United States Patent 8,685,460 (Dantrolene Sodium) scope, claim coverage, and US patent landscape

Executive summary: US Drug Patent 8,685,460 is a US-method-of-treatment and formulation/reconstitution centered estate directed to rapid, IV-safe, low-volume liquid dantrolene sodium defined by particle size (< about 2 microns) and a constrained excipient set (water-soluble polysorbate + sorbitol or mannitol, optionally PVP), with defined concentration ranges (3.33–166.67 mg/mL) and multiple administration timing/volume/dose fallbacks. The claims also cover dry-to-liquid preparation where a dry admixture is reconstitutable by water into the specified colloidal dispersion, including mechanical agitation in ≤1 minute. Risk to competitors is primarily about IV delivery of dantrolene as a colloidal dispersion with sub-2 micron particles and the specific excipient architecture; the most design-around-resistant elements are the particle-size parameter, the polysorbate + polyol pair, and the “safe for intravenous administration” functional constraint.

What does US Patent 8,685,460 claim for dantrolene sodium heat stroke treatment?

Core claim theme: method(s) of treating hyperthermia-related conditions using a therapeutically effective amount of an IV-safe, low-volume liquid formulation of dantrolene sodium characterized by physicochemical and composition features.

Claim 1: heat stroke method using sub-2 micron IV colloidal dantrolene

Claim 1 requires all of the following elements (in practical infringement analysis, all are required):

Indication/method step: treat heat stroke in a mammal.
Administration: administer a therapeutically effective amount of the specified formulation.
Formulation type: “safe for injection, low volume liquid formulation” of dantrolene sodium suitable for IV administration.
Dantrolene concentration: 3.33 mg/mL to 166.67 mg/mL.
Excipient set:
- Water-soluble polysorbate
- Polyol selected from sorbitol and mannitol
- Water as liquid carrier
Dispersion definition: dantrolene sodium and water are present as a colloidal dispersion of dantrolene particles in water.
Particle size: dantrolene particles are less than about 2 microns in average diameter.
Route: formulation is safe for intravenous administration.

Dependent claim bands that tighten concentration

Claim 2: concentration in 30–80 mg/mL or 10–60 mg/mL.
Claims 3–4: “consists essentially of” version of claim 1 with the same concentration options.

Primary modulator language

Claim 5: dantrolene sodium is the primary modulator of intracellular calcium in the formulation (functional statement that can create evidentiary hooks in enforcement, but still tied to the active/administration context).

Optional polymer excipient escalation

Claim 6: formulation further comprises PVP.
Claims 7–8: “consists essentially of” formulation version including PVP plus the same core constraints (sub-2 micron colloidal dispersion, polysorbate, sorbitol/manitol, concentration bands).

Another mannitol-specific ratio limitation

Claim 9: where polyol is mannitol and the formulation has no more than 30 mg mannitol per mg dantrolene.

Administration quantity and dose fallbacks

Claim 10: administer 3–150 mL.
Claim 11: ≤10 mL.
Claim 12: ≤5 mL.
Claim 13: administer a dose of 250–300 mg dantrolene sodium.
Claim 14: same dose limitation with the claim 10 volume context.

Preparation pathway coverage (dry-to-liquid reconstitution)

Claim 15: adds a preparation step: form a dry formulation with:
- dantrolene sodium particles < about 2 microns (average diameter),
- water-soluble polysorbate,
- sorbitol or mannitol,
  which is reconstitutable by water into an IV-safe colloidal dispersion matching the liquid specs, then combining to make the liquid ready for injection.
Claim 16: combining by mechanical agitation.
Claim 17: combining in 1 minute or less.
Claims 18–20: “consists essentially of” variants of the dry formulation, with optional PVP in the dry formulation.

What patents protect dantrolene formulation for malignant hyperthermia or heat stroke in the US?

US 8,685,460 is bifurcated: it claims heat stroke (claim 1 group) and non-normothermia conditions (claim 21 group), where the non-normothermia condition is selected from malignant hyperthermia and heat stroke.

Claim 21: non-normothermia method using the same IV-safe colloidal formulation

Claim 21 parallels claim 1 with:

Indication: non-normothermic condition in a mammal
Non-normothermia selection: malignant hyperthermia and heat stroke (claim 23)
Same formulation architecture and particle-size constraint.

Claim 23: malignant hyperthermia explicit inclusion

This matters for freedom-to-operate (FTO) because it creates direct enforcement hooks in MH use even if a product is marketed for one condition but used clinically for the other.

Claim 25: reconstitution preparation coverage

Claim 25 mirrors claim 15 for the non-normothermia method context, tying preparation and IV injection readiness together.

How broad is the scope of US 8,685,460 claims, and what are the key infringement-critical limitations?

Most infringement-critical limitations

These are the constraints that typically drive whether a competitor’s product reads on the claims:

Sub-2 micron average particle size of dantrolene sodium in water (< about 2 microns).
Colloidal dispersion characterization (dantrolene present together with water as a colloidal dispersion).
Excipient architecture:
- water-soluble polysorbate
- sorbitol or mannitol (and, in claim 9, a mannitol:dantrolene mass ratio ≤30 mg/mg)
IV “safe for injection” and safe for IV administration functional requirement.
Concentration bands: 3.33–166.67 mg/mL, with preferred ranges 10–60 or 30–80 mg/mL depending on dependent claim selection.
Low volume administrative constraints (≤5 mL in claim 12; 3–150 mL in claim 10).

Less limiting vs evidentiary supporting constraints

“Primary modulator of intracellular calcium” is still a formulation/active statement. It can help correlate mechanism but does not add a clear chemical restriction beyond using dantrolene sodium as such.
Quantity/dose and reconstitution timing (≤1 minute) can be strong enforcement triggers if accused products are used and prepared in the claimed manner, but they can also be easier to design around than particle size.

Composition “consists essentially of” vs “comprises”

The estate has both “comprising”-style claims (broader; can tolerate additional excipients) and “consists essentially of” claims (narrower; excludes additional components that materially affect the basic and novel characteristics). The “consists essentially of” variants appear in:
- Claims 3–4 (liquid)
- Claims 7–8 (liquid + PVP)
- Claims 18 (dry)
- Claims 20 (dry + PVP)

For infringement, “consists essentially of” tends to be more sensitive to formulations that include extra stabilizers, salts, buffers, or alternative surfactants.

What formulation parameters are required: particle size, polysorbate, sorbitol/mannitol, PVP, and concentration?

Particle size parameter

“less than about 2 microns in average diameter” applies to:
- liquid colloidal dispersion (claims 1, 3, 15, 18)
- dry formulation particle condition (claims 15, 18, 20)
- reconstituted liquid after adding water (claims 15, 25)

This dual anchoring (dry and reconstituted) improves enforceability because a defendant cannot fully avoid by reformulating only the final liquid without addressing the starting dry-state particle size.

Polysorbate requirement

The claims require a water-soluble polysorbate. The patent does not, in the claim excerpt provided, limit which polysorbate (e.g., polysorbate 20 vs 80), but it does require polysorbate as the water-soluble surfactant class.

Polyol selection

Sorbitol or mannitol is required in the liquid and dry formulation.
For claim 9, if mannitol is used, there is a constrained relationship: ≤30 mg mannitol per mg dantrolene.

PVP optional vs required

Optional via dependent claims (6, 7–8, 19–20).
When included, “consists essentially of” claims limit the rest of the composition.

Concentration envelope

Base: 3.33–166.67 mg/mL.
Narrow concentration dependent:
- 10–60 mg/mL or 30–80 mg/mL.

This is a typical product-line discriminator if a competitor offers a different strength or dosing scheme not matching the concentration bands.

How do the reconstitution and rapid preparation claims expand the patent’s reach?

Dry-to-liquid preparation is claimed as a method

Claim 15 is not just a composition claim. It is a method of preparing the IV-ready colloidal formulation using:

a dry formulation meeting the particle size and excipient constraints, and
reconstituting by water, followed by combining to make the liquid ready for injection.

Mechanical agitation and timing

Claim 16: mechanical agitation.
Claim 17: agitation in ≤1 minute.
If an accused product requires longer reconstitution time or relies on a different preparation modality (e.g., prolonged mixing, heating, ultrasound), it may not meet these dependent limitations, but it could still meet the broader liquid formulation limitations if those are met.

When does US 8,685,460 lose exclusivity, and how do to use key date mechanics?

No filing, priority, patent term adjustment, or patent expiration data for US 8,685,460 is provided in the prompt. With that information missing, a complete and accurate exclusivity/timeline analysis cannot be produced.

What is the Orange Book status of US 8,685,460 and what generic entry risks does it create?

No Orange Book listing, NDA number, supplement number, or regulatory reference product is provided in the prompt. With that information missing, a complete and accurate Orange Book and generic entry analysis cannot be produced.

Which companies are likely implicated by the dantrolene IV colloidal particle-size approach?

No accused products, assignees, applicant records, or litigation captions are provided in the prompt. With that information missing, company attribution cannot be produced.

How strong is the patent estate for sub-micron IV dantrolene, and what design-arounds are most plausible from the claim language?

Design-around levers suggested by claim structure

Because the claims have multiple independent concentration and administration variants, the most viable design-arounds usually target the shared “bedrock” limitations:

Particle size not “< about 2 microns average diameter”
- If a formulation uses larger average particles or a different dispersion state that is not a colloidal dispersion meeting the sub-2 micron criterion, it can avoid the core definition.
Remove or replace the required surfactant system
- The claims require a water-soluble polysorbate. Switching to a non-polysorbate system (if not a polysorbate) risks avoidance.
- But if the competitor still includes polysorbate, design-arounds must shift to other features (e.g., particle size, polyol identity/ratio, “consists essentially of” boundaries).
Use a different polyol or adjust polyol ratio
- Switching from sorbitol/manitol to another compatible polyhydric alcohol could reduce literal coverage.
- For claim 9 specifically, if mannitol is used, staying above the 30 mg/mg cap can avoid that dependent limitation, but independent claim coverage still depends on satisfying claim 1’s “sorbitol or mannitol” element.
Change concentration band
- A formulation outside 3.33–166.67 mg/mL avoids literal concentration coverage for the base claims.
- However, the claim set contains multiple concentration-dependent variants, so concentration alone may not be sufficient if a product falls within the ranges.
Change preparation method or timing
- Dependent preparation claims (mechanical agitation, ≤1 minute) can be avoided by alternative mixing and/or reconstitution procedures. Liquid formulation coverage can still remain if the end-state formulation matches claim 1 elements.

Design-around most difficult to execute

The “hardest” element from a development standpoint is usually: achieving stable IV-safe sub-2 micron average dantrolene particles in water while also satisfying the polysorbate + sorbitol/manitol system (and optionally PVP) without triggering separation, precipitation, or safety issues. The patent also ties the sub-2 micron condition to both dry and reconstituted states.

Key claim-by-claim map (coverage matrix for heat stroke and malignant hyperthermia)

Claim	Treating method scope	Formulation/concentration	Particle size	Surfactant/polyol	IV-safe requirement	Process limitations
1	Heat stroke	3.33–166.67 mg/mL	< ~2 microns avg	Polysorbate + sorbitol or mannitol	Required	None
2	Depends on 1	30–80 or 10–60 mg/mL	Same as 1	Same as 1	Required	None
3	Heat stroke	“consists essentially of” core	< ~2 microns	Polysorbate + sorbitol or mannitol	Required	None
4	Depends on 3	Same narrower ranges	Same	Same	Required	None
5	Heat stroke	As 1	As 1	As 1	Required	Calcium modulation statement
6	Heat stroke	As 1 + PVP	As 1	Polysorbate + sorbitol/manitol	Required	None
7	Heat stroke	“consists essentially of” + PVP	< ~2 microns	Polysorbate + sorbitol/manitol	Required	None
8	Depends on 7	Concentration narrowing	As 7	As 7	Required	None
9	Heat stroke	Mannitol formulation; ratio limit	As 1	Polysorbate + mannitol (ratio cap)	Required	None
10	Heat stroke	Quantity 3–150 mL	As 1	As 1	Required	None
11	Heat stroke	Quantity ≤10 mL	As 1	As 1	Required	None
12	Heat stroke	Quantity ≤5 mL	As 1	As 1	Required	None
13	Heat stroke	Dose 250–300 mg	As 1	As 1	Required	None
14	Heat stroke	Dose 250–300 mg + quantity context	As 1	As 1	Required	None
15	Heat stroke	Adds preparation of dry-to-liquid colloid	< ~2 microns in dry and reconstituted	Polysorbate + sorbitol/manitol	Required	Reconstitutable by water
16	Depends on 15	As 15	As 15	As 15	Required	Mechanical agitation
17	Depends on 16	As 16	As 16	As 16	Required	≤1 minute
18	Depends on 15	“consists essentially of” dry core	< ~2 microns in dry	Polysorbate + sorbitol/manitol	Required	Reconstitutable by water
19	Depends on 15	Dry formulation further includes PVP	< ~2 microns	Polysorbate + polyol + PVP	Required	Reconstitutable by water
20	Depends on 19	“consists essentially of” dry core + PVP	< ~2 microns	Polysorbate + polyol + PVP	Required	Reconstitutable by water
21	Non-normothermia condition	Same formulation specs	< ~2 microns	Polysorbate + polyol	Required	None
22	Depends on 21	Concentration narrowing	Same	Same	Required	None
23	Depends on 21	Condition is malignant hyperthermia or heat stroke	Same	Same	Required	None
24	Depends on 23	Concentration narrowing	Same	Same	Required	None
25	Depends on 21	Adds preparation of dry-to-liquid	< ~2 microns	Polysorbate + polyol	Required	Reconstitutable by water

What patent litigation affects US 8,685,460, and are there settlement agreements?

No litigation record, PGR/IPR history, or settlements are included in the prompt. With that information missing, a litigation impact analysis cannot be produced.

Key Takeaways

US 8,685,460 is built around IV-safe, low-volume dantrolene sodium delivered as a colloidal dispersion with sub-2 micron average particles, using a required polysorbate + sorbitol/manitol excipient system, with optional PVP.
The estate is enforceable across heat stroke and malignant hyperthermia method-of-use framing, with additional constraints on dose/volume and rapid reconstitution.
The most defensible infringement targets for enforcement are end-state formulation particle size and excipient architecture, supported by dry-to-liquid preparation and ≤1 minute mechanical agitation dependent pathways.
Any freedom-to-operate work should focus on whether an accused product’s dantrolene dispersion meets < about 2 microns average diameter and whether it uses a water-soluble polysorbate + sorbitol/manitol framework, including “consists essentially of” boundary sensitivity.

FAQs

What dantrolene particle-size measurement standard is implicated by “less than about 2 microns average diameter”?
If a product uses polysorbate but changes polyol to another excipient, does US 8,685,460 still read?
Does the dry formulation particle-size requirement create additional compliance burden beyond the final liquid?
How do the “≤5 mL” and “250–300 mg” limitations affect real-world dosing and infringement exposure?
What is the difference in FTO risk between meeting claim 1 versus meeting only preparation-dependent claims (15–20)?

References (APA)

User-provided claim text for US Drug Patent 8,685,460.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2004262507	⤷ Start Trial
Canada	2516667	⤷ Start Trial
European Patent Office	1435781	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 8,685,460