United States Drug Patent 6,235,712: Claim Scope, Expiration, and LHRH Formulation Patent Landscape

U.S. Patent No. 6,235,712 covers methods for dissolving LHRH-related peptides, including leuprolide, in stable non-aqueous formulations containing polar aprotic solvents. The broadest technical concept is a concentrated peptide solution, particularly leuprolide acetate in DMSO or a comparable solvent, for parenteral or implant-based administration. The patent issued on May 22, 2001, and its ordinary 20-year patent term has expired. The patent therefore presents no current U.S. blocking right, although its claim structure remains relevant to the historical development of leuprolide delivery systems and to later formulation patents. [1]

What does U.S. Patent 6,235,712 protect?

The patent protects a process rather than a standalone pharmaceutical composition. Claim 1 requires all of the following elements:

A stable formulation.
A non-aqueous formulation.
At least one LHRH-related peptide compound.
At least one polar aprotic solvent.
Dissolution of the peptide in the solvent.

The central claim does not require a specific delivery device, disease, dose, or administration route. Those limitations appear in later claims, although several of those claims have dependency and antecedent-basis problems.

The technical center of gravity is the preparation of a concentrated, water-free peptide formulation that can be used in an injectable or implantable delivery system. The specification and dependent claims identify DMSO as a principal solvent and leuprolide acetate as a principal peptide.

What compounds fall within the patent’s LHRH-related peptide scope?

Claim 4 expressly identifies:

Peptide	Commercial status or historical relevance	Claim relevance
Leuprolide	Used in Lupron, Lupron Depot, Eligard and other products	Expressly listed
LHRH	Native releasing hormone or related peptide	Expressly listed
Nafarelin	Used in Synarel	Expressly listed
Goserelin	Used in Zoladex	Expressly listed

The phrase “LHRH-related peptide compound” is broader than the four named compounds. It may encompass structurally related analogues, salts, derivatives, and peptide forms, subject to the patent’s specification and ordinary claim-construction principles. Claim 4 narrows the scope to the four listed compounds but does not necessarily define the full scope of claim 1.

Leuprolide is generally characterized pharmacologically as an LHRH or GnRH agonist. Claim 15, by contrast, refers to an LHRH antagonist. That distinction creates a material scope issue because leuprolide would not ordinarily satisfy the antagonist limitation in claim 15.

How do the individual claims differ?

Claims 1 through 7: formulation preparation and concentration

Claim	Principal limitation	Practical scope
1	Dissolving an LHRH-related peptide in a polar aprotic solvent to prepare a stable non-aqueous formulation	Broadest process claim
2	At least about 10% w/w peptide dissolved	Concentrated formulation
3	At least about 30% w/w peptide dissolved	Higher-concentration formulation
4	Leuprolide, LHRH, nafarelin or goserelin	Compound-specific narrowing
5	Addition of a non-aqueous protic solvent	Mixed-solvent system
6	About 30% to about 50% w/w leuprolide acetate in DMSO	Narrow DMSO/leuprolide formulation
7	370 mg leuprolide in 1 mL DMSO	Specific concentration and solvent

Claim 1 is broad in solvent selection. A polar aprotic solvent can include DMSO, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide and related solvents, depending on the patent specification and the technical meaning applied during claim construction.

Claim 6 is substantially narrower than claim 1. A formulation using 30% to 50% w/w leuprolide acetate in DMSO would directly address its express limitations, assuming the formulation is stable and prepared by dissolution.

Claim 7 specifies 370 mg of leuprolide in 1 mL of DMSO. That is approximately 370 mg/mL, or 37% w/v. It should not automatically be treated as 37% w/w because the claim uses a mass-to-volume expression while claims 2, 3 and 6 use weight percentages.

Claims 8 through 14: administration, treatment and implant limitations

Claims 8 through 14 refer to parenteral administration, long-term continuous administration, implantable devices, prostate cancer, daily leuprolide dosing and treatment periods of three, six or 12 months.

As supplied, these claims depend on claim 1, which is a method for preparing a formulation. Claim 1 does not recite administration, a subject, prostate cancer, a daily dose or a treatment period. The resulting claims contain apparent antecedent-basis and dependency defects:

Claim 8 refers to “said administration,” although claim 1 does not require administration.
Claim 9 repeats the same issue.
Claim 11 introduces “said condition,” although claim 1 does not identify a condition.
Claim 12 introduces a daily administration dose that is not present in claim 11’s stated base claim.
Claim 14 combines continuous administration and an implantable delivery system without a clean antecedent basis in claim 1.

These defects could create claim-construction and validity arguments. Their practical significance depends on the issued patent record, prosecution history, claim amendments and any judicial interpretation. The formulation limitations in claims 1 through 7 are structurally clearer than the administration claims as reproduced.

Claims 15 through 19: antagonist treatment and manufacturing controls

Claim 15 is a separate treatment claim directed to administering an effective amount of a stable, non-aqueous formulation of an LHRH antagonist in a patient with prostate cancer.

Claims 16 through 19 narrow claim 1 by requiring:

No components containing added water.
Processing under an inert gas atmosphere.
Dry nitrogen as the inert gas.
No conventional bacteriostatic, bactericidal or sporicidal agent.

These claims address manufacturing conditions and formulation composition rather than a particular delivery device. Claim 16 is potentially significant because it excludes formulations made by adding water-containing components. A formulation may still contain residual moisture or water generated through handling unless the claim is construed to prohibit all water, rather than added-water components.

Claim 19 excludes conventional antimicrobial preservatives. That limitation could distinguish the patented process from aqueous multidose formulations, but it would not necessarily exclude a formulation with an alternative preservative or aseptic manufacturing controls.

What formulations are protected by U.S. Patent 6,235,712?

The strongest literal formulation targets are concentrated, non-aqueous peptide solutions using polar aprotic solvents.

Formulation characteristic	Relevance to claim scope
Leuprolide acetate in DMSO	Directly aligned with claims 4, 6 and 7
Leuprolide in NMP	Potentially within claim 1 if NMP is treated as a polar aprotic solvent
Leuprolide in DMF or DMAc	Potentially within the broad solvent language, subject to pharmaceutical suitability
Peptide in a polar aprotic/protic solvent mixture	Potentially within claims 1 and 5
Aqueous peptide solution	Outside the core non-aqueous requirement
Polymer depot containing a peptide but no dissolved peptide in a polar aprotic solvent	May fall outside claim 1 if the peptide is suspended rather than dissolved
Formulation with added water-containing components	Potentially outside claim 16
Formulation containing a conventional antimicrobial agent	Potentially outside claim 19

The distinction between “dissolved” and “dispersed” is critical. A polymeric depot containing suspended peptide particles may not satisfy a claim requiring that the peptide be dissolved in a polar aprotic solvent. Conversely, a polymer solution in NMP containing molecularly dissolved leuprolide could raise a stronger historical overlap issue.

When did U.S. Patent 6,235,712 lose exclusivity?

The patent’s ordinary U.S. term expired in approximately 2019, based on the application and priority information shown in the patent record and the 20-year term applicable to the relevant filing period. [1] It is not an unexpired U.S. patent as of 2026.

The patent does not appear to have received a commercially relevant period of pediatric exclusivity or patent term extension. The expiration of the patent does not eliminate other patents covering:

A particular depot or implant device.
A biodegradable polymer matrix.
A specific solvent-polymer system.
A manufacturing process.
A dosing regimen.
A particular product presentation.
A method of treating a disease.

Patent expiration must therefore be assessed at the product level rather than by treating Patent 6,235,712 as the entire leuprolide patent estate.

What is the Orange Book status of Patent 6,235,712?

Patent 6,235,712 is a process patent directed principally to formulation preparation. Process patents generally do not qualify for Orange Book listing unless they claim an approved drug product, formulation, composition or method of use within the statutory listing framework. [2]

The patent is therefore better understood as an historical formulation-development patent than as a current Orange Book barrier. Product-specific Orange Book patents for leuprolide products may have covered depot formulations, polymer delivery systems, implants or methods of use under separate patent numbers.

Did Patent 6,235,712 create Paragraph IV risk?

No current Paragraph IV risk arises from Patent 6,235,712 because its U.S. term has ended. During its effective term, a generic applicant referencing a product that practiced the claimed formulation process could have evaluated:

A Paragraph IV certification if the patent was listed for the reference product.
A process non-infringement position if the generic used an aqueous or non-dissolution process.
An invalidity position based on prior art concerning peptide solubilization, DMSO systems or depot delivery.
A section viii carve-out if the relevant listed claims were limited to a method of use.

The commercial relevance of any historical Paragraph IV dispute would have depended on whether the patent was listed for the relevant reference product. The patent’s process character made Orange Book listing less straightforward than listing a composition or method-of-use patent.

How does this patent compare with the Eligard and Lupron patent estates?

Eligard

Eligard uses a depot delivery platform associated with Atrix Laboratories’ Atrigel technology. The product combines leuprolide acetate with a biodegradable polymer delivery system and a non-aqueous solvent system. The product label identifies a subcutaneous depot formulation designed to release leuprolide over extended periods. [3]

Patent 6,235,712 is relevant to the general concept of preparing concentrated non-aqueous leuprolide formulations. It is not, by itself, a complete claim to the Eligard product. Later patents could protect:

The polymer composition.
The solvent-polymer matrix.
The two-syringe or dual-component presentation.
In situ depot formation.
Release kinetics.
Specific leuprolide concentrations.
Product-specific manufacturing steps.

Because Patent 6,235,712 expired before 2026, it does not independently block an Eligard-like formulation. Any remaining risk would have to arise from later, unexpired patents.

Lupron Depot

Lupron Depot is a sustained-release leuprolide acetate product using a depot delivery technology distinct from the non-aqueous liquid depot approach associated with Eligard. Its historical patent estate included product formulation, microsphere and depot technology and dosing claims. [4]

The key distinction is that Patent 6,235,712 is centered on dissolution in a non-aqueous polar aprotic solvent. A microsphere product may not infringe that process if the peptide is incorporated into a polymeric microparticle through a different manufacturing route.

Viadur and implant systems

Viadur used an implantable osmotic delivery system for leuprolide. Its relevance to Patent 6,235,712 arises from claims 9, 10 and 14, which refer to long-term continuous administration through an implantable drug delivery system. The claims, as reproduced, do not clearly define the implant architecture, osmotic mechanism or release-control structure.

Device-specific patents, rather than Patent 6,235,712, would have been expected to carry the primary protection for an implant product.

Which companies and products are relevant to the LHRH formulation landscape?

Company or product	Active peptide	Delivery category	Relationship to Patent 6,235,712
AbbVie, Lupron Depot	Leuprolide acetate	Depot injection	Competing leuprolide formulation estate
Tolmar, Eligard	Leuprolide acetate	In situ polymeric depot	Closest commercial formulation comparison
Bayer, Zoladex	Goserelin	Implant depot	Expressly named peptide, different delivery technology
Pfizer, Synarel	Nafarelin	Nasal formulation	Expressly named peptide, generally outside the non-aqueous parenteral focus
Endo, Supprelin LA	Histrelin	Implant	Related GnRH agonist market, different peptide
Generic manufacturers	Leuprolide and related products	Product-specific	Entry depends on product patents and FDA pathway

The patent’s competitive reach was therefore broader than a single leuprolide product but narrower than the entire LHRH market. It addressed a formulation platform, not every formulation or delivery system for every GnRH analogue.

Is there biosimilar risk for leuprolide products?

Leuprolide is a synthetic peptide and is not ordinarily treated as a conventional biologic subject to the biosimilar pathway in the same way as monoclonal antibodies or recombinant proteins. Generic applicants may use an abbreviated new drug application where the reference product and dosage form support that pathway, or a 505(b)(2) application where formulation, delivery system or clinical bridging issues make a full ANDA less suitable. [5]

The principal regulatory barriers are likely to involve:

Complex depot release profiles.
Device or implant equivalence.
Peptide characterization.
In vitro release testing.
Sterility and particulate controls.
Demonstration of equivalent exposure and pharmacodynamic suppression.

Patent 6,235,712 does not create a current biosimilar or generic barrier because it has expired. Product-specific patents and regulatory complexity remain more important than this patent.

How strong was the patent estate, and what are the current generic entry risks?

Historical strength

The patent had moderate historical breadth in the formulation field because claim 1 covered a class of LHRH peptides and a class of polar aprotic solvents. Claims 6 and 7 were narrower but technically concrete.

Its weaknesses included:

Functional language such as “stable.”
Potential ambiguity around “LHRH-related peptide compound.”
The absence of a precise solvent list in claim 1.
The distinction between dissolution and suspension.
The unusual structure of claims 8 through 14.
The antagonist language in claim 15.
Potential written-description and enablement questions for the full scope of all LHRH peptides and all polar aprotic solvents.

Current strength

Current blocking strength is zero because the patent has expired. It can still have evidentiary value in:

Freedom-to-operate reviews involving later patents.
Prior-art analysis.
Obviousness challenges.
Claim-construction disputes over non-aqueous peptide formulations.
Invalidity analysis of continuation or improvement patents.

Generic launch scenarios

Scenario	Patent 6,235,712 impact
Aqueous leuprolide injection	No current impact
Leuprolide microspheres	No current impact; assess separate depot patents
Leuprolide polymer depot using NMP	No current impact from this patent; assess later patents
DMSO leuprolide formulation	No current patent-term barrier
Goserelin or nafarelin non-aqueous formulation	No current barrier from this patent
Implantable leuprolide system	Assess device and release-control patents separately

What patent litigation or settlement agreements affect this patent?

No material current litigation or settlement effect can be assigned to Patent 6,235,712 after expiration. Any historical dispute involving leuprolide products would need to be separated into:

Litigation directly asserting Patent 6,235,712.
Litigation involving later Atrix, Eligard, Lupron, implant or polymer patents.
ANDA litigation under the Hatch-Waxman framework.
Commercial settlements addressing product-specific patents rather than this expired formulation process patent.

A settlement concerning another leuprolide patent would not automatically restrict use of the technology claimed in Patent 6,235,712.

What geographic coverage did the patent have?

The patent provided U.S. rights only. Comparable protection would have required separate national or regional patents in jurisdictions such as Europe, Canada, Japan and Australia. U.S. expiration does not establish the status of foreign counterparts.

For a global freedom-to-operate review, the relevant questions are whether:

Foreign counterparts were granted.
Their terms expired on different dates.
Patent term extensions or supplementary protection certificates applied.
Continuations or divisionals preserved separate claim scope.
Local product patents remain active.

The U.S. patent alone cannot establish worldwide freedom to operate.

Key Takeaways

U.S. Patent 6,235,712 covers preparation of stable, non-aqueous LHRH peptide formulations using polar aprotic solvents.
Leuprolide, goserelin, nafarelin and LHRH are expressly identified in claim 4.
DMSO/leuprolide formulations are the clearest narrow claim target under claims 6 and 7.
The patent is a process patent, not a complete product claim to Eligard, Lupron Depot or an implant.
Claims 8 through 14 contain apparent dependency and antecedent-basis defects as reproduced.
Claim 15 is directed to an LHRH antagonist and does not naturally encompass leuprolide, an LHRH agonist.
The U.S. patent term expired in approximately 2019.
No current Paragraph IV or Orange Book blocking risk arises from this patent alone.
Current generic risk depends on later product, polymer, device, manufacturing and method-of-use patents.
Leuprolide is generally addressed through generic or 505(b)(2) pathways rather than a conventional biosimilar strategy.

FAQs

Does Patent 6,235,712 cover N-methyl-2-pyrrolidone formulations?

Potentially. N-methyl-2-pyrrolidone is a polar aprotic solvent and could fall within claim 1 if the peptide is dissolved, the formulation is non-aqueous and stable, and the process otherwise satisfies the claim. The patent’s expiration removes current U.S. infringement risk.

Does the patent cover leuprolide microspheres?

Not necessarily. A microsphere process may fall outside the claims if leuprolide is encapsulated or suspended rather than dissolved in a polar aprotic solvent. Separate microsphere and depot patents require review.

Does claim 15 cover leuprolide acetate?

Claim 15 requires an LHRH antagonist. Leuprolide acetate is generally classified as an LHRH agonist, so it would not ordinarily satisfy that limitation.

Can an expired patent still be used in an obviousness challenge?

Yes. The patent can be cited as prior art where legally available based on its publication and effective filing dates. Its disclosure may be relevant to later patents covering non-aqueous peptide formulations, polymer depots or implant systems.

Are foreign patents corresponding to U.S. Patent 6,235,712 also expired?

Not automatically. Foreign counterparts require jurisdiction-specific review of grant status, term calculations, maintenance fees and any patent-term adjustment or extension. The U.S. expiration does not determine foreign status.

References

U.S. Patent No. 6,235,712. (2001). Non-aqueous formulations of LHRH-related peptides. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
Tolmar Pharmaceuticals, Inc. (2023). Eligard (leuprolide acetate for injectable suspension) prescribing information. U.S. Food and Drug Administration.
AbbVie Inc. (2023). Lupron Depot prescribing information. U.S. Food and Drug Administration.
U.S. Food and Drug Administration. (2024). Applications covered by section 505(b)(2). FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	007714	⤷ Start Trial
Austria	224199	⤷ Start Trial
Austria	263570	⤷ Start Trial
Australia	3587997	⤷ Start Trial
Australia	739169	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,235,712

Summary for Patent: 6,235,712