United States Patent 9,326,945 (Apixaban Crystalline Particle Size + USP Dissolution Limits): Scope, Claim Map, and US Patent Landscape
What patents protect apixaban crystalline particles with D90 ≤ 89 μm and ≥77 wt% dissolution in 30 minutes at pH 6.8/0.05% SLS?
USP 9,326,945 is a formulation and particle-specification patent for solid oral apixaban compositions that combine:
- Crystalline apixaban particles
- Particle size constraint: D90 ≤ ~89 μm (with dependent claims narrowing to ≤85, ≤50, ≤30, ≤25 μm)
- Dissolution performance constraint: ≥77 wt% dissolved in 30 minutes in pH 6.8 phosphate buffer with 0.05% sodium lauryl sulfate (SLS) (and in claim 12, explicitly defined USP Apparatus 2 conditions)
- Optional but claimed excipient package: 1–2 wt% surfactant, specifically SLS
- Optional physical dosage form: tablet or capsule
- Optional polymorph/solid form: Form N-1 of apixaban
- Optional dosage strength: 2.5 mg and/or 5 mg apixaban
Independent claim 1: what it legally requires
Claim 1 defines infringement by satisfying all elements simultaneously:
- A solid pharmaceutical composition
- Contains therapeutically effective amount of crystalline apixaban particles
- D90 ≤ about 89 μm
- Uses pharmaceutically acceptable diluent/carrier
- Dissolution test requirement: at least 77 wt% dissolves within 30 minutes in the specified pH 6.8 phosphate buffer containing 0.05% sodium lauryl sulfate
This is a product-by-parameter scope: it does not require a particular manufacturing method in the claim, but it does require the measured particle size and dissolution outcomes under defined conditions.
Dependent claims 2–6: narrowing the particle size envelope
- Claim 2 ties the composition to apixaban Form N-1
- Claims 3–6 add progressively tighter D90 caps:
- ≤85 μm
- ≤50 μm
- ≤30 μm
- ≤25 μm
These create a ladder of narrower claim sets. Practically, the broadest quantitative requirement is D90 ≤ ~89 μm.
Dependent claims 7–8: surfactant content
- Claims 7–8 require 1–2 wt% surfactant, and optionally specify sodium lauryl sulfate.
This is significant because generic developers sometimes match dissolution by using different wetting agents or different SLS levels. Claim 7 forces a defined band if you want to stay within the dependent claim scope.
Dependent claims 9–12: dosage strength and explicit dissolution apparatus (claim 12)
- Claims 9–11 specify 2.5 mg and/or 5 mg apixaban strength embodiments.
- Claim 12 repeats the core structure but tightens the testing conditions:
- USP Apparatus 2
- paddle rotation speed 75 rpm
- 900 mL dissolution medium
- 37° C.
- dissolution medium: 0.05 M sodium phosphate at pH 6.8 with 0.05% SLS
- dissolution criterion: ≥77 wt% in 30 minutes
Claim 12 therefore reduces ambiguity in how dissolution is measured and makes testing/quality-control central to enforceability.
Claims 23–38: dosage form and strength permutations
The tablet/capsule language is straightforward:
- Claims 23 and 24: tablet and capsule for claim 1
- Claims 25–32: tablet/capsule mapped onto the 2.5 mg and/or Form N-1 and D90-dependent dependent structures
- Claims 33–38: further mapping by 2.5 mg/5 mg strength and capsule/tablet
Practical claim structure summary (what you would need to design around)
A product would avoid claim coverage only by breaking at least one of the required parameters:
- Raise D90 above the claimed cap (e.g., >89 μm, or above a narrower dependent cap if you’re evaluating a specific theory)
- Fail the dissolution requirement under the claimed conditions (or under whatever dissolution test applies in the court’s infringement analysis)
- Use apixaban solid form not meeting “Form N-1” if relying on dependent claim 2/13
- If targeting to fall outside dependent claim 7, use SLS outside 1–2 wt% or use a different surfactant package if the claim requires the surfactant as part of the dependent structure
- Avoid specific strength language if you are only practicing outside those embodiments (but note: claim 1 is not limited by strength unless the strength is added as a limitation in dependent claims)
How broad is USP 9,326,945 compared with typical apixaban generic formulation patents?
Answer: it is medium-to-narrow on chemistry, broad on performance envelope, and narrower on manufacturing methods.
Why it is narrow compared with “any apixaban” patents
The claims require:
- Crystalline apixaban particles (not amorphous/other state)
- Specific particle size metric (D90)
- Specific dissolution environment (pH 6.8 phosphate buffer + 0.05% SLS)
- Minimum dissolution (≥77% within 30 min)
That makes the patent difficult to read on products whose dissolution performance is achieved through different formulations, surfactant systems, or different particle-size distributions.
Why it is still meaningfully broad for generic development
Even without a method claim, generic developers often try to hit dissolution by tuning:
- milling/grinding and sieving distribution
- crystallinity and polymorph control
- wetting agent and excipient blends
Because the patent uses measurable endpoints (D90 and dissolution %), it can capture a large class of particle-engineered solids, as long as they satisfy the specified endpoints.
Key infringement sensitivity: D90 and dissolution testing protocol
Because the claims specify:
- D90 thresholds
- dissolution medium composition
- and in claim 12, USP Apparatus 2 conditions
the infringement analysis can hinge on lab testing comparability. A generic product with near-threshold D90 values may face higher enforcement risk.
How do D90 limits (≤89 μm, ≤85 μm, ≤50 μm, ≤30 μm, ≤25 μm) affect design-around strategy?
Answer: the more you tighten the D90 requirement, the less likely generic particle engineering is to remain outside the claim set.
Design-around levers
-
Increase D90 above the broad cap
- Claim 1 uses D90 ≤ about 89 μm
- If a product’s D90 consistently exceeds 89 μm, it likely misses claim 1 on particle size.
-
Target only “far” above thresholds
- If you are trying to avoid both claim 1 and dependent claims 3–6, you would need to ensure D90 is above each threshold relevant to the asserted claim theory.
-
Keep D90 within range but change dissolution behavior
- If D90 is within the range but dissolution drops below 77 wt% in 30 minutes in the exact dissolution medium, the product can avoid the dissolution limitation.
- This is a riskier strategy because dissolution is often the endpoint generics optimize to match branded performance.
Measurement risk
- D90 depends on PSD measurement method and sample prep; if a generic uses a PSD method that yields different D90, it may impact outcomes. Claim 12’s USP dissolution apparatus specification reduces ambiguity on dissolution, but D90 methodology can still be a litigation battleground.
What is the role of apixaban Form N-1 in USP 9,326,945?
Answer: Form N-1 is a dependent limitation in claims 2 and 13, meaning it narrows scope but creates a second infringement pathway when Form identity is present.
- Claim 2: claim 1 + “composition comprises Form N-1”
- Claim 13: claim 12 + “Form N-1”
- All other claims (1 and the D90/dissolution constructs) can be infringed without proving Form N-1 if the product meets the crystalline particle and endpoint requirements.
Strategic implication: if a generic developer proves its solid form is not Form N-1 but still meets D90 and dissolution, it may still fall under claim 1/12 depending on crystalline characterization standards.
What does USP Apparatus 2 (75 rpm, 900 mL, 37° C.) change in claim 12?
Answer: claim 12 hardens the dissolution test conditions and reduces “different lab, different outcome” arguments.
Claim 12 specifies:
- USP Apparatus 2
- paddle rotation speed: 75 rpm
- volume: 900 mL
- temperature: 37° C.
- medium: 0.05 M sodium phosphate at pH 6.8 + 0.05% SLS
- dissolution metric: ≥77 wt% in 30 min
Because the claim is anchored to a specific apparatus configuration and operating parameters, infringement analysis is more likely to focus on whether the accused product reproducibly meets the threshold under that exact protocol.
What patent landscape issues matter in the US for apixaban composition patents?
Answer: USP 9,326,945 fits into a typical cluster: solid form and particle engineering patents, followed by formulation and dissolution performance patents, followed by method/process and combination-life-cycle patents.
Where USP 9,326,945 likely sits in the apixaban portfolio logic
Based on claim content alone, it is aligned with:
- Crystalline/specific solid form engagement (Form N-1 dependent)
- Particle size engineering (D90-limited)
- Dissolution and wetting performance (SLS and dissolution endpoint)
- Oral dosage form embodiment (tablet/capsule)
- Strength-specific embodiments (2.5 mg and 5 mg)
This kind of patent is commonly asserted against generics that attempt to match:
- the branded product’s dissolution profile
- Cmax/AUC exposure targets (via dissolution and wetting)
- tablet/capsule drug delivery performance
Typical adjacent claim families (likely in the same enforcement ecosystem)
While the full US patent family chart cannot be produced from the claim text alone, the following adjacent patent categories are directly relevant because they target the same infringement levers as USP 9,326,945:
- Apixaban solid form/polymorph patents (including Form N-1 or related designations)
- Particle engineering patents (milling, particle size distributions, PSD metrics beyond D90)
- Dissolution endpoint/formulation patents (wetting agents, surfactant levels, dissolution media conditions)
- Manufacturing process patents that create PSD and crystalline state
- Combination patents only if the accused product is in a fixed-dose regimen (not indicated here)
How many patents cover D90-constrained apixaban dissolution performance in the US?
Answer: you cannot determine the count from the claim text alone. A complete count requires Orange Book and prosecution-to-grant mapping across the US patent families tied to the specific NDA and the specific apixaban reference product listing.
What is the Orange Book status of USP 9,326,945?
Answer: cannot be determined from the claim text alone. Orange Book status requires the NDA/BLA listing and patent-registration linkage.
When does USP 9,326,945 lose exclusivity?
Answer: cannot be determined from the claim text alone. Expiration depends on:
- filing date
- nonprovisional priority
- term adjustments
- any terminal disclaimers
- maintenance status
- whether it is part of a patent term extension or tied to exclusivity windows
What generic entry risks exist for apixaban tablets/capsules using D90-tuned crystalline particles?
Answer: high risk if the generic can meet both D90 and the dissolution endpoint in the specified medium, regardless of solid form unless Form N-1 is explicitly excluded.
Risk triggers in USP 9,326,945
- Generic formulation hits D90 ≤ 89 μm
- Generic formulation hits ≥77 wt% dissolution at 30 min in pH 6.8 phosphate + 0.05% SLS
- If solid form is Form N-1, risk increases due to dependent claims
Risk reduction triggers
- D90 is consistently above the relevant cap(s)
- Dissolution is below 77% under the claim’s dissolution protocol
- Solid form is proven not to satisfy “Form N-1” and infringement is asserted only under the Form-dependent dependent claims (less likely if claim 1 is asserted broadly)
How does USP 9,326,945 compare with other apixaban formulation patents?
Answer: it is specifically performance-bound to a particle size distribution and a defined dissolution endpoint.
Compared with broader formulation patents, USP 9,326,945:
- is more specific because it uses D90 and a time-limited dissolution threshold
- can be harder to design around if the generic targets dissolution matching, because those targets often imply smaller particle sizes and stronger wetting
Compared with solid-form-only patents, USP 9,326,945:
- is less about crystal identity and more about how the solid behaves in dissolution tests
What litigation and Paragraph IV strategy does USP 9,326,945 imply?
Answer: USP 9,326,945 supports a “test-and-compare” infringement strategy centered on PSD and dissolution outcomes.
Key enforcement angles:
- PSD evidence: D90 measurement of the accused apixaban crystalline particles
- Dissolution evidence: dissolution in the exact media and, for claim 12, using USP Apparatus 2 at 75 rpm in 900 mL at 37° C.
- Role of Form N-1: if asserted under dependent claims 2/13, add solid-state characterization evidence
What formulations are protected by the claims (tablet vs capsule, 2.5 mg vs 5 mg)?
Protected embodiments include:
- Tablets and capsules
- Strengths: 2.5 mg and 5 mg as explicitly called out in dependent claims
- Any pharmaceutically acceptable diluent/carrier, subject to meeting:
- crystalline apixaban particles
- D90 limit(s)
- dissolution endpoint(s)
- optional surfactant content (for dependent claim coverage)
Key Takeaways
- USP 9,326,945 is a performance-anchored formulation patent for solid oral crystalline apixaban defined by D90 particle size limits and a quantified dissolution threshold in pH 6.8 phosphate buffer with 0.05% SLS.
- Core scope (claim 1) requires D90 ≤ ~89 μm and ≥77 wt% dissolution in 30 minutes in the specified medium.
- Dependent claims narrow to tighter PSD caps (≤85, ≤50, ≤30, ≤25 μm), specific solid form (Form N-1), optional surfactant content (1–2 wt% SLS), and dosage embodiments (tablet/capsule, including 2.5 mg and 5 mg).
- Design-around risk concentrates on two measurable parameters: D90 and dissolution performance under the claim’s test conditions; claim 12 hardens dissolution testing via USP Apparatus 2 (75 rpm, 900 mL, 37° C.).
- A complete US landscape (counts of related patents, Orange Book status, and expiration) cannot be derived from claim text alone and therefore is not provided here.
FAQs
1) Does USP 9,326,945 require Form N-1 to infringe?
No. Form N-1 appears in dependent claims (2 and 13). Claim 1 does not require Form N-1 if the D90 and dissolution elements are met.
2) Is the dissolution requirement satisfied if the product matches dissolution in other buffers or without SLS?
No. The claims specify pH 6.8 phosphate buffer with 0.05% sodium lauryl sulfate, and claim 12 specifies USP Apparatus 2 conditions.
3) If a generic exceeds 89 μm D90 but meets dissolution, does it avoid claim 1?
Yes, because claim 1 requires D90 ≤ about 89 μm as an element.
4) Are both tablets and capsules covered?
Yes. Dependent claims expressly cover tablet and capsule embodiments.
5) What matters most for litigation or licensing on this patent?
The measurable evidence: D90 PSD results and dissolution results in the claim-defined medium and (for claim 12) USP Apparatus 2 conditions.
References
- USP 9,326,945 claim text provided in the prompt.
