Details for Patent: 6,458,924

Summary for Patent: 6,458,924

Title:	Derivatives of GLP-1 analogs
Abstract:	The present invention relates to a pharmaceutical composition comprising a GLP-1 derivative having a lipophilic substituent; and a surfactant.
Inventor(s):	Liselotte Bjerre Knudsen, Per Olaf Huusfeldt, Per Franklin Nielsen
Assignee:	Novo Nordisk AS
Application Number:	US09/398,111
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,458,924
Patent Claim Types: see list of patent claims	Use; Composition;

United States Patent 6,458,924: Scope, Claims, Expiration, and GLP-1 Patent Landscape

US Patent 6,458,924 covered a class of acylated GLP-1(7-37) derivatives, including liraglutide. The core claim required modification of Lys26 with a defined lipophilic group, either directly or through specified spacers. The patent also covered pharmaceutical compositions and methods for treating diabetes and obesity.

The patent was issued to Novo Nordisk A/S on October 1, 2002, and its standard 20-year term expired on September 29, 2019. It is no longer an enforceable U.S. patent. Its historical importance remains high because it covered the active pharmaceutical ingredient in Victoza and Saxenda, but later Novo Nordisk patents created additional barriers to generic liraglutide entry.

What does US Patent 6,458,924 cover?

The patent covers GLP-1 derivatives based on the native human GLP-1(7-37) sequence:

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg

The critical modification is at the epsilon-amino group of Lys26. Claim 1 requires that Lys26 carry a lipophilic substituent, with or without a spacer.

The covered GLP-1 derivative can be represented structurally as:

GLP-1(7-37)-Lys26-[spacer]-[lipophilic group]

The claim permits the following lipophilic groups:

Category	Defined substituents
Saturated fatty acyl groups	CH3(CH2)nCO-, where n is 6, 8, 10, 12, 14, 16, 18, 20 or 22
Dicarboxylic acyl groups	HOOC(CH2)mCO-, where m is 10, 12, 14, 16, 18, 20 or 22
Steroid-derived group	Lithocholyl

The patent permits a spacer consisting of:

• An amino acid residue other than cysteine
• Gamma-aminobutanoyl

Dependent claims identify specific spacers, including gamma-glutamyl, beta-asparagyl, glycyl, gamma-aminobutanoyl and beta-alanyl.

Does US Patent 6,458,924 cover liraglutide?

Yes. Liraglutide falls within the technical scope of claim 1.

Liraglutide is an acylated GLP-1 analog with:

• GLP-1(7-37) peptide backbone
• Native Arg34 residue
• Palmitoyl group attached to Lys26
• Gamma-glutamyl spacer between Lys26 and the palmitoyl group

The liraglutide structure is therefore:

GLP-1(7-37)-Lys26-[gamma-Glu]-[palmitoyl]

Palmitoyl corresponds to CH3(CH2)14CO-, which is expressly included in claim 1 because n=14. Gamma-glutamyl is expressly recited in claim 3.

Liraglutide element	Patent requirement	Match
GLP-1(7-37) backbone	Formula I, SEQ ID NO:2	Yes
Modification site	Lys26 epsilon-amino group	Yes
Spacer	Gamma-glutamyl	Yes, claim 3
Lipophilic group	Palmitoyl	Yes, n=14
Therapeutic use	Diabetes and obesity	Claims 19 and 20
Pharmaceutical formulation	Composition with vehicle or carrier	Claim 8 and dependent claims

The patent does not use the later commercial name “liraglutide.” It claims the molecule structurally through sequence and substituent limitations.

How broad is claim 1?

Claim 1 is a genus claim covering multiple acylated GLP-1 compounds. It is materially broader than liraglutide because it includes:

1. Nine different saturated fatty acyl chain lengths.
2. Seven dicarboxylic acyl chain lengths.
3. Lithocholyl substitution.
4. Direct attachment to Lys26.
5. Attachment through multiple permitted spacers.
6. Any amino acid spacer other than cysteine, subject to the claim language.
7. Gamma-aminobutanoyl as a separately identified spacer.

The claim is limited in several important respects. It requires the specified GLP-1 sequence and specifically targets Lys26. It does not broadly cover every GLP-1 analog, every fatty-acylated peptide, or every modification at another residue.

Claim 1: chemical scope

Claim 1 is the principal composition-of-matter claim. It requires all of the following:

• The exact GLP-1 derivative sequence identified as SEQ ID NO:2.
• Substitution at Lys26.
• A lipophilic substituent from the listed Markush groups.
• An optional spacer that fits the claimed categories.

A competing GLP-1 product would not fall literally within claim 1 if it used:

• A different peptide sequence.
• A modification at Lys34, Lys37 or another residue.
• A non-listed lipophilic group.
• A chain length outside the stated n or m values.
• A spacer excluded by the claim.

The doctrine of equivalents could have affected some non-literal variants during the patent term, but that issue is no longer commercially actionable against new U.S. products because the patent has expired.

What do claims 2 through 7 protect?

Claims 2 through 7 narrow the spacer configuration.

Claim	Scope
2	Lipophilic group linked through a spacer
3	Gamma-glutamyl spacer
4	Beta-asparagyl spacer
5	Glycyl spacer
6	Gamma-aminobutanoyl spacer
7	Beta-alanyl spacer

Claim 3 is particularly significant for liraglutide because liraglutide uses a gamma-glutamyl spacer and a palmitoyl group.

Claims 2 through 7 do not create separate active ingredients. They create narrower fallback positions within the broader genus of claim 1. A compound covered by claim 3 would also need to satisfy claim 1.

What formulations are protected by claims 8 through 18?

Claims 8 through 18 cover pharmaceutical compositions containing a compound of claim 1.

Core composition claim

Claim 8 requires:

• A GLP-1 derivative of claim 1; and
• A pharmaceutically acceptable vehicle or carrier.

The composition claim is dependent on the chemical scope of claim 1. It does not independently cover formulations containing unrelated GLP-1 products.

Formulation additives

The dependent claims identify several conventional formulation components:

Claim	Formulation element
9	Isotonic agent, preservative and buffer
10	Sodium chloride, mannitol or glycerol as isotonic agents
11	Phenol, m-cresol, methyl p-hydroxybenzoate or benzyl alcohol as preservatives
12	Sodium acetate or sodium phosphate as buffers
13	Surfactant
14	Zinc
15	Antidiabetic agent
16	Human insulin
17	Hypoglycemic agent
18	Antiobesity agent

These claims have less strategic value than the composition-of-matter claim because many of the listed excipients are conventional pharmaceutical ingredients. Their enforceability would have depended on the underlying GLP-1 derivative also satisfying claim 1.

The formulation claims could have been relevant to an injectable liraglutide product containing defined buffers, preservatives, isotonic agents or co-administered agents. They did not necessarily cover every commercial Victoza or Saxenda formulation unless the formulation met the relevant dependent claim.

What methods of treatment are protected?

Claims 19 and 20 are method-of-use claims.

Claim	Therapeutic method
19	Treating diabetes by administering a therapeutically effective amount
20	Treating obesity by administering a therapeutically effective amount

These claims are broad as to the specific diabetes or obesity indication, but they remain dependent on use of a GLP-1 derivative covered by claim 1.

The claims do not expressly require:

• A particular dose.
• A particular route of administration.
• A particular dosing frequency.
• A particular disease subtype.
• A specific patient population.
• A particular formulation.

During the patent term, a product could therefore have faced method-of-use exposure even if a commercial formulation claim was contested. After expiration, claims 19 and 20 no longer block U.S. commercial use.

When did US Patent 6,458,924 expire?

Event	Date
Earliest priority date	September 29, 1998
U.S. filing date	September 29, 1999
Patent issued	October 1, 2002
Standard expiration	September 29, 2019
Current status	Expired

The patent term was governed by the 20-year term measured from the relevant U.S. nonprovisional filing date, subject to any applicable adjustment or extension. Public patent-status records identify September 29, 2019 as the expiration date for US 6,458,924 (USPTO, n.d.; Google Patents, n.d.).

The patent therefore no longer creates a blocking right against generic liraglutide, follow-on peptide products or other products that would previously have fallen within its claims.

What was the FDA status of liraglutide?

The FDA approved liraglutide under two principal products:

Product	Sponsor	Active ingredient	FDA approval
Victoza	Novo Nordisk	Liraglutide	January 25, 2010
Saxenda	Novo Nordisk	Liraglutide	December 23, 2014

Victoza was approved for glycemic control in adults with type 2 diabetes. Saxenda was approved at a higher dosing regimen for chronic weight management in specified patients with obesity or overweight and weight-related comorbidities (FDA, 2010; FDA, 2014).

Liraglutide is a synthetic peptide drug, not a monoclonal antibody or other biologic requiring a conventional biosimilar pathway. Generic competition proceeds primarily through the abbreviated new drug application pathway, subject to pharmaceutical equivalence, bioequivalence and applicable labeling requirements.

What was the Orange Book status of US Patent 6,458,924?

US 6,458,924 was historically associated with Novo Nordisk’s liraglutide products and appeared in the patent landscape for Victoza. Its expiration in 2019 removed it as a current Orange Book barrier.

The practical Orange Book analysis is:

Issue	Assessment
Historical listing relevance	High
Current enforceable patent right	None
Current generic blocking effect	None
Relationship to later liraglutide patents	Earlier foundational patent; later patents addressed additional protection
Paragraph IV relevance today	No live claim under this patent

An Orange Book listing does not extend patent duration. Once the listed patent expires, it cannot independently support an injunction against a later ANDA product.

Which later patents created liraglutide entry risk?

The U.S. liraglutide estate included later patents directed to additional aspects of the molecule, formulations, dosing and therapeutic use. The most commercially relevant later patent numbers associated with Victoza and liraglutide included:

Patent	General role in the landscape	Status by 2025
US 6,268,343	Earlier GLP-1 derivative protection	Expired
US 6,458,924	Acylated GLP-1 derivative genus, including liraglutide	Expired September 29, 2019
US 7,235,627	Later liraglutide and GLP-1 derivative protection	Expired or no longer a primary current barrier, depending on applicable term records
US 8,129,343	Later liraglutide-related protection	Historically relevant to ANDA litigation
US 8,349,803	Additional product, formulation or use protection	Historically relevant
Later Novo Nordisk patents	Dosing, formulations, device and administration claims	Scope and expiration vary by patent

The exact commercial barrier depended on the ANDA applicant’s proposed label, formulation, device, manufacturing process and Paragraph IV positions. A generic applicant could challenge one patent while carving out a patented indication or avoiding a formulation claim.

Which companies challenged liraglutide exclusivity?

The principal competitive risk came from generic pharmaceutical companies pursuing abbreviated applications for liraglutide injection. Teva Pharmaceutical Industries received FDA approval for a generic version of Victoza in 2024, marking the first U.S. generic liraglutide approval reported by FDA (FDA, 2024).

The relevant competitive categories were:

• Generic liraglutide injection applicants.
• Applicants using Paragraph IV certifications against unexpired Orange Book patents.
• Companies pursuing alternative GLP-1 products rather than liraglutide.
• Manufacturers developing non-infringing peptide synthesis, purification and delivery processes.

The expiration of US 6,458,924 did not by itself guarantee immediate generic entry. Later patents, regulatory review, manufacturing readiness, settlement terms and commercial launch strategy remained relevant.

Were there Paragraph IV challenges and settlements?

Paragraph IV challenges were directed primarily at unexpired later patents associated with liraglutide products, not at the now-expired US 6,458,924.

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable or not infringed. For liraglutide, the commercial dispute centered on whether a proposed generic product would infringe later Novo Nordisk patents covering:

• The active peptide or modified peptide structure.
• Specific formulations.
• Dosing regimens.
• Use in diabetes or obesity.
• Delivery devices or administration systems.

Publicly reported generic approvals indicate that at least some later-patent barriers were resolved through expiration, litigation outcomes, settlement arrangements, label carve-outs or non-infringing product design. The terms of individual settlement agreements may not be fully public, and the legal effect must be assessed patent by patent.

How strong was the patent estate for liraglutide?

The estate was strong during the commercial launch period because it combined multiple protection layers:

1. Foundational composition-of-matter claims.
2. Acylated GLP-1 genus claims.
3. Specific liraglutide species claims.
4. Formulation claims.
5. Diabetes treatment claims.
6. Obesity treatment claims.
7. Dose and administration claims.
8. Device and manufacturing-related rights.

US 6,458,924 itself was technically important but no longer provides practical exclusivity. Its strongest historical feature was the direct structural correspondence between claim 3 and liraglutide: GLP-1(7-37), Lys26 modification, gamma-glutamyl spacer and palmitoyl group.

Its principal limitations were:

• The claim was limited to a defined sequence.
• The permitted lipophilic groups and chain lengths were enumerated.
• The patent had no remaining term after 2019.
• Later generic products could rely on expired foundational protection while contesting later patents separately.

What manufacturing and intellectual-property barriers remain?

Chemical synthesis and purification of liraglutide remain technically demanding even after foundational patent expiry. A manufacturer must control:

• Peptide chain assembly.
• Site-specific Lys26 modification.
• Gamma-glutamyl spacer installation.
• Palmitoyl conjugation.
• Impurity clearance.
• Aggregation and degradation.
• Sterility and injectable-product controls.
• Container-closure and device compatibility.

These technical requirements are distinct from patent rights. A process can be commercially difficult without being covered by an enforceable product patent.

Potential residual IP barriers may include:

• Manufacturing process patents.
• Purification patents.
• Formulation patents.
• Injection-pen patents.
• Device patents.
• Dosing-regimen patents.
• Trademark and trade-dress rights.
• Regulatory exclusivity unrelated to US 6,458,924.

A freedom-to-operate review must therefore examine the full U.S. family and continuation portfolio, not only the claims of the ’924 patent.

How does liraglutide compare with competing GLP-1 drugs?

Drug	Active ingredient	Primary sponsor	Core structural strategy	Patent landscape
Victoza	Liraglutide	Novo Nordisk	GLP-1 analog with Lys26 palmitoylation	Foundational patents expired; later rights historically delayed entry
Saxenda	Liraglutide	Novo Nordisk	Same active ingredient as Victoza, higher obesity dose	Shares core liraglutide estate; obesity-use patents may differ
Ozempic	Semaglutide	Novo Nordisk	GLP-1 analog with longer-acting acyl modification	Separate and later patent estate
Trulicity	Dulaglutide	Eli Lilly	GLP-1-Fc fusion protein	Biologic-like product with separate patent and regulatory framework
Mounjaro/Zepbound	Tirzepatide	Eli Lilly	Dual GIP/GLP-1 receptor agonist	Separate composition, formulation and use patents

Liraglutide has no biosimilar issue in the same sense as a therapeutic antibody. Its principal competitive threat is generic or follow-on peptide entry, while semaglutide and tirzepatide compete through different active ingredients and patent estates.

What generic launch scenarios existed for liraglutide?

Three launch scenarios were commercially relevant:

Immediate launch after patent resolution

A generic applicant could launch after all material blocking patents expired or were held invalid or not infringed. This scenario became more realistic after the expiration of foundational liraglutide patents and FDA approval of generic liraglutide.

At-risk launch

An applicant could launch before final resolution of later patent litigation, accepting potential damages or an injunction if the patent holder prevailed. The risk depended on the applicant’s Paragraph IV position and litigation timeline.

Carved-out launch

An applicant could omit patented indications, dosing instructions or uses from its labeling. A skinny-label strategy could permit entry for non-patented indications while leaving certain branded uses protected.

For US 6,458,924 specifically, none of these scenarios is currently constrained by the patent because the patent expired in 2019.

What is the geographic coverage of the patent family?

US 6,458,924 provided protection only in the United States. Corresponding applications and patents were pursued in other jurisdictions, including Europe and other major pharmaceutical markets.

The geographic risk profile varied by country because:

• Patent term dates differed.
• Patent validity decisions were jurisdiction-specific.
• Supplementary protection certificates could extend European protection.
• Regulatory exclusivity periods differed.
• Patent claims were amended during prosecution.
• Litigation outcomes were not automatically portable between jurisdictions.

A U.S. freedom-to-operate conclusion cannot be applied to Europe, Canada, Japan, China or other markets without reviewing the corresponding national rights.

Key Takeaways

• US 6,458,924 is a foundational acylated GLP-1 patent.
• It covers liraglutide through the combination of GLP-1(7-37), Lys26 acylation, gamma-glutamyl spacing and palmitoyl substitution.
• Claim 1 covers a broader genus of fatty-acylated and lithocholyl GLP-1 derivatives.
• Claims 8 through 18 cover compositions and selected excipients or combination therapies.
• Claims 19 and 20 cover diabetes and obesity treatment methods.
• The patent expired on September 29, 2019.
• It has no current blocking effect against U.S. generic liraglutide entry.
• Later Novo Nordisk patents, device rights, formulation rights and regulatory issues created the more relevant post-2019 entry analysis.
• Liraglutide competition proceeds through generic and follow-on peptide pathways rather than a conventional biosimilar pathway.
• Teva obtained FDA approval for a generic liraglutide product in 2024.

FAQs

Does US 6,458,924 cover Victoza?

Yes. The patent claims the liraglutide structure used in Victoza, although it does not identify the product by its brand name.

Does the patent cover Saxenda?

Yes, the patent covers the liraglutide active ingredient used in Saxenda. Its obesity method claim also relates directly to the therapeutic use underlying Saxenda.

Is liraglutide still patent protected in the United States?

The foundational US 6,458,924 patent is expired. Other later patents may have had different expiration dates, but the ’924 patent itself provides no current U.S. exclusivity.

Is generic liraglutide a biosimilar?

No. Liraglutide is a synthetic peptide drug. U.S. competition is generally pursued through an ANDA or another applicable generic pathway rather than a conventional biosimilar application.

Can a company design around US 6,458,924?

During the patent term, a design-around could have used a different sequence, modification site, lipophilic group, chain length or spacer. Today, design-around is unnecessary for this expired patent, although later patents and manufacturing rights may still require review.

References

1. U.S. Patent and Trademark Office. (2002). U.S. Patent No. 6,458,924, GLP-1 derivatives.
2. U.S. Food and Drug Administration. (2010). Victoza prescribing information.
3. U.S. Food and Drug Administration. (2014). Saxenda prescribing information.
4. U.S. Food and Drug Administration. (2024). FDA approves first generic of Victoza.
5. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
6. Google Patents. (n.d.). US6458924B1, GLP-1 derivatives.
7. Novo Nordisk A/S. (2024). Annual report 2024.

Drugs Protected by US Patent 6,458,924

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

Foreign Priority and PCT Information for Patent: 6,458,924

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Denmark	0931/96	Aug 30, 1996
Denmark	1259/96	Nov 08, 1996
Denmark	1470/96	Dec 20, 1996
Denmark	0263/98	Feb 27, 1998
Denmark	0264/98	Feb 27, 1998
Denmark	0268/98	Feb 27, 1998
Denmark	0272/98	Feb 27, 1998

International Family Members for US Patent 6,458,924

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0944648		CA 2009 00041	Denmark
European Patent Office	0944648		SPC034/2009	Ireland
European Patent Office	0944648		SPC/GB09/058	United Kingdom
European Patent Office	0944648		09C0054	France
European Patent Office	0944648		C00944648/01	Switzerland
Austria	265224
Austria	269103