United States Patent 4,728,721: Scope, Claims, Expiration, and PLGA Patent Landscape

U.S. Patent 4,728,721 covers purified biodegradable polymers made from lactic acid and glycolic acid, including PLA and PLGA, with controlled levels of water-soluble low-molecular-weight impurities. It also covers aqueous or water-miscible-solvent extraction processes used to produce those polymers. The patent issued on March 1, 1988, and its original 17-year patent term expired on March 1, 2005. It no longer blocks manufacture, formulation, or sale in the United States.

The commercial significance of the patent was its focus on polymer purity as a pharmaceutical-excipient property. The claims are directed to the polymer and purification process, not to a specific drug, microsphere product, dosage regimen, or therapeutic indication.

What does U.S. Patent 4,728,721 cover?

The patent covers a biodegradable high-molecular-weight polymer based on lactic acid, glycolic acid, or both. The broad composition claim requires four principal elements:

Claim limitation	Requirement
Polymer type	Lactic acid homopolymer or lactic acid/glycolic acid copolymer
Lactic acid content	About 50-100 mole percent
Glycolic acid content	About 50-0 mole percent
Weight-average molecular weight	About 2,000-50,000
Water-soluble low-molecular compounds	Less than 0.01 mole per 100 grams of polymer, calculated as monobasic-acid equivalents

The claim therefore spans:

Poly(lactic acid), or PLA;
Poly(glycolic acid), or PGA, only to the extent permitted by the claimed lactic-acid range;
Lactic acid/glycolic acid copolymers, commonly called PLGA;
Various lactide:glycolide ratios within the claimed range;
Polymers used as pharmaceutical excipients.

The claim does not require a particular drug, particle size, implant, depot formulation, molecular-weight distribution, end-group chemistry, or release profile.

How should claim 1 be construed?

Claim 1 is a product claim with a purity limitation. A polymer would need to satisfy each material limitation to fall within its literal scope.

Polymer composition

The phrase “about 50-100 mole percent of lactic acid” establishes a lower boundary of approximately 50 mole percent lactic acid. The corresponding glycolic-acid range is approximately 50-0 mole percent. The two ranges describe a binary lactic-acid/glycolic-acid polymer system rather than a broader polyester class.

The claim does not expressly distinguish:

L-lactic acid from D-lactic acid;
Racemic lactic acid from stereochemically enriched lactic acid;
Random copolymers from block or segmented structures;
Acid-terminated from ester-terminated polymers;
Linear from branched structures.

Those characteristics could matter in a claim-construction or infringement analysis if they affect whether the material is a “copolymer or homopolymer of” the specified monomers.

Molecular-weight limitation

The claimed weight-average molecular weight is about 2,000 to 50,000. Claim 2 narrows that range to about 5,000 to 35,000 and adds an inherent-viscosity requirement of about 0.05 to 0.5 dl/g in a 0.5% chloroform solution.

A polymer with a molecular weight above 50,000 would fall outside claim 1 based on that limitation. A polymer below 2,000 would also fall outside the express range. The word “about” creates a potential boundary dispute, but it does not eliminate the need to establish a molecular-weight value reasonably near the claimed range.

The patent uses weight-average molecular weight rather than number-average molecular weight. The analytical method, calibration standard, solvent, and polymer degradation during testing can materially affect the result.

Purity limitation

The central limitation is the requirement that water-soluble low-molecular compounds be below 0.01 mole per 100 grams of polymer.

That threshold equals:

0.0001 mole per gram;
0.1 millimole per 100 grams;
1 micromole per gram.

The claim measures the compounds on the assumption that each is a monobasic acid. The limitation therefore appears directed primarily to residual acidic oligomers, monomers, hydroxy acids, and related water-soluble degradation or synthesis products.

The claim does not state a single analytical test for identifying all “water-soluble low molecular compounds.” That creates a potential dispute over:

The molecular-weight cutoff for “low molecular” compounds;
Whether residual lactide or glycolide is included;
Whether oligomers with multiple acidic groups are counted as one compound or by acid equivalents;
The extraction solvent and extraction time;
The titration or assay used to quantify the compounds;
Whether the test measures free acid only or also hydrolyzable species.

What does claim 2 add?

Claim 2 is a narrower polymer claim. It requires both:

Inherent viscosity of about 0.05-0.5 dl/g; and
Weight-average molecular weight of about 5,000-35,000.

Because claim 2 depends on claim 1, it also retains the lactic-acid/glycolic-acid composition and low-molecular-compound limitation.

The viscosity limitation may have been intended to provide a practical quality-control parameter for pharmaceutical-grade polymer. It does not independently define a drug-delivery formulation. A polymer could satisfy the viscosity and molecular-weight ranges but still fall outside claim 2 if its water-soluble impurity level is at or above the claim 1 threshold.

What purification processes are covered by claims 3 through 10?

Claims 3-10 cover methods for reducing water-soluble low-molecular compounds in a biodegradable polymer.

Claim	Principal added limitation
3	Extracting the compounds from polymer containing at least 0.01 mole per 100 g
4	Solvent is acetone, methanol, ethanol, THF, acetonitrile, or ethyl acetate
5	Solvent is ethanol
6	Water:organic-solvent ratio is about 100/0 to 100/100 by volume
7	Polymer is first dissolved in an organic solvent
8	Extraction occurs under stirring
9	Extraction occurs at about 0°C to 90°C
10	Polymer is dissolved in 3-20 times the amount of organic solvent and poured into water at about 20°C to 70°C under stirring

Claim 3

Claim 3 requires a starting polymer containing not less than 0.01 mole of water-soluble low-molecular compounds per 100 grams. The process then removes those compounds by extraction using water or a water/organic-solvent mixture.

The claim is narrower than a generic polymer-washing process because it requires:

A specified impurity burden in the starting material;
Water or a mixture containing water;
Extraction of the specified water-soluble compounds.

A process that begins with a polymer already below the threshold may not satisfy the starting-material limitation.

Claims 4 and 5

Claim 4 identifies six permitted organic solvents. Claim 5 narrows claim 4 to ethanol. A process using another water-miscible solvent could fall within claim 3 if it satisfies that claim, but it would not fall within claims 4 or 5 unless the solvent is one of the listed substances.

Ethyl acetate is included in claim 4 even though its water miscibility is lower than that of methanol, ethanol, acetone, or tetrahydrofuran. The claim language controls the listed-solvent limitation.

Claims 6 through 9

These claims add process conditions:

Water-to-organic-solvent ratio;
Prior dissolution of polymer;
Stirring;
Temperature.

The “about” language in the ratio and temperature limitations may permit modest process variation. It does not necessarily cover materially different extraction conditions.

Claim 10

Claim 10 describes a precipitation or antisolvent-extraction procedure. The polymer is dissolved in an organic solvent at a solvent-to-polymer ratio of 3 to 20 times, then poured into water under stirring at approximately 20°C to 70°C.

This claim is more technically specific than claim 3. It could be relevant to manufacturing processes in which a polymer solution is added to water to precipitate purified polymer while soluble oligomers remain in the aqueous phase.

What does claim 11 protect?

Claim 11 is a product-by-process claim. It covers the polymer of claim 1 when produced by the extraction process described in claim 3.

For infringement analysis, U.S. product-by-process doctrine generally focuses on the characteristics of the product rather than the process used to make it. The process language may have limited value against an accused polymer that has the claimed composition, molecular-weight range, and impurity level but was made by a different process. The exact effect depends on claim construction and the governing precedent applied to the particular dispute.

Claim 11 therefore adds less practical protection than a conventional composition claim would if the purified polymer can be made through multiple routes.

When did U.S. Patent 4,728,721 lose exclusivity?

The patent issued March 1, 1988. Because it was filed before the 1995 patent-term transition, its ordinary term was 17 years from issuance under the then-applicable patent-term regime. The patent therefore expired on March 1, 2005, absent a special adjustment or enforceable extension.

Event	Date or status
U.S. patent issued	March 1, 1988
Ordinary patent term	17 years from issuance
Expected expiration	March 1, 2005
Current U.S. status	Expired
Current blocking effect	None for U.S. activities based solely on this patent

Patent-term extension under 35 U.S.C. § 156 is generally associated with qualifying regulatory review of a drug or biological product. A standalone polymer-excipient patent would not ordinarily obtain a new enforceable term merely because the polymer was later used in an approved drug product. The patent term framework is described in 35 U.S.C. §§ 154 and 156.

What is the Orange Book status of U.S. Patent 4,728,721?

U.S. Patent 4,728,721 is not a conventional Orange Book drug-product patent. It claims a biodegradable polymer and purification methods rather than:

A drug substance;
A finished dosage form containing a named active ingredient;
A method of using a drug to treat an approved condition.

The FDA Orange Book lists patents submitted for approved drug products under the statutory and regulatory framework governing listed drugs. A general-purpose PLGA excipient patent would not ordinarily be listed as a patent that an ANDA applicant must address for every drug using PLGA.

The practical consequences are:

The patent would not create a current Orange Book Paragraph IV barrier.
An ANDA applicant would not normally certify against this expired excipient patent through the Orange Book.
The patent’s expiration independently removes any current U.S. infringement risk.
Later patents covering a specific PLGA formulation, manufacturing process, drug product, or method of use may still be listed against an approved product.

The Orange Book should be reviewed at the drug-product level, not only at the excipient level. FDA, Approved Drug Products with Therapeutic Equivalence Evaluations, provides the relevant listing framework.[2]

Are there Paragraph IV challenges or settlement agreements involving this patent?

A current Paragraph IV challenge to U.S. Patent 4,728,721 would have no commercial purpose because the patent expired in 2005. Paragraph IV certifications address patents listed in the Orange Book for a reference listed drug. This patent is an expired polymer patent and is not the type of patent that ordinarily creates a live Orange Book certification issue.

There is no current exclusivity period associated with the patent. Any historical litigation or settlement involving a particular PLGA drug product would need to be distinguished from litigation over this patent itself. Agreements relating to leuprolide, exenatide, octreotide, risperidone, naltrexone, or other PLGA products may concern later drug-product, formulation, device, or method-of-use patents rather than U.S. Patent 4,728,721.

How strong was the patent estate for the claimed polymer?

The patent was technically focused but commercially limited in several respects.

Strength	Assessment
Composition coverage	Broad across specified PLA/PLGA composition range
Purity limitation	Narrow and potentially difficult to measure consistently
Molecular-weight range	Limits coverage to 2,000-50,000
Drug-product coverage	None
Delivery-device coverage	None
Method-of-use coverage	None
Manufacturing coverage	Meaningful for specified aqueous extraction routes
Current enforceability	None because the patent expired
Design-around potential	Moderate to high

The strongest feature was the combination of polymer composition, molecular weight, and impurity threshold. The weakest features were the absence of drug-specific claims and the dependence of the process claims on particular extraction conditions.

Potential design-around routes during the patent term could have included:

Using polymer outside the lactic-acid/glycolic-acid ranges;
Using molecular weight outside the claimed range;
Employing a nonaqueous purification process;
Using a different purification mechanism, such as reactive end-group conversion or controlled polymerization;
Avoiding the specified solvent and temperature combinations;
Manufacturing a drug product under later formulation claims without practicing the claimed extraction process.

A design-around would not avoid a composition claim if the resulting polymer independently met every limitation of claim 1.

What later patents may still matter for PLGA products?

The patent landscape moved from polymer purity to application-specific protection. Current freedom-to-operate work for a PLGA drug product should separate at least five patent groups.

Polymer composition and end-group patents

These patents may cover:

Specific lactide:glycolide ratios;
Acid-terminated or ester-terminated PLGA;
Defined molecular-weight distributions;
Residual monomer levels;
Polymer blends;
Stereochemical composition;
Defined degradation rates.

These claims can matter even though U.S. Patent 4,728,721 has expired.

Microsphere and microparticle patents

Later patents frequently claim:

Drug-loaded PLGA microspheres;
Particle-size distributions;
Encapsulation efficiency;
Porosity;
Solvent-removal conditions;
Burst-release controls;
Injectable depot compositions.

A polymer supplier may be free to sell generic PLGA while a finished-product manufacturer remains exposed under a drug-loaded microsphere patent.

Formulation patents

Formulation claims may cover:

Long-acting injectable suspensions;
Specific drug-to-polymer ratios;
Reconstitution media;
Stabilizers and surfactants;
Lyophilized cakes;
Syringe or vial configurations;
Release periods ranging from weeks to months.

These patents are usually more relevant to commercial launch risk than an expired polymer-purity patent.

Method-of-use patents

Approved PLGA depot products may have method claims covering:

Treatment of a specified disease;
A dosing interval;
A loading dose followed by maintenance doses;
Administration through a particular route;
Reduced adverse effects;
A specific patient population.

Method-of-use claims may remain enforceable after composition patents expire.

Manufacturing and scale-up patents

Process protection can cover:

Emulsion-solvent evaporation;
Spray drying;
Coacervation;
Aqueous precipitation;
Continuous particle formation;
Sterile filtration and aseptic processing;
Control of residual solvent;
In-line particle classification.

Manufacturing patents are particularly relevant to contract manufacturers and generic injectable developers because process similarity can create infringement risk even where the active ingredient is off-patent.

How does this patent compare with drug-specific PLGA patent estates?

Issue	U.S. Patent 4,728,721	Drug-specific PLGA patent
Protected subject matter	Purified PLA/PLGA polymer and extraction process	Drug product, formulation, device, use, or manufacturing process
Active ingredient required	No	Usually yes
Orange Book relevance	Generally low	Potentially high
Paragraph IV relevance	None today	Potentially significant
Biosimilar relevance	None	Usually low unless product is a biologic
Generic launch impact	None today	Can delay or restrict launch
Manufacturing relevance	Historical and process-specific	Often high
Expiration	March 1, 2005	Varies by patent family

PLGA itself is not a biologic. A PLGA depot containing a small-molecule drug is normally addressed through the ANDA or 505(b)(2) framework, depending on the reference product and the degree of formulation or clinical differentiation. A PLGA formulation containing a biologic may implicate a biologics application and biosimilar pathway, but U.S. Patent 4,728,721 would still not be a biosimilar barrier.

The FDA Purple Book concerns licensed biological products and biosimilar or interchangeable-product information. It does not establish patent rights for a general-purpose biodegradable polymer.[3]

What geographic coverage does the patent provide?

U.S. Patent 4,728,721 provided rights only in the United States. It did not independently protect:

Manufacturing in Europe, Japan, or China;
Importation into countries without corresponding patents;
Foreign PLGA products;
Foreign drug products using the same polymer.

Foreign counterparts may have been filed in jurisdictions associated with the underlying priority application, but each counterpart required separate prosecution, maintenance, claim scope, and expiration analysis. The U.S. expiration does not establish the status of any foreign family member.

For current international development, the relevant analysis is jurisdiction-specific:

United States: U.S. Patent 4,728,721 is expired.
European Union: assess each national or regional family member and any supplementary protection certificate.
Japan: assess the corresponding Japanese patent and term.
China: assess the Chinese family member, patent term, and manufacturing location.
India and other manufacturing jurisdictions: assess process claims and import exposure independently.

What generic launch risks remain after expiration?

The expired patent creates no direct launch risk. The meaningful risks for a PLGA generic or 505(b)(2) product are elsewhere:

Later patents covering the active ingredient or depot formulation.
Orange Book-listed patents for the reference product.
Method-of-use patents.
Device or reconstitution patents.
Manufacturing patents practiced by the developer or contract manufacturer.
Regulatory requirements for sameness, particle-size distribution, release profile, sterility, residual solvents, and injectability.
Trade-secret barriers involving polymer grades, process controls, and scale-up conditions.

For complex injectable PLGA products, regulatory substitutability can be more difficult than ordinary tablet development. An applicant may need to establish comparable drug release, degradation behavior, particle morphology, and in vivo performance even when the relevant polymer patent estate has expired.

Key takeaways

U.S. Patent 4,728,721 covers purified PLA/PLGA polymers with controlled water-soluble low-molecular-compound content.
Claim 1 requires lactic acid at about 50-100 mole percent, molecular weight of about 2,000-50,000, and impurity content below 0.01 mole per 100 grams.
Claim 2 narrows molecular weight to about 5,000-35,000 and adds an inherent-viscosity range.
Claims 3-10 cover water-based or water-miscible-solvent extraction processes, including ethanol extraction and precipitation into water.
Claim 11 is a product-by-process claim tied to the purification process.
The patent issued March 1, 1988, and expired March 1, 2005.
It has no current Orange Book or Paragraph IV significance as an enforceable U.S. patent.
It does not protect a named drug, depot formulation, microsphere product, therapeutic use, or medical device.
Current PLGA launch risk depends on later formulation, drug-product, method-of-use, device, and manufacturing patents.
Biosimilar analysis is generally irrelevant unless the PLGA system is used with a biological product; even then, this patent is expired.

Frequently asked questions

Does U.S. Patent 4,728,721 cover all PLGA polymers?

No. It covers only polymers within the claimed lactic-acid/glycolic-acid composition, molecular-weight, and water-soluble-impurity ranges.

Can a company manufacture the claimed purified PLGA in the United States?

Yes, because the patent expired on March 1, 2005. Later patents covering a specific product or manufacturing process must still be reviewed separately.

Does the patent cover PLGA microspheres containing drugs?

No. The claims do not require microspheres, encapsulated drug, particle-size limits, release characteristics, or a particular active ingredient.

Is residual lactide necessarily included in the claimed impurity calculation?

The claim refers broadly to water-soluble low-molecular compounds calculated as monobasic-acid equivalents. Whether a particular residual compound is included depends on its solubility, chemical form, assay method, and the construction applied to the claim.

Could this patent block a 505(b)(2) application?

No. An expired patent cannot block approval or commercialization. A 505(b)(2) applicant may still face later patents listed for the reference drug or patents covering the proposed formulation, device, manufacturing process, or method of use.

References

United States Patent No. 4,728,721. (1988, March 1). Biodegradable high molecular polymer and process for preparing same. U.S. Patent and Trademark Office. https://patents.google.com/patent/US4728721A/en
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products. https://purplebooksearch.fda.gov/
United States Code. (2024). 35 U.S.C. § 154: Contents and term of patent; provisional rights. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section154
United States Code. (2024). 35 U.S.C. § 156: Extension of patent term. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section156

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

Details for Patent: 4,728,721

Summary for Patent: 4,728,721