United States Patent 4,703,035: Claim Scope, Sermorelin Coverage, Expiration and Patent Landscape

U.S. Patent No. 4,703,035 covers synthetic human growth hormone-releasing factor peptides corresponding principally to growth hormone-releasing hormone fragment 1-29, now known as sermorelin, together with selected C-terminally extended analogues. The patent claims the peptide molecules, compositions containing them, and their use to stimulate growth hormone release or accelerate growth in nonhuman animals. The patent is expired and does not create a current U.S. barrier to generic, compounded, or follow-on development, subject to separate protection that may have existed in later patents or regulatory exclusivity.

What peptide does U.S. Patent 4,703,035 protect?

The core sequence is:

Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg

This is a 29-residue synthetic peptide corresponding to human growth hormone-releasing hormone, commonly described as human GHRH(1-29) or sermorelin when the C-terminal arginine is amidated.

The patent uses the formula:

H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Y

where Y is one of four C-terminal configurations:

Claim	C-terminal configuration	Approximate peptide designation	Commercial relevance
1	`NH2`, `Gln-NH2`, `Gln-Gln-NH2`, or `Gln-Gln-Gly-NH2`	Markush genus covering 29- to 32-residue forms	Broadest molecule claim
2	`NH2` attached to terminal Arg	GHRH(1-29)-NH2; sermorelin	Principal commercial form
3	Terminal Gln-NH2	GHRH(1-30)-amide analogue	Narrow species claim
4	Terminal Gln-Gln-NH2	GHRH(1-31)-amide analogue	Narrow species claim
5	Terminal Gln-Gln-Gly-NH2	GHRH(1-32)-amide analogue	Narrow species claim

The notation NH2 at the end of claim 2 indicates amidation of the terminal carboxyl group. It does not add a separate amino acid residue. Claims 3 through 5 add one, two, or three residues after the terminal arginine and specify amidation at the new C terminus.

The claims also extend to nontoxic salts. That language potentially covers pharmaceutically acceptable salt forms, including acetate or other counterion forms, when the underlying peptide sequence remains within the claimed structure.

How broad is claim 1 of U.S. Patent 4,703,035?

Claim 1 is the principal composition-of-matter claim. It has four important limitations:

The peptide must be synthetic.
The amino-acid sequence before Y must be exactly the 29-residue sequence recited in the claim.
Y must be one of four specified C-terminal structures.
The product may be present as the free peptide or a nontoxic salt.

The claim is broad across the four listed C-terminal variants, but narrow across the amino-acid sequence. It does not cover every GHRH analogue, every growth hormone secretagogue, or every peptide with growth hormone-releasing activity.

Sequence limitations

A substitution at any of the first 29 positions would ordinarily place a product outside literal claim 1 unless another claim or claim-construction theory applied. The claim does not expressly cover:

D-amino-acid substitutions;
non-natural amino acids;
N-terminal modifications;
PEGylation;
lipidation;
cyclization;
deletion analogues;
point-mutated GHRH analogues;
unrelated growth hormone secretagogues;
small-molecule growth hormone-releasing agents.

A peptide with the same sequence but a different C-terminal structure may also fall outside the literal scope. For example, a free-acid C terminus, esterified C terminus, acetylated C terminus, or unlisted extension would require separate analysis under claim construction and doctrine-of-equivalents principles.

Salt coverage

The phrase “or a nontoxic salt thereof” is significant because it prevents avoidance based solely on the counterion. A sermorelin acetate product would generally be analyzed as the claimed peptide in salt form, rather than as a distinct sequence.

The salt language does not automatically cover every formulation containing the peptide. It covers the peptide salt as a chemical entity. A formulation containing the peptide may also require analysis under claim 6.

What does claim 2 cover?

Claim 2 narrows claim 1 to the 29-residue amidated peptide:

H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2

This is the key claim associated with sermorelin. Sermorelin is also known as growth hormone-releasing hormone fragment 1-29 amide. Commercial sermorelin products have commonly been supplied as sermorelin acetate, a salt form of the amidated peptide.

Claim 2 is narrower than claim 1 but commercially more important because it maps directly onto the principal clinical product form. It is a composition-of-matter claim, not merely a treatment-use claim. While unexpired, it could have been asserted against manufacture, importation, sale, or use of the covered peptide, subject to the patent statute and applicable defenses.

What do claims 3 through 5 cover?

Claims 3 through 5 cover extended C-terminal analogues:

Claim 3: the 30-residue analogue ending in Arg-Gln-NH2;
Claim 4: the 31-residue analogue ending in Arg-Gln-Gln-NH2;
Claim 5: the 32-residue analogue ending in Arg-Gln-Gln-Gly-NH2.

These claims are species claims dependent on claim 1. They do not cover arbitrary C-terminal extensions. An extension with a different residue, a different number of residues, or a different terminal functional group would not satisfy the express limitations of claims 3 through 5.

The C-terminal extensions appear designed to capture biologically related forms and synthetic analogues of the human GHRH sequence. They also reduce the risk that a competitor could avoid the patent by adding selected glutamine or glycine residues at the C terminus.

What compositions are protected by claim 6?

Claim 6 covers:

a composition;
containing an effective amount of a peptide within claim 1; and
an acceptable liquid or solid carrier;
where the composition is for stimulating growth hormone release in an animal.

The claim is functional and formulation-oriented, but it remains dependent on the claimed peptide identity. It does not independently cover a composition containing any growth hormone-releasing agent.

Potentially relevant dosage forms include:

injectable aqueous solutions;
lyophilized powders for reconstitution;
solid pharmaceutical compositions;
peptide salt preparations;
animal-health formulations.

The claim does not recite a particular concentration, pH, buffer, preservative, route of administration, injection device, release profile, or dosage regimen. That gives the claim breadth over conventional liquid and solid carriers, but it does not create a standalone patent on sustained-release systems, depot formulations, nasal delivery, oral delivery, or transdermal delivery.

Are formulation patents separate from U.S. Patent 4,703,035?

Yes. Patent 4,703,035 is principally a peptide and use patent. It does not expressly claim:

microspheres;
biodegradable polymer depots;
liposomes;
nanoparticles;
implantable delivery systems;
specific stabilizer systems;
particular lyophilization cycles;
defined impurity limits;
long-acting release profiles;
device combinations.

Those technologies could have been protected by later patents, but they are not apparent from the claims supplied for Patent 4,703,035. A freedom-to-operate review for a modern sermorelin product therefore requires a separate search of continuation, divisional, formulation, manufacturing, and delivery patents.

What methods are protected by claims 7 and 8?

Claim 7: growth hormone release

Claim 7 covers administering an effective amount of a claim 1 peptide to an animal to stimulate growth hormone release.

The claim does not specify:

human versus nonhuman animal;
route;
dose;
frequency;
treatment duration;
disease;
age;
body weight;
diagnostic criteria;
concurrent therapy.

The absence of those limitations gives claim 7 broad method scope, but the method remains tied to the exact peptide genus in claim 1.

Claim 8: growth acceleration in nonhuman animals

Claim 8 covers administering an effective amount of a claim 1 peptide to accelerate growth in a nonhuman animal.

This claim is directed to animal-health and livestock applications. It does not cover human treatment because it expressly requires a nonhuman animal. The claim could potentially implicate cattle, swine, sheep, poultry, laboratory animals, or other nonhuman species, but the patent does not appear to limit the claim to a particular species.

Claim 8 is commercially distinct from claim 7. A product sold for human endocrinology may implicate claim 7, while veterinary growth-promotion use would be more directly relevant to claim 8.

When did U.S. Patent 4,703,035 expire?

U.S. Patent 4,703,035 was granted on October 27, 1987. For a U.S. utility patent issued before June 8, 1995, the ordinary term was 17 years from grant, subject to any terminal disclaimer, statutory adjustment, or other term-specific event. On that basis, the patent’s ordinary expiration date was October 27, 2004.[1]

Event	Date or status
U.S. patent grant	October 27, 1987
Ordinary pre-1995 patent term	17 years from grant
Ordinary expiration	October 27, 2004
Current enforceability	Expired
Current Paragraph IV risk from this patent	None
Current blocking composition-of-matter right	None

The patent cannot presently be asserted to block manufacture or sale of sermorelin on the basis of its expired claims. Expiration does not erase historical infringement exposure during the enforceable term, but it eliminates prospective enforcement.

What is the FDA and Orange Book status of sermorelin?

Sermorelin acetate was approved by the FDA as Geref under NDA 19-685 for diagnostic and therapeutic uses involving growth hormone secretion. FDA records identify Geref as discontinued. The discontinuation was not classified as a withdrawal for safety or efficacy reasons in the FDA product database.[2]

The regulatory position is separate from patent status:

Issue	Status
Active U.S. composition patent identified from the supplied patent	No
Patent 4,703,035	Expired
FDA-approved sermorelin product	Geref, historically approved
Current marketed FDA-approved reference product	Discontinued
Orange Book relevance	Historical product and patent-listing analysis; no live exclusivity from Patent 4,703,035
Biosimilar pathway	Generally not the primary pathway for a synthetic peptide drug
Compounding	Governed by applicable federal and state requirements, not by an expired patent

Sermorelin is a chemically synthesized peptide rather than a conventional monoclonal antibody or other large biologic. A follow-on product would ordinarily be evaluated under the drug framework applicable to the proposed product and formulation. The precise regulatory pathway depends on the reference product, dosage form, proposed labeling, manufacturing process, and FDA classification.

A discontinued reference product can create regulatory complications for an abbreviated application strategy. Discontinuation alone does not establish that the product was withdrawn for safety or efficacy reasons, but the commercial availability and reference-product status must be evaluated independently from patent expiration.

Are there Paragraph IV challenges to Patent 4,703,035?

No current Paragraph IV challenge can create a live dispute over Patent 4,703,035 because the patent expired in 2004. A Paragraph IV certification is relevant to an unexpired patent listed for an approved drug. An expired patent cannot impose a remaining statutory stay or delay generic approval.

Historical litigation may have occurred during the patent term, but the supplied claim set does not identify a specific litigation docket, defendant, settlement agreement, or terminal disclaimer. No reliable litigation conclusion should be drawn from the claim text alone.

For a current sermorelin entrant, relevant disputes would more likely involve:

FDA reference-product treatment;
product classification;
manufacturing consistency;
sterility and endotoxin controls;
peptide identity and purity;
formulation or device patents filed after 1987;
trade-secret manufacturing processes;
trademark and regulatory-labeling issues.

Which companies challenge or compete with sermorelin?

The relevant competitive set is broader than direct sermorelin generics.

Direct peptide competition

Potential direct competitors include:

compounded sermorelin acetate suppliers;
manufacturers of synthetic GHRH(1-29)-amide;
specialty pharmaceutical companies developing a renewed sermorelin product;
contract manufacturers producing peptide active pharmaceutical ingredient.

Because Patent 4,703,035 has expired, the principal barriers are regulatory, manufacturing, quality, and commercial rather than composition-patent exclusivity.

Pharmacologic alternatives

Sermorelin competes with products that increase growth hormone signaling through different mechanisms, including:

recombinant human growth hormone;
growth hormone secretagogues;
ghrelin-receptor agonists;
long-acting growth hormone products;
other hypothalamic or pituitary-directed therapies.

These products do not fall within the literal peptide claims of Patent 4,703,035. Their patent estates are separate and may be materially stronger if they contain newer formulation, device, or method-of-use patents.

How strong is the patent estate for sermorelin?

The original patent was strong during its enforceable term because claim 2 targeted the exact commercial peptide. Its main strengths were:

exact sequence coverage;
coverage of the amidated 29-residue form;
salt coverage;
dependent species claims;
composition claims;
broad animal method claims;
a nonhuman growth-acceleration claim.

Its weaknesses were structural:

no apparent long-term patent term under modern filing-date rules;
no express formulation platform;
no device claim;
no manufacturing-process claim in the supplied set;
no protection for sequence variants outside the listed C-terminal forms;
no live rights after expiration.

The present estate is therefore commercially relevant as historical prior art and product lineage, but not as an active exclusionary patent position.

What manufacturing and intellectual-property barriers remain?

Patent expiration does not eliminate technical barriers. A current sermorelin program must address:

peptide synthesis and coupling efficiency;
control of deletion sequences and racemization;
C-terminal amidation;
aggregate and oxidation control;
residual solvents and reagents;
peptide identity and potency assays;
sterile manufacturing;
vial or cartridge stability;
reconstitution performance;
cold-chain requirements;
immunogenicity and impurity characterization;
regulatory comparability to any reference product.

Manufacturing know-how may remain protected by trade secrets even where the basic peptide sequence is public-domain subject matter. A manufacturer also may face later patents covering specific processes, purification methods, excipients, delivery systems, or commercial presentations.

What generic launch scenarios exist for sermorelin?

A practical launch assessment has three principal scenarios:

Scenario	Patent position	Principal commercial issue
Synthetic sermorelin acetate product	Patent 4,703,035 expired	FDA pathway and reference-product strategy
Compounded sermorelin	No barrier from Patent 4,703,035	Compounding-law, quality, and enforcement exposure
Long-acting or novel delivery product	Original patent expired	Later formulation, device, or process patents

A conventional short-acting sermorelin acetate product faces no remaining exclusionary right under Patent 4,703,035. A differentiated product with sustained release, a novel delivery device, or a new indication may create new patentable subject matter, but it may also encounter later third-party patents.

Key Takeaways

U.S. Patent 4,703,035 covers synthetic human GHRH-related peptides with a defined 29-residue core.
Claim 2 covers the principal sermorelin molecule, GHRH(1-29)-NH2.
Claims 3 through 5 cover selected C-terminally extended analogues.
Claim 6 covers compositions containing the claimed peptide and an acceptable liquid or solid carrier.
Claim 7 covers administration to stimulate growth hormone release.
Claim 8 covers growth acceleration in nonhuman animals.
The patent’s ordinary expiration date was October 27, 2004.
The patent creates no current Paragraph IV or patent-enforcement risk.
Sermorelin’s remaining commercial barriers are primarily regulatory, manufacturing, quality, formulation, and later-patent issues.
A current product requires a separate search for later formulation, process, delivery, continuation, and device patents.

FAQs

Is sermorelin the same peptide covered by claim 2?

Yes. Claim 2 corresponds to the 29-residue amidated human GHRH fragment commonly called sermorelin. Commercial sermorelin acetate is the salt form of that peptide.

Does Patent 4,703,035 cover recombinant growth hormone?

No. The claims cover defined synthetic GHRH peptides and their uses. They do not claim recombinant human growth hormone.

Does the patent cover all growth hormone secretagogues?

No. The claims require the specific amino-acid sequence and C-terminal structures recited in claim 1.

Can a company patent a new sermorelin formulation?

Potentially, if the formulation satisfies applicable patentability requirements. A later patent could cover a specific excipient system, depot technology, delivery device, stability profile, or manufacturing process, but it would not revive the expired claims of Patent 4,703,035.

Does patent expiration guarantee FDA approval of a sermorelin product?

No. Patent expiration removes one intellectual-property barrier. FDA approval still depends on the applicable regulatory pathway, clinical and quality requirements, manufacturing controls, labeling, and product classification.

References

U.S. Patent No. 4,703,035. (1987). Growth hormone releasing factor. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: Geref (sermorelin acetate), NDA 19-685.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations (Orange Book).
U.S. Code, 35 U.S.C. §§ 154, 271, 282.
U.S. Food and Drug Administration. (n.d.). FDA-approved peptide and protein drug products and regulatory information.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	241452	⤷ Start Trial
Austria	24919	⤷ Start Trial
Austria	25851	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,703,035

Summary for Patent: 4,703,035