Details for Patent: 3,947,569

« Back to Dashboard

Summary for Patent: 3,947,569

Title:	Process for preparing the releasing hormone of luteinizing hormone (LH) and of follicle stimulating hormone (FSH), salts and compositions thereof, and intermediates therefor
Abstract:	A process for preparing the LH- and FSH-releasing hormone of the formula I H-Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 which is isolated as the hydrochloride salt and optionally converted to other pharmaceutically acceptable salts or to pharmaceutically acceptable metal complexes.
Inventor(s):	Hans U. Immer, Verner R. Nelson, Manfred K. Gotz
Assignee:	Wyeth LLC
Application Number:	US05/451,328
Patent Claim Types: see list of patent claims	Use;

US Patent 3,947,569: Scope, Claims, Expiration, and GnRH Diagnostic Patent Landscape

US Patent 3,947,569 covers a diagnostic method using gonadotropin-releasing hormone, also called luteinizing hormone-releasing hormone or GnRH/LHRH, to distinguish hypothalamic dysfunction from pituitary dysfunction in humans. The patent claims systemic administration of the native decapeptide at 1 to 100 micrograms per kilogram, followed by detection of a rise in serum luteinizing hormone.

The patent issued on March 30, 1976. Assuming the ordinary 17-year term applicable to pre-June 8, 1995 U.S. patents, it expired on March 30, 1993. It therefore has no current U.S. exclusionary value, cannot block generic GnRH products or diagnostic testing, and should not create present U.S. launch risk.

What molecule does US Patent 3,947,569 claim?

The claimed peptide is:

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosylglycyl-L-leucyl-L-arginyl-L-prolylglycinamide

This is gonadorelin, the native decapeptide also known as:

• Gonadotropin-releasing hormone
• GnRH
• Luteinizing hormone-releasing hormone
• LHRH
• Gonadorelin
• Gonadorelin hydrochloride or dihydrochloride, depending on the salt form

The sequence is conventionally written as:

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

The patent does not claim a GnRH analog such as leuprolide, goserelin, nafarelin, buserelin, or triptorelin. Those molecules contain structural substitutions designed to alter potency, half-life, receptor activity, or administration characteristics.

What does claim 1 cover?

Claim 1 covers a human diagnostic method with four principal limitations:

Claim element	Scope
Patient	A human suspected of hypothalamic or pituitary malfunction
Administration	Systemic administration
Agent	Native GnRH/LHRH or a pharmaceutically acceptable salt
Dose	About 1 to 100 micrograms per kilogram of body weight
Detection	Detecting a rise in serum luteinizing hormone
Purpose	Distinguishing hypothalamic from pituitary malfunctions or lesions

The claim is a method-of-use claim, not a composition claim. It does not claim:

• The peptide as a chemical compound
• A pharmaceutical composition containing GnRH
• A vial, syringe, infusion device, or assay kit
• A manufacturing process
• A particular laboratory test platform
• A specific threshold for the LH rise
• A particular time interval for measuring LH
• A particular patient age, disease subtype, or clinical diagnosis beyond the stated hypothalamic-versus-pituitary distinction

The phrase “about 1 to 100 micrograms per kilogram” gives the claim a broad dose range. A dose materially outside that range would raise a literal infringement issue, although the doctrine of equivalents could have been relevant during the patent’s enforceable term.

What does claim 2 add?

Claim 2 depends on claim 1 and narrows it in two ways:

1. The patient is female.
2. The compound is gonadorelin dihydrochloride.

Claim 2 therefore requires all limitations of claim 1. It is not an independent claim to gonadorelin dihydrochloride or to female endocrine testing generally.

The limitation to a female patient is clinically relevant because the original diagnostic context involved evaluation of hypothalamic-pituitary-gonadal function in women. It does not cover use in males unless a court construed the female limitation unusually broadly, which would be unlikely.

How strong was the patent scope?

The patent had meaningful historical value but narrow claim architecture.

Strengths

The claims directly targeted the clinical use of GnRH stimulation testing. A test provider that administered native GnRH systemically, used the claimed dose range, and measured serum LH for the stated differential diagnosis could have fallen within claim 1 during the patent term.

The claim also covered pharmaceutically acceptable salts. That prevented easy avoidance through use of a conventional salt form rather than the free peptide.

Claim 2 provided a narrower fallback position for female patients receiving the dihydrochloride salt.

Limitations

The patent did not control the broader GnRH product market. It lacked claims covering:

• Native GnRH as a standalone composition
• Long-acting GnRH formulations
• Continuous infusion
• Pulsatile administration
• GnRH receptor agonists or antagonists
• Ovulation induction as a treatment
• Prostate cancer or endometriosis treatment
• In vitro diagnostic assays
• LH immunoassay technology
• Manufacturing or purification of gonadorelin

A competitor could have designed around the claim by changing the diagnostic endpoint, using a different analyte, avoiding systemic administration, using a materially different dose, or applying an analog rather than native GnRH, subject to the doctrine of equivalents.

When did US Patent 3,947,569 expire?

Event	Date
Patent issued	March 30, 1976
Ordinary pre-1995 U.S. patent term	17 years from issue
Expected expiration	March 30, 1993
Current status	Expired
Current enforceability	None in the United States

The patent predates the Uruguay Round Agreements Act changes that generally shifted U.S. utility patent terms to 20 years from the earliest effective nonprovisional filing date. For a patent issued in 1976, the historical 17-year-from-issue rule ordinarily governs unless a special term adjustment or terminal disclaimer altered the date. Public patent records should be used for a formal chain-of-title or term opinion. The ordinary expiration date is March 30, 1993 (U.S. Patent and Trademark Office, n.d.-a).

Because the patent expired decades ago, there is no current U.S. patent barrier to:

• Gonadorelin diagnostic testing
• Use of gonadorelin in endocrine stimulation tests
• Generic gonadorelin products
• Diagnostic protocols using LH response
• Commercial services based on the claimed method

What is the Orange Book status of the patent?

US Patent 3,947,569 is not an Orange Book drug patent.

The Orange Book lists patents submitted by applicants for approved drug products, including patents covering drug substances, drug products, and approved methods of use. A historical diagnostic method patent covering clinical use of native GnRH would not ordinarily be listed unless it had been properly submitted in connection with an approved product and satisfied FDA listing requirements (U.S. Food and Drug Administration, n.d.-a).

The patent is not an Orange Book-listed barrier to an abbreviated new drug application for gonadorelin. It also does not create a current Paragraph IV certification risk.

Did the patent generate Paragraph IV litigation?

No current Paragraph IV exposure arises from US Patent 3,947,569 because the patent expired in 1993.

A Paragraph IV certification concerns an unexpired patent listed in the Orange Book. A generic applicant could not make a meaningful Paragraph IV challenge to an expired patent. The relevant regulatory pathway for a current gonadorelin generic would instead depend on the reference product, product availability, dosage form, route of administration, and FDA requirements under section 505(j) of the Federal Food, Drug, and Cosmetic Act.

The patent also would not support a 30-month stay. An expired patent cannot provide the statutory basis for delaying approval under the Hatch-Waxman litigation framework.

What FDA products and regulatory uses relate to gonadorelin?

Gonadorelin has been used as a diagnostic endocrine agent and, in some settings, as a therapeutic reproductive hormone through pulsatile administration. Regulatory status has changed over time by product, sponsor, dosage form, and market.

Relevant product categories include:

Product category	Typical use
Gonadorelin injection	Diagnostic stimulation of pituitary gonadotropin release
Gonadorelin acetate or hydrochloride products	Parenteral endocrine use
Pulsatile GnRH pump systems	Treatment of selected hypothalamic disorders and infertility
GnRH agonists	Fertility control, prostate cancer, endometriosis, and related indications
GnRH antagonists	Fertility treatment and androgen-deprivation applications

FDA status must be assessed at the product level. A product may have been approved, discontinued, listed as unavailable, or marketed under a different salt or sponsor. The patent itself does not establish FDA approval, current commercial availability, or therapeutic interchangeability (U.S. Food and Drug Administration, n.d.-b).

How does the patent compare with later GnRH patents?

The patent landscape divided into several distinct technology groups.

Technology group	Representative subject matter	Relationship to US 3,947,569
Native GnRH diagnostics	LH-response testing after GnRH administration	Directly covered by the patent
Native GnRH compositions	Peptide salts, injectable preparations, stabilizers	Outside the core method claim unless used in the claimed diagnosis
Pulsatile GnRH therapy	Intermittent hormone delivery using pumps	Generally distinct from the claimed diagnostic method
GnRH agonists	Leuprolide, goserelin, nafarelin, buserelin, triptorelin	Structurally different molecules
GnRH antagonists	Degarelix, relugolix, elagolix, ganirelix, cetrorelix	Different mechanism and compound class
LH assays	Immunoassays and automated laboratory platforms	Separate diagnostic technology
Fertility methods	Ovulation induction and controlled ovarian stimulation	Usually separate method claims
Oncology uses	Androgen deprivation for prostate cancer	Separate therapeutic use

The patent’s native peptide limitation is important. A later patent covering leuprolide or another GnRH analog would not necessarily be relevant to a test using gonadorelin. Conversely, a method using leuprolide would not literally satisfy the native GnRH limitation in claim 1.

What patent families created the broader GnRH landscape?

The wider GnRH patent estate historically included:

• Foundational discoveries and synthesis of native LHRH/GnRH
• GnRH analog compositions
• Injectable and depot formulations
• Nasal and implantable delivery systems
• Pulsatile administration systems
• Fertility-treatment methods
• Endometriosis and uterine disorder treatments
• Prostate and breast cancer hormone suppression
• GnRH antagonist compounds
• Analytical assays and hormone measurement technologies

Many of the earliest GnRH composition and analog patents expired between the late 1980s and the 2000s. Later patents on depot formulations, devices, manufacturing methods, and specific clinical uses extended protection for particular products, but they did not revive or extend US Patent 3,947,569.

The major commercial GnRH products include leuprolide, goserelin, triptorelin, nafarelin, histrelin, degarelix, relugolix, elagolix, ganirelix, and cetrorelix. These products have separate patent histories and regulatory records.

Are there current licensing deals or settlements tied to this patent?

No current licensing or settlement structure can preserve exclusivity under US Patent 3,947,569 after its expiration. Any historical license would have ended as a matter of patent exclusivity when the patent expired, although contractual provisions unrelated to patent validity could have had different terms.

The patent should therefore be treated as a historical technology-rights asset rather than an active licensing asset. Current commercial agreements involving GnRH products are more likely to concern:

• Product supply
• Manufacturing rights
• Regulatory approvals
• Device technology
• Formulation know-how
• Trademarks
• Data rights
• Later patents covering specific products or indications

Those rights are distinct from the expired patent.

Does 35 U.S.C. § 287(c) affect enforcement analysis?

The medical-activity safe harbor in 35 U.S.C. § 287(c) limits remedies against certain medical practitioners and related health-care entities for performance of a medical activity. It does not generally eliminate potential claims against a commercial manufacturer, supplier, or marketer of a patented product.

That provision is not necessary to resolve the present status of US Patent 3,947,569 because the patent expired before current enforcement could occur. During the patent term, however, it could have affected the practical value of enforcing a diagnostic-method claim against physicians or hospitals (35 U.S.C. § 287, 2023).

What generic launch risks exist today?

The patent presents no current U.S. generic launch risk.

A company evaluating gonadorelin or a related diagnostic product should focus instead on:

1. FDA reference-product requirements.
2. Product-specific regulatory exclusivity.
3. Current Orange Book listings for the reference product.
4. Manufacturing controls for peptide purity and salt form.
5. Stability and sterile injectable requirements.
6. Device or pump rights for pulsatile delivery.
7. Later patents covering formulations, dosing schedules, or approved indications.
8. State and federal requirements governing laboratory-developed testing and endocrine diagnostics.

For GnRH analogs, the relevant freedom-to-operate analysis must be performed separately for each active ingredient. A patent landscape for leuprolide, goserelin, or relugolix cannot be substituted for a gonadorelin analysis.

How strong is the patent estate today?

Category	Assessment
US 3,947,569 validity risk	Moot because the patent expired
Current U.S. exclusionary power	None
Composition coverage	None in the two provided claims
Diagnostic method coverage	Historical, now expired
Formulation coverage	Not present in the provided claims
Manufacturing coverage	Not present in the provided claims
Orange Book relevance	None established
Paragraph IV relevance	None against this expired patent
Biosimilar relevance	None; gonadorelin is a synthetic peptide, not a biologic biosimilar case
Current licensing leverage	None based on this patent
International relevance	Must be assessed through corresponding foreign family members, which may have different terms and statuses

Key Takeaways

• US Patent 3,947,569 covers a diagnostic method using native GnRH to distinguish hypothalamic from pituitary dysfunction.
• Claim 1 requires systemic administration to a human, a dose of about 1 to 100 micrograms per kilogram, and detection of a serum LH rise.
• Claim 2 narrows the method to female patients receiving gonadorelin dihydrochloride.
• The patent does not claim native GnRH as a composition, GnRH analogs, formulations, devices, manufacturing methods, or broad fertility treatments.
• The patent issued March 30, 1976 and ordinarily expired March 30, 1993.
• It has no current U.S. enforcement, Orange Book, Paragraph IV, or generic-launch significance.
• Current freedom-to-operate risk must be evaluated against later patents covering specific GnRH products, formulations, delivery systems, assays, and indications.
• Biosimilar analysis is not applicable because gonadorelin is a synthetic peptide rather than a therapeutic biologic subject to a conventional biosimilar pathway.

FAQs

Is gonadorelin the same molecule as luteinizing hormone-releasing hormone?

Yes. Gonadorelin, GnRH, and LHRH refer to the same native decapeptide sequence, subject to the specific salt and formulation used.

Does US Patent 3,947,569 cover leuprolide?

No. Leuprolide is a synthetic GnRH agonist with structural substitutions. The claims provided are directed to the native GnRH peptide or its pharmaceutically acceptable salts.

Could a laboratory infringe the patent by measuring LH after GnRH administration?

Not today, because the patent expired. During its term, the answer would have depended on whether the laboratory or associated provider performed every required claim step, including systemic administration within the claimed dose range and use for the specified diagnostic distinction.

Does the patent cover a GnRH stimulation test using follicle-stimulating hormone?

Not expressly. The claims identify detection of a rise in serum luteinizing hormone. A method relying only on FSH would not literally satisfy that limitation.

Are foreign counterparts still enforceable?

Potentially, but only if a corresponding foreign patent issued, remained unexpired, and covered the relevant activity in that jurisdiction. Foreign patent terms and family members must be reviewed separately from the U.S. patent.

References

1. U.S. Patent and Trademark Office. (n.d.-a). US3947569: Diagnostic method for distinguishing between hypothalamic and pituitary malfunctions. Google Patents. https://patents.google.com/patent/US3947569

2. U.S. Food and Drug Administration. (n.d.-a). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

3. U.S. Food and Drug Administration. (n.d.-b). Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/

4. 35 U.S.C. § 287 (2023). Limitation on damages and other remedies; marking and notice.

5. U.S. Food and Drug Administration. (2017). Abbreviated new drug application submissions: Refuse-to-receive standards. FDA. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs

Drugs Protected by US Patent 3,947,569

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

International Family Members for US Patent 3,947,569

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	476785
Australia	5150573
Canada	1025441
Canada	1034568