Details for Patent: 7,229,630

Summary for Patent: 7,229,630

Title:	Stabilized formulations of alpha adrenergic receptor antagonists and the uses thereof
Abstract:	The present invention provides compositions and stable liquid formulations comprising alpha adrenergic receptor antagonists and use thereof for increasing blood flow. In one embodiment, the stable liquid formulations of this invention are useful for reversing the effects of an anesthetic agent, preferably a long-lasting local anesthetic agent administered in conjunction with an alpha adrenergic receptor agonist.
Inventor(s):	Andrew X. Chen, Julius Knowles, Eckard Weber
Assignee:	Bank of Montreal
Application Number:	US10/465,810
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Compound; Device; Dosage form;

Scope and US patent landscape for Drug Patent 7,229,630 (stable liquid alpha-adrenergic antagonist with low pH and chelator)

US Patent 7,229,630 is a formulation and packaging patent centered on a low-dose alpha-adrenergic receptor antagonist in water with a pH buffer/acid system at pH about 2.0 to 6.0 and a metal chelator selected from EDTA-family chelators (including EDTA and substituted EDTA analogs). Independent claims cover both (i) the composition and (ii) presentation in dental cartridges or pre-filled sterile syringes, with downstream dependent claims narrowing to phentolamine mesylate, acetate or methanesulfonic acid pH systems, specific concentrations, and embodiments that add tonicity modifiers (mannitol, NaCl, dextrose), antioxidants, and/or complexing agents (α-cyclodextrin, niacinamide). A further claim family covers containers and kits combining an anesthetic in one container with the formulation in another.

Claims 1-2, 14-16, 19-21 are the core infringement hooks, because they define a broad “consisting essentially of” formulation with (a) alpha-adrenergic antagonist class, (b) pH window and (c) enumerated chelators. Claims 2, 19-21 add injection/delivery presentation constraints (dental cartridge or pre-filled sterile syringe), which are typically easier to operationalize for product design-arounds than the chemistry itself. Claim 17 and claim 18 create strong “single-point” coverage for a specific phentolamine mesylate + EDTA + acetate + mannitol formulation at pH ~3.8-4.2, which can be particularly relevant in licensing or Paragraph IV litigation centered on generic or competing cartridges.

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What does US Patent 7,229,630 claim: composition scope for stable low-dose alpha-adrenergic antagonists at pH 2.0–6.0 with metal chelators?

Featured-snippet scope (practical): A “consisting essentially of” aqueous liquid formulation containing a low dose of an alpha-adrenergic receptor antagonist, a pH buffer/acid system, and one of the specified metal chelators (EDTA and analogs), with pH about 2.0 to 6.0.

Key independent claim geometry

The patent uses “consisting essentially of” language in multiple independent claims (1, 2, 14-16, 19-21). That typically means:

• the listed elements are required; and
• additional components are only allowed if they do not materially change the basic and novel characteristics.

In business terms, this formulation structure is broad enough to capture many “same concept” redesigns that keep the same pH range and chelator family, but it creates room for excipients that are consistent with stabilization at low pH.

The “required elements” cluster (from independent claims)

Across claims 1, 2, 14-16, and 19-21, the repeating core elements are:

1. Alpha-adrenergic receptor antagonist (class)
2. Buffer for maintaining pH (or buffer/acid system)
3. Aqueous solvent (water)
4. Metal chelator selected from:
   • diammonium ethylenediamine triacetate
   • hydroxyethyl-ethylenediamine triacetic acid
   • diethylenetriamine pentaacetic acid
   • nitriloacetic acid
   • citric acid
   • EDTA
5. pH of ~2.0 to 6.0 (range varies by claim, e.g., 3.5–4.5 in dependent claims)

Claims 14-16 add additional optional functional ingredients:

• tonicity modifier (claim 14 and dependent 22-23)
• antioxidant (claim 15 and dependent 25-26)
• complexing agent (claim 16 and dependent 27-28)

The delivery-presence constraint (critical for product-level infringement)

Claims 2, 19-21 require that the stable liquid formulation is present in:

• a dental cartridge, or
• a pre-filled sterile syringe.

This is an enforceable product-form factor limitation. If a competitor sells the same chemistry in a different container type, they may still avoid those particular independent claims, while remaining exposed under composition claims that do not require the cartridge/syringe presentation.

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How broad are the claims for alpha-adrenergic antagonists: phentolamine only or full class coverage?

Answer: The claim set covers an enumerated alpha-adrenergic antagonist list in dependent claim 3 (and later narrows to phentolamine mesylate in claims 4, 7, 10, 13, 24, 26, 28). But independent claims 1, 2, 14-16, 19-21 cover “an alpha adrenergic receptor antagonist” without restricting to phentolamine.

Dependent claim 3 list (alpha-adrenergic antagonist species)

• phentolamine
• phentolamine hydrochloride
• phentolamine mesylate
• tolazoline
• yohimbine
• rauwolscine
• doxazosine
• labetalol
• prazosine
• tetrazosine
• trimazosine
• pharmaceutically acceptable salts of the above

Business implication:

• Even if a competitor focuses on a different alpha-blocker (not phentolamine), the patent still has class coverage if they formulate the same way (water + pH system + specific chelator + pH window).

Phentolamine mesylate concentration and formulation precision

• Claim 5: 0.01 mg/mL to 10 mg/mL
• Claim 6: 0.1 mg/mL to 0.25 mg/mL
• Claim 7: phentolamine mesylate (within that window)
• Claim 17 and 18: fixed quantitative embodiments, including:
  • phentolamine mesylate 0.235 mg/mL (in claim 17)
  • multiple configurations of acetate vs methanesulfonic acid vs PPG, and EDTA Na2 0.5 vs 1.0 mg, plus D-mannitol 50 mg and sodium acetate/acetic acid amounts to set pH

This combination of class claims and “fixed-point” embodiments is often where a patent becomes high-value in licensing, because many practical product formulations end up close to one of the specific examples.

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Which chelators are protected under US 7,229,630: EDTA substitutes and acidic chelators?

Answer: The patent enumerates a chelator list that is not limited to EDTA. It explicitly covers:

• diammonium ethylenediamine triacetate
• hydroxyethyl-ethylenediamine triacetic acid
• diethylenetriamine pentaacetic acid
• nitriloacetic acid
• citric acid
• EDTA

Business implication:

• Designing around by swapping EDTA to another “EDTA-family” chelator likely does not avoid the patent.
• Designing around by moving to a chelator that is not in the enumerated list (and still maintains stability at low pH) is the higher-friction path, because stability and metal binding are chemistry-dependent.

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What pH range is covered and how do the buffer system limitations narrow practical infringement?

Answer: Core independent coverage is pH about 2.0 to 6.0. Dependent claims narrow to:

• Claim 11: pH about 3.5 to 4.5
• Claim 12: buffer system includes 10 to 50 mM acetate buffer or methanesulfonic acid

For product design:

• Competitors can attempt pH outside the 2.0–6.0 window, but low-pH stability may be functional to the patent’s novelty. Shifting pH can create downstream compatibility and taste/irritation issues for dental cartridges and pre-filled syringes.

For infringement:

• If a formulation is within pH 2.0–6.0 and uses one of the specified chelators, it tends to land within the independent claim scope.

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What formulations are explicitly disclosed: claim 17 and claim 18 as “exact build” targets?

Answer: Claims 17 and 18 list explicit quantitative formulations for a phentolamine mesylate + EDTA + mannitol + acetate (and also alternatives to methanesulfonic acid) stable liquid at pH ~3.5 to 4.5, volume ~1.0 mL.

Claim 17 fixed formulation (single example)

• Phentolamine mesylate: 0.235 mg/mL
• EDTA: 0.5 mg/mL
• D-mannitol: 5%
• 16.6 mM acetate buffer
• pH: 3.8 to 4.2

Claim 18 multi-variant formulations (cartridge/syringe-style volume with buffers)

Claim 18 enumerates multiple options “selected from” sub-embodiments (a–l). The common pattern is:

• phentolamine mesylate either 0.222 mg or 0.1 mg or 0.235 mg per stated dosage volume
• EDTA Na2 either 0.5 mg or 1.0 mg
• D-mannitol 50 mg
• buffer system using:
  • sodium acetate + acetic acid to achieve pH 3.5–4.2, or
  • methanesulfonic acid to achieve pH 3.5–4.5
• solvent: q.s. to 1.0 mL with WFI or (in one variant) PPG present

Business implication:

• If a competitor’s product formulation matches one of these explicit “selected from” options in both component quantities and pH range, they face direct claim risk.
• Even if not identical, these embodiments define the patent’s “center of gravity” for what combinations likely work in practice.

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What formulations are added beyond the core chelator system: tonicity modifier, antioxidant, complexing agent?

Tonicity modifier (claims 14, 22-24)

• Claim 14 includes a tonicity modifier plus chelator at pH 2.0–6.0
• Claim 22: tonicity modifier selected from NaCl, D-mannitol, dextrose
• Claim 23: D-mannitol at 4–5% (w/v)
• Claim 24: alpha adrenergic antagonist is phentolamine mesylate

This matters for dental and injection products where isotonicity and injection comfort are tightly controlled.

Antioxidant (claims 15, 25-26)

• Claim 15 adds an antioxidant sufficient to prevent oxidization
• Claim 25: antioxidant selected from ascorbic acid, sodium metabisulfite, BHA, BHT
• Claim 26: phentolamine mesylate

Complexing agent (claims 16, 27-28)

• Claim 16 adds a complexing agent
• Claim 27: α-cyclodextrin or niacinamide
• Claim 28: phentolamine mesylate

Design-around implication:

• Since claims are “consisting essentially of,” omitting the optional functional excipient may move products out of those specific dependent-structure claims, but the core claims remain a threat if the essential chelator + pH + alpha-adrenergic antagonist elements remain.

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How do container and kit claims expand protection beyond the formulation itself?

Container claims (claims 29-31)

• Claim 29: container comprising a single dosage form of the stable liquid formulation (any of claims listed)
• Claim 30: container type selected from ampule, dental cartridge, pre-filled sterile syringe
• Claim 31: volume 1.6 to 1.8 mL

These broaden enforcement from chemical composition to physical presentation.

Kit claim (claims 32-33)

• Claim 32: kit with a carrier holding:
  • first container: anesthetic agent (optionally plus alpha-adrenergic agonist)
  • second container: the stable liquid formulation
• Claim 33: second container comprises a single dosage form

Business implication:

• Kits create leverage in commercial bundling and tender supply. Even if a competitor sells a cartridge separately, kits can drive licensing for procurement channels.

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What patent landscape issues are most likely for US 7,229,630: what to expect around overlapping formulation patents?

Without a verified dataset of:

• the patent’s full bibliographic record,
• prosecution history,
• family members,
• related US patents by the same assignee,
• and the Orange Book listing for the relevant FDA product(s),

a complete landscape cannot be generated. What can be stated from the claim structure alone is the most likely “overlap pattern”:

1. Formulation core overlap: EDTA/chelator + low pH buffer/acid + alpha-blocker aqueous solution is a modular stabilization concept. Expect adjacent patents covering:

   • specific pH buffers (acetate vs alternative acids),
   • alternative chelator systems,
   • excipient stability packages (mannitol, antioxidants, complexants).

2. Device/delivery overlap: dental cartridges and pre-filled syringes frequently attract device-formulation combination filings. US 7,229,630’s claims explicitly require those containers in key independent claims.

3. Method-of-use overlap: while US 7,229,630 is formulation-focused, alpha-adrenergic antagonists in dental anesthetic contexts can also be covered by method-of-use patents for reduced vasodilation, altered onset, or hemostasis-related outcomes. Without the full family record, the existence of those patents cannot be asserted here.

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Where are the highest-risk infringement zones for competitors and generics?

1) Low-pH aqueous alpha-blocker + enumerated chelator + pH 2.0–6.0

• If a competitor keeps the same chelator list and pH window, they will likely remain within independent claim coverage (1, 2, 14-16, 19-21).

2) Dental cartridge / pre-filled sterile syringe format

• Claims 2, 19-21 impose a packaging/delivery constraint. A product in a different container type could avoid those specific independent claims while still facing composition claim exposure.

3) Phentolamine mesylate at the specific concentrations

• If a competitor’s product uses phentolamine mesylate concentrations in the 0.1–0.25 mg/mL band and uses EDTA-family chelators at similar concentrations with pH ~3.5–4.5 acetate or methanesulfonic systems, they converge on claims 6, 11-13, 17-18 and related dependent claims.

4) Exact-match embodiments

• Claims 17 and 18 are “pin” points. If a challenger copies an example, the claim structure is likely to be directly met.

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Key Takeaways

• US 7,229,630 is a stable low-pH aqueous formulation patent with enumerated EDTA-family and related chelators and alpha-adrenergic antagonist coverage.
• Independent claims 1, 2, 14-16, and 19-21 define the dominant protection: aqueous liquid + low-dose alpha blocker + pH 2.0–6.0 + specific chelator list, with key independent coverage for dental cartridges and pre-filled sterile syringes.
• Dependent claims narrow to phentolamine mesylate, pH 3.5–4.5, acetate buffer (10–50 mM) or methanesulfonic acid, and excipient add-ons (mannitol tonicity, antioxidants, complexing agents).
• Claims 17 and 18 provide explicit quantitative formulations that create high-value “exact build” infringement targets.
• Container (ampule/cartridge/syringe) and kit claims extend protection to product presentation and bundled anesthetic kits.

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FAQs

1) Can a competitor avoid US 7,229,630 by switching from EDTA to citrate or nitriloacetic acid?
No if they switch among the listed chelators in the claims (citric acid, nitriloacetic acid, and EDTA-analog chelators are explicitly covered).

2) Is phentolamine mesylate required for infringement?
No. The independent claims cover an alpha-adrenergic antagonist class; phentolamine mesylate appears in multiple dependent claims and in explicit examples.

3) If a product is in an ampule instead of a dental cartridge, does that eliminate risk?
It can reduce exposure under independent claims that require dental cartridge or pre-filled sterile syringe, but container and composition claims still create risk because the patent includes ampule and other presentations via container claims.

4) Does adding antioxidants or complexing agents help a challenger design around?
Not necessarily. Antioxidant and complexing agent features are in dependent claims; the core claims remain centered on the alpha blocker + pH buffer/acid + enumerated chelator + pH window.

5) Where is the strongest claim met-likelihood if a formulation is near the patent examples?
Where formulations match claim 17 (0.235 mg/mL phentolamine mesylate + 0.5 mg/mL EDTA + 5% D-mannitol + 16.6 mM acetate buffer at pH 3.8–4.2) or claim 18 variants.

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References (APA)

1. United States Patent 7,229,630.

Drugs Protected by US Patent 7,229,630

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

International Family Members for US Patent 7,229,630

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2003247568
Brazil	0311965
Brazil	PI0311965
Canada	2489526
China	100391460
China	1688312