United States Patent 6,864,258: Ranolazine Sustained-Release Dosing to Hold Plasma Exposure for 24 Hours

US Drug Patent 6,864,258 is a method patent that claims a sustained-release ranolazine dosing regimen for specific cardiovascular indications, with quantified plasma concentration windows over 24 hours, using limited tablet counts per dose and an optional pH-dependent binder system to modulate release in the stomach versus higher pH environments.

What does US 6,864,258 claim at the core?

Claim 1: method and exposure framework

Claim 1 defines the boundary conditions for infringement and is the backbone for all dependent claims. It requires:

Patient/indication: human suffering from cardiovascular disease selected from:
- arrhythmias
- variant and exercise-induced angina
- myocardial infarction
Dosage form type: sustained release pharmaceutical dosage form
Active load: at least 50% by weight ranolazine
Tablet constraint: no more than two tablets per dose
Dosing frequency (over 24 hours): once, twice, or three times
Exposure requirement: maintain ranolazine plasma levels of:
- from about 550 to about 7500 ng base/mL
Duration of maintenance: for at least 24 hours

This claim is fundamentally an exposure- and regimen-driven method claim tied to a specific formulation architecture (high ranolazine wt% in a sustained-release system) and controlled administration (tablet count and dosing frequency).

Claim 2-3: pH-dependent release-control layer

Claim 2 adds a formulation feature that changes the release behavior in simulated GI conditions:

Sustained release dosage form includes at least one pH-dependent binder
Binder behavior:
- in stomach pH aqueous environment: inhibits ranolazine release
- in aqueous solution pH above about 4.5: promotes release of a therapeutic amount
Claim 3 tightens it:
- pH-dependent binder is partially neutralized

Claim 4-5: dosing frequency and tablet packaging details

Claim 4: dosing frequency narrowed to once or twice over 24 hours
Claim 5: dosing structure is two doses in 24 hours, where each dose consists of two tablets
- This effectively implements the “no more than two tablets per dose” limitation in a specific schedule.

Claim 6-7: ranolazine wt% brackets

Claim 6: ~50% to ~95% by weight ranolazine
Claim 7: narrower: ~70% to ~80% by weight ranolazine

Claim 8-12: pH-dependent binder genus and exemplars

Claim 8: pH-dependent binder selected from:
- methacrylic acid copolymers
- hydroxypropyl cellulose phthalate
- hydroxypropyl methylcellulose phthalate
- cellulose acetate phthalate
- polyvinyl acetate
- phthalate
- polyvinylpyrrolidine phthalate
- mixtures
Claim 9: binder is a methacrylic acid copolymer
Claims 10-12:
- methacrylic acid copolymer Type C USP
- binder amount ~5 to ~12 wt% of Type C USP
- and a specific narrower example ~10 wt%

Claim 13-17: optional pH-independent binder

Claim 13: dosage form includes a pH-independent binder
Claim 14: binder selected from:
- hydroxypropyl methylcellulose
- hydroxypropyl cellulose
- poly(meth)acrylate esters
- polyvinylpyrrolidone
- mixtures
Claims 15-17:
- pH-independent binder = hydroxypropyl methylcellulose
- wt% ~1 to ~3%
- specific example ~2%

Claims 18-24: multiple plasma exposure windows

The patent escalates enforceability by carving the broad Claim 1 range into many narrower windows:

Claim 18: 1000-5000 ng base/mL
Claim 19: 1000-3800
Claim 20: 550-5000
Claim 21: 550-3800
Claim 22: 1000-2800
Claim 23: 1700-3900
Claim 24: 550-2000

Claims 25-27: dosage mass ranges

Specific ranolazine mg ranges appear as further dependent limits:

Claim 25: 650-850 mg
Claim 26: 900-1100 mg
Claim 27: 400-600 mg

These mg-range claims connect back to the “no more than two tablets per dose” framework. Under practice, this usually means each tablet (or per-dose total) is engineered to fall within these mass constraints while still meeting the plasma exposure requirements.

Claims 28-30: peak-to-trough control

The final dependent constraints require smoother exposure (lower fluctuation):

Claim 28: peak-to-trough ratio < 4:1 over 24 hours
Claim 29: peak-to-trough ratio < 3:1
Claim 30: peak-to-trough ratio < 2:1

These are dosing-performance targets, not merely formulation features. That can matter in litigation because they require evidence from PK/clinical data or validated bioanalytical runs.

How is claim scope structured for enforceability?

1) Claim 1 establishes a method “operating envelope”

US 6,864,258 is not a pure compound/formulation composition claim. It is a method-of-treatment claim that ties infringement to:

selection of cardiovascular indication
administration of sustained-release ranolazine
meeting formulation loading (>=50% ranolazine by weight)
obeying tablet count per dose (<=2)
obeying dosing frequency (1-3 times/24 hours)
achieving a plasma concentration window for at least 24 hours

This structure creates multiple independent “gates” for an accused product or regimen. A design-around can fail if it misses any gate, including the PK window or tablet dosing mechanics.

2) Claim 2 creates a GI pH-release mechanism hook

Claim 2 adds a functional constraint on how ranolazine is released:

inhibited in stomach pH
released in pH >4.5

That is a strong evidentiary position because it supports mechanistic differences between products that otherwise might meet plasma windows. It also narrows the formulation space to known enteric or pH-dependent polymer systems (phthalates and methacrylic acid copolymers are central).

3) Dependent claims build “knockout” sub-ranges

The dependent plasma windows (Claims 18-24) and PK fluctuation (Claims 28-30) create many enforcement footholds. Even if an accused regimen misses one plasma window, it may still land inside another narrower dependent window if its PK profile overlaps.

4) Polymer identity and loading narrow the formulation

Claims 8-12 and 10-12 restrict the pH-dependent binder identity (methacrylic acid copolymer Type C USP) and loading (5-12 wt%, example 10 wt%). If a competitor uses a different pH-dependent binder class or different loading, it can fall outside those dependent claims, though Claim 2 may still be broader depending on binder choice.

What elements are the key “litigation handles”?

A. Patient population limitation

The cardiovascular disease set is explicitly:

arrhythmias
variant/exercise-induced angina
myocardial infarction

A regimen outside those categories risks non-infringement as to method claims. The patent is framed for physician-directed treatment of those conditions.

B. Dosing logistics

No more than two tablets per dose (Claim 1)
frequency selections: once/twice/three times per 24 hours (Claim 1)
specific packaging: two doses over 24 hours with each dose consisting of two tablets (Claim 5)

These features matter because sustained-release products can meet plasma targets in PK studies while still using different tablet counts or dosing schedules.

C. Plasma exposure targets

The claims specify both:

absolute concentration ranges in ng base/mL
duration: at least 24 hours
optional smoothness: peak-to-trough ratio thresholds (<4:1, <3:1, <2:1)

This creates a technical litigation focus on the accused product’s observed PK profile.

What does the pH-dependent binder language cover in practice?

Claim 2 covers any pH-dependent binder system meeting the functional behavior:

stomach pH aqueous environment: inhibits release
pH above ~4.5: promotes release of a therapeutic amount

Claim 8 then lists specific binder chemistries, and Claims 9-12 lock to methacrylic acid copolymer Type C USP at 5-12 wt% (example ~10 wt%).

Polymer portfolio captured by the patent language (from Claims 8 and 14):

Role	Binder types explicitly named	Key claim hooks
pH-dependent binder	methacrylic acid copolymers; hydroxypropyl cellulose phthalate; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; polyvinyl acetate; phthalate; polyvinylpyrrolidine phthalate	inhibits in stomach pH; releases in pH >4.5 (Claim 2)
methacrylic acid exemplar	methacrylic acid copolymer Type C USP	binder identity + wt% (Claims 9-12)
optional pH-independent binder	hydroxypropyl methylcellulose; hydroxypropyl cellulose; poly(meth)acrylate esters; polyvinylpyrrolidone	inert release component; HPMC range 1-3 wt% with example 2 wt% (Claims 13-17)

Patent landscape implications for ranolazine sustained-release methods

1) The claim set is designed to cover both “mechanism-based” and “PK-based” designs

Mechanism-based: pH-dependent binder presence and behavior (Claim 2)
PK-based: multiple concentration windows and peak-to-trough thresholds (Claims 18-24, 28-30)
Dose-form based: high ranolazine wt%, sustained-release, and specific mg/triangle constraints (Claims 6-7, 25-27)

As a result, US 6,864,258 is positioned to remain relevant even if an alternative formulation uses a different polymer system, so long as it can still achieve the claimed plasma exposure under the claimed dosing regimen. Conversely, a formulation could match general sustained-release behavior but avoid infringement by falling outside the PK windows or peak-to-trough ratio limits.

2) “Narrow dependent windows” increase probability of overlap

The patent does not rely on a single PK window. It lays down overlapping sub-ranges:

550-7500 (broad)
550-5000, 550-3800, 550-2000 (narrower)
1000-5000, 1000-3800, 1000-2800 (narrower)
1700-3900 (narrower)
plus additional performance criterion: Cmax/Cmin style ratios (<4:1, <3:1, <2:1)

This pattern means an accused regimen’s PK profile can unintentionally overlap with at least one dependent window even if it is deliberately optimized for another range.

3) The tablet-count limitation can be a practical design-around

Many sustained-release products dose using a specific number of tablets per administration. Here the patent is explicit:

<=2 tablets per dose (Claim 1)
Claim 5 further locks a common schedule: two doses, each two tablets

A competitor using 3+ tablets per dosing interval can potentially avoid the independent claim scope on that basis, even if it matches exposure.

4) High ranolazine wt% is a formulation constraint with strategic consequences

Claim 6 and Claim 7 require:

ranolazine content ~50-95 wt%
narrower: ~70-80 wt%

That is not typical of many generic oral sustained-release systems, which often use lower API load with extensive excipients. It is a significant formulation design point: to meet the patent, the dosage form must carry ranolazine at a very high mass fraction.

Operational claim map: what must be true for infringement of each claim tier

Independent claim

Claim 1 requires the full set:
- indication in the listed cardiovascular categories
- sustained-release dosage form
- >=50 wt% ranolazine
- <=2 tablets per dose
- dosing frequency 1-3x/24h
- plasma 550-7500 ng base/mL for >=24 hours

Second-tier formulation-dependent

Claim 2 additionally requires:
- pH-dependent binder inhibiting release in stomach pH and promoting release in pH >4.5
Claim 3 further requires:
- pH-dependent binder partially neutralized

Performance and composition refinements

Plasma window refinements (Claims 18-24) require the observed plasma levels fall inside specified ranges.
Polymer identity/loading refinements (Claims 8-12) require those exact polymer selections and wt% (for the dependent versions).
Tablet schedule refinements (Claim 4-5) require exact dosing frequency and tablet counts.
Dose mass constraints (Claims 25-27) require specific mg ranolazine per dosage form tied to the defined tablet schedule.
Peak-to-trough ratio refinements (Claims 28-30) require observed fluctuation limits over 24 hours.

Key Takeaways

US 6,864,258 is a dosing-and-exposure method patent: infringement turns on indication, sustained-release ranolazine dosing mechanics, and measured plasma concentration windows for at least 24 hours.
Scope is multi-gated: to fall within Claim 1, a product must satisfy the >=50 wt% formulation requirement, <=2 tablets per dose, dosing frequency (1-3x/24h), and 550-7500 ng base/mL sustained plasma levels.
Claim 2 adds a GI release mechanism: pH-dependent binder must inhibit release in stomach pH and promote release at pH >4.5, with further tightening by partial neutralization in Claim 3.
The dependent claims multiply enforcement points through numerous overlapping plasma ranges (Claims 18-24) and peak-to-trough ratio thresholds (Claims 28-30), plus specific polymer identities (methacrylic acid copolymer Type C USP) and wt%.
Practical design-arounds are suggested by the claim structure: adjust tablet count per dose, place plasma exposure outside listed windows, or use formulation/excipient systems outside the dependent binder identities or loading constraints.

FAQs

Does US 6,864,258 protect the ranolazine molecule or only a dosing method?
It protects a method of treating with sustained-release ranolazine defined by formulation loading, dosing regimen, and plasma exposure.
What is the broadest plasma range in Claim 1?
About 550 to about 7500 ng base/mL maintained for at least 24 hours.
What does the patent require regarding tablets per dose?
No more than two tablets per dose in Claim 1, with a specific two-dose/two-tablet schedule in Claim 5.
Which pH-dependent binders are explicitly listed?
Methacrylic acid copolymers, hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate, phthalate, polyvinylpyrrolidine phthalate, or mixtures (Claim 8), with methacrylic acid copolymer Type C USP in Claims 9-12.
How does the patent constrain peak-to-trough variability?
It requires peak-to-trough plasma ranolazine levels less than 4:1, 3:1, or 2:1 over 24 hours depending on the dependent claim (Claims 28-30).

References

[1] United States Patent No. 6,864,258. Claims 1-30.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1109558	⤷ Start Trial	PA2008017	Lithuania	⤷ Start Trial
European Patent Office	1109558	⤷ Start Trial	CA 2008 00051	Denmark	⤷ Start Trial
European Patent Office	1109558	⤷ Start Trial	91504	Luxembourg	⤷ Start Trial
European Patent Office	1109558	⤷ Start Trial	PA2008017,C1109558	Lithuania	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,864,258

Summary for Patent: 6,864,258