United States Patent 4,849,228: Scope, Claims, Expiration, and Leuprolide Depot Patent Landscape

U.S. Patent No. 4,849,228 covers injectable sustained-release microcapsules containing an active pharmaceutical ingredient in a biodegradable lactic-acid-based polymer with tightly controlled low-molecular-weight acid impurities. Its strongest commercial application is a depot formulation of leuprolide, the LHRH analogue identified in claim 4. The patent issued on July 18, 1989, and its original 17-year patent term expired on July 18, 2006. It no longer creates an enforceable U.S. patent barrier to generic or competing leuprolide products. [1]

What does U.S. Patent 4,849,228 protect?

The patent protects a product configuration, not leuprolide as a molecule. Its independent claim requires a microcapsule that contains:

An effective amount of an active ingredient.
A biodegradable high-molecular-weight polymer excipient.
A polymer consisting of:
- About 50 to 100 mole percent lactic acid; and
- About 50 to 0 mole percent glycolic acid.
A polymer weight-average molecular weight of about 2,000 to 50,000.
Less than 0.01 mole of water-soluble low-molecular-weight compounds per 100 grams of polymer, calculated as though each compound were a monobasic acid.

The claim therefore targets a formulation process outcome: a biodegradable polymer with an unusually low concentration of water-soluble acidic degradation products or related low-molecular-weight impurities.

The claim does not require leuprolide. Claim 1 covers a broader class of active ingredients, subject to the microcapsule and polymer limitations. Claims 2 through 4 narrow the active ingredient to water-soluble peptides, then to LHRH-like or TRH-like peptides, and finally to the specific peptide leuprolide.

What drug is identified in claim 4?

The peptide in claim 4 is leuprolide, also known as leuprorelin:

(Pyr)Glu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHCH2CH3

Leuprolide is a synthetic gonadotropin-releasing hormone analogue. Commercial products commonly use leuprolide acetate, although the patent claim is directed to the peptide-containing microcapsule rather than to the acetate salt as a standalone chemical composition.

The claim language does not require a particular brand, dosage strength, injection interval, particle-size distribution, capsule morphology, or release profile. Those features may be relevant to infringement analysis only if they are recited in other claims, examples, related patents, or continuation patents.

How should the claims be construed?

Claim 1: broad formulation combination

Claim 1 has five central limitations:

Limitation	Scope
Dosage form	Injectable sustained-release microcapsule
Active ingredient	Any effective pharmaceutical ingredient
Polymer	Homopolymer or copolymer based on lactic acid and glycolic acid
Polymer molecular weight	Weight average about 2,000 to 50,000
Purity parameter	Less than 0.01 mole water-soluble low-molecular compounds per 100 g polymer

The lactic-acid/glycolic-acid limitation covers poly(lactic acid), poly(glycolic acid), and intermediate compositions within the stated molar range. The wording “about” creates an inherent claim-construction issue. A court would assess the permitted numerical variation in light of the specification, analytical method, prosecution history, and ordinary meaning at the relevant time.

The low-molecular-compound limitation is the principal differentiator. A product could use PLGA within the molecular-weight range but fall outside claim 1 if its water-soluble low-molecular-weight acid content equals or exceeds the specified threshold.

Claim 2: water-soluble peptides

Claim 2 limits claim 1 to a water-soluble peptide. It does not require a peptide hormone, a particular amino-acid sequence, or a specific release duration.

Potentially relevant products would need to satisfy both the peptide limitation and every polymer and impurity limitation inherited from claim 1.

Claim 3: LHRH-like or TRH-like activity

Claim 3 narrows claim 2 to peptides with:

Luteinizing hormone-releasing hormone-like activity; or
Thyrotropin-releasing hormone-like activity.

The claim is functional in this respect. A peptide could fall within the claim if it exhibits the required biological activity, even if its sequence differs from the peptide recited in claim 4, subject to the remaining limitations.

Claim 4: leuprolide-specific embodiment

Claim 4 is directed to the leuprolide peptide sequence. It is narrower than claim 3 because it identifies the active peptide structurally.

A leuprolide depot would not infringe claim 4 merely because it contains leuprolide. It would also need to contain a qualifying microcapsule made with the specified lactic-acid-based polymer and impurity profile.

Claim 5: narrower polymer specification

Claim 5 adds two limitations to claim 1:

Inherent viscosity of about 0.05 to 0.5 dl/g, measured using a 0.5 weight-percent chloroform solution; and
Weight-average molecular weight of about 5,000 to 35,000.

Claim 5 is narrower than claim 1. It does not cover every polymer within the 2,000-to-50,000 molecular-weight range. The viscosity test is material because the same polymer can produce different reported values depending on solvent, concentration, temperature, calibration, and measurement procedure.

What formulation technology does the patent cover?

The patent covers biodegradable polyester microcapsules used for parenteral sustained release. Its technical center is the use of a purified lactic-acid/glycolic-acid polymer to encapsulate a drug while controlling release and reducing adverse effects associated with low-molecular-weight water-soluble compounds.

The relevant polymer classes include:

Polylactic acid, commonly abbreviated PLA.
Polyglycolic acid, commonly abbreviated PGA.
Poly(lactic-co-glycolic acid), commonly abbreviated PLGA.
Copolymers with lactic acid as the predominant component.
Copolymers with glycolic acid as the predominant component, subject to the claimed range.

The claims do not expressly require:

A particular encapsulation method.
A particular solvent system.
A particular drying technique.
A particular particle diameter.
A particular injection volume.
A particular release period.
A particular stabilizer, surfactant, plasticizer, or excipient other than the claimed biodegradable polymer.

Those omissions make the claims potentially broad in formulation architecture but narrow in the combination of polymer composition, molecular weight, and impurity content.

How strong is the patent estate for leuprolide depot formulations?

The patent was commercially important when active because it addressed a difficult formulation problem: incorporating a water-soluble peptide into a biodegradable depot system while maintaining acceptable release characteristics.

Its current legal strength is zero because the patent expired in 2006. Its historical technical scope was stronger than its current enforcement value.

Factor	Assessment
Active ingredient coverage	Broad in claim 1; narrowed to peptides and leuprolide in claims 2-4
Polymer coverage	Broad PLA/PLGA range, but subject to molecular-weight and impurity limits
Manufacturing coverage	Limited in the quoted claims; no express process claim appears
Formulation coverage	Injectable sustained-release microcapsules
Biological product relevance	Not a biologic patent in the current regulatory sense
Current enforceability	None; patent expired
Historical blocking value	High for products using the claimed purified polymer system
Current commercial value	Prior-art and freedom-to-operate relevance only

The patent should be treated as expired formulation prior art, not as a live exclusion right.

When did U.S. Patent 4,849,228 lose exclusivity?

U.S. Patent 4,849,228 issued on July 18, 1989. Because it predates the Uruguay Round patent-term changes, its standard term was generally 17 years from grant. On that basis, it expired on July 18, 2006. [1]

There is no indication from the patent’s basic bibliographic record that the patent remains enforceable through a later patent-term adjustment. Patent-term adjustment generally applies to applications filed under the post-1995 term regime and would not ordinarily extend this pre-1995 patent beyond its original statutory term.

Exclusivity timeline

Event	Date
U.S. patent issued	July 18, 1989
Standard pre-1995 patent term	17 years from grant
Patent expiration	July 18, 2006
Current status	Expired
Current Paragraph IV leverage	None based on this patent
Current Orange Book blocking effect	None based on this patent

The patent’s expiration does not eliminate other patents that may have covered particular leuprolide products, delivery systems, manufacturing processes, dosage regimens, or commercial devices.

What is the Orange Book status of U.S. Patent 4,849,228?

U.S. Patent 4,849,228 should not be treated as a current Orange Book patent barrier. An expired patent cannot support a current enforceable patent-listing strategy against an ANDA applicant.

The FDA Orange Book lists patents submitted for approved drug products under the applicable statutory framework. The relevant listed-patent analysis must be performed at the product and NDA level, not solely by searching the active ingredient. For leuprolide products, the potentially relevant NDA records include Lupron Depot and other product-specific formulations. [2, 3]

The practical conclusion is:

U.S. 4,849,228 is expired.
It cannot support a new 30-month stay based on a Paragraph IV certification.
It cannot independently delay approval of an ANDA.
Any remaining patent risk must come from later, unexpired patents covering a specific product, formulation, delivery platform, method of use, or manufacturing process.

Did Paragraph IV challenges affect this patent?

A Paragraph IV certification is available only against a listed patent that an ANDA applicant alleges is invalid, unenforceable, or not infringed. Under the Hatch-Waxman framework, a timely Paragraph IV notice can trigger patent litigation and, in some circumstances, a 30-month stay of approval. [4]

Because U.S. 4,849,228 expired in 2006:

A current ANDA applicant would not need to challenge it to obtain approval.
A Paragraph IV certification directed solely to this patent would have no practical blocking effect.
Any historical Paragraph IV dispute would be relevant as litigation history, not as a current market barrier.
A generic applicant would focus on unexpired listed patents associated with the reference product.

No current generic-entry strategy should assign residual exclusivity value to this patent.

What patent litigation affects leuprolide depot products?

The principal litigation risk for a leuprolide depot product would ordinarily arise from later patents, not from U.S. 4,849,228. Relevant categories include:

Formulation patents

These may claim:

Specific PLGA ratios.
Polymer molecular-weight distributions.
Drug loading levels.
Residual solvent limits.
Microsphere morphology.
Release-period profiles.
Stabilizers or excipients.
Reconstitution systems.

Method-of-use patents

These may cover:

Prostate cancer treatment.
Endometriosis treatment.
Uterine fibroid treatment.
Puberty suppression.
Specific dosing intervals.
Patient populations or treatment schedules.

Manufacturing patents

These may claim:

Double-emulsion methods.
Solvent evaporation.
Polymer purification.
Microsphere hardening.
Particle-size control.
Aseptic processing.
Lyophilization and reconstitution.

A competitor can avoid claim 1 through a non-microcapsule delivery system, a non-PLA/PLGA polymer, a polymer outside the claimed molecular-weight range, or a formulation that does not meet the impurity threshold. That design-around analysis must be performed against each unexpired patent in the product’s patent listing and relevant family.

How does this patent compare with competing leuprolide delivery systems?

Technology	Representative commercial approach	Relationship to U.S. 4,849,228
PLGA microspheres	Lupron Depot-type depot formulation	Closest technical category
ATRIGEL in situ depot	Eligard, using a polymeric delivery system that forms a depot after injection	May avoid a microcapsule limitation depending on product structure
Other injectable depots	Alternative biodegradable or in situ-forming systems	Potential design-around if no claimed microcapsule exists
Noninjectable delivery	Implants or other dosage forms	Outside the express injectable microcapsule limitation
Immediate-release leuprolide	Conventional injection	Outside sustained-release microcapsule scope

The distinction between a preformed microcapsule and an in situ-forming depot is important. A product that forms a depot after injection but does not contain a “microcapsule” at the time of administration presents a different claim-construction and infringement analysis.

What generic launch risks remain after expiration?

The expired patent removes one major historical obstacle but does not guarantee immediate generic substitution. Commercial launch risk can remain because of:

Product-specific Orange Book patents.
Complex peptide characterization.
Demonstration of equivalent release behavior.
Microsphere particle-size controls.
Drug-loading consistency.
Sterility and endotoxin controls.
Reconstitution performance.
Injection-site tolerability.
Limited manufacturing capacity.
Reference-product availability.
Regulatory classification of the proposed product.

Leuprolide depot products can be more difficult to develop than conventional small-molecule tablets because therapeutic equivalence may depend on extended-release performance, peptide stability, depot formation, and clinically relevant pharmacokinetics.

The patent risk from U.S. 4,849,228 itself is no longer material. The regulatory and manufacturing risks can remain substantial.

Does the patent create biosimilar risk?

No. U.S. 4,849,228 is not a current biosimilar barrier.

Leuprolide is a synthetic peptide drug, not a monoclonal antibody or other reference biologic of the type commonly associated with the biosimilar pathway under the Public Health Service Act. A competing leuprolide product would generally be evaluated under the applicable drug approval pathway, including an NDA or ANDA strategy depending on the product and reference product. [5]

The patent can still be cited as prior art against later formulation patents. It cannot block a biosimilar or generic application after expiration.

What geographic coverage does U.S. 4,849,228 provide?

The patent provides rights only in the United States. A U.S. patent does not establish enforceable rights in Europe, Japan, China, Canada, or other jurisdictions.

A complete international freedom-to-operate review would require analysis of:

The priority application.
PCT filings.
National-phase patents.
Continuations and divisionals.
Foreign equivalents.
Local expiration dates.
Patent-term extensions.
Supplementary protection certificates.
Jurisdiction-specific claim amendments.

The U.S. patent’s expiration does not establish that every foreign counterpart expired on the same date. Conversely, foreign rights cannot revive the expired U.S. patent.

What licensing deals are relevant to the patent?

The patent record identifies the patent owner or applicant associated with the U.S. filing, but the claims alone do not establish the existence, scope, or continuing effect of a commercial license.

For business purposes, licensing analysis should distinguish between:

Rights to the leuprolide active ingredient.
Rights to the PLGA or PLA encapsulation platform.
Rights to Lupron Depot or a related NDA.
Rights to manufacturing know-how.
Rights to later delivery systems.
Rights to trademarks and commercial distribution.

An expired patent cannot provide a current royalty-bearing exclusion right unless it is bundled with separate, unexpired patents, trade secrets, know-how, or contractual restrictions. The commercial value of any historical license associated with U.S. 4,849,228 must therefore be separated from the patent’s present legal status.

Key Takeaways

U.S. Patent 4,849,228 covers injectable sustained-release microcapsules using purified lactic-acid-based biodegradable polymers.
Claim 1 requires a PLA/PLGA-type polymer, a 2,000-to-50,000 weight-average molecular weight, and less than 0.01 mole of water-soluble low-molecular compounds per 100 grams of polymer.
Claim 4 specifically covers a microcapsule containing leuprolide.
Claim 5 narrows the polymer to a 5,000-to-35,000 molecular-weight range and adds an inherent-viscosity limitation.
The patent issued July 18, 1989, and expired July 18, 2006.
It is not a current Orange Book or Paragraph IV barrier.
It remains relevant as prior art and as a historical technical reference for leuprolide depot formulations.
Current market-entry risk depends on later patents, product-specific listings, manufacturing know-how, regulatory requirements, and commercial execution.
A preformed microcapsule and an in situ-forming depot may present materially different infringement profiles.
The U.S. patent provides no current rights outside the United States.

FAQs

Can a generic leuprolide product infringe U.S. Patent 4,849,228 today?

No. The patent expired in 2006. A generic product cannot infringe an expired patent, although later patents may remain relevant.

Does claim 4 cover leuprolide acetate by itself?

No. Claim 4 covers a microcapsule containing the specified leuprolide peptide and incorporating the limitations inherited from claims 1 through 3. It is not a standalone compound claim to leuprolide acetate.

Can a PLGA formulation avoid claim 1?

Yes. A PLGA formulation may avoid claim 1 if it does not satisfy one or more required limitations, including the molecular-weight range, impurity threshold, injectable microcapsule structure, or lactic-acid/glycolic-acid composition.

Is a long-acting leuprolide implant within the claim scope?

Not necessarily. Claim 1 expressly requires an injectable sustained-release microcapsule. An implant or a delivery system that forms a depot in situ may fall outside that limitation, depending on its structure and the applicable claim interpretation.

Does patent expiration eliminate FDA approval requirements for a leuprolide depot?

No. Patent expiration removes the patent exclusion right. It does not remove requirements concerning pharmaceutical equivalence, bioequivalence or comparable exposure, quality, sterility, manufacturing controls, labeling, and approval pathway.

References

U.S. Patent No. 4,849,228. (1989). Microcapsule for injectable sustained release preparation. U.S. Patent and Trademark Office.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs. FDA.
U.S. Code, 21 U.S.C. § 355(j). (2024). Abbreviated new drug applications and patent certifications.
U.S. Food and Drug Administration. (2024). Applications covered by section 505(b)(2). FDA.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	60-97617	May 07, 1985

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	87946	⤷ Start Trial
Canada	1262005	⤷ Start Trial
Germany	3688213	⤷ Start Trial
European Patent Office	0202065	⤷ Start Trial
Hong Kong	5796	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,849,228

Summary for Patent: 4,849,228