Details for Patent: 5,932,462

Summary for Patent: 5,932,462

Title:	Multiarmed, monofunctional, polymer for coupling to molecules and surfaces
Abstract:	Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms polya and polyb, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings and ester groups in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure where mPEGa and mPEGb have the structure CH3O-(CH2CH2O)nCH2CH2- wherein n may be the same or different for mPEGa and mPEGb and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000. The mPEG disubstituted lysine can be purified from a reaction mixture by chromatography in water, including gel filtration chromatography and ion exchange chromatography because the carboxyl group is ionizable. Impurities are removed, including unreacted mPEG and mPEG monosubstituted lysine, to provide the polymer in pure form. Ion exchange chromatography permits fractionation of a greater amount of polymer per run.
Inventor(s):	J. Milton Harris, Francesco Maria Veronese, Paolo Caliceti, Oddone Schiavon
Assignee:	Nektar Therapeutics
Application Number:	US08/443,383
Patent Claim Types: see list of patent claims	Use; Dosage form;

US Patent 5,932,462: Claim Scope, Expiration, and Branched PEG Patent Landscape

US Patent No. 5,932,462 covers branched, water-soluble, nonpeptidic polymers, particularly lysine-linked branched polyethylene glycol, or PEG, molecules having a single ionizable reactive group positioned along the polymer backbone. The patent is directed to polymer composition, purification, activation, conjugation, and manufacturing claims.

The commercial center of gravity is the mPEG2-Lys architecture: two monomethoxy PEG arms attached to a lysine core, with the lysine carboxyl group available for conversion into an NHS ester or another electrophilic group. The patent is expired as a blocking right in the United States. Its technical disclosure remains relevant to PEGylated drug design, but current freedom-to-operate analysis must focus on later patents covering specific drug conjugates, linker chemistry, manufacturing processes, and formulations.

What does US Patent 5,932,462 cover?

The patent covers four principal categories:

1. Branched water-soluble polymers with one ionizable reactive group.
2. PEG and related polymer arms attached through nonaromatic, non-ester linkage fragments.
3. Activated polymer derivatives and their conjugates with nucleophilic molecules.
4. Methods for synthesizing and purifying branched PEG, especially disubstituted lysine PEG.

The broadest independent composition claim is claim 1. It requires:

• An essentially pure, water-soluble polymer.
• A moiety located along the polymer backbone.
• A single ionizable reactive group in that moiety.
• Two nonpeptidic, nonreactive polymeric arms.
• Linkages joining the arms to a central carbon-containing structure.
• No aromatic rings or ester groups in the specified linkage fragments.
• Recovery in essentially pure form by ion-exchange chromatography.

The claim is therefore broader than a particular PEGylated drug. It reaches certain activated PEG reagents before conjugation, as well as conjugates formed from those reagents.

What is the core chemical structure protected by the patent?

The principal structure is a branched PEG molecule based on a central linker, often lysine, with two PEG arms and one reactive carboxyl-derived functional group.

A representative commercial architecture is:

mPEG-O- or mPEG-linker
          \
           lysine core - carboxyl-derived reactive group
          /
mPEG-O- or mPEG-linker

Claim 20 narrows the composition to a monomethoxy PEG disubstituted lysine. The two PEG arms may have the same or different molecular weights, with each arm containing approximately 1 to 1,150 ethylene oxide repeat units.

Claim 19 further narrows the molecule to:

• A molecular weight of about 40,000 to 100,000.
• Two PEG arms.
• A single carboxyl group.
• Linkages without aromatic rings or carbonate ester moieties.
• Purification by ion-exchange chromatography.

The patent therefore targets branched PEG reagents of the type later described commercially as 2-arm PEG lysine or mPEG2-Lys derivatives.

Which polymer classes are included?

Claims 5 and 6 identify broad classes of polymer arms, including:

• Polyethylene glycol.
• Polypropylene glycol.
• Poly(oxyethylated) glycerol.
• Poly(oxyethylated) sorbitol.
• Poly(oxyethylated) glucose.
• Poly(vinyl alcohol).
• Polyoxazoline.
• Polyacryloylmorpholine.
• Polyvinylpyrrolidone.
• Copolymers, terpolymers, and mixtures.

The independent claims are not limited to PEG. PEG becomes the dominant practical embodiment through claims 7, 8, 19, and 20 and through the detailed lysine synthesis claims.

How strong are the independent composition claims?

Claim 1

Claim 1 has broad conceptual scope but several cumulative limitations. An accused product would need to satisfy the polymer architecture, the single ionizable reactive group, the nonpeptidic polymer arms, the linkage exclusions, and the stated purification limitation.

The purification requirement is particularly important. The claim does not merely require a polymer capable of being purified by ion exchange. It states that the polymer is recovered in essentially pure form by ion-exchange chromatography. That language creates a potential product-by-process or process-dependent issue in an infringement analysis. A product made by a materially different purification route may present a stronger noninfringement position, although the effect depends on claim construction and the evidentiary treatment of the purification language.

Claim 18

Claim 18 extends the architecture to three polymeric arms. It requires a central structure with a third polymer arm connected through a linkage fragment. This claim reaches branched polymers beyond the two-arm lysine structure.

Claim 19

Claim 19 is narrower and more commercially focused. It requires PEG arms, a molecular weight range of 40,000 to 100,000, a single carboxyl group, and specific linkage exclusions. The narrowness improves structural certainty but reduces coverage outside high-molecular-weight PEG carboxyl reagents.

Claim 20

Claim 20 is the most identifiable composition claim for mPEG2-Lys. It requires:

• A monomethoxy PEG disubstituted lysine.
• Two mPEG arms.
• PEG repeat-unit ranges of approximately 1 to 1,150.
• Recovery in essentially pure form by ion exchange chromatography.

This claim is potentially relevant to the unactivated intermediate, not only to an NHS ester or drug conjugate.

What activated PEG derivatives are covered?

Claims 3, 11, 12, and 21 through 24 cover activation of the single ionizable group for reaction with nucleophiles.

The listed activating groups include:

• Trifluoroethylsulfonyl.
• Isocyanate.
• Isothiocyanate.
• Active esters.
• Active carbonates.
• Aldehydes.
• Vinylsulfones.
• Maleimides.
• Iodoacetamides.
• Iminoesters.

Claim 12 specifically identifies:

• N-hydroxysuccinimidyl ester.
• N-hydroxysuccinimidyl carbonate.
• p-nitrophenyl carbonate.
• Trichlorophenyl carbonate.

For a lysine-based PEG reagent, the most commercially relevant embodiment is the activated carboxyl group, particularly the NHS ester. That reagent reacts with amino groups on proteins, peptides, antibodies, enzymes, and other biologically active molecules.

Claim 24 reaches a conjugate of a biologically active molecule and the activated mPEG-disubstituted lysine, with the NHS ester identified in claim 23.

Which conjugates fall within the claimed scope?

Claims 4, 13 through 18, and 22 through 24 extend protection from the polymer reagent to conjugates.

The nucleophilic moiety may be:

• An amino group.
• A thiol group.
• A hydroxyl group.

The biologically active molecule may be:

• An enzyme.
• A peptide.
• A polypeptide.
• A nucleotide.
• A polynucleotide.
• A lipid.

Claim 16 also covers conjugates involving a solid surface, with claim 17 identifying liposomes. The patent therefore has platform scope extending beyond therapeutic proteins.

A conjugate analysis requires at least four structural questions:

Issue	Relevance
PEG arm number	Distinguishes linear PEG from two-arm or multi-arm PEG
Central linker	Determines whether the structure is lysine-based or another claimed linker
Reactive group	Determines whether the polymer is activated or conjugated
Purification history	May affect claim elements requiring ion-exchange recovery

A drug may use PEG chemistry that is technically similar to the claimed platform without falling within the claims if it uses a different arm architecture, a different central linker, a prohibited or excluded linkage, or a different purification sequence.

What manufacturing methods are claimed?

Claims 25 through 48 cover synthesis and purification methods.

General branched-polymer synthesis

Claim 25 requires:

1. Reacting two or more monofunctional polymers of the form poly-W.
2. Reacting them with a linker molecule having at least two active sites.
3. Retaining a single ionizable reactive group on the linker.
4. Forming a branched polymer.
5. Recovering the polymer in essentially pure form by ion-exchange chromatography.

The linkage may be formed in one step under claim 27 or in sequential steps under claim 28. Claim 29 specifies aqueous buffer for the first linkage and a nonaqueous medium for the second.

Lysine-specific synthesis

Claims 39 through 48 focus on mPEG-disubstituted lysine. The disclosed route includes:

• Reaction of lysine-derived functionality with activated mPEG reagents.
• Aqueous reaction conditions, including a pH of about 8.0.
• Organic-solvent steps, particularly methylene chloride.
• Isolation by ion-exchange chromatography.
• Activation of the recovered carboxyl group.
• Formation of the succinimidyl ester.

Claims 43, 45, and 48 are important process claims because they combine purification, activation, and conjugation or NHS-ester formation. Their practical scope depends on whether a competing manufacturer uses the same sequence, substantially the same reaction conditions, and the claimed purification method.

When did US Patent 5,932,462 expire?

Event	Date or status
Patent number	US 5,932,462
Issue date	August 3, 1999
Patent type	Utility patent
Expected ordinary term	Twenty years from the earliest effective nonprovisional filing date
Current US status	Expired
Current blocking effect	No enforceable US patent exclusivity from this patent

The patent’s enforceable term ended no later than the applicable statutory term calculated from its earliest effective nonprovisional filing date, subject to any patent-term adjustment or terminal disclaimer recorded in the official file. The patent should not be treated as a current US exclusion right.

The expiration of this patent does not eliminate risk from:

• Continuations or divisionals.
• Later patents claiming particular PEGylated products.
• Patents covering a specific therapeutic protein.
• Formulation patents.
• Manufacturing improvements.
• Drug-device combinations.
• Foreign counterparts with different legal histories.

What is the Orange Book status of US Patent 5,932,462?

US Patent 5,932,462 is not an Orange Book patent for a small-molecule drug product. It is a platform patent directed to polymers, activated polymer reagents, conjugates, and manufacturing methods.

The Orange Book generally lists patents submitted for approved drug products under the Hatch-Waxman framework. A polymer platform patent may be commercially important without being listed for a particular FDA-approved drug. Its absence from the Orange Book does not determine whether a drug product uses the disclosed chemistry.

For biologic products, the relevant FDA framework is generally the Public Health Service Act and the Purple Book rather than Orange Book patent certification. A PEGylated biologic may have patent protection from product, formulation, method-of-use, and manufacturing patents that are separate from this patent.

Did the patent create generic or biosimilar entry barriers?

During its enforceable term, the patent could have created a platform-level barrier for products using covered branched PEG reagents. The effect differed by product type.

Small-molecule products

If a small-molecule drug were covalently linked to a covered PEG reagent, an ANDA applicant could have faced a Paragraph IV issue if the patent were listed in the Orange Book. The patent’s platform nature and lack of ordinary Orange Book status would have limited that pathway.

Biologic products

For a PEGylated biologic, a biosimilar applicant would evaluate:

• Whether the reference product uses a covered PEG architecture.
• Whether the biosimilar uses the same or a different PEG reagent.
• Whether the product, formulation, and manufacturing patents remain in force.
• Whether the reference sponsor has entered a patent dance or litigation under the Biologics Price Competition and Innovation Act.

The expired status of US 5,932,462 reduces platform risk. It does not remove later patent barriers tied to the reference product.

Which companies and products are commercially relevant?

The patent is associated with the development of branched PEG chemistry by Shearwater Polymers and its successor commercial ecosystem. Shearwater’s PEG platform was later associated with Nektar Therapeutics, which commercialized and licensed PEGylation technologies for pharmaceutical applications.

Relevant commercial categories include:

Category	Examples of relevance
PEG reagent suppliers	Producers of linear, branched, multi-arm, and site-specific PEG reagents
Protein therapeutics	PEGylated enzymes, cytokines, hormones, and antibodies
Peptide drugs	Long-acting PEGylated peptides
Liposomal products	PEG-lipid and PEG-liposome surfaces
Licensing counterparties	Drug companies using PEGylation under platform or product-specific licenses
Biosimilar developers	Companies designing non-infringing PEGylation routes or follow-on biologics

The platform has commercial relevance to products such as PEGylated interferons, PEGylated enzymes, PEGylated growth factors, and PEGylated peptide products. Product-specific conclusions require a separate mapping of the actual conjugation reagent and the live patent family covering each drug.

How does this patent compare with linear PEG and multi-arm PEG patents?

Technology	US 5,932,462 relevance	Typical distinction
Linear monofunctional PEG	Limited unless incorporated into a claimed branched structure	One polymer arm and one functional terminus
Two-arm branched PEG	Core technology	Two nonpeptidic arms connected through a central linker with one reactive group
Three-arm PEG	Covered by claim 18 in qualifying structures	Three arms connected to a central structure
PEG-maleimide	Potentially covered if the claimed architecture and activation limitations are met	Maleimide generally targets thiol groups
PEG-NHS ester	Central commercial embodiment	Reacts with amino groups
PEG-lipid	Potentially relevant under conjugate and solid-surface claims	Requires analysis of the polymer architecture and attachment chemistry
Dendritic or multi-arm PEG	May fall outside the central claims if the structure exceeds the claimed architecture	Often covered by later, separate platform patents

The patent is narrower than a generic “all PEG conjugates” patent. It is stronger against a specific two-arm or three-arm branched architecture with a central ionizable reactive group and the listed linkage and purification features.

What patent landscape surrounds the technology?

The relevant landscape has five layers.

Foundational PEGylation patents

Earlier patents established the use of PEG to modify proteins, peptides, enzymes, and other biologically active molecules. These patents generally focused on conjugation and pharmacokinetic improvement rather than the exact branched lysine reagent.

Branched PEG reagent patents

US 5,932,462 occupies this layer. Its central contribution is a branched polymer with a single reactive group along the backbone, especially mPEG-disubstituted lysine.

Site-specific PEGylation patents

Later patents often claim:

• Selective cysteine conjugation.
• N-terminal protein modification.
• Defined PEG-to-protein ratios.
• Site-specific antibody conjugation.
• Linkers that control hydrolysis or release.

These patents may remain relevant even though US 5,932,462 has expired.

Product and formulation patents

Drug-specific estates commonly include:

• Composition-of-matter claims for the PEGylated active ingredient.
• Formulation claims.
• Dosing regimens.
• Treatment methods.
• Stability and storage claims.
• Device or delivery-system claims.

These patents usually control commercial exclusivity more directly than the expired platform patent.

Manufacturing and quality patents

Later patents may cover:

• Narrow molecular-weight distributions.
• Removal of unreacted PEG.
• Control of positional isomers.
• Chromatographic purification.
• Scale-up methods.
• Residual solvent limits.
• Conjugation-site control.

These patents create the main manufacturing risk for a modern entrant.

What geographic coverage exists?

The patent’s US rights were limited to the United States and have expired. Foreign counterpart patents may have had different:

• Filing dates.
• Grant dates.
• Claim scope.
• Patent-term adjustments.
• Supplementary protection or restoration periods.
• Expiration dates.
• Opposition or nullity outcomes.

A global freedom-to-operate review should separately examine Europe, Japan, Canada, Australia, China, and jurisdictions where PEGylated biologics are manufactured or sold. A US expiration does not establish freedom to operate in those markets.

What litigation and settlement issues should be evaluated?

The provided claim set does not establish a reported Paragraph IV case, biosimilar dispute, or settlement involving US 5,932,462. Because the patent is expired, any historical litigation would have limited current exclusionary significance unless it produced binding claim construction or affected a related continuation.

For a current commercial program, the relevant litigation questions are:

1. Were continuation patents granted from the same disclosure?
2. Were any claims terminally disclaimed?
3. Did a license cover the specific PEG reagent or only the platform?
4. Did a settlement restrict launch timing after patent expiry?
5. Does a later patent cover the active pharmaceutical ingredient or conjugation site?
6. Are there pending infringement claims based on manufacturing or formulation patents?

A license to a PEG platform may still have commercial value through technical know-how, supply rights, regulatory files, or access to proprietary PEG reagents. It should not be confused with continued enforceability of the expired patent.

What generic launch scenarios exist?

Scenario 1: Direct use of the expired architecture

A manufacturer using an mPEG2-Lys-NHS reagent may generally avoid infringement of US 5,932,462 solely because the patent has expired. Later patents must still be screened.

Scenario 2: Non-PEG branched polymer

A non-PEG polymer may fall within claims 1, 5, or 6 if it satisfies the broad polymer-arm and linkage limitations. The practical risk depends on the exact polymer, linker, activation group, and purification process.

Scenario 3: Alternative linker

A manufacturer using a linker with aromatic or ester-containing fragments may avoid claims containing express exclusions, subject to the precise claim construction and other claim elements.

Scenario 4: Different purification method

A process that does not recover the product by ion-exchange chromatography may create a stronger position against claims requiring that recovery step. Product claims must be analyzed separately from process claims.

Scenario 5: Follow-on biologic

A biosimilar developer may use a chemically distinct PEG reagent or conjugation process. The program must be evaluated against the reference product’s live product, formulation, method, and manufacturing patents, not only against US 5,932,462.

Key Takeaways

• US 5,932,462 is a foundational branched PEG patent centered on two-arm and three-arm water-soluble polymers with a single ionizable reactive group.
• The most commercially important embodiment is monomethoxy PEG disubstituted lysine, particularly its carboxyl-derived NHS ester.
• Claims cover compositions, activated reagents, biologic and liposome conjugates, and manufacturing methods.
• The patent is expired in the United States and no longer provides current US patent exclusivity.
• The purification-by-ion-exchange limitation is material to both claim scope and infringement analysis.
• The patent is not an ordinary Orange Book drug patent.
• Current risk is more likely to arise from later patents covering specific PEGylated drugs, site-specific conjugation, formulations, manufacturing controls, or biologic products.
• A US freedom-to-operate conclusion cannot be based on this patent alone, especially for commercial biologics or global launches.

FAQs

Does US Patent 5,932,462 cover PEGylated proteins?

It covers certain branched PEG reagents and conjugates with biologically active molecules, including proteins, when the claimed structural, activation, linkage, and purification limitations are satisfied.

Is mPEG2-Lys-NHS still patent-protected in the United States?

US Patent 5,932,462 is expired. mPEG2-Lys-NHS may still be subject to later patents covering a particular composition, purity profile, manufacturing process, or pharmaceutical product.

Does this patent cover linear PEG-NHS?

Not categorically. The principal claims require branched polymer architecture with two or more polymeric arms connected to a central linker or backbone moiety.

Can an expired PEG platform patent block a biosimilar?

The expired patent itself should not block a biosimilar in the United States. Later product, formulation, method-of-use, manufacturing, or device patents may still create entry barriers.

Are PEGylated drugs protected by the Orange Book?

Some small-molecule products may have Orange Book-listed patents, but biologic PEG conjugates are generally assessed under the biologics patent framework and the Purple Book ecosystem rather than through ordinary Orange Book listing.

References

1. United States Patent and Trademark Office. (1999). Branched poly(ethylene glycol) derivatives, U.S. Patent No. 5,932,462. https://patents.google.com/patent/US5932462

2. United States Patent and Trademark Office. (2024). Patent term adjustment and patent term information. https://www.uspto.gov/patents/laws/patent-term-adjustment

3. 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-overview

4. U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products. https://purplebooksearch.fda.gov/

5. Nektar Therapeutics. (2024). Annual report. U.S. Securities and Exchange Commission. https://www.sec.gov/edgar/browse/?CIK=906709

6. U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

7. U.S. Congress. (2010). Biologics Price Competition and Innovation Act of 2009, Pub. L. No. 111-148, §§ 7001-7003, 124 Stat. 119.

Drugs Protected by US Patent 5,932,462

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 5,932,462

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	4755596
World Intellectual Property Organization (WIPO)	9621469