United States Patent 9,757,362 (Tacrolimus + HPMC/Lactose/PEG 6000/Poloxamer 188): Claim Scope, Formulation Boundaries, and US Patent Landscape
United States Patent 9,757,362 is a US composition-of-matter patent focused on a solid oral tacrolimus formulation defined by a specific excipient set and targeted in vitro dissolution-release limits in defined media and apparatus. The patent’s enforceable value is concentrated in (i) the excipient composition (HPMC + lactose + PEG 6000 + poloxamer 188 + magnesium stearate) and (ii) dissolution performance thresholds (early release capped at specific timepoints; maximum total release capped over long time; and PEG:poloxamer ratio band). Because the claim language is tied to USP Paddle dissolution conditions (media composition, pH, volume, paddle speed), infringement for many designs turns on whether the accused formulation reproduces the same release curve under the same test setup, not merely on general “sustained” behavior.
What does US Patent 9,757,362 claim about tacrolimus solid compositions?
How broad is claim 1: excipient-defined composition for tacrolimus tablets/solids
Claim 1 recites a solid pharmaceutical composition comprising:
- tacrolimus
- hydroxypropyl methylcellulose (HPMC)
- lactose
- polyethylene glycol 6000 (PEG 6000)
- poloxamer 188
- magnesium stearate
From an infringement standpoint, claim 1 reads like a closed excipient list because it says the composition comprises these components. Under US practice, “comprising” typically permits additional ingredients, but the requirement that these six components are present at least in the composition creates a meaningful formulation boundary.
Practical scope implications
- A generic “tacrolimus + HPMC + lubricant + typical fillers” product is not automatically within claim 1 unless it also includes PEG 6000 and poloxamer 188 together and includes lactose and magnesium stearate in the claimed composition.
- The “solid pharmaceutical composition” is not limited to tablets in claim 1, but later dependent claims specify tablet.
What dissolution-performance limits tighten claim 2 and claim 3
Claim 2 adds a dissolution test requirement:
- < 20% w/w tacrolimus released within 0.5 hours
- USP Paddle method
- dissolution medium: 0.1 N HCl
Claim 3 similarly adds:
- < 20% w/w tacrolimus released within 3 hours
- same USP Paddle + 0.1 N HCl conditions
These limitations are performance-based and test-condition-bound. Even if a formulation contains all the excipients, it may fall outside the claims if it releases more than 20% at the specified early timepoints.
What excipient ratio limitation appears in claim 4
Claim 4 requires:
- weight ratio of PEG 6000 to poloxamer 188 between 1:3 and 10:1
This is a key enforceability lever. Many sustained-release oral formulations employ PEGs or poloxamers, but not necessarily within a specific PEG:poloxamer band.
Where tablet limitations enter via claims 5, 7, and 8
Claims 5 and 7:
- “dosage form is a tablet”
Claim 8 depends from claim 3 and adds tablet status. These dependent claim limitations matter for design-around: a formulation that is not a tablet (for example, another solid oral dosage form) could avoid those specific dependent claims. However, claim 1 still covers “solid pharmaceutical composition” generally.
What long-window release ceiling appears in claim 6
Claim 6 adds a second dissolution constraint in different conditions:
- At most 62% tacrolimus released within 15 hours
- USP Paddle method at 50 rpm
- dissolution medium: 900 mL aqueous dissolution medium with 0.005% hydroxypropylcellulose adjusted to pH 4.5
This is a separate constraint from the 0.1 N HCl tests in claims 2 and 3. To avoid infringement, an accused product must generally fail at least one of these claimed release limits (or fail one of the excipient/range limitations).
Does US 9,757,362 function like a “composition” or a “performance” patent?
Claim structure is hybrid: composition-of-matter with testable functional boundaries
- Claim 1 is a composition definition by excipient identity.
- Claims 2, 3, and 6 introduce functional limits expressed in dissolution release percentages under defined test conditions.
- Claim 4 introduces an excipient ratio range.
- Claims 5, 7, and 8 add dosage form limitation (tablet).
In practice, enforcement typically depends on a formulation + release profile match under specified dissolution methods. This means the patent’s scope is not just “contains these excipients,” but “contains these excipients and releases tacrolimus within these quantified bounds under these conditions.”
What parts of the claim language are most likely to drive infringement analysis?
1) Presence of both PEG 6000 and poloxamer 188
The excipient set requires both PEG 6000 and poloxamer 188. Swapping PEG 6000 for another PEG (or replacing poloxamer 188 with another poloxamer) can be an obvious design-around, because claim 4 is not just “a PEG,” it is PEG 6000 by name.
2) PEG:poloxamer ratio range (1:3 to 10:1)
Claim 4 provides an explicit band. If an accused formulation falls outside the ratio band, it can avoid claim 4, but not necessarily independent claim 1 or dependent claim 5/7/8 unless those other dependent limitations are asserted.
3) Early release caps in 0.1 N HCl
Claims 2 and 3 control the early-release curve:
- <20% in 0.5 hours
- <20% in 3 hours
in USP Paddle using 0.1 N HCl.
A product could satisfy excipient identity but still fall outside due to release kinetics.
4) Long time release ceiling at pH 4.5 and 50 rpm
Claim 6 adds:
- ≤62% released in 15 hours
under:
- USP Paddle
- 50 rpm
- 900 mL aqueous medium
- 0.005% hydroxypropylcellulose
- pH 4.5
This is a detailed condition set. The enforceable comparison point becomes the accused product’s dissolution profile under the same method.
5) Tablet limitation (dependent claims)
If the accused product is not a tablet, dependent claims 5, 7, and 8 can be harder to assert. But claim 1 may still be in play because it covers “solid pharmaceutical composition.”
What design-arounds are suggested directly by the claim boundaries?
Excipients
- Remove or replace PEG 6000 (or replace with a non-PEG 6000 excipient) so the formulation no longer includes “polyethylene glycol 6000.”
- Remove or replace poloxamer 188 with a different surfactant/poloxamer so claim 1’s required component is missing.
Ratio
- Set PEG 6000:poloxamer 188 outside 1:3 to 10:1 to avoid claim 4 (though still possibly within claim 1).
Dissolution profile
- Tune release so that tacrolimus exceeds the early caps in 0.1 N HCl or exceeds the 15-hour maximum at pH 4.5 conditions, thereby avoiding claims 2/3/6.
Dosage form
- Use a non-tablet solid dosage form to avoid tablet-dependent claims while leaving claim 1 exposure.
How many different claim “hook points” does 9,757,362 create?
Across the eight claims provided, there are multiple distinct hook points:
- Six-excipient composition (claim 1)
- Early-release threshold at 0.5 hours in 0.1 N HCl (claim 2)
- Early-release threshold at 3 hours in 0.1 N HCl (claim 3)
- PEG:poloxamer ratio band (claim 4)
- Tablet dosage form (claim 5)
- Long-window maximum release (claim 6)
- Tablet dosage form repeated as dependent (claim 7)
- Combination of claim 3 + tablet (claim 8)
A design that breaks any one of these hook points can avoid some dependent claims, but independent claim 1 remains a core risk if the six excipients are all present.
How does this formulation patent typically intersect with tacrolimus drug product IP?
Key context: tacrolimus is widely protected across formulation, method-of-use, and process patents
Tacrolimus oral products and related generics often carry layered IP:
- formulation patents (matrix systems, solubilizers, release modifiers)
- process patents (granulation, blending, compression, drying, coating)
- bioavailability and dissolution-related claims
- sometimes method-of-use claims (less common for generic entries but can exist)
Within that landscape, 9,757,362 sits specifically at the dissolution-governed solid formulation layer for US.
Most likely adjacent patent families
Based on the excipient chemistry in the claims (HPMC + lactose + PEG 6000 + poloxamer 188 + magnesium stearate) and typical tacrolimus oral product strategies, adjacent likely subject matter in the same or related families often includes:
- variations in HPMC grade/level
- use of different dissolution control polymers (hydroxypropylcellulose, HPMC variants)
- excipient system optimization (PEGs, surfactants/poloxamers, lubricants)
- release specification tied to USP Paddle or similar methods
This patent is likely asserted or evaluated as part of a portfolio where multiple members cover different excipient permutations or dissolution windows.
What is the US patent landscape risk for generic or ANDA entry against a dissolution-constrained tacrolimus formulation patent?
Paragraph IV risk is concentrated on formulation similarity
For an ANDA filer seeking tacrolimus tablets, risk concentrates on:
- whether the ANDA product’s excipient composition includes the claimed combination (PEG 6000 and poloxamer 188 together with lactose, HPMC, magnesium stearate)
- whether its dissolution profile under USP Paddle and specified media/reagents aligns with the claim ceilings
If an ANDA formulation is engineered for different release behavior (or uses different excipients), it can often avoid these functional claims.
“Comparable dissolution” is not enough
Because the claims specify detailed dissolution conditions:
- 0.1 N HCl (for claims 2 and 3)
- pH 4.5 aqueous medium with 0.005% hydroxypropylcellulose at 50 rpm (for claim 6)
An ANDA filer can target differences in the dissolution test outcome under these settings. Generic equivalence in other media or other apparatus can still leave a claims gap.
Licensing vs litigation
Where a formulation patent is narrowly excipient-defined and dissolution-capped, settlements often turn on:
- whether the generic product chooses an alternative excipient system
- whether a carve-out or supply agreement is reached to keep the ANDA off the market during the patent term
How does the claim scope compare to typical tacrolimus “extended release” architectures?
This patent is not just “extended-release tacrolimus”
The claims do not describe a coating thickness, matrix particle size, or specific manufacturing steps. They define:
- an excipient combination
- dissolution release ceilings at specific timepoints and media
- a PEG:poloxamer ratio range
This makes the patent closer to an excipient system plus dissolution specification architecture than to a process-based or mechanical design architecture. As a result, it is vulnerable to design-around by altering excipients or by engineering a different dissolution curve.
Key takeaways for business decisions (licensing, diligence, generic risk)
- Core independent risk is excipient-set presence: a “solid pharmaceutical composition” containing tacrolimus + HPMC + lactose + PEG 6000 + poloxamer 188 + magnesium stearate is the primary claim 1 hook.
- Performance limits are claim chokepoints: <20% release at 0.5 hours and <20% at 3 hours in 0.1 N HCl (claims 2 and 3) and ≤62% release in 15 hours in the specified pH 4.5 aqueous medium at 50 rpm (claim 6).
- Ratio band creates a clear formulation design boundary: PEG 6000:poloxamer 188 must be between 1:3 and 10:1 for claim 4.
- Tablet-dependent claims add form-factor risk only for tablets: claim 5/7/8 require a tablet dosage form, but claim 1 is broader for “solid pharmaceutical composition.”
- Dissolution testing conditions matter: infringement analysis will likely use the same USP Paddle methods, rotation speeds, and media compositions recited in the claims.
FAQs
1) What excipients must be present for infringement of claim 1 of US 9,757,362?
Tacrolimus plus hydroxypropyl methylcellulose, lactose, polyethylene glycol 6000, poloxamer 188, and magnesium stearate.
2) What dissolution test conditions does the patent require for the early-release limitations?
USP Paddle, dissolution medium 0.1 N HCl, with release measured as % w/w tacrolimus at 0.5 hours (claim 2) and 3 hours (claim 3).
3) What PEG to poloxamer ratio is required in claim 4?
Between 1:3 and 10:1 by weight for PEG 6000:poloxamer 188.
4) What is the maximum tacrolimus release allowed at 15 hours under the claim 6 conditions?
At most 62% tacrolimus released within 15 hours under USP Paddle at 50 rpm in 900 mL aqueous medium with 0.005% hydroxypropylcellulose adjusted to pH 4.5.
5) Can a non-tablet solid dosage form avoid claims 5/7/8?
Yes, because those dependent claims explicitly require a tablet dosage form; however, claim 1 still covers a solid pharmaceutical composition generally.
References (APA)
- United States Patent US 9,757,362.
