United States Patent 5,631,020: Claim Scope, Expiration, and Leuprolide Depot Patent Landscape

U.S. Patent No. 5,631,020 covers a manufacturing method for a stabilized, prolonged-release injectable microcapsule containing a specific leuprolide peptide. The claimed process requires redispersing preformed drug-containing microcapsules in mannitol, sorbitol, lactose, or glucose, followed by solidification. The patent also claims the resulting product through a product-by-process claim.

The patent issued on May 20, 1997. Because it belongs to the pre-URAA patent-term regime, its ordinary statutory term was 17 years from issuance, placing the base expiration date at May 20, 2014, absent patent-term adjustment or a later enforceable extension. The patent is therefore no longer an active exclusionary right. Its commercial importance is historical: it addressed reconstitution stability in PLGA microsphere products, particularly leuprolide depot formulations.

What does U.S. Patent 5,631,020 cover?

The patent covers a specific process for producing an injectable prolonged-release microcapsule. The claim is narrower than a general PLGA depot formulation claim because it requires a combination of:

A spherical microcapsule with an average diameter of 2 to 200 micrometers.
A water-soluble drug contained in particles dispersed within a spherical polymer matrix.
A matrix made from lactic acid-glycolic acid polymer.
A lactic acid:glycolic acid comonomer ratio from approximately 100:0 to 50:50.
A polymer average molecular weight from approximately 5,000 to 200,000.
Redispersion of the microcapsule in a specified excipient.
Solidification after redispersion.
Improved stability after reconstitution in an injectable vehicle.
The specific peptide identified as leuprolide, also known as leuprorelin.

The patent does not broadly cover every leuprolide depot injection, every PLGA microsphere, or every stabilization process. Each required limitation must be present for literal infringement of independent claim 1.

What drug is identified in the claims?

The claimed peptide is leuprolide:

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

Leuprolide is a synthetic gonadotropin-releasing hormone agonist. Commercial products have used leuprolide acetate in injectable depot formulations for prostate cancer, endometriosis, uterine fibroids, and central precocious puberty.

The claim is directed to the peptide structure rather than merely to the drug class. A formulation containing another GnRH agonist would not satisfy the express leuprolide limitation. A formulation containing leuprolide in a different delivery system could avoid claim 1 if it also lacks one or more of the required process or structural limitations.

How should claim 1 be construed?

Claim 1 is a process claim with both structural and functional limitations.

Required starting material

The process begins with a spherical microcapsule. The microcapsule must have an average diameter of 2 to 200 micrometers. The claim requires particles containing the water-soluble drug to be dispersed in a spherical microcapsule matrix.

This language distinguishes the claimed product from:

A simple drug-polymer film.
A non-spherical implant.
A conventional aqueous leuprolide solution.
A drug-loaded nanoparticle outside the claimed size range.
A formulation in which leuprolide is dissolved uniformly in a polymer without the claimed particle-in-matrix arrangement.

The 2 to 200 micrometer range is commercially relevant. Injectable microsphere products commonly use a size distribution selected to permit syringeability, controlled release, and acceptable injection-site behavior. The claim specifies an average diameter, not necessarily that every individual microsphere falls within the range.

PLGA matrix limitations

The matrix must be composed of a polymer of lactic acid and glycolic acid. The claimed comonomer range is approximately 100:0 to 50:50.

This encompasses:

Lactic acid:glycolic acid ratio	Status under claim 1
100:0	Within the stated range
90:10	Within the stated range
75:25	Within the stated range and separately claimed by claim 2
65:35	Within the stated range
50:50	Within the stated range
40:60	Outside the stated range

The claim therefore covers homopolymeric polylactic acid at one end and a 50:50 lactide:glycolide copolymer at the other. In commercial practice, the 75:25 ratio is important because it is expressly singled out in claim 2 and is commonly associated with relatively prolonged degradation compared with more glycolide-rich polymers.

The polymer average molecular weight must be approximately 5,000 to 200,000. A polymer below 5,000 or above 200,000 would fall outside the literal numerical range, subject to any applicable doctrine-of-equivalents analysis.

Redispersion and solidification steps

The process requires redispersing the preformed microcapsule in one of four excipients:

Mannitol
Sorbitol
Lactose
Glucose

The redispersion is followed by solidification. The claimed purpose is to improve stability after the resulting product is reconstituted in an injectable vehicle.

This limitation is central. A process that dries or solidifies microspheres without the claimed redispersion step would not literally meet claim 1. A process using trehalose, sucrose, glycine, or another bulking agent would also fall outside the express excipient list unless an equivalent were established.

The claim appears directed to a freeze-drying or related solidification operation in which the excipient helps maintain microsphere dispersibility and reduces aggregation or physical instability during storage and reconstitution.

Functional stability limitation

Claim 1 requires that the reconstituted microcapsule provide greater stability than a corresponding product produced without redispersion.

This limitation introduces a comparative performance requirement. The comparison is not simply between the claimed product and an unrelated formulation. It is between a product made using the redispersion step and a product made without that step.

Relevant stability measurements could include:

Sedimentation behavior.
Microsphere aggregation.
Resuspendability.
Particle-size change after reconstitution.
Drug distribution in the vehicle.
Syringeability.
Chemical stability of leuprolide.
Maintenance of controlled-release properties.

The specification and prosecution history would be important in determining what "greater stability" means and what test conditions establish that limitation. The claim language alone does not set a numerical threshold.

What does claim 2 add?

Claim 2 narrows claim 1 by requiring a lactic acid:glycolic acid ratio of 75:25.

A product using a 75:25 PLGA matrix must still satisfy every other limitation of claim 1. Claim 2 does not independently cover a 75:25 polymer in any formulation. It remains tied to:

The leuprolide peptide.
The microsphere size range.
The particle-in-spherical-matrix structure.
The molecular-weight range.
Redispersion in one of the four listed excipients.
Solidification.
Improved stability after reconstitution.

The narrower ratio may have been intended to capture a preferred commercial embodiment or to provide fallback protection if the broader polymer-ratio range were challenged.

What does claim 3 cover?

Claim 3 covers a prolonged-release injectable microcapsule produced by the method of claim 1. It is a product-by-process claim.

The claim does not simply cover any leuprolide microsphere. The product must be produced by the process limitations incorporated from claim 1. Under U.S. product-by-process doctrine, infringement generally turns on whether the accused product has the claimed product characteristics and, depending on the issue, whether the process limitation is satisfied. Process language is especially important where the claimed manufacturing operation produces a structural or functional characteristic that cannot be defined independently.

A competitor could reduce risk by showing that its product:

Uses a different excipient.
Does not use a redispersion step.
Has a different particle architecture.
Uses a polymer outside the claimed ratio or molecular-weight range.
Contains a different active ingredient.
Does not exhibit the claimed comparative stability.

When did U.S. Patent 5,631,020 expire?

The patent issued May 20, 1997. For a pre-URAA application, the standard term was generally 17 years from issuance. On that basis, the ordinary expiration date was May 20, 2014.

Event	Date or status
U.S. patent	5,631,020
Issue date	May 20, 1997
Standard statutory term	17 years from issue
Base expiration date	May 20, 2014
Current enforceable patent term	Expired
Patent-term extension relevance	No active term is apparent from the patent’s ordinary term

The expiration of the patent eliminates current infringement exposure based solely on the unexpired claims of U.S. Patent 5,631,020. It does not eliminate exposure under separate patents covering leuprolide composition, dosing, delivery systems, manufacturing methods, or competing depot technologies.

What is the Orange Book status of the patent?

A patent is not automatically listed in the FDA Orange Book merely because it covers a pharmaceutical formulation. Listing depends on whether the patent is submitted for an approved drug product and whether it falls within the FDA’s listing categories.

Formulation and method-of-use patents may be submitted for an approved product. Manufacturing-process patents generally are not eligible for Orange Book listing under the ordinary drug-product patent listing framework. U.S. Patent 5,631,020 is principally a manufacturing and formulation-process patent, which limits its Orange Book relevance.

Even if the patent was historically listed against a leuprolide product, its 2014 expiration means it would not create a current Paragraph IV barrier. The FDA Orange Book must be checked for the specific reference-listed drug, strength, dosage form, and historical patent-listing record because leuprolide products have been approved under multiple products and delivery technologies.[2]

Did the patent create a Paragraph IV challenge risk?

Before expiration, an ANDA applicant could have faced a Paragraph IV issue if the patent was listed against the relevant reference-listed leuprolide product and the applicant’s proposed product was alleged to infringe.

The practical Paragraph IV risk would have depended on whether the proposed generic used:

Leuprolide in a PLGA microsphere.
A 2 to 200 micrometer average particle size.
A polymer within the claimed composition and molecular-weight ranges.
Redispersion in mannitol, sorbitol, lactose, or glucose.
The claimed solidification sequence.
The same or equivalent stability result.

A conventional leuprolide acetate solution would not ordinarily fall within the claims. A depot microsphere product using a different drying process or excipient could have had stronger non-infringement positions.

Because the patent expired in 2014, it cannot support a new statutory 30-month stay based on a current ANDA certification. Any historical Paragraph IV challenge would have been overtaken by expiration unless it involved damages or an earlier launch dispute.

What other patents are relevant to the leuprolide depot landscape?

The relevant landscape has several layers rather than a single patent family.

Foundational leuprolide and microcapsule patents

Earlier Takeda-related patents addressed sustained-release microcapsules containing water-soluble physiologically active substances, including peptide drugs. U.S. Patent No. 4,652,441 is a key historical reference in this area. Its technology is associated with the development of injectable peptide depot systems and predates U.S. Patent 5,631,020.[3]

The earlier patents generally addressed the core microsphere concept. U.S. Patent 5,631,020 focused on a later manufacturing and stabilization improvement.

Leuprolide depot product patents

Leuprolide depot products have been protected through combinations of:

Active pharmaceutical ingredient patents.
PLGA microsphere composition claims.
Release-rate and dosing claims.
Reconstitution and administration claims.
Manufacturing-process claims.
Product-specific patents submitted to the FDA.

The relevant patent set differs between Lupron Depot, Lupron injection, and other leuprolide delivery products. A patent covering a monthly depot product may not cover a daily solution or a three-month formulation.

Competing delivery systems

The principal competitive alternative is not always another PLGA microsphere. Eligard uses the ATRIGEL delivery system, in which leuprolide acetate is delivered through a biodegradable in situ gel system rather than the same conventional preformed microsphere process.[4]

This distinction matters because a product using an in situ gel may avoid the structural and process limitations of Patent 5,631,020, even though both products provide prolonged leuprolide release.

How strong was the patent estate?

The patent was strong against a narrow class of products that copied the claimed process. Its strength was lower against alternative formulations and manufacturing routes.

Risk category	Assessment
Leuprolide solution	Low relevance
PLGA microsphere using claimed excipient and redispersion	Historically high
PLGA microsphere using 75:25 polymer	Historically high if other limitations matched
PLGA microsphere using sucrose or trehalose	Lower literal risk
In situ gel delivery system	Low literal risk
Non-leuprolide peptide	Outside express claim
Polymer outside claimed molecular-weight range	Lower literal risk
Product using a different particle architecture	Lower literal risk
Current enforcement risk	None from the expired patent

The principal vulnerability was claim narrowness. The patent required a specific active ingredient, a specific class of excipients, a defined microsphere structure, defined polymer parameters, and a comparative stability result. Those limitations could support validity and infringement positions against close copies, but they also created multiple design-around routes.

What manufacturing and intellectual-property barriers remain?

Expiration of Patent 5,631,020 does not make a leuprolide depot product commercially straightforward. Remaining barriers can include:

Complex PLGA microsphere manufacturing.
Control of peptide loading and encapsulation efficiency.
Initial burst-release control.
Reconstitution time and syringeability.
Sterility assurance for injectable microspheres.
Long-term stability of the dried product.
Consistent particle-size distribution.
Bioequivalence to the reference product.
Product-specific FDA requirements.
Other unexpired patents covering delivery systems or dosing regimens.
Commercial access to reference-product clinical and pharmaceutical data.

For an ANDA applicant, the principal regulatory burden is likely to be pharmaceutical equivalence, bioequivalence, and manufacturing consistency rather than this expired patent. For a 505(b)(2) applicant, formulation and clinical bridging issues may be more significant, particularly where the proposed product differs in release profile or administration interval.[5]

Which companies are relevant competitors?

The commercial landscape has included:

AbbVie and affiliated entities associated with Lupron products.
Takeda-related entities associated with the underlying leuprolide and depot technology.
Tolmar and related entities associated with Eligard.
Generic and specialty pharmaceutical companies developing leuprolide acetate injections or depot products.
Contract manufacturers with PLGA microsphere capabilities.

The competitive distinction is between conventional leuprolide depot microspheres, daily injectable solutions, and in situ gel systems. Patent clearance must be performed by product architecture, not only by active ingredient.

Key Takeaways

U.S. Patent 5,631,020 claims a process for stabilizing injectable leuprolide PLGA microcapsules.
The required steps are redispersion in mannitol, sorbitol, lactose, or glucose followed by solidification.
The claimed microcapsules must have an average diameter of 2 to 200 micrometers and use a lactic acid:glycolic acid polymer within the stated ranges.
Claim 2 narrows the polymer ratio to 75:25.
Claim 3 is a product-by-process claim tied to claim 1.
The patent issued May 20, 1997, and its ordinary 17-year term expired May 20, 2014.
The patent is no longer an active U.S. barrier to generic or follow-on leuprolide development.
Its historical relevance is greatest for close-copy PLGA microsphere processes.
In situ gel products such as Eligard use a different delivery architecture and present a separate patent and regulatory analysis.
Current clearance work must focus on other leuprolide, formulation, dosing, delivery-system, manufacturing, and regulatory rights.

FAQs About U.S. Patent 5,631,020

Does Patent 5,631,020 cover all leuprolide depot injections?

No. It covers a defined leuprolide microcapsule process and the product produced by that process. It does not broadly cover every leuprolide injection or every sustained-release delivery system.

Is a 75:25 PLGA leuprolide microsphere automatically covered?

No. The product must also satisfy the particle-size, molecular-weight, microcapsule architecture, excipient, redispersion, solidification, and stability limitations.

Can an expired patent still block FDA approval?

An expired patent cannot create a current patent-based launch injunction, Paragraph IV stay, or exclusionary right. FDA approval may still require analysis of other unexpired patents and regulatory requirements.

Are mannitol and sorbitol interchangeable under the patent?

They are separate expressly listed alternatives in claim 1. A product using either may meet the excipient limitation if the remaining claim requirements are satisfied. Equivalence questions depend on the particular formulation and evidence.

Does an in situ leuprolide gel infringe this patent?

An in situ gel generally would not satisfy the claimed spherical PLGA microcapsule and redispersion process. It must be analyzed against the full claim language and other relevant patents.

References

United States Patent No. 5,631,020. (1997). Prolonged release microcapsule for injection. U.S. Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
United States Patent No. 4,652,441. (1987). Microcapsules containing a water-soluble physiologically active substance. U.S. Patent and Trademark Office.
Tolmar Pharmaceuticals, Inc. (2024). Eligard prescribing information. U.S. Food and Drug Administration.
U.S. Food and Drug Administration. (2023). ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of recombinant origin: Guidance for industry. FDA.

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
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,631,020

Summary for Patent: 5,631,020