U.S. Patent 6,114,304 covers methods using defined cyclic amylin analogues to reduce gastric motility, delay gastric emptying, treat dumping syndrome, and reduce postprandial hyperglycemia. Its strongest commercial relevance is to pramlintide-like human amylin analogues, particularly 25,28,29-proline human amylin. The patent is now expired under the ordinary U.S. patent-term framework, so it does not currently block generic, follow-on peptide, or other amylin-agonist development.

U.S. Drug Patent 6,114,304: Claim Scope, Expiration, Litigation, and Amylin Patent Landscape

What does U.S. Patent 6,114,304 protect?

U.S. Patent 6,114,304 is a method-of-use patent directed to administering an amylin or amylin agonist to a mammal to:

Reduce gastric motility.
Delay gastric emptying.
Treat gastrointestinal spasms.
Support gastrointestinal diagnostic procedures.
Treat postprandial dumping syndrome.
Treat postprandial hyperglycemia.

The independent claims do not cover every amylin molecule. They require the administered agonist to be an amylin analogue within specified sequence-defined Markush groups. The analogue must contain:

A human-amylin-related peptide backbone.
Variable residues at selected positions.
A chemically linked intramolecular structure between residues represented by X and Y.
A permitted C-terminal group represented by Z.
In specified native-sequence cases, at least one D-amino-acid substitution and a non-amino C-terminal group.

The patent therefore combines therapeutic-use limitations with detailed peptide-structure limitations.

Claim group	Principal subject matter	Key narrowing limitation
Claims 1-3	Reduced gastric motility or delayed gastric emptying	First defined amylin-analogue genus
Claims 4-6	Same gastrointestinal motility indications	Second sequence genus with expanded J1 options
Claims 7-9	Same indications	Third sequence genus with altered I1/J1 positioning
Claims 10-12	Same indications	Fourth sequence genus
Claims 13-16	Dependent sequence selections	Arg at D1, Val at I1 or J1, hydrogen at A1
Claims 17-23	Named amylin analogues	Specific residue substitutions
Claims 24-25	Salt forms	Acetate and hydrochloride salts
Claims 26-28	Diagnostic use	Radiological examination and magnetic resonance imaging
Claims 29-31	Gastrointestinal disorders	Spasm, diverticulitis, biliary tract and Sphincter of Oddi disorders
Claims 32-33	Dumping syndrome	Includes 25,28,29-proline human amylin
Claims 34-35	Postprandial hyperglycemia	Includes 25,28,29-proline human amylin

How broad are claims 1, 4, 7, and 10?

Claims 1, 4, 7, and 10 are the four principal independent claims. Each is a method claim, not a composition claim.

Claim 1

Claim 1 requires administration of an amylin or amylin agonist analogue having a defined 37-residue human-amylin-type sequence. The claim permits substitutions at A1 through K1 and permits three classes of internal linkage:

Disulfide bond.
Lactam linkage.
Thioether linkage.

The C terminus may be amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy, or aralkyloxy.

Claims 2 and 3 narrow claim 1 to a disulfide-linked analogue and then to an amino C terminus.

Claim 4

Claim 4 is similar to claim 1 but changes the sequence architecture and expands the permitted options for J1. It also contains two alternative provisos that address specified sequences. If one of those sequences otherwise corresponds closely to the native peptide, the claim requires a D-amino-acid substitution and a non-amino C terminus.

Claims 5 and 6 narrow the claim to a disulfide bond and amino C terminus.

Claim 7

Claim 7 covers another sequence genus in which the residues around positions 25 through 30 differ from the earlier claim groups. Claims 8 and 9 narrow this genus to disulfide-linked analogues with an amino C terminus.

Claim 10

Claim 10 covers a further sequence genus, with a distinct placement of the variable residues near the C-terminal region. Claims 11 and 12 narrow the genus to disulfide-linked compounds with an amino C terminus.

What peptide structures fall within the patent?

Claims 17 through 23 identify specific analogues. The named structures include:

18-Arg, 25,28-Pro human amylin.
Des-1-Lys, 18-Arg, 25,28-Pro human amylin.
25,28,29-Pro human amylin.
Des-1-Lys, 25,28,29-Pro human amylin.
18-Arg, 25,28,29-Pro human amylin.
Des-1-Lys, 18-Arg, 25,28,29-Pro human amylin.
25-Pro, 26-Val, 28,29-Pro human amylin.

The most commercially significant structure is 25,28,29-proline human amylin, the active peptide associated with pramlintide. Human amylin aggregates and forms amyloid fibrils, while proline substitutions at positions 25, 28, and 29 reduce aggregation and preserve amylin activity. The patent’s claims expressly capture that analogue and its use in gastric-emptying and glucose-control indications.

Claims 24 and 25 cover acetate and hydrochloride salts, but only when incorporated into the underlying method claims. They do not create standalone composition claims for the salts.

What are the key limitations in the independent claims?

The principal limitations are as follows:

Therapeutic administration

The accused activity must involve administering the analogue to a mammal in a therapeutically effective amount. Mere manufacture, possession, or sale of a peptide would not by itself meet the literal elements of the method claims.

Functional result

The use must reduce gastric motility, delay gastric emptying, treat postprandial dumping syndrome, or treat postprandial hyperglycemia, depending on the claim.

Sequence identity

The peptide must fall within one of the specified sequence genera or be one of the named analogues in claims 17 through 23. A structurally related amylin receptor agonist that falls outside the listed residue options would not literally satisfy the sequence limitation.

Intramolecular linkage

Claims 1, 4, 7, and 10 require X and Y to have side chains chemically bonded to form an intramolecular linkage. Claims 2, 5, 8, and 11 narrow that requirement to cysteine residues linked by a disulfide bond.

C-terminal group

The claims distinguish amino-terminal amylin analogues from analogues with substituted C-terminal groups. In several provisos, the native-like sequence is excluded unless a D-amino acid and non-amino C-terminal group are present.

What is the likely claim-construction risk?

The patent contains several prosecution and claim-construction pressure points.

First, the claims use extensive Markush language. A challenger could argue that the listed residue alternatives do not provide a uniform inventive concept across all combinations. The patent holder would respond that the sequence framework, intramolecular linkage, and amylin activity define a coherent genus.

Second, each independent claim includes a functional treatment result. In an infringement case, the patentee would need to establish that the accused administration is directed to, or produces, the claimed gastrointestinal or glycemic effect. Label language, clinical protocols, promotional statements, and physician instructions could be relevant.

Third, the provisos create complicated exclusions and inclusions. For some sequence combinations, the claim requires a D-amino acid and a non-amino C terminus. A peptide with the same residue sequence but an amino C terminus may fall outside that portion of the claim.

Fourth, the supplied claim text contains apparent typographical or drafting irregularities, including inconsistent notation for H1 and references to K1 in claim 10’s proviso even though K1 is not clearly included in the preceding list. Such issues would be evaluated against the issued patent, prosecution history, specification, and any certificate of correction. They do not automatically invalidate the claims.

When did U.S. Patent 6,114,304 lose exclusivity?

U.S. Patent 6,114,304 issued on September 5, 2000. Under the Uruguay Round Agreements Act, utility patents generally expire 20 years from the earliest effective U.S. nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and applicable continuity rules.[1][2]

The patent is no longer enforceable as a live U.S. patent. Its ordinary patent term has ended. No current commercial exclusivity should be attributed to U.S. Patent 6,114,304.

Event	Date or status
U.S. patent issued	September 5, 2000
Patent type	Utility, method-of-use patent
Standard statutory framework	20 years from earliest effective nonprovisional filing
Current status	Expired
Current blocking effect	None from this patent alone

The exact day of expiration should be distinguished from the broader conclusion that the patent is expired. The exact term calculation depends on the complete continuity chain and USPTO term records, including any patent-term adjustment or terminal disclaimer.

What is the Orange Book status of Patent 6,114,304?

U.S. Patent 6,114,304 is not, by its claim form, a conventional composition or formulation patent. It is principally a method-of-use patent. Its relevance to the FDA Orange Book would depend on whether the patent was submitted for an approved drug product and whether the FDA accepted it as a patent that claims an approved method of use.[3]

For pramlintide, the relevant product is Symlin, marketed by AstraZeneca following its acquisition of the diabetes business associated with Amylin Pharmaceuticals. Symlin was approved by the FDA in 2005 as an adjunct to mealtime insulin for adults with type 1 or type 2 diabetes.[4]

An Orange Book listing does not extend the underlying patent term. If listed, the patent could have supported a Paragraph IV certification or a section viii carve-out during its unexpired term. It does not create a current regulatory barrier after expiration.

Did the patent generate Paragraph IV litigation?

The supplied record does not establish a Paragraph IV challenge specifically directed to U.S. Patent 6,114,304. No current Paragraph IV risk attaches to the patent because the patent has expired.

During the patent’s term, a generic applicant could have used:

A Paragraph IV certification alleging invalidity, unenforceability, or noninfringement.
A section viii statement carving out a patented method of use.
A certification based on the absence of a relevant Orange Book listing.

Because the claims are method claims, a section viii strategy could have been commercially important if a generic applicant sought approval for glucose-control uses while excluding gastric-emptying or dumping-syndrome language. The practical result would depend on the approved labeling and the scope of any listed method claims.

What is the relationship between this patent and pramlintide?

Pramlintide is the principal commercial analogue relevant to the patent. It is a synthetic amylin analogue with proline substitutions at positions 25, 28, and 29. Claims 19, 20, and 33 expressly identify 25,28,29-proline human amylin or a closely related des-1-Lys form.

Product or analogue	Relationship to Patent 6,114,304
Pramlintide	Directly relevant to claims identifying 25,28,29-proline human amylin
Symlin	FDA-approved pramlintide product
Native human amylin	Within the broader biological subject matter but not necessarily within every sequence-specific claim
GLP-1 receptor agonists	Outside the claimed amylin-analogue sequence framework
Long-acting amylin analogues	Potentially outside the literal claims unless their sequence and linkage meet the specified limitations

The patent is more relevant to historical protection for pramlintide’s gastrointestinal and glycemic uses than to current freedom to operate.

What formulation patents protect amylin products?

Patent 6,114,304 does not principally protect:

A liquid injectable formulation.
A sustained-release depot.
A prefilled syringe.
A pen injector.
A nasal or oral delivery system.
A specific excipient combination.
A manufacturing process for commercial-scale peptide production.

A current competitor would therefore need to review separate formulation, device, manufacturing, stability, and process patents. Those rights may have different owners, filing dates, and expiration dates. They are not established by the claims supplied for Patent 6,114,304.

The patent does protect salt forms only as dependent method limitations. Claims 24 and 25 do not independently prevent a company from making or selling an acetate or hydrochloride salt without practicing one of the claimed methods.

Does the patent create biosimilar risk?

Pramlintide is a peptide drug rather than a conventional therapeutic protein such as a monoclonal antibody. A follow-on pramlintide product may be pursued through an abbreviated pathway under the Federal Food, Drug, and Cosmetic Act, including a potential 505(b)(2) strategy, rather than relying exclusively on the biosimilar pathway under the Public Health Service Act.[5]

Patent 6,114,304 does not create current biosimilar or follow-on peptide exclusivity because it has expired. Residual barriers could arise from:

Manufacturing know-how.
Peptide purity and impurity controls.
Aggregation and stability control.
Device compatibility.
Clinical bridging requirements.
Separate formulation patents.
Trade secrets and supply-chain capacity.

Those barriers are commercial and regulatory rather than attributable to the expired patent.

How strong is the patent estate for the claimed indications?

The patent had meaningful historical scope because it combined a broad therapeutic concept with multiple sequence genera and named analogues. Its strongest claim positions were:

The explicit coverage of 25,28,29-proline human amylin.
The disulfide-linked analogue embodiments.
The postprandial hyperglycemia claims.
The dumping-syndrome claims.
The use of amylin agonists during gastrointestinal diagnostic procedures.

Its weaker positions were:

Dependence on precise sequence and linkage limitations.
Potential design-around opportunities using nonclaimed residue substitutions.
Functional-result requirements.
Possible restrictions from the provisos.
Lack of standalone composition, formulation, device, or manufacturing claims.

The patent’s historical strength was therefore use-specific and molecule-specific, not platform-wide.

What generic launch scenarios exist today?

Because the patent is expired, the principal launch scenarios are:

Pramlintide follow-on

A sponsor may pursue an abbreviated or 505(b)(2) application for a pramlintide product. The sponsor would evaluate whether the proposed label includes the same glycemic indications, whether a clinical bridge is required, and whether separate formulation or device rights remain active.

Label carve-out

A follow-on product could omit indications associated with gastric motility, dumping syndrome, or diagnostic procedures if those uses were protected by another unexpired method patent. Patent 6,114,304 itself no longer requires a carve-out.

New amylin agonist

A next-generation amylin agonist may avoid the patent through sequence changes, non-peptide chemistry, altered receptor activity, or a different delivery system. New composition and formulation patents would become the primary protection.

Combination product

Amylin or amylin/GLP-1 combinations would require a separate patent analysis. Patent 6,114,304 does not expressly claim a combination regimen.

What geographic coverage does the patent have?

U.S. Patent 6,114,304 provides U.S. rights only. Related foreign applications may have produced patents in Europe, Canada, Japan, Australia, or other jurisdictions, but those rights must be assessed separately. Foreign counterparts may differ in:

Claim scope.
Patent term.
Patent-term adjustment.
Opposition history.
Supplementary protection certificates.
National validity.
Litigation status.

The U.S. expiration does not determine the status of foreign counterparts.

Key Takeaways

U.S. Patent 6,114,304 is a method-of-use patent for amylin and defined amylin analogues.
Claims 1, 4, 7, and 10 cover sequence-specific genera with internal disulfide, lactam, or thioether linkages.
Claims 17 through 23 identify specific analogues, including 25,28,29-proline human amylin associated with pramlintide.
Claims 24 and 25 cover acetate and hydrochloride salts only as dependent method limitations.
Claims 26 through 31 extend to diagnostic procedures, gastrointestinal spasms, diverticulitis, biliary disorders, and Sphincter of Oddi disorders.
Claims 32 through 35 cover dumping syndrome and postprandial hyperglycemia.
The patent is expired and does not create current U.S. exclusivity.
No current Paragraph IV barrier arises from this patent.
Follow-on pramlintide risk now depends mainly on regulatory requirements, formulation and device rights, manufacturing controls, and any separate unexpired patents.
The patent’s historical strength was concentrated in pramlintide-like sequences and gastrointestinal or glycemic uses rather than formulations or manufacturing.

FAQs

Is pramlintide covered by U.S. Patent 6,114,304?

Yes. Claims 19, 20, and 33 expressly identify 25,28,29-proline human amylin or closely related forms corresponding to pramlintide-type molecules.

Does Patent 6,114,304 cover semaglutide or tirzepatide?

No. The claims require amylin or amylin-analogue structures. Semaglutide is a GLP-1 receptor agonist, and tirzepatide is a dual GIP/GLP-1 receptor agonist.

Does the patent cover oral amylin formulations?

Not as a standalone formulation right. The claims require administering a qualifying amylin analogue, but they do not specify an oral formulation, excipient system, or delivery technology.

Can a company launch a pramlintide generic without this patent?

This patent does not prevent launch because it is expired. The sponsor must still address FDA requirements and any separate active patents covering formulation, device, manufacturing, or labeling.

Are the claimed amylin analogues limited to disulfide-linked peptides?

No. The independent claims permit disulfide, lactam, and thioether intramolecular linkages. Dependent claims 2, 5, 8, and 11 narrow the scope to cysteine disulfide bonds.

References

United States Patent and Trademark Office. (n.d.). Patent term adjustment. U.S. Department of Commerce. https://www.uspto.gov/patents/laws/patent-term-adjustment
United States Patent and Trademark Office. (n.d.). Patent term calculator. U.S. Department of Commerce. https://www.uspto.gov/patents/laws/american-inventors-protection-act-1999/patent-term-calculator
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugsatfda
U.S. Food and Drug Administration. (2005). FDA approves Symlin to treat diabetes. https://www.fda.gov/
U.S. Food and Drug Administration. (n.d.). 505(b)(2) applications. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda
U.S. Patent No. 6,114,304. (2000). Methods of reducing gastric motility using amylin agonists. United States Patent and Trademark Office.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	197549	⤷ Start Trial
Australia	7685894	⤷ Start Trial
Bulgaria	100463	⤷ Start Trial
Brazil	9407424	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,114,304