide. A generic or hybrid drug pathway is generally more relevant than the biosimilar pathway.

Do the claims cover icatibant acetate?

Claim 14 covers icatibant and physiologically tolerable salts. Icatibant acetate is the salt form used in Firazyr.

Do the claims cover injectable formulations?

Claims 27, 30 and 33 cover pharmaceutical compositions containing claimed peptides and a pharmaceutically acceptable vehicle. They do not specify the detailed Firazyr formulation or a particular prefilled-syringe system.

What is the principal current patent risk for a generic icatibant product?

The principal risk comes from later patents covering formulation, manufacturing, delivery devices, regulatory exclusivity or other product-specific features. US 5,648,333 itself is expired.

References

United States Patent and Trademark Office. (1997). US Patent No. 5,648,333, Bradykinin antagonists.
U.S. Food and Drug Administration. (2011). Firazyr (icatibant acetate) prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	38 39 581.9	Nov 24, 1988
Germany	39 16 291.5	May 19, 1989
Germany	39 26 225.8	Jun 03, 1989
Germany	39 26 822.5	Aug 14, 1989
Germany	40 13 270.6	Apr 26, 1990

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0370453	⤷ Start Trial	91499	Luxembourg	⤷ Start Trial
European Patent Office	0370453	⤷ Start Trial	300359	Netherlands	⤷ Start Trial
European Patent Office	0370453	⤷ Start Trial	09C0002	France	⤷ Start Trial
European Patent Office	0370453	⤷ Start Trial	SPC/GB09/002	United Kingdom	⤷ Start Trial
European Patent Office	0370453	⤷ Start Trial	C300359	Netherlands	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,648,333

Summary for Patent: 5,648,333