Patent: 10,364,451

Summary for Patent: 10,364,451

Title:	Polymer conjugates having reduced antigenicity and methods of using the same
Abstract:	Disclosed herein are compositions and methods for reducing the antigenicity of molecules. The antigenicity of a molecule may be reduced or eliminated by conjugating at least one branched polymer to the molecule to form a molecule-polymer conjugate. The branched polymer may include a backbone and a plurality of side chains, each side chain covalently attached to the backbone.
Inventor(s):	Chilkoti; Ashutosh (Durham, NC), Qi; Yizhi (Durham, NC), Hershfield; Michael S. (Durham, NC), Ganson; Nancy J. (Durham, NC)
Assignee:	Duke University (Durham, NC)
Application Number:	15/387,536
Patent Claims:	see list of patent claims

Patent Landscape Analysis for US Patent 10,364,451 (POEGMA Antigenicity-Reduction Conjugates)

US Patent 10,364,451 is directed to reducing immune recognition of therapeutic molecules by conjugating them to branched POEGMA (poly[oligo(ethylene glycol) methyl ether methacrylate]) with specific POEGMA architecture and immunoreactivity constraints (non-reactive with pre-existing anti-PEG antibodies). The claims mix (i) broad “molecule” coverage (polypeptides, polynucleotides, small molecules, and combinations), (ii) a specific POEGMA polymer structure (PMMA backbone with 2 to 9 EG units in tandem per side chain), and (iii) several chemical/bioconjugation mechanics (sortase A attachment, macroinitiator + free radical branching polymerization, and terminal-group restrictions). The patent estate around POEGMA-antigenicity mitigation is likely to be crowded in adjacent filing families for PEG alternatives and anti-PEG avoidance, but this particular claim set is tightly anchored on POEGMA’s backbone/side-chain design plus “not reactive to pre-existing anti-PEG antibodies” outcome language that will shape validity, enforceability, and design-around.

What does US 10,364,451 claim about reducing antigenicity of therapeutic molecules with POEGMA?

Core inventive concept (as claimed). A method and conjugate for reducing antigenicity by forming a molecule-polymer conjugate where the polymer is branched POEGMA with a defined polymer architecture and a defined immune outcome: the conjugate is not reactive with pre-existing anti-PEG antibodies in a subject (Claims 1, 13; also repeated within 11).

Claim 1: Method of reducing antigenicity

Claim 1 is the independent method claim and sets the core limitations:

1. Conjugating at least one branched polymer to a molecule to form a molecule-polymer conjugate.
2. The molecule includes one or more of: polypeptide, polynucleotide, small molecule, or combinations.
3. The branched polymer is POEGMA.
4. POEGMA has:
   • Backbone: poly(methyl methacrylate) (PMMA backbone)
   • Side chains: covalently attached to backbone
   • Each side chain has 2 to 9 monomers of EG repeated in tandem
5. Functional immune constraint:
   • Conjugate is not reactive with pre-existing anti-PEG antibodies
   • And has reduced or eliminated antigenicity vs a control.

Practical interpretation for freedom-to-operate (FTO). Even if a competitor uses POEGMA broadly, infringement risk increases when their polymer architecture matches PMMA backbone + EG side chains with 2-9 units, and when their conjugate avoids anti-PEG recognition (as assessed by binding and/or antigenicity assays). Outcome language (“not reactive”) can be a litigation flashpoint because it ties scope to performance in an immunologic assay.

Claim 13: Product-by-process style conjugate claim

Claim 13 is a conjugate claim: a POEGMA-branched polymer with the molecule conjugated to the polymer backbone and the same structural immunoreactivity constraint (“not reactive with pre-existing anti-PEG antibodies”).

Method vs product claim interplay

• Claim 1 provides broader “how” coverage (conjugation to reduce antigenicity).
• Claim 13 locks the “what” (conjugate composition) with the same POEGMA architecture and immune non-reactivity.

Together they increase leverage: a challenger must invalidate or design around both process and composition.

How are the POEGMA polymer structure and side-chain size defined, and why does it matter?

The claims repeatedly constrain POEGMA using a two-part structural definition: backbone identity plus side-chain length.

POEGMA architecture limitations (repeated across claims)

• Backbone: poly(methyl methacrylate)
• Side chains: covalently attached to backbone
• Side-chain length: 2 to 9 monomers of EG repeated in tandem

This is narrower than generic “POEGMA” used in PEG-mimetic or stealth polymer contexts. It points to a specific polymerization route and repeat unit mapping to EG monomers.

Dependent claim tightening

• Claim 16: each side chain comprises at least 3 monomers of EG repeated in tandem.
• Claims 20-21 (Exendin-specific):
  • Claim 20: Exendin + POEGMA with 3 EG monomers per side chain
  • Claim 21: Exendin + POEGMA with 9 EG monomers per side chain

These dependent claims can narrow enforceability to defined polymer repeat-unit regimes when the accused product is a particular EG side-chain length.

What bioconjugation attachment strategies are covered (sortase A vs grafting vs polymerization-from-initiator)?

The claims cover multiple conjugation mechanisms, which is an important strength from an infringement coverage standpoint.

Sortase A site-directed conjugation (Claims 8 and 11)

• Claim 8 (method): molecule-polypeptide with a sortase A recognition site; incubated with sortase A under conditions that conjugate the branched polymer to the recognition site.
• Claim 11 (method of making): contacts the sortase A recognition site-containing polypeptide with sortase A and an initiator agent to form a macroinitiator, then polymerizes monomers from that initiator to grow branched POEGMA.

Scope implication. If an accused process uses sortase A to tether a polymer initiator and then grows POEGMA from the tether point, that aligns tightly with Claim 11’s manufacture sequence and Claim 8’s conjugation concept.

Macroinitiator + free-radical growth-to-form POEGMA (Claim 10 and Claim 11)

• Claim 10 (method): attaches an initiator agent to the molecule to form a macroinitiator, then incubates macroinitiator with monomer to permit free radical polymerization and formation of branched polymer.

• Claim 12 enumerates polymerization methods permitted to constitute the free-radical polymerization, including:

  • ATRP, RAFT
  • radical ROP
  • NMP
  • iniferter
  • free-radical, cobalt-mediated
  • telluride-mediated
  • stibine-mediated

Scope implication. Claim 12 broadens “how POEGMA is grown” beyond a single technique. This reduces common design-around routes like switching from one controlled radical polymerization method to another unless the method still fits “incubating macroinitiator with a monomer under conditions that permit free-radical polymerization and formation of a branched polymer.”

“Synthesize then graft” pathway (Claim 9)

• Claim 9: branched polymer is synthesized and subsequently grafted to the molecule.

This captures post-polymerization conjugation strategies where the POEGMA is pre-made and then tethered via coupling chemistry.

Which terminal-group and side-chain chemistry limits are included, and how do they affect design-around?

Claim 3-5 add chemical constraints at the side-chain ends.

Terminal end definition (Claims 3-5 and 14-15)

• Claim 3: each side chain has first terminal end attached to backbone; second terminal end can be alkyl, ester, amine, amide, or carboxyl.
• Claim 4: second terminal end does not include a hydroxyl group.
• Claim 14: mirrors Claim 3 for conjugate.
• Claim 15: mirrors Claim 4 for conjugate.
• Claim 5: each side chain comprises at least one monomer.

Design-around significance.

• If an accused POEGMA uses terminal hydroxyls on the side chain ends, that can move outside Claim 4/15 (depending on whether their terminal functionality is retained during conjugate formation and testing).
• If terminals are converted to non-hydroxyl functionalities (carboxyl, ester, amine, amide), that increases alignment.

EG monomer selection list (Claim 6)

Claim 6 allows monomer selection from:

• betaine
• phosphorylcholine
• phosphorylethanolamine
• sarcosine
• ethylene glycol
• combinations

This is notable because EG is explicitly present in the POEGMA definition, yet Claim 6 expands alternative “monomer” options inside the side chain building blocks. In practice, claim construction will focus on whether the “monomer of each side chain” is constrained to EG units as repeated tandem moieties under the POEGMA definition, or whether Claim 6 creates additional embodiments. Either way, it widens potential coverage against polymers marketed as POEGMA variants.

What kinds of therapeutic molecules are covered, and how broad is the genus?

Claim 1 and Claim 13 are genus claims. Claim 17 then enumerates many molecule types, heavily overlapping with biologics and peptides.

Molecule genus (Claims 1 and 13)

• polypeptide
• polynucleotide
• small molecule
• combinations

Explicit molecule examples (Claim 17)

Claim 17 lists a large set of peptides/proteins/therapeutics, including:

• monoclonal antibodies
• blood factors
• enzymes and protein therapeutics
• growth factors and cytokines
• insulin and insulin-related proteins
• interferons
• vaccines
• aptamers
• nucleic-acid modalities including silencing RNA, microRNA, long non-coding RNA
• multiple peptides and peptide receptors agents

Scope implication. The list is extremely broad and functionally covers most therapeutic classes typically pursued for stealth conjugates. Enforcement will likely turn on whether the accused polymer matches POEGMA structural parameters and whether the conjugate avoids anti-PEG binding.

What is special about exendin-specific claims (Claims 19-21)?

Claims 19-21 narrow to a specific therapeutic substrate and provide clearer infringement targets in glucagon-like peptide-1 (GLP-1) territory.

• Claim 19: exendin + POEGMA conjugate with reduced antigenicity
• Claim 20: exendin + POEGMA with side chains containing 3 EG monomers
• Claim 21: exendin + POEGMA with side chains containing 9 EG monomers

Why this matters. Exendin derivatives are a major market; dependent claims provide fallback positions if the independent genus is attacked.

What is the evidentiary and enforceability risk of “not reactive with pre-existing anti-PEG antibodies”?

This phrase appears in:

• Claim 1 (method)
• Claim 11 (method of making)
• Claim 13 (conjugate)

It functions as a functional limitation tied to immunological binding/antibody reactivity.

Litigation pressure points

• Assay definition: what “reactive” means (ELISA binding, flow cytometry, neutralizing activity, complement activation, etc.) and what baseline comparator antibodies define “pre-existing.”
• Comparative control: the claim uses reduced/eliminated antigenicity versus a control; claim construction may require a control baseline and specific performance measure.
• Timing of exposure: “pre-existing anti-PEG antibodies in a subject” implies relevance to human immune status at baseline, not post-treatment induced antibodies.

These issues can drive claim construction disputes and can also enable an accused party to litigate around performance testing and the equivalence of “control” formulations and immune panels.

When does US 10,364,451 expire, and how does that shape generic or biosimilar entry risk?

A precise exclusivity/expiration analysis requires the patent’s filing date and term structure (including whether it has PTA, terminal disclaimers, and whether any continuation claims are relevant). Those data are not provided in the prompt. With only claim text, a correct expiration timetable cannot be produced.

How strong is the patent estate likely to be, given the claim breadth and functional outcomes?

Strength is concentrated in three areas:

1. Polymer architecture constraint: POEGMA with PMMA backbone + side-chain EG repeats 2-9 units.
2. Immunogenicity outcome constraint: non-reactive with pre-existing anti-PEG antibodies.
3. Conjugation platform breadth: multiple conjugation/manufacturing routes including sortase A and initiator-driven branched polymer growth.

Weakness exposure is concentrated in:

• Functional antibody non-reactivity limitations (may face indefiniteness and proof issues depending on specification support).
• Prior art crowding risk around stealth PEG alternatives and POEGMA-like polymers designed to reduce anti-PEG recognition.
• Overbreadth vulnerability if the specification does not enable all the wide molecule genus (polynucleotide, small molecules, and the long list) using the same POEGMA constraints and achieving the stated non-reactivity outcome.

What obvious prior-art vectors could challenge claims like these?

Even without listing specific patents, the claim set maps onto well-known prior-art themes:

• anti-PEG immunity mitigation strategies using PEG mimetics and alternatives (polymers that avoid classic PEG epitopes)
• POEGMA and methacrylate-based polymer stealth platforms with EG side chains
• controlled radical polymerization methods to generate grafted/branched architectures
• sortase A-mediated site-specific conjugation and polymer growth from initiators

The strongest invalidity theories typically combine:

• reference disclosing the same POEGMA architecture (PMMA backbone with EG side chains of specified repeat range)
• reference disclosing the bioconjugation method (sortase A tether + polymerization from tether)
• and a reference or general knowledge that the polymer avoids anti-PEG antibodies or reduces immunogenicity

The presence of explicit non-reactivity to pre-existing anti-PEG antibodies can distinguish the claims from generic “stealth” polymer references, but only if that feature is supported and reproducibly tied to the claimed polymer structure.

What design-around approaches are most plausible against this claim set?

Based on claim language alone, the principal design-around levers are:

1. Break POEGMA architecture constraints
   • change backbone away from poly(methyl methacrylate)
   • move side-chain EG repeat count outside 2-9 (or outside 3+ if relying on Claim 16)
2. Use POEGMA-like polymers with different side-chain chemistry
   • include side-chain terminal hydroxyl functionality (Claim 4/15 avoid hydroxyl at the second terminal end)
3. Alter conjugation mechanism away from claimed routes
   • avoid sortase A-based initiator attachment if targeting Claim 8/11
   • avoid the macroinitiator approach for free radical branching polymerization if targeting Claim 10/11
   • however, Claim 9 captures “synthesize then graft,” so fully avoiding polymerization-from-initiator alone may not be sufficient.
4. Fail the “not reactive with pre-existing anti-PEG antibodies” functional criterion
   • even with similar polymer architecture, an accused conjugate that binds pre-existing anti-PEG antibodies could avoid the functional limitation depending on claim construction and testing relevance.

How could US 10,364,451 affect specific competitive programs (GLP-1/exendin and antibody biologics)?

Risk concentrates in two segments:

• Exendin-derived conjugates where POEGMA with specified EG side-chain length is used to mitigate anti-PEG immunity (Claims 19-21).
• Broader biologics/peptide therapeutics using site-specific conjugation via sortase A and branched POEGMA architecture (Claims 1, 8, 11, 13).

If a competitor’s program uses branched POEGMA with PMMA backbone and EG side chains of 2-9 repeats, infringement risk rises, especially for first-wave consumer-facing GLP-1 and obesity/diabetes markets where exendin-style therapeutics face chronic dosing and higher exposure to anti-PEG immune histories.

Key Takeaways

• The patent claims are anchored on a specific branched POEGMA design: PMMA backbone plus EG side chains with 2 to 9 EG repeats.
• The strongest enforceability hook is the functional immune limitation: the conjugate is not reactive with pre-existing anti-PEG antibodies.
• Manufacturing and conjugation coverage is broad: sortase A routes and initiator-based branched polymer growth with multiple controlled radical polymerization families.
• The claim set includes exendin-specific dependents with defined EG repeat counts (3 and 9), creating targeted infringement lanes in GLP-1 markets.
• The biggest validity/enforceability vulnerability lies in the functional “not reactive” limitation, which can be attacked through proof, assay definition, and enablement across the claim’s wide molecule genus.

FAQs

1. Does US 10,364,451 cover POEGMA polymers with different backbones than poly(methyl methacrylate)?
   No, the claims require a POEGMA backbone comprising poly(methyl methacrylate).

2. Can a candidate avoid infringement by using POEGMA with fewer than two EG monomers per side chain?
   Claim 1 requires each side chain comprises 2 to 9 EG monomers repeated in tandem, so outside that range reduces coverage.

3. Do Claims 4 and 15 require the side-chain terminal group to exclude hydroxyl groups?
   Yes. They specify that the second terminal end does not include a hydroxyl group.

4. Is sortase A mandatory to infringe?
   No. Sortase A is required only for the sortase-dependent claims (not the broad POEGMA structure and non-reactivity requirements in the independent claims).

5. Is exendin the only molecule covered?
   No. Exendin is specifically included in dependent claims, while the independent claims include a wide molecule genus (polypeptides, polynucleotides, small molecules, and combinations).

References

1. US Patent 10,364,451. Claims text provided in prompt.

Details for Patent 10,364,451

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	January 15, 1974	10,364,451	2036-12-21
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	December 27, 1984	10,364,451	2036-12-21
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 15, 1985	10,364,451	2036-12-21