Patent: 10,124,056

Summary for Patent: 10,124,056

Title:	Alkylated influenza vaccines
Abstract:	The present invention provides, among other things, improved influenza vaccines based on hemagglutinins containing one or more alkylated cysteine residues. In particular, the present invention provides influenza vaccines containing hemagglutinins treated with an alkylating agent and methods of making the same. Inventive influenza vaccines provided by the present invention have a remarkable ability to retain potency as determined by Single Radial Immunodiffusion (SRID) assay upon storage.
Inventor(s):	Milner; Brooke S. (Easton, PA), Haines; Jonathan (Effort, PA), Hauser; Steven L. (Easton, PA), Poli; Janet Beebe (Bethlehem, PA)
Assignee:	Sanofi Pasteur Inc. (Swiftwater, PA)
Application Number:	14/829,158
Patent Claims:	see list of patent claims

US Patent 10,124,056: What the Alkylated-HA Claims Actually Cover and Where the Landscape Blocks or Opens It

United States Patent 10,124,056 claims an influenza vaccine in which the hemagglutinin (HA) is treated with an alkylating agent (specific examples listed), while the final vaccine is “substantially free of alkylating agent” and retains ≥ about 90% potency by SRID after 6 months at 1 to 30°C. Dependent claims further define how many cysteines are alkylated, how extensively free thiols are capped, which alkyl groups are installed (methylated cysteine), which alkylating agents are used, and whether the vaccine is split, recombinant, egg-based, cell-produced, and valency-adjusted (mono to quadrivalent).

This is a relatively clean chemical-process-and-product boundary: it is not a claim about influenza antigens generally, nor about any “influenza stabilization” excipient package. It is anchored on (i) HA thiol chemistry, (ii) residual alkylating agent limits, and (iii) a potency-retention metric under defined storage.

What is the claim core (and what is it trying to exclude)?

Independent claim 1 defines a three-part product constraint

Claim 1 is effectively a “product by process” with a performance gate:

1. Substance: an influenza vaccine comprising HA treated with an alkylating agent.
2. Residual chemistry control: the vaccine is substantially free of alkylating agent.
3. Stability performance: retains at least about 90% potency as determined by SRID after about 6 months stored at 1-30°C.

The practical legal effect is that the patentee does not just claim “alkylated HA.” It claims alkylated HA vaccine that meets a residual-agent and shelf-ability potency threshold.

Dependent claims tighten the HA modification pattern

Claims 2 to 5 define the extent and nature of alkylated cysteine residues:

• Claim 2: HA contains 1-5, 1-4, 1-3, or 1-2 alkylated cysteine residues.
• Claim 3: alkylated cysteine residues are about 1-50%, 1-40%, 1-30%, 1-20%, or 1-10% of total cysteines.
• Claim 4: substantially all cysteines with free sulfhydryl groups are alkylated.
• Claim 5: alkylated cysteines are methylated cysteine residues (implies methanethiosulfonate chemistry or equivalent that installs methyl).

These ranges are broad enough to capture multiple oxidation-state baselines and reaction endpoints, but narrow enough to avoid a purely “any alkylation” theory.

Claim 6 enumerates alkylating agents

Claim 6 lists specific agents, which is a major landscape lever because it limits coverage to specific chemistries (and combinations) unless doctrine-of-equivalents arguments apply:

• 2-iodoacetamide (IOAM)
• iodoacetic acid
• 2-bromoacetamide
• glutathione bromoacetamide
• bromoacetic acid
• 1,3-propane sultone
• methyl methanethiosulfonate
• methoxycarbonylmethyl disulfide
• maleamide
• maleimide-PEG
• vinylpyridine
• N-ethylmaleimide
• tosylacetamide
• combination thereof

Claim 7 to 11 expand the vaccine format without changing the HA chemistry

These dependent claims are mostly coverage expansion:

• Claim 7: split influenza virus vaccine
• Claim 8: recombinant influenza vaccine
• Claim 9: egg-based influenza vaccine
• Claim 10: produced in insect, mammalian, yeast, viral, fungus, algae
• Claim 11: monovalent to quadrivalent

Legally, these do not add a new stability or chemistry constraint. They ensure the same HA-thiol-alkylation concept can land across major manufacturing routes.

Claim 12 anchors a narrower storage window

• Claim 12: 2-10°C storage temperature.

Claim 1 already includes 1-30°C; claim 12 provides a more conventional cold-chain window as an additional dependent narrowing.

Claim 13 picks out IOAM

• Claim 13: alkylating agent is IOAM.

This is a classic “fallback” because IOAM has a long industrial footprint and is frequently used in thiol-reactive protein chemistry.

Claim-by-claim strength: enforceability vs. design-around

Highest enforceability features

1. SRID potency retention threshold tied to storage time and temperature
   “≥ about 90% potency as determined by SRID after about 6 months at 1-30°C” is a measurable product-performance element that can create evidentiary leverage in infringement analyses and in validity challenges (data integrity, reproducibility, enablement, and written description).
2. Residual alkylating agent constraint
   “Substantially free” is legally flexible but can be pinned down with specification examples, analytical methods, and prosecution history.
3. Defined HA thiol alkylation pattern (counts and fractions)
   The cysteine quantitation constraints can be tested with mass spectrometry or thiol assays paired with total cysteine mapping.

Primary design-around surfaces

1. Avoid the named alkylating agents (Claim 6/13) If an accused product uses a different thiol chemistry (even if it is functionally similar), literal infringement may fail unless equivalents are argued and a “substantially equivalent” function-way-result case can be made.
2. Break the potency retention outcome A manufacturer could attempt to demonstrate that the treated vaccine does not meet “≥ about 90% SRID potency” under the claimed storage conditions.
3. Change the cysteine modification endpoint If alkylation is partial or the “free sulfhydryl” state is not “substantially all” capped, or the number/fraction of alkylated cysteines falls outside the claim windows, literal infringement narrows.
4. Change HA chemistry target If the modification is not on HA cysteines (or not on cysteines in the HA population in the required quantities), claim 1 can be avoided.

Critical patent landscape analysis: where other filings likely collide

Because you provided only the claim text (not the specification, priority date, prosecution history, cited art, or the full list of related patents), the landscape analysis below focuses on claim-type collisions that recur in influenza antigen stability and thiol modification portfolios and identifies the categories of patents most likely to be relevant to infringement/invalidity strategies.

1) Thiol-modified influenza HA patents are the most immediate collision class

Across influenza vaccine R&D, thiol-reactivity strategies are common: HA contains cysteines whose redox state can affect antigen stability, folding, and aggregation propensity.

How the collision typically plays out against US 10,124,056:

• Prior art tends to claim “chemically modified HA” broadly, with emphasis on improved stability or reduced aggregation.
• US 10,124,056 distinguishes itself by adding the residual alkylating agent condition and the SRID-based potency-retention after storage at 1-30°C.
• A defendant can argue anticipation or obviousness if prior art already disclosed alkylated HA vaccines and included potency retention data under comparable storage.

What the patentee likely needs to show (for validity and for infringement):

• The cited prior art either did not use alkylating agents matching the enumerated list, did not reach the required extent of cysteine alkylation, or did not establish potency retention with SRID after 6 months in 1-30°C.

2) Process-and-product stability patents may attack the “substantially free” and potency gate

A major validity approach in vaccine chemistry cases is to argue that the performance gate is:

• not tied to the claimed structural feature, or
• already achieved by other stabilization methods (buffers, surfactants, lyophilization, in-process purification steps), or
• achieved without meeting the “substantially free of alkylating agent” condition.

Even if alkylated HA is known, the key question in obviousness is whether a skilled person would reasonably expect ≥90% SRID potency after 6 months across 1-30°C using the claimed residual-agent endpoint.

3) “Vaccine format” dependent claims are broad, so novelty likely lies in chemistry and data

Claims 7 to 11 expand across split/recombinant/egg and cell substrates. That breadth can create a structural pressure in prosecution history:

• If prior art already covers split/recombinant/egg workflows, those dependent claims rarely add novelty.
• Novelty and non-obviousness must therefore be anchored in HA thiol alkylation and performance.

From a litigation standpoint, that means:

• The core fight is about chemistry and the SRID retention metric, not the manufacturing format.

4) IOAM-specific prior art is a predictable invalidity vector

Claim 13 makes IOAM a named fallback. IOAM is widely used for protein thiol alkylation.

Typical legal effect:

• If prior art already disclosed IOAM-treated HA with adequate potency retention, US 10,124,056 risks validity exposure.
• If prior art disclosed IOAM-treated proteins generally but did not disclose influenza HA vaccine performance meeting the specific SRID threshold under the specified storage window, then US 10,124,056 can still hold on the performance gate and residual agent language.

What the claim set implies about the chemistry (and where measurement risks sit)

Alkylated cysteine count and fraction suggests controllable thiol reaction endpoints

Claims 2 and 3 together imply that the applicant established that the reaction endpoint can be tuned and quantified into discrete windows:

• 1-2 to 1-5 alkylated cysteines, and
• 1-10% through 1-50% of total cysteines.

That is consistent with a deliberate protocol that controls degree of thiol alkylation rather than a “fully reacted” bulk chemistry approach.

“Substantially all free sulfhydryl” is a thiol-reactivity endpoint

Claim 4 uses a typical protein chemistry standard. Litigation tends to focus on:

• definition of “free” thiols at time of reaction,
• how much is considered “substantially all,” and
• what analytical method is used to assess the residual thiol population.

Methylated cysteine indicates a methylthiolation route

Claim 5 indicates methylated cysteine residues. That aligns with chemistries like:

• methyl methanethiosulfonate, and potentially
• disulfide-mediated alkylation routes that transfer a methyl group under certain conditions.

This makes Claim 5 a meaningful narrowing lever: an accused product that uses different alkyl group transfer chemistries likely falls outside literal infringement.

Practical infringement map: what a challenger would test

A defendant challenging US 10,124,056 would focus on four measurable points:

1. Is the antigen HA and does it carry alkylated cysteines?
   • Measure cysteine modifications on HA by MS.
2. Does the final vaccine meet “substantially free” residual alkylating agent?
   • Analytical chemistry for residual IOAM or other named alkylating agents.
3. Does SRID potency after 6 months at 1-30°C remain ≥ about 90%?
   • SRID potency testing across time points.
4. Does the pattern of alkylation fall into the claim windows?
   • Count of alkylated cysteines and fraction of total cysteines.

If any one element fails, literal infringement becomes harder because claim 1 is conjunctive: vaccine comprises alkylated HA, is substantially free of alkylating agent, and meets the potency retention threshold under the storage window.

Key takeaways

• The patent’s enforceability rests on a specific HA thiol alkylation + residual-agent removal + SRID potency retention after 6 months at 1-30°C package, not merely on “alkylated HA.”
• Claims 2 to 5 define how much alkylation (count and percentage) and which cysteine state (free thiols capped) is required; claims 6 and 13 narrow to named alkylating agent chemistries with IOAM called out explicitly.
• Dependent claims on split/recombinant/egg/cell production and mono-to-quadrivalent are coverage expansions that do not materially add novelty.
• The most likely prior art collisions are thiol-modified influenza HA approaches that either omit the potency retention gate or do not meet the residual alkylating agent requirement or do not match the named alkylating agents/cysteine endpoint.

FAQs

1) What is the single most important measurement in claim 1?
SRID potency retention: ≥ about 90% potency after about 6 months at 1-30°C.

2) Does claim 1 require complete removal of alkylating agent?
No. It requires the vaccine is “substantially free of alkylating agent,” leaving room for residual amounts consistent with the patent’s definition and testable thresholds.

3) Can a vaccine avoid infringement by using a different alkylating agent not listed in claim 6?
A different alkylating agent can be a strong literal design-around if it avoids the enumerated list in claim 6 and claim 13 (IOAM), unless equivalents arguments apply.

4) Do the dependent claims on split vs recombinant materially narrow the invention?
They narrow the “type of influenza vaccine,” but they do not appear to change the core chemical constraint, which remains HA alkylation with the potency and residual-agent conditions from claim 1.

5) What endpoint does claim 5 add?
It narrows the chemistry to methylated cysteine residues on the HA, implying the installed alkyl group is specifically methyl.

---

References

1. United States Patent 10,124,056 (claims as provided).

Details for Patent 10,124,056

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Seqirus Vaccines Limited	FLUVIRIN	influenza virus vaccine	Injection	103837	3-Nov-98		2035-08-18
Sanofi Vaccines Us Inc.	FLUZONE, FLUZONE HD QUADRIVALENT, FLUZONE HIGH DOSE, FLUZONE INTRADERMAL, FLUZONE QUADRIVALENT	influenza virus vaccine	Injection	103914	9-Dec-99		2035-08-18
Sanofi Vaccines Us Inc.	FLUZONE, FLUZONE HD QUADRIVALENT, FLUZONE HIGH DOSE, FLUZONE INTRADERMAL, FLUZONE QUADRIVALENT	influenza virus vaccine	Injection	103914	23-Dec-09		2035-08-18