United States Patent 4,110,438: Claim Scope, Expiration, and Luteinizing Hormone-Releasing Hormone Patent Landscape

U.S. Patent 4,110,438 covers the use of luteinizing hormone-releasing hormone, also called gonadotropin-releasing hormone or GnRH, to treat stress-induced depression. Its dependent claims narrow the invention by dose, hydrochloride salt, and parenteral administration. The patent issued on August 29, 1978, and its ordinary U.S. patent term expired in 1995. It does not create a current blocking patent for GnRH products, depression treatments, or later-developed GnRH analogs.

What does U.S. Patent 4,110,438 claim?

The patent claims a therapeutic method rather than a new chemical compound. Claim 1 is the broadest claim:

A method of treating a patient suffering from stress-induced depression by administering a therapeutically effective amount of luteinizing hormone-releasing hormone or a therapeutically acceptable salt.

The claim has four central limitations:

The subject must be a patient.
The patient must suffer from stress-induced depression.
The active substance must be luteinizing hormone-releasing hormone or a therapeutically acceptable salt.
The substance must be administered in a therapeutically effective amount.

The patent therefore does not claim all uses of GnRH. It targets a specific psychiatric condition and a specific therapeutic mechanism involving native luteinizing hormone-releasing hormone.

Claim-by-claim scope

Claim	Subject matter	Scope
1	Treatment of stress-induced depression with GnRH or a therapeutically acceptable salt	Broadest method claim
2	Claim 1 using 100 to 800 mcg	Dose-limited method
3	Claim 1 using 200 to 500 mcg	Narrower dose-limited method
4	Claim 1 using the hydrochloride acid-addition salt	Salt-specific method
5	Claim 1 using parenteral administration at 1.0 to 20 mcg/kg/month	Route- and weight-based dosing method

Claims 2 through 5 are dependent claims. They incorporate every limitation of claim 1 and add narrower conditions. A product or treatment would need to satisfy both the base claim and the additional limitation to fall within a dependent claim.

What molecule does the patent cover?

Luteinizing hormone-releasing hormone is the naturally occurring decapeptide commonly called GnRH or gonadorelin. Its sequence is:

pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

The patent language is directed to the native hormone, not every compound that later became known as a GnRH agonist or antagonist.

Native GnRH versus later GnRH analogs

The principal commercial GnRH products include:

Gonadorelin
Leuprolide
Goserelin
Nafarelin
Triptorelin
Histrelin
Relugolix
Degarelix
Elagolix

These products do not have identical claim treatment.

Native gonadorelin is structurally different from substituted GnRH agonists such as leuprolide, goserelin, nafarelin, triptorelin, and histrelin. GnRH antagonists such as degarelix, relugolix, and elagolix are still farther removed in structure and mechanism.

A claim expressly directed to luteinizing hormone-releasing hormone generally should not be read automatically to cover a structurally modified analog. Coverage would depend on the patent’s specification, claim construction, prosecution history, and whether the asserted product falls within the claim language or an applicable doctrine of equivalents. On the supplied claims alone, the strongest literal coverage is for native GnRH and its covered salts.

How broad is claim 1?

Claim 1 is broad in treatment format but narrow in disease indication.

Breadth of the treatment limitation

The phrase “administering to said patient a therapeutically effective amount” does not specify:

Oral, injectable, intranasal, or implantable administration
A particular dosing schedule
A particular formulation
A particular treatment duration
A particular patient age
A particular severity of depression
A particular diagnostic test
A particular source or manufacturing process

The claim could therefore reach multiple administration formats if they use the claimed hormone and treat the claimed condition.

Limitation created by “stress induced depression”

“Stress induced depression” is a material limitation. It distinguishes the claim from a method directed to:

Major depressive disorder generally
Endogenous depression
Bipolar depression
Anxiety without depression
Depression caused by a neurological or endocrine disease
Depression unrelated to stress

The practical scope depends on how a court would define and identify stress-induced depression. The term may require evidence that stress caused or materially contributed to the depressive condition. A generic antidepressant label without that disease characterization would present a weaker infringement case.

Limitation created by “therapeutically effective amount”

The claim does not define a universal effective dose. The amount must be effective for the claimed patient and condition. This creates a factual issue involving clinical evidence, treatment protocol, patient response, and the patent specification.

A defendant could dispute whether the administered dose was intended or shown to treat stress-induced depression. That issue would be separate from whether the product contained GnRH.

What do claims 2 and 3 protect?

Claims 2 and 3 protect specific absolute-dose ranges:

Claim 2: 100 to 800 mcg
Claim 3: 200 to 500 mcg

Claim 3 is nested within claim 2. Every dose within 200 to 500 mcg falls within both ranges, assuming the other claim 1 limitations are met.

Dose-range interpretation

The claims do not state whether the dose is:

Per administration
Per day
Per treatment cycle
Total dose
Bolus dose
Infusion dose

The ordinary interpretation would depend on the specification and prosecution history. If the patent describes the amount as a single administered dose, that context would narrow the claim. If the specification uses the range without a clear administration interval, infringement analysis becomes more dependent on claim construction.

The claims also do not specify whether the amount is based on:

Free-base equivalent
Salt weight
Active peptide content
Total formulation weight

That distinction can matter for hydrochloride or other salt forms.

What does claim 4 protect?

Claim 4 covers the hydrochloride acid-addition salt of luteinizing hormone-releasing hormone when used in the method of claim 1.

This claim does not claim the hydrochloride salt as a composition. It claims a method of treating stress-induced depression using that salt.

Commercial relevance of claim 4

The claim could have been relevant to:

Injectable GnRH hydrochloride
A parenteral solution containing the hydrochloride salt
A lyophilized product reconstituted before injection
Other dosage forms using the claimed salt

The claim does not expressly require parenteral administration. Claim 5 separately adds the parenteral limitation and weight-based monthly dose.

The distinction matters because claim 4, on its face, is not limited to the 1.0 to 20 mcg/kg/month range in claim 5. A hydrochloride formulation used within the broader claim 1 method could potentially implicate claim 4 without satisfying claim 5.

What does claim 5 protect?

Claim 5 covers parenteral administration at 1.0 to 20 mcg per kilogram of body weight per month.

The claim adds two restrictions:

The hormone or salt must be administered parenterally.
The monthly dose must fall within the stated weight-based range.

“Parenterally” ordinarily includes administration by injection or another route that bypasses the gastrointestinal tract. The exact scope would depend on the specification and applicable claim construction. It most clearly covers subcutaneous, intramuscular, intravenous, or similar injectable administration.

Relationship between claims 2, 3, and 5

Claims 2 and 3 use absolute amounts. Claim 5 uses a weight-adjusted monthly amount. They are not automatically coextensive.

For example:

Patient weight	Claim 5 monthly range
50 kg	50 to 1,000 mcg/month
70 kg	70 to 1,400 mcg/month
100 kg	100 to 2,000 mcg/month

A 70-kg patient receiving 200 mcg could fall within claim 3 and claim 5 if the dose is administered parenterally and the monthly dosing calculation is satisfied. A 50-kg patient receiving 50 mcg would fall within claim 5 but not claims 2 or 3.

The phrase “per month” also creates a dosing-schedule issue. A monthly total could be delivered as:

One monthly injection
Multiple injections whose aggregate equals the claimed amount
A continuous infusion
A depot or implant releasing the claimed amount over the month

The patent specification would control whether the claim permits aggregation across administrations.

When did U.S. Patent 4,110,438 lose exclusivity?

U.S. Patent 4,110,438 issued on August 29, 1978. For a pre-Uruguay Round Agreements Act patent, the ordinary term was 17 years from issuance. On that basis, the patent expired on August 29, 1995, subject to any adjustment, disclaimer, or unusual term event shown in the official prosecution record.[1][2]

Event	Date
Patent issued	August 29, 1978
Ordinary 17-year term	August 29, 1995
Current status for ordinary enforcement purposes	Expired

No post-1995 patent-term extension under modern Hatch-Waxman provisions would ordinarily revive this patent. Patent term extension generally applies to qualifying regulatory review periods and was enacted after this patent issued. Patent term adjustment also does not ordinarily alter the analysis for a patent of this vintage.[2][3]

Can the patent currently block a generic or new drug?

No. An expired patent cannot support an ordinary infringement action for conduct occurring after expiration. Its claims may remain relevant historically, but they do not provide current exclusivity over native GnRH, GnRH salts, or the claimed depression method.

The patent also cannot be used to block:

A current generic gonadorelin product
A 505(b)(2) product using native GnRH
A formulation patent filed after the patent’s expiration
A later-developed GnRH analog
A modern depression therapy that does not practice the claimed method

What is the Orange Book status of U.S. Patent 4,110,438?

The patent should not be treated as a current Orange Book barrier.

The FDA Orange Book lists patents submitted by sponsors for approved drug products. A 1978 method-of-use patent may not appear as a current listed patent for modern GnRH products, and its 1995 expiration would eliminate any present-day blocking effect even if historical listing information exists.[4]

Orange Book relevance depends on the approved product, the NDA holder, the patent submission, and the patent’s expiration status. A patent covering a method of treating stress-induced depression would not automatically be listed against every GnRH product. The listed drug must have a corresponding approved use or other statutory basis for listing.

Orange Book implications for generic applicants

For an applicable listed drug, an ANDA applicant could address an expired patent through a certification that the patent has expired or through the applicable statutory certification framework. A Paragraph IV certification is generally used to assert that a listed patent is invalid, unenforceable, or not infringed before expiration. It would not be necessary to challenge an already expired patent as a current barrier.[5]

Do Paragraph IV challenges affect this patent?

No current Paragraph IV risk should remain because the patent expired in 1995.

Paragraph IV litigation is relevant when a generic applicant seeks approval before a listed patent expires and asserts that the patent is invalid, unenforceable, or not infringed. For U.S. Patent 4,110,438, the commercial timing is now immaterial. Any historic Paragraph IV filing would not create present exclusivity.

A modern applicant relying on native gonadorelin would instead focus on:

Current Orange Book-listed patents for the reference product
New formulation patents
Device patents
Manufacturing patents
Regulatory exclusivity
Labeling and indication strategy
Any later patents covering a specific depot, infusion, or delivery system

What patent landscape surrounds GnRH products?

The commercially important GnRH patent landscape moved away from the broad therapeutic concept in Patent 4,110,438 and toward analogs, formulations, delivery systems, and treatment-specific methods.

Native GnRH and gonadorelin

Native GnRH products may raise IP issues involving:

Peptide synthesis
Purification
Stabilization
Injectable formulations
Infusion devices
Diagnostic or reproductive-endocrinology uses
Specific dosing protocols

The 4,110,438 claims do not cover manufacturing processes or formulation composition claims on their face.

GnRH agonists

Products such as leuprolide, goserelin, nafarelin, triptorelin, and histrelin rely on modified peptide structures or delivery systems. Their historical patent estates generally centered on:

Specific amino-acid substitutions
Long-acting depot formulations
Microspheres
Implants
Injectable suspensions
Controlled-release systems
Prostate cancer, endometriosis, fibroid, or reproductive indications

Those claims are technically and legally distinct from the supplied claims of Patent 4,110,438.

GnRH antagonists

Degarelix, relugolix, and elagolix are not straightforward extensions of the patent’s coverage. Their patent estates typically involve small molecules or distinct peptide antagonists, with claims directed to:

Chemical composition
Salt and polymorph forms
Formulations
Combination therapy
Dosing regimens
Specific endocrine indications
Manufacturing processes

Patent 4,110,438 does not create a credible current barrier to these products.

Are biosimilar issues relevant to this patent?

Biosimilar risk is limited because the patent concerns a short peptide and a method of use, not a monoclonal antibody or complex biologic.

Native GnRH may be regulated as a drug or peptide product rather than through the conventional 351(k) biosimilar pathway used for licensed biologics. The regulatory route depends on the product’s classification, reference product, formulation, dosage form, and FDA determination.[6]

The relevant competitive pathways may include:

ANDA approval for a pharmaceutically equivalent product
505(b)(2) approval for a product with differences from a reference product
A standalone NDA where no suitable reference pathway exists
Compounded or institutional-use products, subject to applicable law

The expired patent presents no biosimilar or generic blocking period.

What manufacturing and formulation barriers remain?

Patent 4,110,438 does not claim a manufacturing process, dosage-form composition, device, or release profile. It therefore presents no apparent manufacturing barrier based on the supplied claims.

Potential modern barriers could arise from later patents covering:

Solid-phase peptide synthesis
Protection and deprotection chemistry
Oxidation control
Lyophilized formulations
Buffer systems
Preservatives
Injectable stability
Depot microspheres
Implantable delivery systems
Infusion-pump protocols
Container-closure systems
Combination products

These later rights must be analyzed separately. They cannot be inferred from Patent 4,110,438.

How strong is the patent estate for stress-induced depression?

As a current commercial estate, it is weak because the patent is expired and contains only six method claims, five of which were supplied here as numbered claims 1 through 5.

As a historical patent, claim 1 had potentially meaningful breadth within a narrow indication. Its principal weaknesses would have included:

The ambiguity of “stress-induced depression”
The need to prove a therapeutically effective amount
The absence of a defined diagnostic standard
Potential prior-art issues involving GnRH and neuropsychiatric uses
Questions concerning whether modified GnRH analogs fall within the claim
Possible enablement and written-description challenges across broad administration formats

The dose claims are narrower and easier to design around. A treatment using a dose below 100 mcg, above 800 mcg, or outside the specified monthly weight-based range could avoid claims 2, 3, and 5 while still requiring analysis under claim 1.

What generic launch scenarios would have existed?

Before expiration, potential launch scenarios included:

Scenario	Potential patent exposure
Native GnRH for stress-induced depression at 100 to 800 mcg	Potential claim 1 and claim 2 exposure
Native GnRH at 200 to 500 mcg	Potential claims 1, 2, and 3 exposure
GnRH hydrochloride salt for the claimed indication	Potential claims 1 and 4 exposure
Injectable GnRH at 1 to 20 mcg/kg/month	Potential claims 1 and 5 exposure
GnRH analog such as leuprolide	Literal coverage less apparent; requires claim construction
GnRH for infertility or diagnostic use	Generally outside the stress-induced depression limitation
Oral GnRH antagonist	Structurally and therapeutically distinct; unlikely to fall within the supplied claims

After August 29, 1995, these patent-based launch risks ended, although later patents and regulatory requirements could still affect a product.

What litigation or settlement agreements affect the patent?

No current litigation or settlement significance can be attributed to Patent 4,110,438 based on the supplied claims and its expired term. An expired 1978 method patent would not ordinarily support present-day Hatch-Waxman litigation.

The relevant litigation review would instead focus on later patents covering:

Gonadorelin products
GnRH agonist depots
GnRH implants
Injectable formulations
Controlled-release systems
Modern GnRH antagonists
Product-specific approved indications

A settlement involving a later GnRH product would not automatically affect the validity, scope, or expiration of Patent 4,110,438.

How does Patent 4,110,438 compare with later GnRH patents?

Issue	U.S. Patent 4,110,438	Later GnRH patent estates
Core subject	Treatment method	Compounds, formulations, devices, manufacturing, or regimens
Active ingredient	Native luteinizing hormone-releasing hormone	Native GnRH, agonists, antagonists, or modified products
Main indication	Stress-induced depression	Cancer, endometriosis, infertility, fibroids, contraception, or endocrine disorders
Dosage claims	100 to 800 mcg; 200 to 500 mcg; 1 to 20 mcg/kg/month	Often product- and formulation-specific
Formulation claims	None apparent from supplied claims	Common in depot and implant products
Manufacturing claims	None apparent	Common in complex peptide and small-molecule estates
Term status	Expired in 1995	Depends on filing date and patent family
Current blocking risk	None	Potentially material for unexpired rights

What geographic coverage did the patent have?

The patent provided rights only in the United States. Any corresponding foreign applications or patents would require separate identification and term analysis.

U.S. expiration did not automatically terminate foreign rights before their own expiration dates, although most foreign counterpart patents from the same era would also now be expired. Geographic analysis should distinguish:

U.S. patent rights
European national or regional rights
Japanese rights
Canadian rights
Patent Cooperation Treaty applications
Continuations, divisionals, and improvement patents

The supplied claims establish no foreign coverage.

Key takeaways

U.S. Patent 4,110,438 claims treatment of stress-induced depression with native luteinizing hormone-releasing hormone or an acceptable salt.
Claim 1 is broad in administration format but narrow because it requires stress-induced depression.
Claims 2 and 3 cover 100 to 800 mcg and 200 to 500 mcg, respectively.
Claim 4 is directed to the hydrochloride acid-addition salt in the claimed treatment.
Claim 5 covers parenteral administration at 1.0 to 20 mcg/kg/month.
The patent issued August 29, 1978, and its ordinary 17-year term expired August 29, 1995.
The patent does not currently block gonadorelin, GnRH analogs, GnRH antagonists, generics, or 505(b)(2) products.
The claims do not cover manufacturing processes, formulations, delivery devices, or GnRH analog compositions on their face.
Current diligence should focus on later product-specific patents, Orange Book listings, formulation rights, device patents, regulatory exclusivity, and litigation involving the relevant commercial product.

FAQs about U.S. Patent 4,110,438 and GnRH exclusivity

Does Patent 4,110,438 cover leuprolide?

Not clearly. The supplied claims recite luteinizing hormone-releasing hormone, which most directly identifies native GnRH. Leuprolide is a structurally modified GnRH agonist. Literal coverage would require analysis of the full patent record and claim construction.

Can an applicant file a Paragraph IV certification against Patent 4,110,438 today?

The patent expired in 1995, so it should not present a current patent barrier requiring a Paragraph IV challenge. The applicant would need to assess current listed patents associated with the relevant reference product.

Does the patent cover treating ordinary major depressive disorder?

Not necessarily. The claim requires “stress induced depression.” A treatment for major depressive disorder without a stress-related diagnosis may fall outside the express claim limitation.

Does claim 5 cover a monthly GnRH depot injection?

Potentially, if the depot provides parenteral administration and the total delivered amount is 1.0 to 20 mcg/kg per month. The patent’s expiration makes the issue historical rather than a current infringement risk.

Is native GnRH eligible for a biosimilar application?

The relevant FDA pathway depends on the product’s legal classification and reference product. Native GnRH is more likely to be evaluated through a drug approval pathway such as an ANDA or 505(b)(2) application than through the standard biologic biosimilar pathway, subject to FDA classification.

References

U.S. Patent No. 4,110,438. (1978). Treatment of stress induced depression with luteinizing hormone-releasing hormone. United States Patent and Trademark Office.
35 U.S.C. § 154. (2024). Contents and term of patent; provisional rights.
35 U.S.C. §§ 155, 156, 315. (2024). Patent term adjustment and extension provisions.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
21 U.S.C. § 355(j)(2)(A)(vii). (2024). Abbreviated applications and patent certifications.
U.S. Food and Drug Administration. (2024). Biosimilar and interchangeable biosimilar products. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Belgium	865156	⤷ Start Trial
Japan	S53115808	⤷ Start Trial
Japan	S6047246	⤷ Start Trial
South Africa	7801361	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 4,110,438