US Patent 6,565,874: Scope, Claim Construction, Expiration, and Leuprolide Implant Patent Landscape

US Patent 6,565,874 covers Atrigel-type injectable, in situ-forming biodegradable implants containing uncomplexed leuprolide acetate. Its core claim requires three elements: a biodegradable thermoplastic polyester, a water-miscible or water-dispersible biocompatible polar aprotic solvent, and leuprolide acetate as the only leuprolide source. The patent also reaches manufacturing methods, in situ implant formation, cancer and LH-reduction treatment methods, combination kits, and solid implants with a core-and-skin microporous structure.

The patent expired in late 2020 based on the 20-year term from its US nonprovisional filing date. It therefore has no current exclusionary force, although it remains relevant as prior art and as part of the historical patent foundation for Eligard and related delivery technology. [1][2]

What does US Patent 6,565,874 protect?

The patent protects a solvent-exchange implant system rather than a conventional preformed depot. Before injection, the product is a flowable polymer solution or dispersion. After subcutaneous administration, the solvent diffuses into surrounding body fluid, the polymer precipitates or coagulates, and a solid biodegradable depot forms in situ.

Core technical architecture

Required element	Claim scope
Biodegradable polymer	Thermoplastic polyester substantially insoluble in aqueous medium or body fluid
Solvent	Biocompatible polar aprotic solvent that is miscible to dispersible in aqueous medium or body fluid
Active ingredient	Uncomplexed leuprolide acetate
Leuprolide source	Leuprolide acetate must be the only source of leuprolide
Administration	Injectable, generally subcutaneous, in situ implant
Release mechanism	Diffusion, polymer erosion, or both
Product forms	Flowable composition, solid implant, kit, and treatment method

The central commercial concept is the use of a volatile or diffusible solvent to transform a low-viscosity injectable composition into a solid polymeric implant inside the patient. The claims do not require a separate preformed microsphere, implant rod, or conventional aqueous suspension.

How broad is independent claim 1?

Claim 1 is the principal composition claim. It has a broad functional structure but important chemical limitations.

A composition is within claim 1 if it contains:

A biodegradable thermoplastic polyester that is at least substantially insoluble in body fluid.
A biocompatible polar aprotic solvent selected from broad chemical classes.
Uncomplexed leuprolide acetate.
No other source of leuprolide.

The solvent limitation is broad because it covers amides, esters, carbonates, ketones, ethers, and sulfonyl compounds. The claim is narrowed by the requirement that the solvent be biocompatible and miscible to dispersible in aqueous medium or body fluid.

The polymer limitation is also broad at the independent-claim level. The dependent claims identify polylactide, polyglycolide, polycaprolactone, PLGA copolymers, terpolymers, and combinations.

Principal claim limitations

The most commercially significant limitations are:

"Uncomplexed leuprolide acetate."
"The only source of leuprolide."
A biodegradable thermoplastic polyester.
A water-compatible or water-dispersible polar aprotic solvent.
Suitability for a controlled-release implant.

A formulation using leuprolide acetate with no second leuprolide-containing compound is the closest literal target. A formulation containing a chemically complexed leuprolide species, a different leuprolide salt, or another leuprolide-containing active would require separate analysis because the "only source" limitation may prevent literal infringement.

What polymers and solvents are covered?

Polymer claims

Claims 2 through 7 identify the primary polymer families and composition ranges.

Claim	Polymer or parameter
2	Polylactide, polyglycolide, polycaprolactone, copolymers, terpolymers, combinations
3	Polylactide, polyglycolide, copolymers, terpolymers, combinations
4	50/50 poly(DL-lactide-co-glycolide), carboxy-terminal
5	75/25 poly(DL-lactide-co-glycolide), without a carboxy terminal group
6	Polymer at approximately 30-40 wt.% or 40-50 wt.%
7	Average molecular weight of approximately 15,000-24,000 or 23,000-45,000

The claims distinguish polymer composition, terminal-group chemistry, concentration, and molecular weight. These limitations are relevant to release rate, implant integrity, solvent exchange, degradation, and drug loading.

The 50/50 carboxy-terminated PLGA and 75/25 non-carboxy-terminated PLGA embodiments are narrower than the broad polyester genus. A product outside those specific polymer compositions may still fall within claim 1, but it would not fall within claims 4 or 5.

Solvent claims

Claims 8 through 11 list solvents and concentration ranges.

Claim	Solvent or concentration
8	N-methyl-2-pyrrolidone, 2-pyrrolidone, DMF, DMSO, propylene carbonate, caprolactam, triacetin, or combinations
9	N-methyl-2-pyrrolidone
10	Approximately 60-70 wt.% solvent
11	Approximately 50-60 wt.% solvent

N-methyl-2-pyrrolidone, or NMP, is the most important named solvent because it is a standard solvent in Atrigel-type systems and is specifically recited in claim 9.

A composition using NMP at 50-70 wt.% with PLGA and uncomplexed leuprolide acetate would present a strong historical literal-overlap case with the narrower dependent claims, subject to the remaining limitations.

Which claims cover injectable monthly and longer-acting products?

Claims 14 through 19 target injectable subcutaneous systems and dosing intervals.

Claim	Limitation
14	Injectable subcutaneous delivery system
15	Approximately 0.20-0.40 mL
16	Approximately 0.30-0.50 mL
17	Administration about once per month
18	Administration about once per three months
19	Administration about once every four to six months

These claims are directed to product configuration and intended dosing frequency. They are narrower than claim 1 because they require a subcutaneous system and, in some cases, specified volume or dosing interval.

The claim language uses "about," which gives practical range flexibility but can create claim-construction disputes at the boundaries. The dosing claims also raise questions about whether a product must be expressly labeled for the claimed interval or whether the formulation's pharmacokinetic performance is sufficient.

What manufacturing and in situ implant claims are covered?

Composition manufacturing claims

Claim 20 covers mixing the polyester, solvent, and uncomplexed leuprolide acetate in any order for a sufficient time to form the flowable implant composition.

Claim 21 narrows the process to:

Mixing the polymer and solvent.
Forming a polymer-solvent mixture.
Mixing that mixture with leuprolide acetate.

The process claims can reach manufacturing operations even if the final product is supplied in separate containers. They focus on the method used to create the flowable composition, not only the finished dosage form.

In situ implant claims

Claims 22 and 26 cover injection into a patient followed by solvent dissipation and formation of a solid biodegradable implant.

Claims 24 and 27 specify drug release by:

Diffusion.
Polymer erosion.
A combination of diffusion and erosion.

Claim 25 requires adherence of the solid implant to tissue. Claims 23 and 26 expressly address a living human patient.

These claims are directed to the transformation that occurs after administration. They would be relevant to a solvent-depot product even if the manufacturer characterized the dosage form as a solution, suspension, gel, or injectable implant.

What treatment methods are protected?

Claims 28 through 32 cover use of the composition for:

Treating cancer.
Treating prostate cancer.
Reducing LH levels.
Treating endometriosis through LH reduction.

The claims are method-of-treatment claims. They do not establish exclusivity over leuprolide as a molecule or over all prostate-cancer uses. Their scope depends on administering the claimed flowable composition.

The treatment claims would have been commercially relevant to products such as Eligard, which uses leuprolide acetate for androgen-deprivation therapy in prostate cancer. They would not necessarily cover a conventional leuprolide depot that does not satisfy the composition limitations.

What kit and solid-implant claims are covered?

Kit claims

Claims 33 through 39 cover a two-container presentation:

A first container holding the polymer and solvent.
A second container holding uncomplexed leuprolide acetate.
Optional syringes.
Lyophilized leuprolide acetate.
Instructions.
Containers capable of direct connection.

These claims are important because they address a product supplied as separate components rather than a premixed composition. A dual-syringe or connected-container system could therefore be evaluated under the kit claims even if the leuprolide is not mixed until immediately before administration.

Solid implant claims

Claims 40 through 46 cover a solid implant containing:

A biodegradable thermoplastic polyester.
Uncomplexed leuprolide acetate.
A solid or gelatinous microporous matrix.
A core surrounded by a skin.

The claims further address:

Residual biocompatible organic solvent.
A decreasing amount of solvent over time.
Core pores of approximately 1 to 1,000 microns.
Smaller pores in the outer skin.
A functionally nonporous skin relative to the core.

These claims are structurally distinct from the broader flowable-composition claims. They may apply after solvent loss, when the implant has developed a differentiated outer layer and internal pore structure.

When did US Patent 6,565,874 expire?

US Patent 6,565,874 was granted on May 20, 2003. Its term was governed by the post-1995 patent-term rule, which generally provides 20 years from the earliest effective US nonprovisional filing date, subject to patent-term adjustment and terminal-disclaimer issues. Public patent records identify the patent as expired in late 2020. [1]

Event	Date or period
US patent grant	May 20, 2003
Nominal patent term	20 years from the applicable US nonprovisional filing date
Expiration	Late 2020
Current enforceability	Expired
Current blocking effect	None

Expiration removes the patent's ability to block current manufacture, sale, use, or importation. It does not remove the patent from the prior-art record, invalidate historical infringement claims, or eliminate its relevance to freedom-to-operate analyses involving related patents.

What is the Orange Book status of US 6,565,874?

The patent was associated with the Eligard leuprolide acetate injectable implant product and was historically relevant to the product's Orange Book patent listing. Eligard is approved under NDA 021343 for multiple strengths and dosing intervals. [2][3]

Because US 6,565,874 expired in late 2020, it is no longer an enforceable Orange Book barrier. FDA Orange Book records can continue to display expired patent information for historical and regulatory-reference purposes, but a listed expired patent does not support a current patent-based delay of generic approval.

The relevant distinction is:

FDA listing is a regulatory record.
Enforceability is a legal-status question.
Approval delay under the Hatch-Waxman framework depends on a valid, unexpired listed patent and the statutory conditions applicable to the ANDA.

Are there Paragraph IV challenges to this patent?

A current Paragraph IV challenge to US 6,565,874 would have little practical value because the patent expired in late 2020. An ANDA applicant could have challenged the patent before expiration, but the commercial incentive would have depended on the remaining term and the status of other Eligard patents.

The principal patent-risk issue for historical generic applicants was not this patent alone. It was the combined estate covering:

The Atrigel delivery platform.
Leuprolide implant compositions.
Specific polymer and solvent combinations.
Product dosing intervals.
Related formulations and manufacturing methods.

A Paragraph IV certification against an expired patent does not create the same litigation or 30-month-stay consequences as a challenge to an unexpired listed patent. [4]

Which companies commercialized or challenged the technology?

Commercial developers

Atrix Laboratories developed the Atrigel delivery platform and associated leuprolide implant technology. Commercial rights to Eligard were licensed and later transferred through arrangements involving Sanofi-Aventis and Tolmar. Tolmar is the current US commercial sponsor associated with Eligard. [3][5]

The commercial chain is separate from patent ownership. Patent assignment records, product licenses, and commercial supply agreements must be analyzed independently. A company may hold product rights without owning every patent in the platform estate.

Generic and competing manufacturers

The competitive field includes:

Eligard and other Tolmar leuprolide acetate injectable products.
Lupron Depot and related leuprolide depot products.
Generic leuprolide products approved through the ANDA pathway.
Potential follow-on products using microspheres, in situ gels, implants, or alternative depot technologies.

A conventional microsphere product may compete commercially without practicing the asserted claim set if it does not use the claimed polymer-solvent in situ precipitation mechanism. Conversely, a product marketed under a different formulation name could still implicate the claims if it uses the same PLGA/NMP/leuprolide architecture.

How strong was the patent estate?

Historical strength

The patent was historically strong against products using the same core Atrigel configuration because the independent claims combined:

A defined polymer platform.
A defined solvent function.
A specific active ingredient.
A controlled-release implant purpose.

The dependent claims created multiple fallback positions around PLGA ratio, terminal groups, molecular weight, solvent identity, loading, volume, dosing interval, and kit configuration.

Weaknesses and design-around points

The principal technical and legal limitations were:

The requirement for uncomplexed leuprolide acetate.
The requirement that leuprolide acetate be the only leuprolide source.
The required polar aprotic solvent behavior in body fluid.
The required biodegradable thermoplastic polyester.
The functional connection to an implant or controlled-release system.

Potential design-around categories included:

Preformed microspheres rather than in situ solvent precipitation.
Non-polyester biodegradable matrices.
A different active form or chemical complex.
A solvent system outside the claimed chemical and biocompatibility classes.
A noninjectable implant.
A formulation that does not produce the claimed core-and-skin microporous structure.

These design-around concepts would have been relevant before expiration. They have no current value as a means of avoiding infringement of US 6,565,874 because the patent is expired, but they remain relevant to related unexpired family members and competing patent estates.

How does US 6,565,874 compare with competing leuprolide patent strategies?

Technology	Typical dosage form	Main patent focus	Relationship to US 6,565,874
Atrigel-type leuprolide implant	Injectable in situ depot	PLGA plus water-miscible polar aprotic solvent	Directly aligned
Microsphere leuprolide depot	Preformed injectable microspheres	Particle structure, encapsulation, release profile	Potential design-around
Preformed implant	Rod, implant, or solid depot	Implant geometry and drug loading	Generally outside flowable composition claims
Aqueous suspension	Injectable suspension	Salt, particle size, dosing, formulation	Usually different mechanism
Non-polyester biodegradable system	Injectable or implantable depot	Alternative polymer chemistry	Outside polyester limitation, subject to other patents

The expired patent remains important because it defines a known technical baseline. Current competition is more likely to be constrained by later formulation, manufacturing, device, use, and product-specific patents than by US 6,565,874 itself.

Is there biosimilar risk?

There is no biosimilar pathway issue for leuprolide acetate. Leuprolide acetate is a peptide drug, not a biological product regulated as a biosimilar reference product under the Public Health Service Act's 351(k) pathway.

The relevant competitive routes are generally:

ANDA approval for a generic drug where statutory requirements are met.
A new drug application for a formulation or delivery system that cannot qualify as an ANDA.
Other abbreviated or hybrid regulatory strategies depending on the product and reference listed drug.

The principal regulatory difficulty is formulation and delivery equivalence. An in situ biodegradable implant may raise clinical, pharmacokinetic, device, manufacturing, and substitutability issues beyond ordinary small-molecule tablet or injection development. [2][4]

What manufacturing and IP barriers remain?

US 6,565,874 no longer creates a manufacturing barrier. Commercial barriers can remain in other areas:

Control of PLGA molecular weight and terminal chemistry.
Reproducible leuprolide loading.
Sterility and aseptic filling.
Solvent residual limits.
Syringe or dual-container compatibility.
In situ implant geometry and release consistency.
Subcutaneous tolerability.
Long-term stability of the polymer-drug mixture.
Clinical and regulatory evidence for monthly, quarterly, or longer dosing.

These barriers are technical and regulatory rather than rights created by the expired patent.

What is the revenue exposure from this patent?

The patent's historical revenue exposure was concentrated in leuprolide products using the Atrigel-type in situ implant system, particularly Eligard strengths designed for monthly, three-month, four-month, and six-month administration.

After expiration, US revenue is no longer legally protected by this patent. Revenue exposure now depends on:

Later-expiring patents.
Regulatory exclusivity.
Product manufacturing know-how.
Brand recognition.
Formulation complexity.
Generic approval and launch timing.
Physician and payer acceptance.

The patent should therefore be treated as an expired platform patent, not as a current standalone moat.

Key Takeaways

US 6,565,874 covers injectable, in situ-forming biodegradable leuprolide acetate implants.
Claim 1 requires PLGA or another biodegradable thermoplastic polyester, a biocompatible polar aprotic solvent, and uncomplexed leuprolide acetate as the only leuprolide source.
NMP, PLGA, subcutaneous administration, and controlled release are central commercial embodiments.
Claims also cover manufacturing, treatment, two-container kits, and solid implants with microporous core-and-skin structures.
The patent expired in late 2020 and does not create a current US infringement or Orange Book blocking risk.
It is not a biosimilar patent issue. Generic or hybrid drug pathways are more relevant.
Current diligence should focus on later family patents, formulation patents, device patents, manufacturing claims, and product-specific regulatory protections.

FAQs

Does US 6,565,874 cover Eligard?

Yes. The patent's claimed PLGA-solvent-leuprolide in situ implant architecture is closely associated with the Eligard delivery platform and was historically relevant to Eligard patent protection.

Can a company currently sue for infringement of US 6,565,874?

No prospective infringement action can be based on an expired patent. The patent may remain relevant to historical infringement claims subject to applicable limitation periods and other legal requirements.

Does using NMP automatically infringe US 6,565,874?

No. NMP alone is insufficient. The product must also satisfy the polymer, leuprolide, source-of-leuprolide, and controlled-release implant limitations.

Does the patent cover all leuprolide depot injections?

No. The claims are directed to a specific biodegradable polyester and biocompatible polar aprotic solvent architecture. Conventional microspheres, aqueous suspensions, and other depot systems may fall outside the claims.

Is a dual-syringe leuprolide product covered by the patent?

Historically, it could have implicated claims 33 through 39 if the containers held the claimed polymer-solvent composition and uncomplexed leuprolide acetate and were configured for connection. The patent's expiration eliminates current infringement risk.

References

United States Patent and Trademark Office. (2003). U.S. Patent No. 6,565,874, Biodegradable polymeric compositions for the delivery of biologically active agents.
U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (2023). Eligard: Leuprolide acetate for injectable suspension, prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products and therapeutic equivalence evaluations: Regulatory guidance.
Tolmar Pharmaceuticals, Inc. (2023). Eligard product information and prescribing materials.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	259217	⤷ Start Trial
Austria	296088	⤷ Start Trial
Austria	458469	⤷ Start Trial
Australia	1331200	⤷ Start Trial
Australia	2001292931	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,565,874