United States Patent 5,631,021: Scope, Claims, Expiration, and Leuprolide Microsphere Patent Landscape

US Patent No. 5,631,021 covers a specific injectable, prolonged-release microcapsule technology for water-soluble peptide drugs, with the principal commercial embodiment directed to leuprolide. The claims require a redispersed spherical microcapsule containing a peptide-loaded particulate phase, a lactic acid/glycolic acid polymer matrix, and a specified sugar or polyol excipient. The patent is expired and no longer creates a current U.S. patent barrier to generic or follow-on leuprolide depot development.[1]

What does US Patent 5,631,021 cover?

US 5,631,021 covers a manufacturing-defined injectable microcapsule rather than leuprolide as a molecule. Its central innovation is the redispersion and resolidification of drug-containing particles within a biodegradable polymer matrix to improve stability after reconstitution for injection.

The claim requires all of the following elements:

Claim element	Required limitation
Dosage form	Prolonged-release microcapsule for injection
Particle structure	Spherical microcapsule with an average diameter of 2 to 200 micrometers
Drug phase	Particles containing a water-soluble drug
Polymer matrix	Polymer of lactic acid and glycolic acid
Polymer ratio	Lactic acid:glycolic acid ratio from about 100:0 to 50:50
Polymer molecular weight	About 5,000 to 200,000
Excipient	Mannitol, sorbitol, lactose or glucose
Process	Redispersion of the spherical microcapsule followed by solidification
Drug class	Specified polypeptide or a salt of that polypeptide
Functional result	Greater stability after reconstitution than without the redispersion step

The patent therefore does not broadly cover every PLGA microsphere, every injectable peptide depot, or every leuprolide formulation. It covers a narrower combination of composition, particle structure, process history, excipient selection and post-reconstitution stability.

What drug is specifically claimed by US 5,631,021?

Claim 2 specifically covers the peptide:

(Pyr)Glu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NH-C2H5

This is leuprolide, also called leuprorelin. Commercial products generally use leuprolide acetate, which is a salt form of the peptide.

The claim 1 Markush formula also covers related gonadotropin-releasing hormone analogues having the specified substitutions at R1, R2, R3, R4 and R5. Claim 2 narrows the scope to leuprolide. The use of the salt language in claim 1 extends the claim to pharmaceutically acceptable salt forms, subject to the other limitations.

The patent does not claim:

The basic chemical structure of leuprolide;
Leuprolide acetate without the claimed microsphere structure;
Immediate-release leuprolide injections;
All sustained-release leuprolide formulations;
Implants, in situ gels or non-microcapsule delivery systems;
A PLGA formulation lacking the claimed redispersion and solidification process.

How do the five claims differ?

Claim 1: Principal combination claim

Claim 1 is the broadest claim, but it is still technically constrained. It requires both a defined formulation and a defined manufacturing history.

The most important limitation is the requirement that the spherical microcapsule be redispersed and then solidified. This is a product-by-process limitation. Whether the limitation is assessed solely by the final physical characteristics or also by the manufacturing process would depend on the applicable infringement and claim-construction analysis. A competing product with similar particle size and composition could still avoid literal infringement if it lacks the claimed redispersion-solidification history or does not satisfy the resulting stability limitation.

The functional phrase "provides greater stability" compares the reconstituted product with a product made without the redispersion step. This creates an evidentiary issue. A patent owner would need to establish the relevant stability metric, test conditions, comparator and duration.

Claim 2: Leuprolide species claim

Claim 2 narrows claim 1 to leuprolide. It is the commercially relevant claim for leuprolide depot products.

A product would need to satisfy the claim 1 microcapsule, polymer, excipient, size, molecular-weight, process and stability requirements before claim 2 becomes relevant. Leuprolide alone is not enough.

Claim 3: 75:25 PLGA ratio

Claim 3 narrows the polymer to a 75:25 lactic acid:glycolic acid ratio. This ratio is a conventional PLGA composition used in biodegradable controlled-release systems.

The claim can be commercially important because a product using PLGA 75:25 may fall within the dependent claim even if a broader infringement theory under claim 1 is contested. The phrase "75/25" may require analysis of whether the ratio is measured by monomer feed, polymer composition, or another formulation parameter.

Claim 4: Mannitol excipient

Claim 4 narrows the excipient to mannitol. Mannitol can act as a bulking agent, cryoprotectant or lyoprotectant in a reconstituted injectable microsphere product.

A competing formulation using sorbitol, lactose or glucose would not literally satisfy claim 4, although it could remain within claim 1.

Claim 5: Injectable preparation

Claim 5 covers an injectable preparation containing a therapeutically effective amount of the claimed microcapsule. It shifts the claim from the microcapsule itself to the finished injectable preparation.

The claim does not specify a particular dose, injection interval, indication or vehicle. It therefore could reach a range of finished injectable preparations if the underlying microcapsule satisfies claim 1.

What is the technical scope of the PLGA limitation?

The polymer limitation is central to the patent's scope. Claim 1 covers a lactic acid/glycolic acid copolymer with a comonomer ratio from approximately 100:0 to 50:50 and an average molecular weight from approximately 5,000 to 200,000.

This range includes:

Poly(lactic acid) at the 100:0 endpoint;
PLGA compositions such as 75:25;
PLGA compositions approaching 50:50;
Relatively low- and high-molecular-weight biodegradable polymers within the stated range.

The claim does not expressly cover:

PLGA with a glycolic-acid content above 50%;
Polymers outside the molecular-weight range;
Polycaprolactone or other non-lactic/glycolic biodegradable polymers;
Nonpolymeric sustained-release carriers;
Liposomes or crystalline peptide suspensions lacking the claimed microcapsule matrix.

The broad polymer range is offset by the narrow particle and process limitations. A formulation using the claimed polymer but delivered through an in situ gel, implant or different particulate architecture would not automatically fall within the patent.

What formulations are protected by US 5,631,021?

The most directly covered formulation profile is:

Parameter	Claimed profile
Active ingredient	Leuprolide or a covered GnRH analogue
Drug state	Water-soluble drug contained in particles
Carrier	Spherical PLGA or polylactic-acid microcapsule
Particle size	2 to 200 micrometers average diameter
PLGA ratio	100:0 to 50:50 lactic acid:glycolic acid
Polymer molecular weight	5,000 to 200,000
Excipient	Mannitol, sorbitol, lactose or glucose
Processing	Redispersion followed by solidification
Administration	Injection after reconstitution
Performance	Improved stability after reconstitution

The claim is strongest against a product that reproduces the same manufacturing sequence and uses leuprolide, PLGA 75:25, mannitol and a microsphere size within the stated range.

It is materially weaker against products using a different delivery platform, different excipient system, a different polymer family or a manufacturing process that does not include the claimed redispersion step.

When did US 5,631,021 lose exclusivity?

US 5,631,021 is expired. The patent issued in 1997, and its enforceable term ended under the pre-1995 U.S. patent-term regime, subject to any applicable term adjustment or terminal disclaimer recorded in the official patent file.[1][2]

The practical result is that US 5,631,021 cannot currently be asserted to block U.S. manufacture, approval or sale of a product that would have fallen within its claims during the patent term.

Patent expiration does not eliminate the historical relevance of the patent. It can still affect:

Prior-art analysis;
Obviousness and written-description disputes;
Freedom-to-operate opinions concerning related patents;
Ownership and inventorship analysis;
Formulation-development strategy;
Interpretation of later continuation or family patents.

What is the Orange Book status of US 5,631,021?

US 5,631,021 is not a current Orange Book exclusivity barrier. It is an expired formulation patent and does not provide an active patent term for a current leuprolide acetate product.

The Orange Book evaluates patents and exclusivity associated with approved drug products, not every patent that historically covered a formulation or manufacturing method. Current product-specific patent status must therefore be assessed against the relevant NDA and current Orange Book listings for products such as Lupron Depot, Eligard, Fensolvi and Camcevi.[3]

An expired patent may have appeared in historical patent portfolios or litigation records without remaining an active Orange Book-listed obstacle.

Does US 5,631,021 create a Paragraph IV risk?

No current Paragraph IV risk arises from this patent because the patent is expired.

During its active term, a generic applicant could have faced a Paragraph IV issue if the patent had been listed for the relevant NDA and the applicant sought approval before expiration. A Paragraph IV certification would assert that the listed patent was invalid, unenforceable or not infringed.

For present-day leuprolide depot development, the relevant Paragraph IV analysis concerns other unexpired patents, including later formulation, delivery-system, dosing-regimen and manufacturing patents. US 5,631,021 itself should be treated as expired prior art rather than an active launch blocker.

Which companies compete in the U.S. leuprolide depot market?

The principal U.S. commercial products use different dosage-form and delivery-system approaches.

Product	Sponsor or manufacturer	Typical depot interval	Delivery approach
Lupron Depot	AbbVie, historically associated with TAP and Abbott	1, 3, 4 or 6 months depending on presentation	Microsphere depot
Eligard	Tolmar	1, 3, 4 or 6 months	ATRIGEL in situ polymeric delivery system
Fensolvi	Tolmar	6 months	Polymer-based depot formulation
Camcevi	Accord BioPharma	6 months	Long-acting leuprolide formulation

Product details and approvals vary by indication and presentation. Lupron Depot and Eligard are primarily associated with prostate cancer treatment, while Fensolvi is approved for central precocious puberty. Camcevi is approved for advanced prostate cancer.[4][5][6][7]

The competition is not limited to the active ingredient. The principal differentiation points are:

Duration of release;
Injection volume;
Reconstitution requirements;
Needle and administration requirements;
Polymer delivery platform;
Storage and handling;
Approved indication;
Physician-office workflow;
Patent and regulatory exclusivity.

How does US 5,631,021 compare with Eligard and other leuprolide products?

US 5,631,021 is most closely aligned with a conventional biodegradable microsphere platform. Eligard uses the ATRIGEL delivery system, which is generally characterized as an in situ gel system rather than a preformed injectable microsphere product.[5]

That distinction matters for claim scope. A product using a polymer solution that forms a depot after injection may avoid literal infringement of a claim requiring a spherical microcapsule with an average diameter of 2 to 200 micrometers.

Fensolvi and Camcevi also require separate product-specific analysis. Their regulatory labels and patent positions cannot be inferred solely from the fact that they contain leuprolide. The active ingredient is public-domain technology, while the commercial barriers may arise from:

Delivery-system patents;
Formulation patents;
Manufacturing patents;
Dosage-regimen patents;
Device patents;
Regulatory exclusivity.

What manufacturing and IP barriers remain after expiration?

The expired patent removes one historical barrier but does not eliminate all development risk.

Manufacturing barriers

A follow-on manufacturer may need to reproduce or independently develop:

Uniform microsphere size;
Peptide loading and encapsulation efficiency;
Controlled release over the target interval;
Low residual solvent levels;
Sterility and endotoxin control;
Consistent reconstitution behavior;
Acceptable syringeability;
Stability after reconstitution;
Scale-up from laboratory emulsification to commercial production.

Leuprolide is a potent peptide, and the formulation must control initial release while preserving peptide integrity during manufacture, storage and injection.

Regulatory barriers

A generic or follow-on product may need to establish pharmaceutical equivalence and bioequivalence through a product-specific FDA pathway. Long-acting injectable products are difficult to characterize because conventional single-dose pharmacokinetic comparisons may not fully capture depot release behavior.

FDA review may focus on:

Drug release profiles;
Peptide identity and purity;
Particle-size distribution;
Polymer characterization;
Residual solvents;
In vitro/in vivo correlation;
Local tolerability;
Immunogenicity or peptide-related safety;
Reconstitution and administration instructions.

Intellectual-property barriers

Current freedom-to-operate analysis should separate:

Expired foundational microsphere patents;
Active formulation patents;
Active manufacturing patents;
Active delivery-device patents;
Active method-of-use patents;
Regulatory exclusivity;
Trade secrets covering scale-up and process controls.

A competitor can avoid US 5,631,021 while still infringing a later patent covering a specific depot interval, polymer composition, injection system or manufacturing step.

What patent litigation affects leuprolide depot products?

US 5,631,021 is not a current litigation driver because it is expired. Historical disputes involving leuprolide products have generally focused on commercial product portfolios, later patents, formulation technology and market entry rather than the enforceability of this expired patent.

The relevant litigation screen should include:

District court cases involving Lupron Depot, Eligard, Fensolvi or Camcevi;
ANDA litigation under the Hatch-Waxman Act;
Inter partes review proceedings;
Patent-term and Orange Book disputes;
Licensing and settlement agreements involving leuprolide depot products.

No active enforcement right should be attributed to US 5,631,021 based solely on its historical coverage of leuprolide microspheres.

What licensing deals are relevant to the patent landscape?

Leuprolide commercialization historically involved licensing and collaboration arrangements between Takeda and U.S. commercial partners, including the predecessor organizations associated with Lupron. Those commercial arrangements are distinct from the current enforceability of US 5,631,021.

A historical license may explain:

Why a Japanese-origin peptide technology reached the U.S. market;
How rights to leuprolide and depot technology were divided;
Which entity controlled prosecution or enforcement;
Why a commercial product can have a broader patent portfolio than a single formulation patent.

A license does not extend an expired patent term. Contractual rights, know-how, trademarks and regulatory assets may continue after patent expiration, but they do not restore patent exclusivity.

How strong is the patent estate represented by US 5,631,021?

As an active enforcement asset, the estate is weak because the patent has expired. As a technical disclosure and prior-art reference, it remains important.

Factor	Assessment
Active patent term	None
Claim breadth	Moderate to narrow
Leuprolide relevance	High through claim 2
Platform relevance	High for PLGA microspheres
Process specificity	High
Design-around potential	Meaningful
Current launch-blocking risk	None from this patent
Prior-art value	High
Regulatory relevance	Historical and technical
Litigation value today	Primarily defensive or evidentiary

The most vulnerable claim feature for a literal-infringement case would be the specific redispersion and solidification process, together with the comparative stability requirement. The most commercially important feature is the combination of leuprolide, PLGA microspheres and an excipient such as mannitol.

Key Takeaways

US 5,631,021 covers a prolonged-release injectable microcapsule made using a redispersion and solidification process.
Claim 2 specifically targets leuprolide, including its salt forms through the dependency on claim 1.
The patent requires a spherical microcapsule, a 2-to-200-micrometer average diameter, a lactic acid/glycolic acid polymer, a specified molecular-weight range and one of four listed excipients.
Claim 3 narrows the polymer to a 75:25 lactic acid:glycolic acid ratio.
Claim 4 narrows the excipient to mannitol.
Claim 5 covers an injectable preparation containing the claimed microcapsule.
The patent is expired and does not create a current U.S. Paragraph IV or Orange Book barrier.
Modern leuprolide competition includes Lupron Depot, Eligard, Fensolvi and Camcevi, which use product-specific delivery technologies and patent portfolios.
Current launch risk must be assessed against later patents, not against US 5,631,021 alone.
The patent remains relevant as prior art for PLGA microsphere formulation, manufacturing and stability issues.

Frequently Asked Questions

Does US 5,631,021 cover leuprolide acetate itself?

No. It covers a particular prolonged-release microcapsule containing leuprolide or a covered salt, not the active ingredient as a standalone compound.

Can a competitor avoid the patent by using a non-PLGA polymer?

A product using a polymer outside the claimed lactic acid/glycolic acid framework would not literally satisfy the polymer limitation. Equivalents analysis would depend on the product and the asserted claim.

Does the patent cover Eligard?

Not automatically. Eligard uses the ATRIGEL delivery system, which is materially different from a preformed spherical microcapsule. A product-by-product claim comparison would be required.

Is mannitol required for infringement?

No. Mannitol is required only for dependent claim 4. Claim 1 also covers sorbitol, lactose and glucose.

Can the expired patent still block FDA approval?

No. An expired patent does not independently block FDA approval or create a current Paragraph IV certification obligation. Later patents and regulatory requirements may still affect approval and launch timing.

References

U.S. Patent and Trademark Office. (1997). U.S. Patent No. 5,631,021, prolonged release microcapsule preparation. https://patents.google.com/patent/US5631021A/en
U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term information. https://www.uspto.gov/patents/laws/patent-term-adjustment
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
U.S. Food and Drug Administration. (n.d.). Lupron Depot prescribing information. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (n.d.). Eligard prescribing information. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (n.d.). Fensolvi prescribing information. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (n.d.). Camcevi prescribing information. https://www.accessdata.fda.gov

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	58-207760	Nov 04, 1983

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	42197	⤷ Start Trial
Bulgaria	60493	⤷ Start Trial
Canada	1233414	⤷ Start Trial
Germany	3477732	⤷ Start Trial
European Patent Office	0145240	⤷ Start Trial
Spain	8605983	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,631,021

Summary for Patent: 5,631,021