Details for Patent: 5,792,477

Summary for Patent: 5,792,477

Title:	Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent
Abstract:	A method for preparing biodegradable, biocompatible microparticles. A first phase is prepared that includes a biodegradable, biocompatible polymeric encapsulating binder, and an active agent having limited water solubility dissolved or dispersed in a solvent. An aqueous second phase is prepared. The first and second phases are combined to form an emulsion in which the first phase is discontinuous and the second phase is continuous. The two phases are separated. The discontinuous first phase is washed with water, or an aqueous solution of water and a solvent for residual solvent in the first phase, to reduce the level of residual solvent in the microparticles to less than about 2% by weight of the microparticles. Also disclosed are a microencapsulated drug prepared by the method for preparing biodegradable, biocompatible microparticles, and a pharmaceutical composition that includes biodegradable and biocompatible microparticles in a pharmaceutically acceptable carrier.
Inventor(s):	Michael E. Rickey, J. Michael Ramstack, Danny H. Lewis, Jean Mesens
Assignee:	Janssen Pharmaceutica NV , Alkermes Inc
Application Number:	US08/850,679
Patent Claim Types: see list of patent claims	Use; Composition; Process;

# US Patent 5,792,477: Claim Scope, Expiration, Orange Book Status, and Risperidone Microparticle Patent Landscape

US Patent 5,792,477 covers manufacturing processes and compositions for biodegradable polymeric microparticles containing poorly water-soluble active agents, with particular embodiments directed to risperidone and 9-hydroxyrisperidone. Its central technical combination is a solvent-based emulsion process using biodegradable lactide/glycolide polymers, aqueous washing, and residual organic-solvent reduction below 2% by weight.

The patent is expired. Its claims may remain relevant as prior art and as a technical reference for formulation design, but they do not create a current US patent barrier to generic manufacture. The patent is associated with the manufacturing technology used for long-acting risperidone microspheres, including the formulation platform commercialized in Risperdal Consta.

What does US Patent 5,792,477 cover?

US 5,792,477 covers four related subject-matter groups:

Claim group	Claims	Principal subject
General microparticle process	1-15, 33, 40-42, 46	Emulsion formation, phase separation, washing, and solvent reduction
Risperidone-specific process	16, 20	Risperidone or 9-hydroxyrisperidone in PLGA-type microparticles
Product-by-process claims	17-19, 34, 43-45, 47	Microencapsulated drugs made by the claimed process
Composition claims	21-32, 35-36	Microparticles with defined polymer, solvent, drug loading, size, and residual solvent
Static-mixer process	37-39, 48	Simultaneous flow of two phases through a static mixer
Washing process	49-52	Removing residual organic solvent using heated water or a water-miscible solvent

The patent does not broadly claim every risperidone depot formulation. Its strongest technical focus is the combination of:

1. A biodegradable polymer matrix.
2. A limited-water-solubility active agent.
3. An organic first solvent, often ethyl acetate and benzyl alcohol.
4. An aqueous second phase.
5. Emulsion formation.
6. Microparticle isolation.
7. Washing to reduce residual solvent below approximately 2% by weight.

When did US Patent 5,792,477 expire?

US Patent 5,792,477 expired in 2016 under the ordinary US patent term applicable to the patent. The statutory term was measured from the relevant nonprovisional filing date, subject to any applicable patent-term adjustment or disclaimer recorded in the USPTO file. Public patent records identify the patent as expired-lifetime. (U.S. Patent and Trademark Office, n.d.-a; Google Patents, n.d.)

Event	Date or status
US patent application	Filed in the mid-1990s
Patent issuance	August 11, 1998
Patent term	Approximately 20 years from the relevant US filing date
Current status	Expired
Current blocking effect	None for ordinary US patent enforcement
Continuing commercial relevance	Prior art, process benchmark, and historical Risperdal Consta technology

The expiration of 5,792,477 does not establish that all later patents covering long-acting risperidone products have expired. Separate patents may have covered dosage regimens, injection devices, manufacturing controls, particle characteristics, or other product features.

What are the independent claims in US 5,792,477?

The principal independent claims are 1, 16, 17, 20, 21, 32, 37, and 49.

Claim 1: General emulsion and washing process

Claim 1 requires:

• A first phase containing a biodegradable, biocompatible polymer and a poorly water-soluble active agent.
• A second aqueous phase.
• Mixing to form an oil-in-water-type emulsion.
• Separation of the discontinuous phase.
• Washing with water at approximately 25°C to 40°C, or with an aqueous solution containing a solvent for the residual first solvent.
• Reduction of residual first solvent to less than approximately 2% by weight.

Claim 1 is process-focused. It is not limited to risperidone, PLGA, ethyl acetate, benzyl alcohol, polyvinyl alcohol, or a static mixer unless those limitations are added through dependent claims.

Claim 16: Narrow risperidone process

Claim 16 is materially narrower. It requires:

• A polymer selected from polyglycolic acid, poly(d,l-lactic acid), poly(l-lactic acid), or copolymers.
• Risperidone, 9-hydroxyrisperidone, or a pharmaceutically acceptable salt.
• An ethyl acetate and benzyl alcohol solvent blend.
• No halogenated hydrocarbons.
• Polyvinyl alcohol in water as the second phase.
• A static mixer.
• A quench step.
• Washing with water and ethanol.
• Benzyl alcohol reduced below approximately 2% by weight.

This claim is a process claim, not a general claim to every risperidone long-acting injection.

Claim 17: Product-by-process claim

Claim 17 claims a microencapsulated drug prepared by the process of claim 1. Product-by-process claims are generally assessed based on the product limitations and the legal treatment of process language in the relevant infringement context. A product made by a materially different process may still raise questions if the resulting product has the same legally relevant structural characteristics, although the claim's process wording remains important.

Claim 20: Risperidone product-by-process claim

Claim 20 combines the narrow process elements of claim 16 with a product-by-process format. It is directed to microencapsulated risperidone or 9-hydroxyrisperidone prepared using:

• Lactide/glycolide-type biodegradable polymer.
• Ethyl acetate and benzyl alcohol.
• A halogenated-hydrocarbon-free solvent system.
• Polyvinyl alcohol.
• Static mixing.
• Quenching.
• Water/ethanol washing.
• Less than approximately 2% residual benzyl alcohol.

Claim 21: Broad composition claim

Claim 21 covers biodegradable, biocompatible microparticles in a pharmaceutically acceptable carrier, with:

• A polymeric encapsulating binder.
• An active agent dispersed or dissolved in the binder.
• Less than approximately 2% residual solvent.

Unlike claims 16 and 20, claim 21 does not expressly require risperidone, a particular polymer, a specific solvent, a static mixer, or a particular particle size.

Claim 32: Narrow composition claim

Claim 32 is the most commercially specific composition claim. It requires:

• Microparticles of approximately 25 to 180 microns.
• A poly(glycolic acid)/poly(d,l-lactic acid) copolymer.
• Lactide:glycolide molar ratio of approximately 85:15 to 50:50.
• Approximately 35% to 40% risperidone, 9-hydroxyrisperidone, or a salt.
• Approximately 0.5% to 1.5% benzyl alcohol.

This claim most closely maps to a long-acting risperidone microsphere formulation, although the claim does not by itself establish a particular dose, injection interval, release profile, or finished dosage form.

Claim 37: Static-mixer process

Claim 37 focuses on simultaneous flow of two phases through a static mixer. It requires:

• A first phase containing active agent, biodegradable polymer, and first solvent.
• A second phase substantially immiscible with the first.
• Separate first and second flow rates.
• Simultaneous passage through the static mixer.
• Formation and isolation of active-agent-containing microparticles.
• Washing to reduce residual first solvent below approximately 2%.

This claim is more dependent on equipment configuration and process operation than claim 1.

Claim 49: Solvent-removal process

Claim 49 is directed to washing preformed microparticles. It requires:

• Microparticles containing polymer, active agent, and organic solvent.
• Contact with an aqueous washing system.
• Reduction of residual organic solvent below approximately 2%.
• Either elevated-temperature water or water containing a water-miscible solvent.
• Recovery of the microparticles.

Claim 49 could reach a broader class of manufacturing operations than the emulsion claims because it does not require the patentee's specific phase-formation sequence.

What formulations are protected by US 5,792,477?

The most specifically defined formulation is the composition in claim 32.

Parameter	Claim 32 range
Active ingredient	Risperidone, 9-hydroxyrisperidone, or salt
Polymer	Glycolide/lactide copolymer
Lactide:glycolide ratio	85:15 to 50:50
Drug loading	35% to 40%
Particle size	25 to 180 microns
Residual benzyl alcohol	0.5% to 1.5%

The broader composition claims cover:

• Polymer matrices based on polyglycolic acid and polylactic acid.
• Copolymers of those materials.
• Active-agent loading from approximately 1% to 90%.
• Particle sizes from approximately 1 to 500 microns.
• Residual solvent below approximately 2%.
• Active agents containing at least one basic moiety.

The claims are not limited to injectable products. The composition claims refer to a pharmaceutically acceptable carrier, but the claims supplied do not expressly require intramuscular administration, a particular syringe, reconstitution medium, dose, or release duration.

How strong is the patent estate for risperidone microspheres?

The patent estate represented by 5,792,477 was technically strong during its term because the claims covered both manufacturing steps and resulting microparticle compositions. Its strongest features were the combination of:

• Biodegradable PLGA-type polymers.
• Basic active agents such as risperidone.
• Ethyl acetate and benzyl alcohol.
• Static mixing.
• Aqueous quenching and washing.
• Quantified residual-solvent limits.
• Particle-size and drug-loading ranges.

The estate was less comprehensive than a product patent covering the active molecule or an independent patent covering all long-acting risperidone formulations. A competitor could attempt to design around individual limitations by changing:

• The solvent system.
• The emulsification equipment.
• The quench operation.
• The wash solvent.
• The polymer ratio.
• The active-agent loading.
• The particle-size distribution.
• The manufacturing sequence.

During the patent term, design-around analysis would have required claim construction, prosecution-history review, and testing of literal infringement and equivalents. After expiration, these limitations remain relevant primarily for historical freedom-to-operate analysis and technical differentiation.

What is the Orange Book status of US 5,792,477?

US 5,792,477 was associated with the patent landscape for Risperdal Consta, the long-acting injectable risperidone product developed by Janssen and based on Alkermes microsphere technology. Risperdal Consta received FDA approval under NDA 021346 in 2003. (U.S. Food and Drug Administration, 2003)

The Orange Book must be reviewed by NDA and supplement because listed patents and use codes can change over time. A patent listing does not itself prove that every claim covers the approved product. It identifies patents submitted by the NDA holder as potentially relevant to the product or an approved method of use. (U.S. Food and Drug Administration, n.d.)

Regulatory issue	Assessment
Product	Risperdal Consta
Active ingredient	Risperidone
FDA pathway	New drug application
Dosage form	Long-acting injectable microspheres
NDA	021346
Patent relevance	Manufacturing and microparticle formulation technology
Current patent barrier from 5,792,477	None, because the patent is expired

Were there Paragraph IV challenges to US 5,792,477?

Paragraph IV litigation involving generic versions of Risperdal Consta could address patents listed for the NDA, including formulation, manufacturing, delivery, or method-of-use patents. The presence of a Paragraph IV notice would not automatically establish that 5,792,477 was the only asserted patent, nor that the patent claims were ultimately found invalid or not infringed.

A Paragraph IV certification is a regulatory position that a listed patent is invalid, unenforceable, or not infringed. It is not a judicial determination. (21 U.S.C. § 355; FDA, n.d.)

Because 5,792,477 has expired, a current applicant does not need to overcome this patent through a present-day Paragraph IV challenge. Any historical litigation must be separated from current entry analysis. Later patents, regulatory exclusivities, product-specific requirements, and approval timing may have been more important to actual generic entry.

Which companies challenged or competed with the Risperdal Consta estate?

The competitive field includes three categories:

Generic pharmaceutical companies

Generic companies seeking approval for long-acting risperidone products would face technical and regulatory barriers beyond the expired patent:

• Demonstrating equivalent microsphere performance.
• Establishing comparable release kinetics.
• Matching particle-size distribution and drug loading.
• Demonstrating impurity and residual-solvent control.
• Validating reconstitution and injection performance.
• Satisfying FDA requirements for complex injectable products.

Janssen and Johnson & Johnson

Janssen commercialized Risperdal Consta. Its regulatory and commercial position depended on the approved product, clinical data, manufacturing controls, and any unexpired patents listed for the NDA, not solely on 5,792,477.

Alkermes

Alkermes developed the biodegradable microsphere technology and entered into commercial arrangements with Janssen relating to Risperdal Consta. The commercial relationship is relevant to technology provenance and manufacturing capability, but it does not extend the expired term of 5,792,477.

What licensing deals affected the patent landscape?

The relevant commercial structure was the collaboration between Alkermes and Janssen for long-acting risperidone. Alkermes supplied microsphere technology and manufacturing capabilities, while Janssen held the branded product commercialization role. Public company disclosures describe collaboration and supply arrangements connected with Risperdal Consta. (Alkermes, Inc., various annual reports)

The business implications were:

• Janssen controlled the branded regulatory and commercial platform.
• Alkermes contributed proprietary microsphere manufacturing expertise.
• The patent was one part of a broader technology package.
• Expiration of the patent did not eliminate manufacturing know-how, validation data, quality systems, or regulatory barriers.

What manufacturing and intellectual-property barriers remain after patent expiration?

Patent expiration removes the exclusionary right under 5,792,477. It does not eliminate non-patent barriers.

Manufacturing barriers

A competitor must reproduce a commercially viable microsphere process with control over:

• Emulsion droplet formation.
• Static-mixer residence time.
• Phase flow rates.
• Polymer molecular weight.
• Lactide:glycolide ratio.
• Drug loading.
• Particle-size distribution.
• Residual benzyl alcohol.
• Sterility and endotoxin levels.
• Reconstitution and injection behavior.
• In vitro and in vivo release profiles.

Regulatory barriers

Long-acting injectable microspheres are complex products. FDA approval may require substantial evidence addressing:

• Pharmaceutical equivalence.
• Impurity profiles.
• Drug-release comparability.
• Product performance.
• Stability.
• Device or administration compatibility.
• Clinical or bridging evidence, depending on the applicable pathway.

Know-how barriers

The patent claims disclose process parameters, but commercial success may depend on undisclosed know-how, including:

• Scale-up conditions.
• Mixer geometry.
• Feed preparation.
• Quench timing.
• Washing cycles.
• Drying conditions.
• Sterile processing.
• Batch-release specifications.

What generic launch scenarios exist for Risperdal Consta?

A generic launch would not be blocked by 5,792,477 itself. The practical scenarios are:

Scenario	Commercial effect
No approved generic	Janssen retains product share despite patent expiration
First complex generic approval	Potential 180-day or market-exclusivity advantages may arise under applicable FDA rules
Multiple generic approvals	Price erosion and payer substitution become more likely
Alternative long-acting antipsychotic growth	Risperdal Consta faces erosion from competing products even without direct generic substitution
Manufacturing delay	Patent-free entry is postponed by scale-up, equivalence, or regulatory issues

The largest risk to the branded product is usually not the expired patent alone. It is the combination of complex-product approval requirements, manufacturing capacity, clinical differentiation, and the availability of competing long-acting antipsychotics.

How does US 5,792,477 compare with other risperidone patent categories?

Patent category	Typical scope	Relationship to 5,792,477
Active-ingredient patents	Risperidone chemical compound or salts	Separate and earlier patent family
Formulation patents	Polymer composition, particle size, loading, release	Overlaps with claims 21-32
Manufacturing patents	Emulsion, static mixing, quenching, washing	Core subject of claims 1-20 and 37-52
Method-of-use patents	Dosing, administration, disease treatment	Not the principal subject of the supplied claims
Device patents	Syringe, reconstitution, injection system	Separate technology
Regulatory exclusivity	FDA exclusivity tied to approval	Separate from patent term
Trade secrets	Scale-up and manufacturing know-how	Not eliminated by patent expiration

Key Takeaways

• US Patent 5,792,477 covers biodegradable microparticle manufacturing and compositions, not risperidone generally.
• The central process uses an organic polymer phase, an aqueous phase, emulsion formation, particle isolation, and aqueous solvent removal.
• The most specific risperidone claims require PLGA-type polymer, ethyl acetate/benzyl alcohol, polyvinyl alcohol, static mixing, quenching, ethanol washing, and defined residual-solvent limits.
• Claim 32 targets microparticles with 25-180 micron size, 35%-40% drug loading, a 50:50 to 85:15 lactide:glycolide ratio, and 0.5%-1.5% residual benzyl alcohol.
• The patent expired in 2016 and is no longer a current US enforcement barrier.
• Risperdal Consta was approved under NDA 021346 in 2003.
• Current generic-entry analysis must focus on later patents, FDA requirements, complex injectable-product comparability, and manufacturing know-how.
• Biosimilar analysis is not applicable because risperidone is a chemically synthesized small molecule, not a biologic.
• The expired patent remains relevant as prior art and as a disclosure of the technical process used in long-acting risperidone microsphere development.

References

1. Alkermes, Inc. (various years). Annual reports and securities filings. https://investors.alkermes.com
2. Google Patents. (n.d.). US5792477A, methods for preparing microparticles. https://patents.google.com/patent/US5792477A/en
3. U.S. Food and Drug Administration. (2003). Risperdal Consta approval history, NDA 021346. https://www.accessdata.fda.gov
4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book
5. U.S. Patent and Trademark Office. (n.d.-a). Patent Center: US Patent 5,792,477 prosecution and term records. https://patentcenter.uspto.gov
6. U.S. Patent and Trademark Office. (n.d.-b). Patent term adjustment and patent term information. https://www.uspto.gov/patents/laws/patent-term-calculator
7. United States Code, 21 U.S.C. § 355. New drugs. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title21-section355

Drugs Protected by US Patent 5,792,477

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,792,477

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	012820
Argentina	046034
Austria	223206
Austria	357218
Australia	2897297
Australia	733199
Bulgaria	102854