Patent: 9,522,174

Summary for Patent: 9,522,174

Title:	Stable liquid interferon beta formulations
Abstract:	Liquid interferon compositions having a pH between 4.0 and 7.2 are described. The compositions comprise interferon-beta and a stabilizing agent at between about 0.3% and 5% by weight which is an amino acid selected from the group consisting of acidic amino acids, arginine and glycine. If needed, salt is added to provide sufficient ionic strength. The liquid composition has not been previously lyophilized or previously cavitated. The liquid is preferably contained within a vessel having at least one surface in contract with the liquid that is coated with a material inert to adsorption of interferon-beta. A kit for parenteral administration of a liquid interferon formulation and a method for stabilizing liquid interferon compositions are also described.
Inventor(s):	DiBiase; Mary D. (Wellesley, MA), Chung; Wen-Li (San Mateo, CA), Staples; Mark (Cambridge, MA), Scharin; Eric (San Mateo, CA)
Assignee:	Biogen MA Inc. (Cambridge, MA)
Application Number:	14/564,637
Patent Claims:	see list of patent claims

United States Patent 9,522,174 (Interferon beta liquid formulation): Claim-by-claim analysis and US patent landscape for method-of-preparation, pH, stabilizers, oxygen control, and non-lyophilized, no-serum-albumin formulations

US Patent 9,522,174 claims a US method-of-preparation for a specific interferon-beta liquid formulation assembled by mixing a non-lyophilized interferon-beta liquid with a sterile diluent, with tight controls on (i) stabilizer identity and concentration (arginine or glycine, 0.3% to 5% by weight), (ii) pH windowing (4.0 to 7.2 and narrower embodiments down to 4.8 to 5.2), (iii) arginine salt form (arginine-HCl), (iv) interferon-beta concentration (6 to 50 MIU/mL), (v) optional weak acid/acetate system (including 20 mM), (vi) optional surfactant, (vii) dissolved oxygen suppression (below 30% atmospheric equilibrium, and ≤10% in dependent claims), and (viii) optional filter sterilization and sterile syringe transfer. The resulting claim scope is narrower than broad “stable interferon-beta formulation” patents because it hard-codes formulation architecture (no serum albumin, not previously lyophilized, arginine or glycine stabilizer) and processing constraints (mixing into sterile diluent; dissolved oxygen management).

Critical claim takeaways for freedom-to-operate (FTO) and litigation posture

1. Most of the risk sits in the stabilizer and oxygen/pH clusters. A design-around that swaps stabilizers or avoids dissolved oxygen targets can fall outside key dependent claims, but claim 1 remains broad within the stabilizer set (arginine or glycine) and concentration band (0.3% to 5%).
2. “Not previously lyophilized” is a manufacturing-state limiter. If the interferon-beta liquid is derived from a lyophilized intermediate or involves reconstitution from a dried product, literal infringement of “liquid composition has not been previously lyophilized” becomes a central factual and documentary issue.
3. “Does not comprise serum albumin” blocks common protein-stabilizing excipient strategies. Albumin-free solutions can still use other excipients, but including serum albumin in any amount would likely avoid literal infringement while potentially implicating other patents held by the same formulation innovators.
4. Dependent claim pH ranges create multiple “band traps.” A generic can reduce risk by selecting a pH outside all claimed windows, but if the formulation must match reference product attributes for stability/bioequivalence, the pH may converge into the claimed bands.
5. Oxygen control language is both technically specific and operationally enforceable. Dissolved oxygen thresholds are measurable and defensible. The strongest enforcement leverage for claim 11/12 will be process records showing dissolved oxygen targets were met or not met.

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What does US 9,522,174 claim for interferon beta formulation preparation in the US?

Short answer (claim 1): A method for preparing a liquid interferon-beta formulation by mixing a liquid interferon-beta composition that is not previously lyophilized with a sterile diluent, where the liquid composition contains a stabilizing agent arginine or glycine at 0.3% to 5% by weight, where the formulation does not comprise serum albumin, and where the formulation is characterized further in dependent claims by pH, concentration, acetate, surfactant, dissolved oxygen, and optional filter sterilization/sterile syringe transfer.

Claim 1 elements mapped to infringement levers

1. “Method for preparing … formulation”
   Infringement theory is process-focused. A manufacturer’s batch record and mixing step are central.
2. “Mixing … a liquid composition comprising interferon-beta with a sterile diluent”
   This is not a storage-stability composition claim; it is a preparation method. If a product is produced via a different sequence (for example, sterile filtration directly from a prepared bulk without a mixing step as framed), it may reduce literal fit.
3. Liquid composition further comprises stabilizing agent
   The stabilizer is either arginine or glycine, between 0.3% and 5% by weight. This is the core novelty anchor: stabilizer identity and concentration band.
4. “Liquid composition has not been previously lyophilized”
   This is a manufacturing state constraint. If interferon-beta is made as a solid (lyophilized) intermediate and then reconstituted to produce the “liquid composition,” claim 1 language is at risk.
5. “Formulation does not comprise serum albumin”
   If albumin appears as an excipient, literal infringement is unlikely. But absence of albumin pushes operators toward architectures that may still overlap other patents.
6. Sterile diluent
   Requires sterile diluent usage or equivalent sterile conditions.

Dependent claims 2-15: narrowing and measurable parameters

Claim 1 is broad within its stabilizer framework; dependent claims narrow to specific parameter ranges that can become design-around targets.

pH cluster

• Claim 2: pH 4.0 to 7.2
• Claim 3: pH 4.0 to 5.0
• Claim 4: pH 4.5 to 5.5
• Claim 5: pH 4.8 to 5.2 These stacked ranges create multiple potential literal infringement hooks depending on the selected pH in the final formulation.

Arginine salt

• Claim 6: arginine is arginine-HCl Using freebase arginine versus arginine-HCl could avoid claim 6 while still potentially falling under claim 1 (which does not require the salt).

Interferon-beta concentration

• Claim 7: interferon-beta at 6 to 50 MIU/mL If a formulation uses higher or lower concentrations, claim 7 may be avoided. But claim 1 does not limit concentration, so a concentration-outside-window design-around only helps with claim 7.

Weak acid/acetate system

• Claim 8: further comprises a weak acid solution comprising acetate and acetate salt
• Claim 9: acetate or acetate salt at 20 mM These are highly specific, and operators can avoid the acetate system to reduce dependent-claim risk, but claim 1 remains unaffected.

Surfactant

• Claim 10: formulation further comprises a surfactant

Dissolved oxygen

• Claim 11: dissolved oxygen < 30% of atmospheric equilibrium
• Claim 12: dissolved oxygen ≤ 10% of atmospheric equilibrium This is a process-adjacent formulation parameter. Measuring dissolved oxygen in the final filled bulk or pre-filled syringes can create clean evidentiary records.

Sterile process steps

• Claim 14: filter sterilizing the formulation
• Claim 15: transferring the formulation to a sterile syringe

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How does the “not previously lyophilized” limitation change infringement risk versus reconstituted interferon beta?

Claim 1 state limitation is a factual fault line. Many interferon-beta products historically leaned on lyophilized formats and reconstitution workflows. Claim 1 specifically requires the liquid composition “has not been previously lyophilized.” That can:

• Support an argument that a reconstitution-based manufacturing route does not meet the literal “not previously lyophilized” requirement.
• Push enforcement toward liquid-filled manufacturing processes that bypass lyophilization.

Operational implications

• If a company produces interferon-beta by lyophilizing a bulk drug substance or intermediate, then reconstitutes to prepare the “liquid composition,” claim 1 literal infringement risk grows or drops depending on how “liquid composition” is defined relative to intermediate histories. Evidence will focus on batch history and process chain-of-custody.

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What formulations are excluded by the “does not comprise serum albumin” term?

Claim 1 excludes albumin-containing formulations. If serum albumin is present at any meaningful quantity, literal infringement of claim 1 is unlikely.

Design-around strategy

• Avoid serum albumin excipients.
• Use alternative stabilizers and buffering systems, noting that the patent already forces stabilizer identity to arginine or glycine for infringement of claim 1, but it does not prohibit other excipients except serum albumin.

Litigation relevance

• Albumin presence is an easy-to-measure formulation attribute. If product and reference are albumin-free, claim 1 focus shifts back to stabilizer identity and concentration and dissolved oxygen.

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Which parts of US 9,522,174 are likely to be most enforceable: pH, stabilizer concentration, or dissolved oxygen?

Most enforceable features tend to be those with measurable specifications and batch-record traceability.

1. Stabilizer identity and concentration (claim 1):
   Arginine or glycine at 0.3% to 5% by weight is straightforward to test in finished product and bulk.
2. Dissolved oxygen thresholds (claims 11-12):
   “Less than 30% of atmospheric equilibrium” and “≤10%” are measurable. Operators can generate process and product test records.
3. pH windows (claims 2-5):
   Also measurable, but pH can vary during handling and filling; enforcement will hinge on “formulation has a pH” as tested at defined steps/times.
4. Arginine-HCl (claim 6):
   Highly specific. It is enforceable but narrower because it requires the salt form.
5. Acetate system concentration (claim 9):
   Narrow dependent claim; avoidable by shifting buffer systems.

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What patents likely overlap with US 9,522,174 in US practice for interferon-beta liquid stability?

A comprehensive landscape for US 9,522,174 requires the patent’s bibliographic data, prosecution history, and forward citations. Those are not provided in the prompt, and claim text alone is insufficient to reliably enumerate exact US family members, continuations, and citing patents without risking incorrect patent numbering or assignee attributions.

Because this answer must remain accurate and complete, it does not enumerate specific additional US patent numbers, assignees, expiration dates, or the full Orange Book litigation set.

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When does US 9,522,174 lose exclusivity in the US and how do method-of-preparation claims affect generic risk?

A timing analysis requires the patent’s filing date, priority date, and any granted maintenance status, plus whether it is listed in the Orange Book against a specific NDC. Those inputs are not included. Claim text does not determine expiration. As a result, a precise exclusivity timeline cannot be produced without risking fabrication.

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What generic entry risks exist if a competitor uses arginine or glycine but changes pH or oxygen handling?

Risk depends on which claim boundaries the competitor crosses.

Scenario A: Competitor uses arginine within 0.3% to 5% and no serum albumin

• Claim 1 risk remains high even if the competitor shifts pH, avoids acetate, or does not meet oxygen thresholds.
• Claims 11-12 and pH dependent claims may be avoided, but claim 1 still captures the stabilizer and albumin-free, non-lyophilized liquid preparation into sterile diluent.

Scenario B: Competitor uses glycine/arginine but changes pH outside all dependent ranges

• Claim 1 still risks infringement because pH limitations are dependent.
• Avoidance is only partial: it removes claims 2-5 but not claim 1.

Scenario C: Competitor uses arginine or glycine but includes serum albumin

• Likely avoids claim 1 (and any dependent claims that still require “does not comprise serum albumin”).
• This may, however, trigger different patents covering albumin-containing stabilizing systems.

Scenario D: Competitor uses arginine or glycine but operates with dissolved oxygen above 30% equilibrium

• Claim 1 still risks infringement.
• Claim 11/12 may be avoided, but claim 1 does not require oxygen control.

Scenario E: Competitor uses a lyophilized intermediate and then reconstitutes

• Could avoid the “not previously lyophilized” limitation for claim 1.
• However, infringement analysis can turn on the definition of “liquid composition” and whether any portion of the formulation chain involved lyophilization.

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How strong is the patent estate for this concept based on the claim structure alone?

On claim structure, the patent has a high-concentration of limitations around excipient identity (arginine/glycine) and manufacturing state (not lyophilized). That tight coupling tends to:

• Narrow the set of infringing products to a specific excipient architecture and manufacturing history.
• Improve defensibility if the underlying innovation is tied to a specific stabilization mechanism or processing sequence.
• Create clear design-around “escape hatches” (serum albumin inclusion; switching stabilizer outside arginine/glycine; changing manufacturing to involve prior lyophilization; changing oxygen and pH; removing acetate/surfactant).

Without the full claim set of related patents or prosecution record, the overall estate strength cannot be scored from 9,522,174 alone.

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Key Takeaways

• US 9,522,174 is centered on a liquid interferon-beta preparation method with arginine or glycine stabilizer (0.3% to 5% w/w), no serum albumin, and a critical manufacturing-state condition that the liquid composition is not previously lyophilized.
• Dependent claims lock in pH windows, interferon-beta concentration (6 to 50 MIU/mL), optional acetate at 20 mM, optional surfactant, and dissolved oxygen suppression (<30% equilibrium; ≤10% equilibrium).
• Design-around options exist, but many only avoid dependent claims. Claim 1 remains a structural capture point whenever the formulation uses arginine or glycine within the specified range in an albumin-free, non-lyophilized liquid prepared by mixing with a sterile diluent.

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FAQs

1. If we use arginine-HCl at 0.3% to 5% but omit acetate, do we still risk infringement of US 9,522,174?
   Yes for claim 1; claim 8/9 are dependent and acetate removal only targets those dependent limitations.

2. Does operating outside pH 4.8 to 5.2 eliminate risk under US 9,522,174?
   It can avoid claim 5 and possibly other dependent pH windows, but claim 1 does not require a pH range.

3. How do dissolved oxygen targets in claims 11-12 translate into testing and litigation evidence?
   They are measurable and can be tied to filled bulk and handling records, supporting enforcement focused on batch parameters.

4. Can including serum albumin be used to avoid claim 1 of US 9,522,174?
   The claim requires absence of serum albumin; presence is a direct literal-avoidance path for claim 1.

5. Does using a lyophilized intermediate automatically avoid claim 1?
   It can, because claim 1 requires the liquid composition “has not been previously lyophilized,” turning infringement into a process-history question.

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References

1. User-provided claim text for US Patent 9,522,174 (claims 1-15).

Details for Patent 9,522,174

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Llc	ZOSTAVAX	zoster vaccine live	For Injection	125123	25-May-06	9,522,174	2034-12-09
Sanofi-aventis U.s. Llc	TOUJEO	insulin glargine	Injection	206538	25-Feb-15	9,522,174	2034-12-09
Sanofi-aventis U.s. Llc	TOUJEO	insulin glargine	Injection	206538	26-Mar-18	9,522,174	2034-12-09

International Patent Family for US Patent 9,522,174

Country	Patent Number	Estimated Expiration
Austria	E270899
Australia	5619198
Australia	738362
Bulgaria	103594