Details for Patent: 6,451,289

Summary for Patent: 6,451,289

Title:	Albuterol formulations
Abstract:	Albuterol formulations packaged in an oxygen-permeable plastic container have a long shelf life at room temperature. The formulations consist essentially of albuterol or a pharmaceutically acceptable salt thereof, sodium chloride, and water, have a pH of about 4, and contain less than 0.08% by weight of albuterol aldehyde and less than 1 ppm dissolved oxygen.
Inventor(s):	Robert J. Wherry, III, Stewart H. Mueller
Assignee:	Sumitomo Pharma America Inc
Application Number:	US09/815,150
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

US Patent 6,451,289 (Albuterol) — Claims Scope and US Patent Landscape

United States Patent 6,451,289 protects a narrow but technically specific packaging and manufacturing approach for preservative-free aqueous albuterol (and salts), focused on oxygen control to limit albuterol aldehyde formation and maintain stability through 12+ month shelf life.

At a claim level, the patent is structured around three enforceable pillars:

1. Formulation purity and excipient exclusions (no chelators, sequestering agents, antioxidants, or preservatives; specific aldehyde and dissolved oxygen limits; pH about 4; sodium chloride and water as the core excipients).
2. Oxygen-permeable primary container that is fabricated by forming an oxygen-permeable plastic hollow cylinder into a container after nitrogen purging to create a reduced oxygen atmosphere inside.
3. Oxygen-impermeable wrapper that encloses an internal gas phase with <2% by weight oxygen (or related dependent thresholds) and no oxygen-absorbent.

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What exactly do the independent claims cover?

Claim 1 (method)

Claim 1 covers a method of manufacturing a packaged albuterol formulation with shelf life at least 12 months. The method is defined by a sequence of conditions that collectively narrow infringement to a packaging process that matches all critical parameters.

Core technical elements of Claim 1:

• Primary container formation

  • Blow nitrogen gas through a hollow cylinder of an oxygen-permeable plastic
  • Mold the hollow cylinder into an oxygen-permeable container
  • This step yields at least partial enclosure of a reduced oxygen atmosphere in the molded container.

• Filling the container

  • Fill with aqueous albuterol or pharmaceutically acceptable salt
  • The aqueous formulation must be:
  • free of chelating agents, sequestering agents, antioxidants, and preservatives
  • contain <0.05% by weight albuterol aldehyde
  • contain <1 ppm dissolved oxygen

• Packaging into a low-oxygen external structure

  • Enclose the oxygen-permeable container under an atmosphere containing < about 2% by weight oxygen
  • Wrap it in an oxygen-impermeable wrapper
  • The package must enclose an atmosphere containing < about 2% by weight oxygen
  • Must not contain an oxygen-absorbent

Practical reading for enforcement: Claim 1 is not just “store albuterol in low oxygen.” It is a process claim requiring a very specific fabrication method for the oxygen-permeable container (nitrogen purge through a hollow oxygen-permeable cylinder, then molding) paired with precise oxygen and aldehyde/dissolved oxygen limits and explicit excipient exclusions.

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What do the independent product claims cover?

Claim 2 (stable, preservative-free packaged formulation)

Claim 2 covers a stable packaged preservative-free pharmaceutical formulation consisting essentially of:

• albuterol or pharmaceutically acceptable salt
• sodium chloride
• water

with:

• pH about 4
• <0.08% by weight albuterol aldehyde
• <1 ppm dissolved oxygen
• contained within an oxygen-permeable container (not a fully oxygen-impermeable bottle)
• and must remain <0.08% by weight albuterol aldehyde after storage at 40°C for six months
• the formulation does not contain:
  • chelating agents
  • sequestering agents
  • antioxidants
  • preservatives

Key enforceability feature: the claim ties stability to a defined stress condition: 40°C for six months, with an aldehyde ceiling.

Dependent product claims that materially narrow scope

Claims 3–16 and 17–20 further define container gas composition, materials, wrapper structure, and drug identity.

• Claim 3: gas phase in the oxygen-permeable container has < about 5% oxygen
• Claim 4: oxygen-permeable container enclosed within a sealed wrapper comprising oxygen-impermeable material
• Claim 5: sealed wrapper gas phase has < about 5% by weight oxygen
• Claim 6: multiple oxygen-permeable containers in one oxygen-impermeable wrapper
• Claims 7–8: specific stereochemistry: (R)-albuterol and (R)-albuterol hydrochloride
• Claims 9–10: wrapper and container materials
  • oxygen-impermeable material: foil laminate
  • oxygen-permeable material: low density polyethylene (LDPE)
• Claims 11: preservative-free unit dosage formulation for inhalation with explicit numeric composition:
  • 0.18–1.4 mg albuterol (or salt)
  • 27 mg sodium chloride
  • 2–4 mL water
  • pH about 4
  • <1 ppm dissolved oxygen
  • <0.08% by weight albuterol aldehyde after 40°C six months
  • no chelators, sequestrants, antioxidants, preservatives
• Claims 12–16 and 19–20 repeat and narrow combinations for the “packaged preservative-free” system and for material selection.

Net effect: the patent is best viewed as protecting a system: specific chemistry + oxygen management architecture (oxygen-permeable inner + oxygen-impermeable outer) + oxygen ceilings + aldehyde ceilings + excipient exclusions.

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Where is the “scope” tightest vs broadest?

Tightest claim hooks

These elements likely define the largest barriers to design-around and capture the strongest infringement risk:

• Excipients excluded
  • no chelating agents, sequestering agents, antioxidants, preservatives
• Quantified oxidation products and dissolved oxygen
  • <0.05% aldehyde (Claim 1 method) and <0.08% aldehyde (product claims)
  • <1 ppm dissolved oxygen
• Oxygen gas ceilings
  • wrapper atmosphere: < about 2% oxygen by weight (Claim 1)
  • gas phase options: < about 5% oxygen by weight (Claims 3 and 5)
• No oxygen-absorbent
  • Claim 1 expressly excludes oxygen-absorbent in the package
• Primary container formed from oxygen-permeable plastic via nitrogen purge
  • Claim 1 requires nitrogen blow-through of a hollow cylinder of oxygen-permeable plastic before molding

Broadest portions

The broadest elements are in the flexibility of the drug identity within the claimed categories:

• “albuterol or pharmaceutically acceptable salt thereof” (subject to dependent claim narrowing)
• wrapper material can be oxygen-impermeable unless limited by dependent claims (foil laminate in dependent claim 9; method wrapper includes foil laminate in claim 19)

Still, the numeric oxygen and aldehyde limits restrain practical coverage.

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Claim-to-implementation mapping (what a product must look like to infringe)

A manufacturer aiming to match the claim language would need, at minimum:

1. Aqueous formulation (core excipients only):
   • albuterol or salt + sodium chloride + water
   • pH about 4
   • no chelators/sequestrants/antioxidants/preservatives
2. Dissolved oxygen control:
   • <1 ppm dissolved oxygen in the filled solution
3. Oxygen-permeable primary packaging:
   • oxygen-permeable plastic container (LDPE appears in dependent claim 10, but Claim 2 requires only oxygen-permeable)
4. Oxygen-impermeable outer wrapper:
   • sealed wrapper made of oxygen-impermeable material
5. Low-oxygen internal atmospheres:
   • outer wrapper atmosphere and/or internal gas phase under < about 2% or < about 5% oxygen by weight depending on the claim asserted
6. Stability performance:
   • aldehyde remains below <0.08% after 40°C for 6 months (for Claim 2/12/11-type product positioning)
7. No oxygen absorbent (Claim 1)

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How does the patent landscape likely cluster around this technology?

Even without reproducing other patents’ text here, the landscape tends to cluster into three adjacent protection zones that commonly coexist in the oxygen-stabilized, preservative-free inhalation packaging field:

1. Formulation chemistry patents
   • defining aldehyde/oxygen control approaches, excipient systems, pH targets, and stabilizing chemistry (including chelator/antioxidant/preservative tradeoffs)
2. Packaging material and barrier patents
   • oxygen-permeable container materials (polyolefins, film structures) and oxygen-impermeable wrapper laminates (foils, multilayer films)
3. Manufacturing process patents
   • gas purging strategies (nitrogen, controlled atmospheres)
   • container formation processes that trap reduced oxygen in the headspace
   • sealing methods and wrapper atmosphere control

US 6,451,289 sits at the intersection: it covers both a process pathway (Claim 1) and a packaged product with specific performance and exclusions (Claim 2), and it locks these together using numeric oxygen and aldehyde thresholds.

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Where are the most likely design-arounds? (Claim-aware, not generic)

Design-around lever 1: remove the “aldehyde limit” profile

If the competing formulation does not meet the claimed <0.08% aldehyde after 40°C six months (product claims) or <0.05% aldehyde (method claim), it can fall outside the numeric limitation. That is a direct claim escape route if stability can be managed without meeting these thresholds.

Design-around lever 2: use a different oxygen strategy

Because Claim 1 and Claim 2 require oxygen-permeable primary containers combined with oxygen-impermeable wrappers under low oxygen atmospheres (and Claim 1 excludes oxygen-absorbent), competitors may target one of the required architecture elements:

• switch to fully oxygen-impermeable primary containers
• eliminate the low-oxygen atmosphere requirement
• include oxygen-absorbent (for Claim 1)

Design-around lever 3: change excipient set

The patent explicitly removes multiple formulation classes:

• chelating agents
• sequestering agents
• antioxidants
• preservatives

A product that uses any of these excipient categories (depending on claim interpretation of “free of”) can avoid the “consisting essentially of”/“free of” limitations.

Design-around lever 4: avoid the nitrogen-through-hollow-cylinder molding process

Claim 1 is method-specific: blow nitrogen through a hollow cylinder of oxygen-permeable plastic and mold it into the oxygen-permeable container. Competitors can pursue an alternative container manufacture method that does not match that process.

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Landscape risk posture (how to think about freedom-to-operate)

For a company launching a preservative-free inhaled albuterol that relies on oxygen control, the patent is best treated as a high-friction blocker if the program uses:

• pH around 4
• sodium chloride + water formulation
• oxygen-permeable LDPE-like inner container and oxygen-impermeable foil laminate outer wrapper
• low dissolved oxygen (<1 ppm)
• low aldehyde targets after thermal stress
• sealed low oxygen headspace/wrapper atmosphere

Programs deviating on these parameters can reduce risk, but the numeric thresholds and explicit exclusions make this patent unusually “checklistable” for validity and infringement analysis.

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Key Takeaways

• US 6,451,289 protects an oxygen-managed packaging system for preservative-free aqueous albuterol: low dissolved oxygen (<1 ppm), low aldehyde limits (<0.05% or <0.08% depending on claim), and low oxygen atmospheres inside the package (< about 2% by weight for Claim 1; < about 5% by weight for dependent claims).
• Claim 1 is a manufacturing method requiring nitrogen purge through a hollow cylinder of oxygen-permeable plastic followed by molding, plus low oxygen wrapper atmosphere and no oxygen-absorbent.
• Claim 2 is a packaged product definition centered on “consisting essentially of” excipients (albuterol/salt, sodium chloride, water; pH about 4), plus stability after 40°C for six months and explicit exclusions (no chelators, sequestrants, antioxidants, preservatives).
• Dependent claims narrow materials and configurations (LDPE oxygen-permeable container; foil laminate oxygen-impermeable wrapper; optional gas phase ceilings; multiple containers per wrapper; specific (R)-albuterol hydrochloride).
• Design-around is most feasible by breaking at least one hard numeric limitation (dissolved oxygen, aldehyde after thermal stress, oxygen % in headspace/wrapper) or by breaking one hard architectural/excipient condition (oxygen-permeable inner container, low oxygen wrapper atmosphere, no oxygen-absorbent for Claim 1, or excipient category exclusions).

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FAQs

1) Does the patent require an oxygen-absorbent?
No. Claim 1 explicitly requires that the package does not contain an oxygen-absorbent.

2) What dissolved oxygen limit is required?
The claims require less than 1 ppm dissolved oxygen in the aqueous formulation.

3) What aldehyde limits does the patent use?

• Claim 1: <0.05% by weight albuterol aldehyde
• Claim 2 and dependent product/unit claims: <0.08% by weight albuterol aldehyde and remaining below that after 40°C for six months

4) Are chelators, sequestrants, antioxidants, and preservatives allowed?
No. The formulation is required to be free of those categories and/or does not contain them, per Claim 1 and Claim 2.

5) What packaging structure is required?
A two-layer oxygen architecture: an oxygen-permeable plastic container enclosing the formulation and an oxygen-impermeable sealed wrapper enclosing the low-oxygen atmosphere.

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References

[1] US Patent 6,451,289.

Drugs Protected by US Patent 6,451,289

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate