United States Patent 4,395,403: Scope, Claims, Expiration, and Octreotide Patent Landscape

U.S. Patent 4,395,403 is a foundational Sandoz patent covering somatostatin analog polypeptides, including the octreotide-type sequence H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol. The patent issued July 26, 1983, and its original 17-year term expired July 26, 2000. It no longer creates an enforceable U.S. patent barrier to generic octreotide products.

The claims cover a broad class of disulfide-cyclized peptide analogs with substitutions at the N-terminal residue, aromatic residues, lysine, threonine or alanine, and the C-terminal amino alcohol or amide region. Claims 19-21 extend protection to methods for treating excess growth-hormone secretion and gastrointestinal disorders and to pharmaceutical compositions.

The patent was commercially important for Sandostatin, whose active ingredient is octreotide acetate. Its present value is historical and technical rather than exclusionary. Current market protection depends on later formulation, depot-delivery, manufacturing, regulatory and device-related rights, not on U.S. Patent 4,395,403.

What drug and peptide does U.S. Patent 4,395,403 cover?

The patent covers synthetic analogs of somatostatin. The principal commercial compound associated with the patent is octreotide, also known as SMS 201-995.

Octreotide is generally represented as:

H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol

The two cysteine residues form a disulfide bridge. The terminal "Thr-ol" group is a threoninol residue rather than a conventional carboxy-terminal threonine. The sequence preserves selected somatostatin pharmacophore elements while increasing metabolic stability and extending biological activity.

The supplied claims also encompass compounds with:

D- or L-phenylalanine at the N-terminal region;
D- or L-tryptophan, including alpha-N-methylated and ring-substituted variants;
lysine, alpha-N-methyllysine or epsilon-N-methyllysine;
threonine or alanine in L- or D-configuration;
amino alcohol, amino amide, ester and related terminal groups;
alternative residues at the first and sixth positions;
pharmaceutically acceptable salts and complexes.

The claim language uses "polypeptide," but many covered molecules are short cyclic peptides or peptide analogs.

What is the core technical scope of claim 1?

Claim 1 is an omnibus genus claim. It defines a peptide framework by variables A, A', B, C, D, E and F rather than by a single named compound.

Variable	Principal claimed subject matter
A	C1-C12 alkyl, phenylalkyl, acyl group, amino-acid residue or dipeptide residue
A'	Hydrogen or selected alkyl or phenylalkyl groups
B	Phenylalanine, including substituted phenylalanine
C	D- or L-tryptophan, including N-methyl and ring-substituted forms
D	Lysine, including alpha-N- or epsilon-N-alkyl variants
E	Threonine or alanine, in D- or L-configuration
F	A structurally variable C-terminal amino-acid, amino alcohol, amide or ester region
Positions 1 and 6	D- and/or L-cysteine residues, subject to the stated provisos
Y1/Y2	Hydrogen or a direct bond, allowing the specified ring or linkage state

The claim is broad in four ways.

First, it covers multiple N-terminal acyl and amino-acid substituents. The N-terminal group can be a simple alkyl or phenylalkyl substituent, an acyl group, a phenylalanine residue, an asparagine residue, another natural amino-acid residue, or a dipeptide.

Second, the central sequence tolerates stereochemical and substitutional variation. The tryptophan and lysine residues may be N-methylated or otherwise substituted, and threonine may be replaced by alanine.

Third, the C-terminal region is deliberately expansive. It includes terminal alcohols, amides, esterified groups and side-chain-linked extensions.

Fourth, the claim covers acid-addition salts and complexes. A salt form does not escape claim 1 if the underlying peptide satisfies the structural limitations.

The principal narrowing limitation is the cysteine requirement. The claim specifies that D- and/or L-cysteine residues occur at the 1- and 6-positions only. That limitation defines the disulfide-cyclized somatostatin analog architecture and excludes many unrelated peptide structures.

How do dependent claims 2 through 12 narrow the patent scope?

Claims 2-12 select narrower chemical subgenera from claim 1.

Claims	Main narrowing feature
2	R3 is hydrogen, C1-C3 alkyl or phenyl
3	Specific restriction on X when R5 is benzyl
4-5	R4 is a side-chain group of formula -CH(R5)-X
6	N-terminal acyl or amino-acid choices are narrowed
7	Specific R3, R5 and X substituents are selected
8-9	B is Phe, C is D-Trp, D is Lys or methylated Lys, and E is Thr
10-11	X is -CH2OR2
12	N-terminal group, terminal region and stereochemical variables are narrowed substantially

Claims 8 and 9 are commercially significant because they identify the central octreotide-like sequence:

B: Phe;
C: D-Trp;
D: Lys or a methylated lysine derivative;
E: Thr.

These claims remain broader than octreotide because they permit different N-terminal groups, lysine methylation states, terminal substituents and stereochemistry.

Claim 12 narrows the N-terminal group toward short alkyl or phenylalkyl groups and specified amino-acid residues. It also requires R2 to be hydrogen and imposes selected values for R3, R7, Y1 and Y2.

What do claims 13 through 18 protect?

Claims 13 and 14 are structure-specific claims. The supplied text identifies the claims by formula images rather than a machine-readable structure. Their legal function is to isolate specific peptide embodiments from the broader genus of claim 1.

Claim 15 is a Markush selection claim. It covers a listed group of specific compounds, including:

H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol

That sequence is the octreotide-type compound most directly associated with Sandostatin. Claim 15 also covers other listed analogs that vary the N-terminal residue, the threonine-derived terminal group and related structural elements.

Claim 16 narrows the invention to compounds with:

an N-terminal acyl or amino-acid residue;
phenylalanine at the B position;
threonine, D-threonine or D-alanine at the E position;
selected side-chain groups in the F region;
specified D- or L-configurations.

Claim 17 lists individual compounds identified by different combinations of A, E and F. The listed variants include D-phenylalanine, norleucine, asparagine, D-methylphenylalanine, D-alanine, D-threonine, serine, threonine, phenylalaninol and related terminal structures.

Claim 18 separately confirms that E may be L-threonine, D-threonine or D-alanine. Because claim 18 depends on claim 1, every other limitation of claim 1 remains applicable.

What do claims 19 through 21 protect?

Claims 19-21 are use and composition claims.

Claim 19: excess growth-hormone secretion

Claim 19 covers administering a claimed polypeptide to treat disorders comprising or associated with excess growth-hormone secretion. The principal commercial disease association is acromegaly.

The claim requires:

a subject in need of treatment;
administration of an effective amount;
a polypeptide falling within claim 1 or an acceptable salt or complex.

The claim is not limited to one dose, route, formulation or disease subtype. It is also not limited expressly to octreotide.

Claim 20: gastrointestinal disorders

Claim 20 covers treatment of gastrointestinal disorders with the claimed peptide class. The scope is broad at the disease level and potentially includes disorders in which somatostatin analogs are used to reduce gastrointestinal secretions or treat hormone-secreting tumors.

Claim 21: pharmaceutical compositions

Claim 21 covers a claimed polypeptide combined with a pharmaceutically acceptable diluent or carrier. It is a conventional composition claim. The claim does not require a particular concentration, excipient, container, dosage form or manufacturing process.

Because claims 19-21 depend on claim 1, a product or method must first satisfy the chemical limitations of the peptide genus.

When did U.S. Patent 4,395,403 expire?

U.S. Patent 4,395,403 issued on July 26, 1983. As a pre-Uruguay Round patent, its ordinary term was 17 years from issuance. The patent therefore expired on July 26, 2000, absent an unusual term adjustment or enforceable extension.

Event	Date
U.S. patent issue	July 26, 1983
Original patent term	17 years from issue
Estimated statutory expiration	July 26, 2000
Current enforceability	Expired
Current Paragraph IV relevance	None for this patent

The patent is not a current Orange Book exclusivity barrier. Patent expiration eliminates infringement liability for activities occurring after expiration, subject to any separate later patent rights. It does not eliminate possible historical damages claims for conduct occurring before expiration.

What is the Orange Book status of the patent?

U.S. Patent 4,395,403 cannot currently provide Orange Book exclusivity because it expired more than two decades ago.

The patent was historically associated with the octreotide product franchise, but current Orange Book analysis must distinguish:

the original octreotide molecule patent;
later patents covering depot microspheres or long-acting formulations;
device or delivery-system patents;
manufacturing-process patents;
patents covering specific compositions or concentrations.

The FDA Orange Book lists patents submitted by approved drug applicants. A listed patent may affect ANDA certification while active, but an expired patent does not block approval through an active patent term. The FDA does not determine patent validity or infringement. Those issues remain within federal judicial authority under the Hatch-Waxman framework. [1, 2]

When did Sandostatin receive FDA approval?

Sandostatin injection, containing octreotide acetate, was approved by the FDA in 1988 for acromegaly. The label later included indications involving severe secretory diarrhea or flushing associated with metastatic carcinoid tumors and vasoactive intestinal peptide tumors. [3]

Sandostatin LAR Depot was later approved as a long-acting intramuscular formulation. Its commercial protection was based on later product development and patent rights rather than the expired term of U.S. Patent 4,395,403.

Octreotide acetate is a chemically defined peptide drug. It is not regulated as a conventional monoclonal-antibody biologic for purposes of the biosimilar pathway.

Are biosimilar risks relevant to octreotide?

Biosimilar risk is limited because octreotide products are generally pursued through abbreviated-drug pathways applicable to synthetic peptide products rather than through the section 351(k) biosimilar pathway used for biological products.

The principal competitive routes are:

ANDA approval for octreotide acetate injection;
separate applications for long-acting depot products;
formulation-specific regulatory submissions;
potential 505(b)(2) applications for modified delivery systems.

The practical distinction matters. A generic immediate-release octreotide injection does not automatically establish substitutability for Sandostatin LAR Depot. Depot products may require separate clinical, pharmacokinetic, device or formulation evidence.

What generic entry risks exist for octreotide products?

Immediate-release injection

The molecule-level patent barrier ended in 2000. Generic entry risk for immediate-release octreotide injection therefore depends primarily on:

FDA product-specific requirements;
active formulation or process patents;
manufacturing capability;
peptide purity and impurity control;
supply of pharmaceutical-grade octreotide acetate;
state substitution rules.

A Paragraph IV challenge to U.S. Patent 4,395,403 would have had no current commercial value because the patent has expired. Any historical Paragraph IV litigation involving later Sandostatin patents must be analyzed patent by patent.

Long-acting depot products

Sandostatin LAR presents a different risk profile. The active ingredient is old, but the depot microsphere system, release profile, manufacturing method and product performance can create separate barriers.

Potentially relevant claim categories include:

biodegradable polymer microspheres;
peptide loading and encapsulation;
particle-size distribution;
residual solvent controls;
release kinetics;
reconstitution systems;
administration devices;
manufacturing methods;
formulation stability.

A generic or follow-on depot product may need to show that its formulation performs sufficiently like the reference product. A molecule-only freedom-to-operate analysis is insufficient.

Which companies have competed in the octreotide market?

The original reference product was developed and commercialized by Sandoz, later associated with Novartis after the Ciba-Geigy and Sandoz merger.

The competitive field includes:

Segment	Principal competitive basis
Octreotide injection	API access, ANDA approval, manufacturing cost and supply reliability
Long-acting octreotide	Depot technology, formulation equivalence and manufacturing scale
Lanreotide	Competing somatostatin analog and long-acting product
Pasireotide	Different somatostatin-receptor profile and clinical positioning
Hospital and specialty distributors	Product availability, contracting and reimbursement

Lanreotide is the closest commercial comparator in the long-acting somatostatin analog segment, but it is chemically distinct and is not covered by U.S. Patent 4,395,403.

How does the patent estate compare with lanreotide and pasireotide?

Product	Active ingredient	Relationship to U.S. 4,395,403	Main protection issues
Sandostatin	Octreotide acetate	Directly associated with claimed octreotide-type analogs	Expired molecule patent; later formulation and product rights
Sandostatin LAR	Long-acting octreotide acetate	Uses the same active peptide class	Depot formulation, manufacturing and regulatory equivalence
Somatuline Depot	Lanreotide acetate	Outside the claimed octreotide sequence	Separate composition, formulation and use patents
Signifor	Pasireotide	Outside the claimed peptide genus as a commercial product	Separate molecule, formulation and method-of-use rights

The expired patent gives octreotide a low molecule-level patent risk but does not remove the competitive advantage of proprietary depot manufacturing or regulatory data.

How strong is the patent estate for U.S. Patent 4,395,403?

The patent was strong for its period because it combined:

a broad chemical genus;
sequence-specific subgenera;
stereochemical coverage;
salt and complex coverage;
selected individual compounds;
treatment claims;
composition claims.

Its current legal strength is zero as an enforceable exclusion right because the patent expired. Its residual commercial value is historical: it established the foundational chemical and therapeutic platform for octreotide.

The strongest historical claims were likely claims 8, 9 and 15 because they moved from a broad structural genus toward the commercial octreotide sequence. The broadest coverage was in claim 1, but broad genus claims generally face greater vulnerability to written-description, enablement, anticipation and obviousness challenges than narrow compound claims.

What licensing and settlement issues matter today?

No current license or settlement can revive the expired exclusionary term of U.S. Patent 4,395,403. A license may still matter for:

know-how;
manufacturing processes;
analytical methods;
confidential formulation technology;
trademarks;
regulatory files;
later patents;
supply agreements.

Historical settlements involving later patents should not be treated as evidence that U.S. Patent 4,395,403 remains enforceable. Any settlement analysis must identify the asserted patent numbers, claims, expiry dates, licensed rights and generic launch date.

Key Takeaways

U.S. Patent 4,395,403 covers a broad genus of somatostatin analog peptides.
The patent directly encompasses octreotide-type structures, including H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol.
Claims 1-18 focus on chemical structures, stereochemistry, terminal groups, salts and selected embodiments.
Claims 19-21 cover treatment of excess growth-hormone secretion, gastrointestinal disorders and pharmaceutical compositions.
The patent issued July 26, 1983, and expired July 26, 2000.
It is not a current Orange Book patent barrier.
Octreotide is a synthetic peptide drug, so biosimilar analysis is less central than ANDA and 505(b)(2) analysis.
Immediate-release generic entry is primarily a regulatory, manufacturing and supply issue.
Long-acting octreotide products may retain meaningful protection through depot formulation, manufacturing, device and product-specific patents.
Lanreotide and pasireotide are competitive products but are not covered by this patent’s octreotide sequence claims.

FAQs

Does U.S. Patent 4,395,403 cover Sandostatin LAR?

It covers the octreotide peptide class associated with Sandostatin, but it does not by itself establish current exclusivity for the Sandostatin LAR depot formulation. Later formulation and manufacturing rights must be analyzed separately.

Is octreotide protected by an active U.S. molecule patent?

No. The principal U.S. molecule patent represented by U.S. Patent 4,395,403 expired in 2000. Active protection, if any, must arise from later patents or regulatory exclusivities.

Can a generic company make octreotide acetate today?

The expired molecule patent does not prevent manufacture. A company must still satisfy FDA approval requirements, comply with applicable active patents and establish adequate manufacturing, quality and supply controls.

Does a salt of octreotide avoid the patent claims?

No. Claim 1 expressly includes pharmaceutically acceptable acid-addition salts and complexes. A salt form would not avoid the patent during its term merely because it used a different counterion.

Is lanreotide an infringing analog under this patent?

Lanreotide is a different somatostatin analog and is not automatically within the claimed octreotide-type structures. Infringement would require a claim-by-claim comparison of the exact chemical structure against every limitation.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations, patent and exclusivity information. FDA.
U.S. Food and Drug Administration. (2023). Sandostatin (octreotide acetate) injection prescribing information. FDA.
United States Patent and Trademark Office. (1983). U.S. Patent No. 4,395,403: Novel polypeptides. U.S. Department of Commerce.
Novartis Pharmaceuticals Corporation. (2023). Sandostatin LAR Depot prescribing information. Novartis.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	10524/79	Nov 27, 1979
Switzerland	4574/80	Jun 13, 1980

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0029579	⤷ Start Trial	SPC/GB93/097	United Kingdom	⤷ Start Trial
Austria	2512	⤷ Start Trial
Australia	543198	⤷ Start Trial
Australia	6468880	⤷ Start Trial
Canada	1182109	⤷ Start Trial
Czechoslovakia	228140	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,395,403

Summary for Patent: 4,395,403