Details for Patent: 4,244,946

Summary for Patent: 4,244,946

Title:	Water-soluble peptides affecting gonadal function
Abstract:	[im-Bzl D-His6]LRF and [D-His6(im-Bzl), Pro9-NEt]LRF exhibit hydrophillicity comparable to that of LRF and act as superagonists exhibiting potencies, respectively, about 12 and more than 200 times that of LRF. The peptides or their nontoxic salts can be administered by intravenous subcutaneous, sublingual, oral, intravaginal, intranasal or rectal routes. The peptides can be used to regulate fertility in male and female mammals, including human beings.
Inventor(s):	Jean E. F. Rivier, Wylie W. Vale, Jr.
Assignee:	Salk Institute for Biological Studies
Application Number:	US06/047,026
Patent Claim Types: see list of patent claims	Use;

US Patent 4,244,946: Leuprolide Scope, Claims, Expiration, and Patent Landscape

US Patent 4,244,946 covers leuprolide-type gonadotropin-releasing hormone analogs, including leuprolide itself, protected synthetic intermediates, resin-bound peptide forms, and methods for regulating fertility and gonadotropin or sex-steroid production. The patent issued January 13, 1981, and its ordinary 17-year term expired January 13, 1998. It does not provide an enforceable US patent barrier to leuprolide products today. Current commercial risk is concentrated in formulation, delivery-device, manufacturing, and product-specific patents rather than in the expired composition claims of US 4,244,946. [1]

What drug does US Patent 4,244,946 cover?

The principal active compound is leuprolide, also known as leuprorelin.

Its peptide sequence is:

p-Glu-His-Trp-Ser-Tyr-D-His(im-Bzl)-Leu-Arg-Pro-NH-CH2CH3

The abbreviation identifies a decapeptide GnRH agonist with:

• A pyroglutamic acid residue at the N-terminus;
• A D-histidine substitution at position 6;
• A benzyl-protected imidazole nitrogen in the claimed nomenclature;
• An ethylamide terminus.

The alternative terminal structure in the patent is:

p-Glu-His-Trp-Ser-Tyr-D-His(im-Bzl)-Leu-Arg-Pro-Gly-NH2

That compound is generally identified as a leuprolide-related GnRH analog rather than the commercial leuprolide molecule. Claim 3 covers the ethylamide form corresponding to leuprolide. Claim 2 covers the Pro-Gly-NH2 analog.

Leuprolide is a synthetic GnRH agonist used in prostate cancer, endometriosis, uterine fibroids, central precocious puberty, and other hormone-dependent conditions. Commercial products include Lupron, Lupron Depot, Eligard, Fensolvi, and related formulations. The same active ingredient may be described as leuprolide acetate when formulated as a salt. [2]

What are the claims of US Patent 4,244,946?

The patent has six claims. Claims 1 through 3 are compound claims. Claims 4 through 6 are therapeutic method claims.

Claim	Subject matter	Practical scope
1	Broad compound class and nontoxic salts	Covers two terminal peptide structures and a large set of protected intermediates and synthetic forms
2	Compound of claim 1 with Pro-Gly-NH2 terminus	Covers the glycinamide analog
3	Compound of claim 1 with Pro-NH-CH2-CH3 terminus	Covers leuprolide-type ethylamide
4	Fertility and endocrine regulation method	Covers administering either named peptide or a nontoxic salt
5	Method using Pro-Gly-NH2 analog	Narrower method claim
6	Method using Pro-NH-CH2-CH3 analog	Leuprolide method claim

The central therapeutic sequence in claims 4 through 6 is:

p-Glu-His-Trp-Ser-Tyr-D-His(im-Bzl)-Leu-Arg-R

where R is either:

• Pro-Gly-NH2; or
• Pro-NH-CH2-CH3.

The method claims cover administration to male or female mammals for regulating fertility and production of gonadotropins and sex steroids.

How broad is claim 1?

Claim 1 is materially broader than a claim directed only to finished leuprolide acetate.

It includes two structural formulae:

1. The deprotected therapeutic peptide class with R equal to Pro-Gly-NH2 or Pro-NH-CH2-CH3; and
2. A protected and partially extended peptide class containing X1 through X6 substituents.

The second formula captures peptide-synthesis intermediates. It allows:

• N-terminal amino protection;
• Histidine imidazole protection;
• Serine hydroxyl protection;
• Tyrosine phenol protection;
• Arginine side-chain protection;
• C-terminal amines, alkylamines, phenethylamine, or resin-support attachments.

X1: N-terminal protection

X1 may be hydrogen or an alpha-amino protecting group. The claim therefore reaches both an unprotected N-terminus and protected intermediates used during peptide assembly.

X2: Histidine imidazole protection

The listed X2 groups include:

• Tosyl;
• Benzyl;
• Trityl;
• Fluoroalkyl benzyloxycarbonyl derivatives;
• 2,4-Dinitrothiophenyl.

These groups protect the histidine imidazole nitrogen during synthesis.

X3: Serine hydroxyl protection

The claim lists acetyl, benzoyl, tetrahydropyranyl, tert-butyl, trityl, benzyl, and 2,6-dichlorobenzyl protection.

X4: Tyrosine phenol protection

The claim lists tetrahydropyranyl, tert-butyl, trityl, benzyl, benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, and 2,6-dichlorobenzyl groups.

X5: Arginine protection

The arginine nitrogen may be protected with:

• Nitro;
• Tosyl;
• Benzyloxycarbonyl;
• Adamantyloxycarbonyl;
• BOC;

or may be hydrogen.

X6: C-terminal attachment

X6 may be:

• Dimethylamine;
• An alkylamine containing one to five carbon atoms;
• Phenethylamine;
• O-CH2-resin support;
• Gly-O-CH2-resin support;
• Gly-NH-resin support.

This language reaches protected peptide fragments and solid-phase synthesis intermediates. It does not mean that every chemically unrelated compound with one of the listed protecting groups falls within the claim. The compound must retain the required peptide backbone and substitution pattern.

Does claim 1 cover leuprolide acetate?

Yes, substantively. Claim 1 covers the leuprolide peptide structure and its nontoxic salts. Leuprolide acetate is the acetate salt of leuprolide and falls within the salt language if the peptide is otherwise structurally consistent with the claim.

The claim does not depend on the commercial product name, depot vehicle, vial configuration, or dosage schedule. It is a composition claim directed to the active peptide and selected intermediates.

The salt language would not automatically cover every formulation containing leuprolide. A formulation also requires the claimed active compound plus additional formulation elements. Claim 1 does not expressly claim:

• Microspheres;
• Polymer depots;
• In situ gels;
• Pre-filled syringes;
• Specific concentrations;
• Particular release profiles;
• Particular excipients;
• Injection devices.

Those features would need separate claim coverage.

What is the scope of the method-of-use claims?

Claims 4 through 6 cover administering the named peptides to regulate:

• Fertility;
• Gonadotropin production;
• Sex-steroid production.

The claims apply to male and female mammals. They are functional treatment claims, not claims limited to a particular disease.

The language is broad enough to encompass therapeutic uses that alter the hypothalamic-pituitary-gonadal axis. It does not specify:

• A particular dose;
• Route of administration;
• Depot interval;
• Disease diagnosis;
• Patient age;
• Duration of therapy;
• Pharmaceutical formulation.

Because the patent expired in 1998, these method claims no longer create current US exclusivity.

When did US Patent 4,244,946 expire?

US Patent 4,244,946 issued January 13, 1981. For a US patent filed before June 8, 1995, the ordinary term was the longer of 17 years from issuance or 20 years from the earliest effective nonprovisional filing date. The 17-year issue-date term therefore controlled for this patent, producing an expiration date of January 13, 1998. [1,3]

Event	Date
US Patent 4,244,946 issued	January 13, 1981
Ordinary patent term	17 years from issue
Expiration	January 13, 1998
Current status	Expired

No current patent term extension or pediatric extension can revive the expired patent. Patent term extension under 35 U.S.C. §156 applies to qualifying regulatory delay but does not convert an already expired legacy patent into an active exclusion right. [3]

What is the Orange Book status of leuprolide products?

The Orange Book identifies approved drug products and associated patent and exclusivity information. The existence of a listed patent depends on the specific reference product and dosage form. A historic Orange Book listing does not extend an expired patent term. [4]

Leuprolide products have been approved in several distinct presentations:

Product or product family	Active ingredient	Delivery format	Patent relevance
Lupron Injection	Leuprolide acetate	Injectable solution	Active-ingredient patent is expired; product-specific patents may have applied historically
Lupron Depot	Leuprolide acetate	Depot microspheres	Formulation, polymer, process, and administration patents may differ from the base peptide patent
Eligard	Leuprolide acetate	Atrigel in situ depot	Delivery-system and formulation patents are more relevant than US 4,244,946
Fensolvi	Leuprolide acetate	Six-month depot	Product-specific formulation and regulatory exclusivity issues apply
Pediatric leuprolide products	Leuprolide acetate	Injectable depot	Pediatric labeling and product-specific patents may affect competition

The Orange Book must be reviewed by reference product and strength. Patent listings can be delisted, expire, or become commercially irrelevant at different times. US 4,244,946 itself is not a current Orange Book barrier because it expired in 1998.

What patents protect leuprolide formulations?

The main commercial patent distinction is between the leuprolide molecule and the delivery platform.

Lupron Depot

Lupron Depot uses a sustained-release depot approach based on biodegradable polymeric microspheres. Patent protection historically focused on:

• Encapsulation of leuprolide;
• Polymer composition;
• Particle characteristics;
• Release kinetics;
• Injectable depot preparation;
• Stability and reconstitution.

Those claims are distinct from the composition claims in US 4,244,946.

Eligard

Eligard uses the Atrigel delivery system, an in situ forming depot. The relevant technical features include:

• A polymer dissolved in a biodegradable solvent;
• Mixing with a leuprolide-containing component;
• Formation of a depot after injection;
• Controlled release over a defined period.

The key patent analysis for Eligard therefore concerns the delivery system and formulation architecture. A product can avoid an expired active-ingredient patent while still raising infringement issues under an active formulation or device patent.

Fensolvi

Fensolvi is a longer-duration leuprolide acetate formulation for central precocious puberty. Its patent position may involve:

• Six-month release;
• Polymer matrix or depot composition;
• Particle or microsphere characteristics;
• Reconstitution and administration;
• Pediatric indication.

The relevant patent set is product-specific and cannot be inferred from US 4,244,946.

Are there paragraph IV challenges to US Patent 4,244,946?

No live paragraph IV challenge can target US 4,244,946 because the patent expired decades ago.

A paragraph IV certification is relevant when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. For an expired patent, an applicant does not need to wait for patent expiration and generally has no commercial reason to litigate that patent. [5]

For leuprolide products, any historical paragraph IV litigation would have focused on later patents covering:

• Depot formulations;
• Polymer systems;
• Release profiles;
• Manufacturing processes;
• Product-specific methods of use;
• Injection or reconstitution systems.

The expiration of US 4,244,946 removes the base peptide patent from the generic-entry analysis. It does not establish that every leuprolide depot formulation is free of later patent risk.

Which companies have commercial exposure to leuprolide patent rights?

The principal commercial parties have included:

Company	Relevant products or role
AbbVie, historically through Abbott/TAP	Lupron and Lupron Depot
Tolmar Pharmaceuticals	Eligard
Tolmar and related commercial partners	Fensolvi
Generic and specialty pharmaceutical manufacturers	Potential leuprolide acetate injectable or depot products
Peptide and injectable contract manufacturers	API, sterile fill-finish, and depot manufacturing

The largest exposure is tied to depot products rather than immediate-release leuprolide. Depot products generally have higher technical barriers because a competitor must reproduce a sustained-release profile, maintain peptide stability, meet sterility standards, and demonstrate bioequivalence or clinical comparability.

How strong is the patent estate for leuprolide today?

The estate has low strength at the active-ingredient level and potentially greater strength at the product level.

Patent category	Status under US 4,244,946	Current strategic significance
Leuprolide composition	Expired	No current exclusion
Leuprolide salts	Expired	No current exclusion
GnRH agonist method of use	Expired	No current exclusion
Protected peptide intermediates	Expired	No current exclusion
Depot formulation	Not claimed by the patent	Must be analyzed separately
Polymer delivery system	Not claimed by the patent	Potential later-patent barrier
Manufacturing process	Only partly implicated through intermediates	Process patents require separate review
Device and administration	Not claimed	Product-specific review required
Pediatric indication	Not claimed specifically	Regulatory exclusivity and later patents may matter

The patent estate is therefore fragmented. US 4,244,946 is historically foundational but commercially obsolete as an exclusion right.

What generic launch scenarios exist for leuprolide?

Immediate-release injectable leuprolide

A manufacturer developing a conventional leuprolide acetate injection faces no barrier from US 4,244,946. The primary requirements are API quality, sterile manufacturing, formulation equivalence, labeling, and FDA approval.

Monthly or three-month depot

A depot entrant must address:

• Polymer selection;
• Drug loading;
• Release kinetics;
• Microsphere size;
• Residual solvent;
• Sterility;
• Reconstitution;
• Injection performance;
• Patent claims covering the reference product.

The regulatory pathway may be more complex than a conventional solution product because equivalence involves a controlled-release system.

Six-month depot

A six-month product presents the highest technical and commercial entry barriers. A competitor must demonstrate sustained exposure and reliable release over a substantially longer interval. Pediatric labeling and product-specific exclusivity may also affect timing.

Alternative GnRH agonists

Competitors such as goserelin, histrelin, nafarelin, and triptorelin are not covered by the leuprolide composition claims merely because they share a therapeutic class. Their patent landscapes are separate.

Does US Patent 4,244,946 create manufacturing or licensing barriers?

No current US patent licensing requirement follows from US 4,244,946. The patent expired in 1998, so its protected peptide synthesis routes and listed intermediates are available for use in the United States, subject to other active patents and regulatory requirements.

Historical licensing or collaboration arrangements may still be relevant to commercial history, but they do not extend the patent term. Any current freedom-to-operate analysis must separate:

1. Leuprolide API manufacture;
2. Salt formation;
3. Sterile fill-finish;
4. Microsphere or in situ depot manufacture;
5. Device assembly;
6. Manufacturing in foreign jurisdictions.

A US patent does not, by itself, determine freedom to manufacture or sell in Europe, Japan, China, or other jurisdictions. Geographic analysis must be performed patent family by patent family.

What litigation and settlement issues remain relevant?

US 4,244,946 cannot support a new infringement suit because it is expired. Historical litigation involving leuprolide products may have concerned later patents and cannot be attributed automatically to this patent.

For current diligence, the relevant questions are:

• Whether a reference product has Orange Book-listed patents;
• Whether an ANDA applicant filed paragraph IV certifications;
• Whether the NDA holder sued within the statutory period;
• Whether a settlement includes a licensed launch date;
• Whether the settlement contains manufacturing, supply, or authorized-generic provisions;
• Whether later patents cover the same depot technology.

A settlement involving Lupron, Eligard, or Fensolvi would not revive US 4,244,946 or alter its January 13, 1998 expiration.

How does US Patent 4,244,946 compare with later leuprolide patents?

Issue	US 4,244,946	Later product patents
Primary subject	Leuprolide analogs and methods	Formulations, depots, devices, processes, dosing
Claim type	Composition and method	Often formulation, process, or product-by-process
Commercial target	Active peptide	Specific commercial presentation
Expiration	January 13, 1998	Varies by patent and term adjustments
Current value	Historical and technical	Potentially relevant to launch timing
Regulatory linkage	Foundational active ingredient	Reference-product and Orange Book specific

The distinction is decisive. A competitor can practice the expired leuprolide molecule without practicing a later patented depot system.

Key Takeaways

• US Patent 4,244,946 covers leuprolide-type GnRH analogs, including the Pro-NH-CH2-CH3 ethylamide corresponding to leuprolide.
• Claim 1 also covers protected peptide intermediates and resin-supported synthesis forms.
• Claims 4 through 6 cover fertility and endocrine-regulation methods using the two specified peptide structures.
• The patent issued January 13, 1981, and expired January 13, 1998.
• Leuprolide acetate is within the substantive scope of the expired composition claim.
• The patent no longer blocks manufacture, sale, or use of leuprolide in the United States.
• Current risk lies in later patents directed to depot formulations, polymer delivery systems, manufacturing methods, devices, and product-specific uses.
• No live paragraph IV challenge can target US 4,244,946.
• Generic-entry risk is low for the active ingredient and higher for complex long-acting depot products.
• Any current freedom-to-operate opinion must analyze later patent families separately by product, formulation, process, and jurisdiction.

FAQs

Is US Patent 4,244,946 the original leuprolide patent?

Yes. It is an early foundational US patent covering the leuprolide peptide structure, a related glycinamide analog, protected intermediates, and endocrine-regulation methods.

Does leuprolide acetate infringe US Patent 4,244,946 today?

No actionable infringement claim remains because the patent expired January 13, 1998.

Can a generic company use the peptide synthesis intermediates listed in claim 1?

Yes, the US patent no longer prevents use of those intermediates. Separate active patents, trade secrets, process restrictions, or foreign rights must be assessed independently.

Are Lupron Depot and Eligard protected by the same patent?

Not necessarily. Their delivery systems and formulations differ. Lupron Depot and Eligard require separate patent-family and Orange Book analyses.

Does expiration of the leuprolide composition patent guarantee immediate generic depot entry?

No. A generic company may avoid the expired composition patent while still facing formulation, delivery-system, regulatory, manufacturing, or device patents.

References

1. United States Patent and Trademark Office. (1981). US Patent No. 4,244,946, Peptide analogs of LH-RH. https://patents.google.com/patent/US4244946
2. U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/
3. United States Code. (2024). 35 U.S.C. §§ 154 and 156. https://uscode.house.gov/
4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
5. U.S. Food and Drug Administration. (2024). ANDA submissions: Refuse-to-receive standards and patent certifications. https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/breviated-new-drug-application-anda-forms-and-submissions

Drugs Protected by US Patent 4,244,946

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 4,244,946

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	2617
Australia	533348
Australia	5866380
Canada	1154758
Germany	3062118
Denmark	149896
Denmark	241780