U.S. Patent 5,686,411: Amylin Analogue Claims, Pramlintide Coverage, and Patent Landscape

U.S. Patent No. 5,686,411 covers a broad genus of chemically modified amylin peptides, including the specific analogue later known as pramlintide, or 25,28,29 Pro-human amylin. The patent claims peptide sequence variants, intramolecularly cyclized analogues, C-terminal modifications, pharmaceutically acceptable salts, diabetes-treatment methods, peptide-insulin combinations, and pharmaceutical compositions.

The patent issued on November 11, 1997, and its ordinary 20-year term from the earliest claimed nonprovisional filing date has expired. It therefore does not currently block manufacture, use, or sale of a covered amylin analogue in the United States. Its historical importance remains substantial because it is a foundational composition patent for pramlintide and related amylin analogues.

What drug does U.S. Patent 5,686,411 protect?

The patent protects analogues of human amylin, also called islet amyloid polypeptide or IAPP. Human amylin is a 37-amino-acid peptide cosecreted with insulin by pancreatic beta cells.

The most commercially important compound within the claims is:

25,28,29 Pro-human amylin, also known as pramlintide.

Pramlintide substitutes proline residues at positions 25, 28, and 29 of human amylin. These substitutions reduce the peptide's aggregation tendency while preserving amylin receptor activity. Pramlintide was developed by Amylin Pharmaceuticals and marketed by AstraZeneca under the brand name Symlin and SymlinPen.

The relevant human amylin sequence is:

Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-
Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-
Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-
Ser-Asn-Thr-Tyr-NH2

Pramlintide contains the substitutions Pro25, Pro28, and Pro29 and retains the native disulfide bond between Cys2 and Cys7. The amidated C terminus is material to the peptide's identity and activity.

What are the principal claim categories in Patent 5,686,411?

The 45 claims fall into five functional groups.

Claim group	Claims	Subject matter
Broad analogue genera	1, 4, 7, 10	Variable amino-acid residues, cyclization, and terminal groups
Disulfide and amidated analogues	2-3, 5-6, 8-9, 11-12	Cys-Cys disulfide bond and amino C terminus
Specific named peptides	17-23	Defined human-amylin substitution patterns
Salts	24-29	Acetate, trifluoroacetate, and hydrochloride salts
Treatment and composition claims	30-45	Diabetes treatment, insulin combinations, and pharmaceutical compositions

The claims are primarily composition claims. They do not depend on a particular manufacturing process, device, formulation excipient, or dosing schedule.

How broad are the composition claims?

Claims 1, 4, 7, and 10 define large sequence genera. They allow specified substitutions at multiple positions, subject to defined residue lists. The claims also cover three types of intramolecular linkage:

Disulfide bonds;
Lactam linkages; and
Thioether linkages.

The claims further cover multiple C-terminal groups, including:

Amino;
Alkylamino;
Dialkylamino;
Cycloalkylamino;
Arylamino;
Aralkylamino;
Alkyloxy;
Aryloxy; and
Aralkyloxy.

The broadest practical commercial embodiment is the native amylin-like peptide with a Cys2-Cys7 disulfide bridge and an amidated C terminus. Claims 3, 6, 9, and 12 narrow the broader genera to compounds with a disulfide bond and an amino terminal group.

The patent uses Markush-style residue definitions. Each listed residue expands the number of possible peptide sequences. The resulting genus is much broader than pramlintide itself, although infringement would require a peptide to fall within the specific residue, linkage, and terminal-group limitations of an asserted claim.

Does Patent 5,686,411 specifically claim pramlintide?

Yes. Claim 19 expressly recites:

25,28,29 Pro-h-amylin.

That is the defining substitution pattern of pramlintide.

Claims 35, 37, 43, and 45 also specifically address 25,28,29 Pro-human amylin in:

Diabetes-treatment methods;
Combination treatment with insulin;
Pharmaceutical compositions; and
Pharmaceutical compositions containing insulin.

The patent therefore contains both direct composition coverage and downstream method and formulation coverage for pramlintide.

What specific amylin analogues are named in the claims?

Claims 17 through 23 identify seven defined analogues.

Claim	Named analogue
17	18 Arg25,28 Pro-human amylin
18	des-1 Lys18 Arg25,28 Pro-human amylin
19	25,28,29 Pro-human amylin
20	des-1 Lys25,28,29 Pro-human amylin
21	18 Arg25,28,29 Pro-human amylin
22	des-1 Lys18 Arg25,28,29 Pro-human amylin
23	25 Pro26 Val28,29 Pro-human amylin

The “des-1 Lys” notation generally indicates removal of the N-terminal Lys residue. The named compounds show that the inventors pursued both residue substitutions and N-terminal modification.

Claim 19 is the commercially important claim because it corresponds to pramlintide. Claims 17, 18, and 21-23 cover research and development analogues that are distinct from pramlintide but structurally related.

What is the scope of the disulfide-bond claims?

Claims 2, 5, 8, and 11 require X and Y to be cysteine residues linked through a disulfide bond. For the human-amylin framework, this corresponds to the native Cys2-Cys7 bridge.

These claims are narrower than claims 1, 4, 7, and 10 because they exclude lactam and thioether linkages. They are also narrower than the full C-terminal-group alternatives because claims 3, 6, 9, and 12 require the amino terminal group.

A peptide containing the correct amylin sequence but using a lactam bridge instead of a disulfide bridge could fall outside the narrower Cys-disulfide claims while potentially remaining within a broader claim, depending on the other sequence and terminal-group limitations.

What do the method-of-use claims cover?

Claims 30 through 37 cover treatment of diabetes mellitus in a mammal using the claimed amylin analogue.

The treatment claims include:

Claims 30, 31, 32, and 33: use of the broad disulfide/amidated analogue classes;
Claim 34: use of any of the named compounds in claims 17-23;
Claim 35: use of 25,28,29 Pro-human amylin;
Claim 36: administration of an analogue with insulin;
Claim 37: administration of pramlintide with insulin.

These claims are method-of-treatment claims, not claims to a specific route, dose, injection device, patient subgroup, or glycemic endpoint. Their practical value was strongest before expiration, when they could have supported infringement allegations against commercial use of the covered peptide for diabetes.

After expiration, the claims no longer create a live U.S. patent barrier. Method claims also cannot extend the expired composition patent's term.

What formulations and salts are protected?

Claims 24 through 29 cover pharmaceutically acceptable salts of the claimed analogues.

The named salts are:

Acetate;
Trifluoroacetate; and
Hydrochloride.

Claims 38 through 45 cover pharmaceutical compositions containing the analogues in a pharmaceutically acceptable carrier. Claims 44 and 45 cover compositions containing both an amylin analogue and insulin.

These are formulation and composition claims, but they are relatively general. They do not claim a detailed excipient system, preservative combination, pH range, concentration window, injection device, or stability profile. A later formulation patent could therefore have provided separate protection for a specific liquid formulation, container closure, delivery device, or storage condition.

What is the legal status and expiration date of Patent 5,686,411?

Patent 5,686,411 is expired.

Item	Status
U.S. patent	5,686,411
Issue date	November 11, 1997
Patent holder at issuance	Amylin Pharmaceuticals, Inc.
Technology	Amylin analogues
Regulatory product associated with key claim	Pramlintide, Symlin
Ordinary patent term	Expired
Current U.S. exclusionary effect	None

The patent was filed under the pre-Uruguay Round patent-term system, under which the term was generally 17 years from issuance. The patent's ordinary term therefore ended in 2014, subject to any applicable terminal disclaimer or patent-term adjustment analysis. Under either the issuance-based term or a 20-year-from-filing calculation based on the earliest relevant filing, the patent is no longer enforceable.

The precise historical expiration date should be determined from the complete patent file, continuity data, and any terminal disclaimer or patent-term adjustment records. That distinction does not change the current conclusion: Patent 5,686,411 is expired and cannot support a present-day U.S. infringement action.

What is the Orange Book status of Patent 5,686,411?

Patent 5,686,411 is not a current exclusivity barrier for Symlin or a pramlintide generic.

FDA Orange Book listings are product-specific and depend on the NDA holder's submission, FDA acceptance, and the patent's continuing enforceability. A patent may appear in historical Orange Book records even after its term has ended. Historical listing does not revive the patent or create a new exclusivity period.

Symlin was approved under NDA 021332. FDA approval covered pramlintide acetate injection for adjunctive use in patients with type 1 or type 2 diabetes using mealtime insulin. FDA labeling identifies pramlintide acetate as a synthetic analogue of human amylin. The approval did not create patent rights beyond the term of the listed patents. [2]

The current commercial and regulatory analysis must distinguish:

Patent expiration;
FDA regulatory exclusivity;
Orange Book listing;
NDA ownership; and
Availability of an ANDA or 505(b)(2) pathway.

Patent 5,686,411 supplies no current regulatory exclusivity.

Were Paragraph IV challenges relevant to this patent?

A Paragraph IV certification would have been relevant while Patent 5,686,411 was listed and unexpired against a pramlintide reference product.

A generic applicant making a Paragraph IV certification would assert that the patent is invalid, unenforceable, or not infringed. The NDA holder could then bring litigation within the statutory period, potentially triggering a 30-month stay under the Hatch-Waxman framework. [3]

For Patent 5,686,411, the commercial relevance of a Paragraph IV challenge has ended because the patent is expired. A present applicant would not obtain meaningful market protection by challenging this patent alone. Any current patent dispute would have to involve a later patent covering a formulation, delivery device, manufacturing process, dosage regimen, or other product-specific feature.

The available claim set does not establish that a Paragraph IV litigation occurred against this patent. The patent text alone cannot support a reliable conclusion about historical filing, settlement, or launch dates.

What patent landscape surrounds pramlintide?

The pramlintide landscape has several layers.

Foundational composition patents

Patent 5,686,411 is a foundational composition patent. It covers pramlintide directly and also claims broad classes of related analogues.

Later formulation patents

Later patents could target:

Aqueous pramlintide formulations;
Chemical and physical stability;
Preservatives;
Concentration and pH ranges;
Multidose containers;
Pen-injector delivery;
Coformulation with insulin; and
Reduced injection burden.

Those rights are legally distinct from Patent 5,686,411. Expiration of the foundational peptide patent does not automatically eliminate later formulation or device rights.

Method-of-use patents

Potential later rights could claim:

Use in type 1 diabetes;
Use in type 2 diabetes;
Weight-management effects;
Postprandial glucose control;
Specific titration methods;
Combination use with insulin; or
Use in selected patient populations.

Patent 5,686,411 itself has broad diabetes-treatment claims but no narrow patient-selection or dosing limitations.

Manufacturing patents and trade secrets

Pramlintide is a synthetic peptide. Commercial barriers may include:

Solid-phase peptide synthesis;
Site-specific disulfide formation;
Control of aggregation;
Purification of closely related peptide impurities;
C-terminal amidation;
Peptide oxidation and deamidation control;
Sterile filling; and
Stability during refrigerated storage.

A manufacturing patent could create a separate barrier even after composition-patent expiration. Process know-how and analytical methods may remain commercially important without creating patent exclusivity.

How strong was the patent estate?

Patent 5,686,411 was strong as a foundational composition patent because claim 19 identifies pramlintide by name and claims 35, 43, and 45 extend to its use and compositions.

Its principal strengths were:

Direct coverage of pramlintide;
Broad sequence genera;
Coverage of multiple chemical linkages;
Coverage of salts;
Coverage of compositions;
Coverage of diabetes treatment; and
Coverage of combination treatment with insulin.

Its principal limitations were:

No current enforceable term;
General rather than highly specific formulation claims;
No detailed device claim;
No defined manufacturing-process claim in the supplied claims;
Potential claim-construction issues in the variable sequence language; and
Dependence on the specification for interpretation of the sequence diagrams and residue numbering.

The patent was strongest against a product chemically identical to pramlintide. It was less certain against a substantially modified analogue using nonclaimed residues, a different terminal group, or a different cyclization chemistry.

What generic entry risks exist for pramlintide?

Patent 5,686,411 creates no current generic-entry risk because it is expired. The relevant risks are regulatory and commercial.

A potential competitor would need to address:

FDA pathway selection;
Reference-product exclusivity;
Bioequivalence or comparative clinical requirements;
Peptide characterization;
Immunogenicity and impurity control;
Device compatibility;
Stability;
Manufacturing scale-up; and
Any later-expiring patents.

Pramlintide is a peptide rather than a conventional small-molecule drug. The applicable approval pathway may depend on whether FDA treats the proposed product as eligible for an ANDA referencing Symlin or whether a 505(b)(2) application is more appropriate. FDA's regulatory treatment of complex peptides and product-specific sameness can materially affect timing and development cost. [4]

Biosimilar terminology is generally less precise for pramlintide than for biologics licensed under the Public Health Service Act. A competing pramlintide product would more likely be assessed under an abbreviated drug pathway or 505(b)(2), depending on FDA's determination and the product's formulation and delivery system.

Which companies are associated with the pramlintide market?

Amylin Pharmaceuticals originated pramlintide and commercialized Symlin. AstraZeneca acquired Amylin in 2012 and obtained the associated commercial portfolio. The product was later marketed under AstraZeneca's diabetes business.

The relevant competitive set includes:

Branded pramlintide;
Potential generic or follow-on pramlintide products;
Insulin products used in combination with pramlintide;
GLP-1 receptor agonists;
Dual and triple incretin agonists; and
Other postprandial glucose-control therapies.

Pramlintide's commercial position has been affected by injection burden, titration requirements, nausea, hypoglycemia management, and competition from newer incretin-based therapies. No reliable product-specific revenue figure can be derived from Patent 5,686,411 itself.

Key Takeaways

Patent 5,686,411 is a foundational U.S. patent for amylin analogues.
Claim 19 expressly covers 25,28,29 Pro-human amylin, the peptide known as pramlintide.
Claims 35, 37, 43, and 45 cover pramlintide treatment and compositions, including use with insulin.
Claims 24-29 cover acetate, trifluoroacetate, and hydrochloride salts.
The patent also covers broad sequence genera, disulfide analogues, lactam and thioether variants, and multiple terminal groups.
The patent is expired and does not currently block U.S. commercialization.
Any current freedom-to-operate analysis must focus on later formulation, device, process, manufacturing, or method-of-use patents.
A pramlintide competitor would face greater regulatory and manufacturing issues than a live composition-patent barrier.
The relevant regulatory pathway may be an ANDA or 505(b)(2), depending on FDA treatment of the proposed peptide product.

FAQs

Does Patent 5,686,411 cover Symlin?

Yes. The patent expressly claims 25,28,29 Pro-human amylin, which is pramlintide, the active peptide in Symlin.

Is pramlintide still patent protected in the United States?

Patent 5,686,411 no longer provides enforceable U.S. protection. Later patents, if any, must be reviewed separately for formulation, device, process, or method-of-use coverage.

Is pramlintide a biosimilar?

Pramlintide is a synthetic peptide drug. A competing product would generally be analyzed under an abbreviated drug or 505(b)(2) framework rather than assumed to use the biosimilar pathway applicable to licensed biologics.

Does the patent claim insulin-pramlintide combination therapy?

Yes. Claims 36, 37, 44, and 45 cover treatment or compositions involving both an amylin analogue and insulin.

What is the most commercially important claim in Patent 5,686,411?

Claim 19 is the central commercial claim because it expressly identifies 25,28,29 Pro-human amylin, the active peptide known as pramlintide.

References

U.S. Patent No. 5,686,411. (1997). Amylin analogues. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2005). Symlin (pramlintide acetate) injection, prescribing information. FDA.
U.S. Food and Drug Administration. (n.d.). Hatch-Waxman Letters. FDA.
U.S. Food and Drug Administration. (2023). M13A: Bioequivalence for immediate-release solid oral dosage forms. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	205854	⤷ Start Trial
Australia	1245697	⤷ Start Trial
Australia	3075392	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,686,411

Summary for Patent: 5,686,411