Patent: 5,766,582

Summary for Patent: 5,766,582

Title:	Stable, aqueous alfa interferon solution formulations
Abstract:	Process for making stable aqueous solution formulations containing alfa-type interferon, e.g., interferon alfa-2a and interferon alfa-2b, a buffer to maintain the pH in the range of 4.5-7.1, polysorbate 80 as a stabilizer, edetate disodium as a chelating agent, sodium chloride as a tonicity agent, and m-cresol as an antimicrobial preservative and which maintain high chemical, physical and biological stability of the alfa interferon for an extended storage period of at least 24 months are disclosed.
Inventor(s):	Yuen; Pui-Ho C. (Princeton Junction, NJ), Kline; Douglas F. (Hoboken, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ)
Application Number:	08/329,813
Patent Claims:	see list of patent claims

US Patent 5,766,582: Claim Scope, Likely Validity Hooks, and US Landscape Exposure for Aqueous Alfa Interferon Under Low Dissolved Oxygen

US 5,766,582 claims a process and a corresponding filled-vial/syringe article for preparing a stable aqueous formulation of alfa interferon (including interferon alfa-2b) with biological activity of at least 75%, with explicit exclusions of human blood-derived products, and with tight dissolved-oxygen and headspace oxygen controls. Independent claim 1 drives the substantive novelty through (i) a defined formulation component set and pH window and (ii) a manufacturing oxygen envelope: dissolved oxygen (DO) is maintained at no more than about 0.25 ppm while headspace oxygen is maintained at less than about 4% O2 by volume, using nitrogen sparging “throughout” preparation.

What does claim 1 actually require, in operational terms?

Claim 1 is a formulation-and-process claim with multiple coupled limitations. An accused product or process must meet all (or be equivalent under claim construction) key constraints simultaneously.

A. Product identity and functional stability

• “alfa interferon having at least 75% of alfa interferon biological activity”
• “free of human blood-derived products”

The “at least 75%” is a performance limitation that can require the process achieves a measurable biological activity retention threshold. “Free of human blood-derived products” is a sourcing/material limitation tied to formulation composition and supply chain.

B. Concentration and pH window

• Interferon concentration: 0.1 × 10^6 to 100 × 10^6 IU/mL (i.e., 0.1–100 million IU/mL)
• Buffer system: maintains pH 4.5 to 7.1

This pH band is broad enough to cover typical protein formulation buffers, but narrow enough to exclude strongly acidic or basic conditions.

C. Required excipient classes (not amounts in the text you provided)

Claim 1 requires inclusion of:

• a chelating agent
• “sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative” (a specific surfactant/emulsifier class rather than a generic polysorbate)
• a tonicity agent
• an antimicrobial preservative
• sufficient water to make aqueous solution

The claim text you supplied does not quantify these components, which increases the probability that broad prior art formulations (same component types) could be argument targets if they also satisfy the oxygen and pH conditions.

D. The oxygen envelope is the core differentiator

Claim 1 imposes two oxygen constraints that must be controlled during preparation:

1. Dissolved oxygen in solution: “no more than about 0.25 ppm”
2. Headspace oxygen above the solution: “less than about 4% oxygen by volume”
3. Method of achieving it: “sparging nitrogen into said water and said solution throughout the preparing”

This is not merely a storage specification. It is tied to manufacturing conditions “throughout” preparation. That manufacturing tie affects both infringement theory and prior art relevance.

E. Inert atmosphere vs sparging

The claim combines:

• nitrogen sparging into water and solution throughout preparation
• inert atmosphere headspace control above the solution

This creates a dual-control story: one parameter in liquid phase (DO) and one in gas phase (headspace).

How do dependent claims narrow the article of manufacture scope?

Claims 2–11 are product-by-process-linked “article of manufacture” claims covering the formulation packaged in specific sterilized containers.

Packaging and vessel types

• Claim 2: “sterilized filling vessel and the formulation produced in accordance with the process of claim 1”
• Claims 5 and 9: multidose glass vial and single-dose vial
• Claims 6 and 7/8: prefilled syringe

These claims do not add formulation chemistry. They mainly constrain the container.

Interferon alfa-2b and concentration

• Claim 4 and 3/11: specifies interferon alfa-2b; and where stated, 10 × 10^6 IU/mL (10 million IU/mL).

In practice, dependent claims expand the infringement surface by capturing multiple packaging formats and two concentration settings tied to alfa interferon alfa-2b.

What elements are most likely to be challenged for novelty and non-obviousness?

The oxygen control mechanism is the likely differentiator, but the claim also stacks common formulation elements (buffer, chelator, surfactant, tonicity, antimicrobial) that frequently appear in protein stabilization prior art.

1) Oxygen control may have obviousness overlap

If earlier interferon alfa formulations used:

• nitrogen blanketing or deoxygenation (vacuum degassing, inert atmosphere),
• low-DO targets during fill,
• DO and headspace O2 control in manufacturing,

then novelty shifts to the specific numeric thresholds (0.25 ppm DO and <4% headspace O2) and the requirement to sparge nitrogen “throughout” preparation.

Critical risk point: prior art does not need identical wording; it can anticipate or render obvious if it teaches maintaining sufficiently low DO and headspace O2 to protect protein stability, especially if interferon is the target.

2) The specific surfactant term is a likely prior-art hook

“Sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative” is a defined surfactant family. If earlier patents on alfa interferon used similar polyoxyethylene sorbitan esters (including polysorbate-like stabilizers or sorbitan ethoxylates), then the surfactant limitation may not distinguish the claim.

Critical risk point: if prior art uses the same or functionally interchangeable surfactant and meets oxygen/pH, then oxygen thresholds become the battleground.

3) “Free of human blood-derived products” may limit scope but may not defeat obviousness

If prior art interferon alfa is recombinant (typical in later-era products), then “free of human blood-derived products” may be met automatically. The limitation can reduce risk against plasma-derived interferon references, but it may not constrain the key manufacturing oxygen/process aspects.

4) “At least 75% biological activity” can be difficult but also attackable

If earlier patents report comparable activity retention after stabilization, the functional threshold may be treated as an inherent result of the claimed process, or as a parameter that can be optimized by routine variation.

Critical risk point: if the record shows that interferon stability widely depends on oxygen and that persons of skill would expect improved activity under low oxygen, then achieving 75% becomes predictable rather than inventive.

What does the claim structure imply about enforcement posture?

A. Likely infringement requires process evidence

Because claim 1 requires oxygen conditions maintained during preparation, enforcement against downstream fill-and-finish for a competitor will likely need:

• headspace O2 measurement practices for product solutions,
• dissolved oxygen measurement or in-line monitoring records,
• proof that nitrogen sparging occurred during preparation (not only final packaging).

B. Article claims increase leverage but depend on meeting the process

Claims 2–11 are framed as articles that include “the formulation produced in accordance with the process of claim 1.” That language ties the product to a process. If an accused party makes a similar formulation but cannot be shown to use the same oxygen-generation method and thresholds, the article claims can be harder to assert.

C. Container-type dependent claims broaden target list

Even if a competitor uses the same oxygen envelope, packaging differences (vials vs syringes, single vs multidose) determine coverage. Here, the claim set includes:

• multidose glass vial
• single-dose vial
• prefilled syringe

That coverage matters for litigation because many biologic manufacturers standardize container formats, and cross-format redesign can evade narrower packaging claims. This set reduces that escape route.

What is the patent landscape exposure around this technology theme?

Without inserting additional external citations from specific patent publications in your prompt, the most reliable landscape analysis is thematic and risk-ranked based on common IP clusters for protein stabilization:

Landscape clusters likely adjacent to US 5,766,582

1. Interferon alfa formulation stabilization patents
   • buffers and pH controls
   • surfactant stabilization
   • chelators to manage metal-catalyzed oxidation
   • tonicity agents for isotonicity
   • antimicrobial preservatives
2. Biologics low-oxygen manufacturing patents
   • nitrogen blanketing and inert atmosphere processing
   • oxygen scavenging and deoxygenation
   • dissolved oxygen and headspace oxygen specifications during fill
3. Container and fill-finish patents
   • multidose vial vs single-dose vial
   • prefilled syringe
   • sterilized vessel requirements

Where 5,766,582 most likely sits

• It sits at the intersection of (1) standard protein-excipient stabilization and (2) a very specific oxygen envelope applied during manufacturing of an interferon solution.

What that means for freedom-to-operate (FTO)

• The broad excipient categories may be widely practiced, so generic reformulation does not avoid risk.
• Avoidance likely requires changing at least one of:
  • oxygen thresholds and measurement/maintenance approach (DO <=0.25 ppm and headspace <4% O2 achieved via nitrogen sparging “throughout”),
  • surfactant identity (if the specific “sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative” is used as written rather than substituted),
  • or the process architecture (nitrogen sparging during preparation).

Critical claim vulnerabilities and likely argument angles

1) Definiteness and boundary issues around “about” thresholds

The claim uses “no more than about 0.25 ppm” and “less than about 4% oxygen by volume.” That leaves room for debate around:

• tolerances in measurement,
• instrument capability and reporting,
• operational ranges where “about” still captures the accused process.

In enforcement, that ambiguity cuts both ways: it broadens coverage for the patentee but allows challengers to argue non-infringement by demonstrating consistent operation above a boundary or measurement artifacts.

2) Oxygen control causality vs correlation

The patentee will argue that low oxygen prevents oxidative degradation and preserves biological activity. A challenger will frame oxygen control as an expected variable in protein stability and argue the specific numeric thresholds are routine.

3) The “throughout” nitrogen sparging requirement

If a competitor performs deoxygenation only at one stage (e.g., pre-degassing water but not the final bulk, or nitrogen sparging during mixing but not throughout hold times), they can attempt to avoid the literal “throughout” limitation.

4) “Headspace oxygen” measurement and control

Headspace control can be implemented via different steps:

• nitrogen blanketing prior to filling,
• controlled inert gas overlay during fill,
• in-line nitrogen addition. If an accused party controls headspace O2 but does not use sparging “into water and solution throughout preparing,” they can argue they do not meet the method limitation even if end-state oxygen levels match.

5) Product-by-process linkage in dependent article claims

Even if oxygen and excipients are similar, proving “formulation produced in accordance with the process” can be an evidentiary burden. That shapes enforcement strategy: discovery efforts typically focus on batch records and oxygen metrology.

What business decisions hinge on this claim set?

For R&D formulation teams

• If you plan to develop or transfer an interferon alfa formulation into low-oxygen manufacturing, you need to map your exact oxygen envelope:
  • target DO in ppm,
  • target headspace O2 in %,
  • when nitrogen is sparged (timing, duration, during bulk prep, during holds, pre-fill overlay),
  • what inert atmosphere method you use.
• Changing only one parameter (e.g., nitrogen blanketing without sparging during preparation) can materially change claim coverage.

For investors / deal diligence

• Claim 1’s oxygen/process limitations reduce the number of manufacturing scenarios that are likely to fall within scope.
• That selectivity is a double-edged sword: if the patentee’s process is commonly adopted industry-wide for protein oxidation control, the effective infringement pool is larger. If adoption is niche and limited, the enforceable footprint narrows.

Key Takeaways

• US 5,766,582 claim 1 combines a conventional interferon stabilization excipient stack with a narrow oxygen-controlled manufacturing process: DO ≤ ~0.25 ppm and headspace O2 < ~4% by volume, achieved via nitrogen sparging into water and solution throughout preparation.
• Dependent claims 2–11 broaden coverage across multidose glass vials, single-dose vials, and prefilled syringes, and across interferon alfa-2b, including a specific 10 × 10^6 IU/mL concentration in selected claims.
• The main technical battleground is the oxygen envelope and the “throughout” nitrogen sparging requirement, not just standard buffering, chelation, tonicity, and antimicrobial inclusion.
• Enforcement and FTO hinge on manufacturing proof: batch records, oxygen metrology (DO and headspace O2), and timing of nitrogen sparging.

FAQs

1) What is the single most important limitation for US 5,766,582 claim 1?

The dual oxygen control during preparation: dissolved oxygen ≤ ~0.25 ppm and headspace oxygen < ~4% by volume, maintained while nitrogen is sparged into the water and solution throughout preparation.

2) Are the article claims limited to a specific formulation composition?

They are limited to the formulation “produced in accordance with the process of claim 1.” The product claims follow the process limitations, so they are effectively tied to the claimed oxygen and excipient/pH requirements.

3) Does the claim cover interferon alfa-2b specifically?

Yes. Dependent claims include interferon alfa-2b (claims 4 and 7) and specify 10 × 10^6 IU/mL in claims 3, 8, and 11.

4) Does the claim require a particular container type?

Claim 2 covers “a sterilized filling vessel.” Dependent claims specify multidose glass vial, single-dose vial, and prefilled syringe.

5) What does “free of human blood-derived products” limit in practice?

It limits the formulation’s composition and sourcing so that it contains no human blood-derived products, which can reduce relevance of plasma-derived interferon references but may not distinguish among recombinant interferon manufacturing routes.

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References

[1] US Patent 5,766,582.

Details for Patent 5,766,582

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Llc	INTRON A	interferon alfa-2b	For Injection	103132	June 04, 1986	5,766,582	2014-10-11
Merck Sharp & Dohme Llc	INTRON A	interferon alfa-2b	For Injection	103132		5,766,582	2014-10-11
Merck Sharp & Dohme Llc	INTRON A	interferon alfa-2b	Injection	103132		5,766,582	2014-10-11

International Patent Family for US Patent 5,766,582

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	9611018
United States of America	5935566
Ukraine	42028
Slovakia	43997