United States Patent 9,233,077 (US9233077): Scope, Claims, and US Landscape for Delayed-Release Cysteamine Beads
US 9,233,077 is directed to a specific delayed-release cysteamine solid oral dosage form built from enteric-coated beads with tightly bounded bead size distribution, enteric membrane dissolution onset, enteric membrane composition amount, and in vivo exposure targets in fasted, healthy subjects dosed with 600 mg free cysteamine base inside capsules. The independent claim 1 drives scope by combining: (1) bead architecture (cysteamine core + binder + enteric membrane), (2) bead size distribution windows, (3) enteric dissolution kinetics and membrane load, and (4) specific pharmacokinetic acceptance ranges for mean Cmax and mean AUC(0-inf_D).
What is claimed in US 9,233,077?
What does claim 1 require to infringe?
Claim 1 is a multi-parameter apparatus-performance claim for a “pharmaceutical dosage form” containing delayed-release cysteamine beads with defined physical, chemical, and pharmacokinetic attributes. The minimal claim elements, as provided, are:
A. Bead and membrane structure
- “Delayed-release cysteamine beads”
- Beads comprising:
- Core particle: cysteamine (or pharmaceutically acceptable salt) + binder
- Enteric membrane: “an enteric membrane surrounding the core particle”
B. Bead size distribution
- Beads have a particle size distribution in about 0.7 mm to about 2.8 mm.
C. Enteric membrane dissolution onset
- Enteric membrane “begins to dissolve” in pH 4.5 to 6.5.
D. Enteric membrane amount
- Enteric membrane is present in about 25% to about 35% by weight, based on core particle weight.
E. Capsule, fasted dosing, and exposure performance
- Administration in a capsule to fasted healthy normal subjects at 600 mg free cysteamine base
- PK targets (mean):
- Cmax in 2.3 ± 0.6 mg/L, or 80% to 125% of that value
- AUC (0-inf_D) in *0.84 ± 0.19 minmg/L/mg, or 80% to 125%** of that value
This combination means claim 1 is not satisfied by a simple enteric coating and cysteamine core. It requires a particular bead size distribution and particular enteric kinetics plus a bio-performance envelope tied to mean exposure in a defined dosing scenario.
What do the dependent claims narrow?
Dependent claims add granular limitations that tighten the product definition into manufacturable and testable ranges.
Bead size cut points and sieve/mesh distribution (claims 2–12, 16)
- Claim 2: particle size range 0.7 mm to 2.5 mm
- Claim 3: “at least 80% by weight” beads in 850 μm to 1180 μm
- Claims 4 and 16 (mesh retention/pass-through):
- ≤5% retained on #12 mesh (1.68 mm)
- ≤10% pass through #20 mesh (0.84 mm)
- Claim 5: <5% retained on 1400 μm sieve
- Claim 6: <30% retained on 1180 μm sieve
- Claim 7: <70% retained on 1000 μm sieve
- Claim 8: <20% retained on 850 μm sieve
- Claim 9: ≥15% retained on 1180 μm sieve
- Claim 10: ≥50% retained on 1000 μm sieve
- Claim 11: ≥10% retained on 850 μm sieve
- Claim 12: median particle size 850 μm to 1180 μm
These claims convert bead size distribution from a broad range (claim 1) into a numerical sieve profile. A product can fall inside claim 1’s “0.7 to 2.8 mm” but still fail multiple dependent limitations.
Core formulation variations (claims 13–15)
- Claim 13: core particle further comprises a filler
- Claim 14: free-base cysteamine in core at ≥10 wt.%
- Claim 15: cysteamine (or salt) is specifically a pharmaceutically acceptable salt of cysteamine
Enteric dissolution and acid resistance specifications (claims 17–18, 21)
- Claim 17: acid resistance such that not more than 10% of cysteamine dissolved after 2 hours in 0.1N HCl
- Claim 18: dissolution such that 80% cysteamine released within 20 minutes in pH 6.8 buffer
- Claim 21: enteric membrane begins to dissolve at pH about 5.5 in aqueous solution
These limit both gastric robustness and intestinal release readiness. They also sharpen the dissolution onset portion of claim 1.
Capsule configuration and bioequivalence aspects (claims 19–20)
- Claim 19: dosage form further comprises a capsule shell enclosing the plurality of beads
- Claim 20: beads inside a capsule are bioequivalent to beads administered without capsule shell (same fasted PK endpoints as in claim 1)
Claim 20 is a second-layer claim about relative performance with/without capsule shell, indicating the inventor treated capsule presence as either not altering exposures materially or as part of the defined clinical context.
PK target tightening (claims 22–23)
Claim 22 and 23 re-state claim 1’s PK envelopes with specific numeric forms:
- Claim 22: mean Cmax 2.3 ± 0.6 mg/L and mean AUC *0.84 ± 0.19 minmg/L/mg**
- Claim 23: mean Cmax 2.3 mg/L (with 80% to 125% window) and mean AUC *0.84 minmg/L/mg** (with 80% to 125% window)
Practically, these claims reinforce that the product must land inside mean-exposure acceptance criteria for the defined study design.
How broad is the claim scope?
Where is the “core” of infringement risk?
The highest-risk area is claim 1 because it combines structural, size, dissolution onset, coating load, and in vivo exposure. If a competing product misses any one axis, it may avoid claim 1 but could still be caught by narrower dependent claims only if those dependents align and are asserted in combination.
Key scope levers:
-
Bead size distribution is bounded, not open-ended
- Claim 1: 0.7 to 2.8 mm
- Dependents: explicit sieve/mesh and median windows (850 μm to 1180 μm concentration; low fines and high inclusion at 1000 μm class)
-
Enteric dissolution onset is pH-windowed
- Claim 1: begins dissolving pH 4.5 to 6.5
- Claim 21: begins dissolving around pH 5.5
-
Enteric membrane load is fixed as a weight fraction
- Claim 1: 25% to 35% by weight relative to core particle weight
-
PK performance is tied to dosing context and mean exposures
- Capsule, fasted, 600 mg free cysteamine base
- Mean Cmax and mean AUC windows defined
What product design choices may still land inside the claim space?
Within claim logic, many internal formulation choices could remain unclaimed if they do not violate explicit restrictions. For example, fillers are explicitly covered (claim 13), so adding fillers likely does not escape.
However, the dependent claims make it hard to “tune” around the patent using bead engineering alone because:
- multiple sieve retention thresholds constrain fines and larger bead fractions, and
- acid resistance and dissolution profiles constrain enteric behavior beyond pH onset.
Practical claim-to-testing map (what a lab must show)
How do the claims translate into measurable specifications?
Below is a direct mapping from claim language into the likely testing framework:
| Claim element |
Quantitative requirement (from provided claims) |
Typical measurement pathway |
| Bead size distribution |
0.7 mm to 2.8 mm (claim 1) |
sieving/granulometry |
| High concentration size band |
≥80 wt% in 850 μm to 1180 μm (claim 3) |
sieving + weight fraction |
| Fine tail limits |
≤5 wt% on #12 (1.68 mm); ≤10 wt% pass #20 (0.84 mm) (claims 4, 16) |
mesh sieving |
| Upper large fraction |
<5 wt% retained on 1400 μm (claim 5) |
sieve retention |
| Mid-size tail limits |
<30 wt% retained on 1180 μm (claim 6); <70 wt% retained on 1000 μm (claim 7) |
sieve retention |
| Lower tail limits |
<20 wt% retained on 850 μm (claim 8) |
sieve retention |
| Inclusion floors |
≥15 wt% retained on 1180 μm (claim 9); ≥50 wt% retained on 1000 μm (claim 10); ≥10 wt% retained on 850 μm (claim 11) |
sieve retention |
| Median |
850 μm to 1180 μm (claim 12) |
cumulative distribution |
| Acid resistance |
≤10% cysteamine dissolved after 2 hours in 0.1N HCl (claim 17) |
dissolution in gastric simulated fluid |
| Intestinal release |
80% released within 20 minutes at pH 6.8 (claim 18) |
dissolution in buffer |
| Enteric dissolution onset |
begins dissolving in pH 4.5 to 6.5 (claim 1) / ~pH 5.5 (claim 21) |
pH-dependent dissolution onset |
| Enteric membrane load |
25% to 35% by weight relative to core particle weight (claim 1) |
formulation weight accounting |
| PK in defined human study |
Mean Cmax 2.3 ± 0.6 mg/L and mean AUC 0.84 ± 0.19 min*mg/L/mg; 80% to 125% windows (claims 1, 22, 23) |
clinical PK study; compare mean exposures |
Patent landscape in the United States: how US 9,233,077 will be positioned
What is the litigation and freedom-to-operate shape implied by these claims?
US 9,233,077 is not a “method of treatment” claim set. It is a formulation-and-performance claim set that is likely to drive:
- Product-specific infringement analysis anchored to bead engineering and dissolution testing
- Evidence-heavy disputes in which accused products are tested for sieve distributions, enteric dissolution onset, coating load, and human PK outcomes under a defined dosing regime
Because claim 1 includes mean Cmax and AUC acceptance ranges tied to fasted dosing with a specific dose amount, a realistic infringement position often depends on whether the accused product delivers the same exposure envelope in that scenario, not only whether it uses an enteric coating.
How likely are design-arounds to work?
Given the dependencies, design-arounds face a tight funnel:
- Changing bead size distribution must avoid failing multiple sieve thresholds simultaneously.
- Changing enteric polymer type or coating thickness must preserve:
- dissolution onset between the claim pH bounds,
- dissolution amount (coating load 25% to 35% by weight),
- acid resistance (≤10% dissolved at 2 hours in 0.1N HCl), and
- release timing (80% within 20 minutes at pH 6.8).
- Even if dissolution and size are matched, the product still must hit the human mean exposure windows.
In this structure, small manufacturing changes could shift bead size distributions or enteric coating thickness enough to miss a dependent limitation. But the same structure also means enforcement can focus on the specific parameter(s) that are easiest to show are out of range.
Scope analysis by claim clusters
Cluster 1: Bead size control (claims 1–12, 16)
These claims define a narrow bead size profile. The most enforceable boundaries are:
- median 850 μm to 1180 μm (claim 12)
- ≥80% in 850 μm to 1180 μm (claim 3)
- low fines: ≤5% on #12 and ≤10% pass #20 (claims 4, 16)
- explicit fractional inclusion/exclusion by multiple sieve cut points (claims 5–11)
Business impact: If a generic or follow-on attempts to replicate overall particle size but has a different distribution (especially wider tails), it can avoid dependent limitations even while still fitting within claim 1’s broad 0.7 to 2.8 mm.
Cluster 2: Enteric kinetics and loading (claims 1, 17–18, 21)
Key constraints:
- dissolution onset within pH 4.5 to 6.5 (claim 1)
- onset around pH 5.5 (claim 21)
- enteric membrane amount 25% to 35% by weight of core (claim 1)
- acid resistance: ≤10% dissolved after 2 hours in 0.1N HCl (claim 17)
- intestinal release: 80% within 20 minutes at pH 6.8 (claim 18)
Business impact: This cluster is where excipient selection and coating process control matter. It is also the portion most likely to show up in product characterization testing.
Cluster 3: PK performance (claims 1, 20, 22–23)
Core endpoints:
- mean Cmax: 2.3 ± 0.6 mg/L
- mean AUC(0-inf_D): 0.84 ± 0.19 min*mg/L/mg
- acceptance ranges: 80% to 125% in claim 1 and the re-stated bounds in 22–23
- capsule context (claim 1) and bioequivalence with/without capsule shell (claim 20)
Business impact: This cluster can set the ultimate “gate” for infringement. A product can match formulation and dissolution specs but still miss the clinical mean exposure window, or vice versa.
Design-around and product positioning risk checklist
What specifications should an internal R&D team assume are on the claim map?
The claims indicate the likely “must-pass” gates for a contested product.
-
Bead size distribution must satisfy:
- overall range (claim 1) and
- any asserted dependent sieve/mesh profile (claims 3–12, 16)
-
Enteric dissolution behavior must satisfy:
- pH onset (claims 1, 21)
- acid resistance (claim 17)
- release timing (claim 18)
- coating load (claim 1)
-
Human exposure under fasted dosing of 600 mg free cysteamine base in a capsule must satisfy:
- mean Cmax and mean AUC windows (claims 1, 22, 23)
Key Takeaways
- US 9,233,077 claim 1 is a tightly coupled formulation-performance claim: enteric-coated cysteamine beads with defined bead size distribution, defined enteric dissolution onset and coating load, and mean clinical PK acceptance ranges in fasted healthy subjects dosed with 600 mg free cysteamine base in capsules.
- Dependent claims narrow bead size further via multiple sieve/mesh thresholds, constrain enteric behavior via acid resistance and pH 6.8 release rate, and add explicit dissolution onset around pH 5.5.
- The enforcement and freedom-to-operate posture implied by the claim set is evidence-heavy: infringement arguments can be built from bead sieving plus dissolution testing and can culminate in human PK matching the defined mean Cmax and AUC(0-inf_D) windows.
- Design-around risk is elevated because the dependent claims constrain multiple independent variables at once: bead distribution tail behavior, enteric dissolution window, coating load, and clinical exposure.
FAQs
1) Does claim 1 require a specific enteric material identity?
No explicit polymer identity is provided in the claim text you supplied. Claim 1 requires an enteric membrane that begins to dissolve in pH 4.5 to 6.5 and is present at 25% to 35% by weight relative to the core, with additional dissolution behavior covered in dependents.
2) Can a product be inside claim 1’s broad bead size range but still avoid infringement?
Yes. Claim 1 only requires a 0.7 mm to 2.8 mm distribution, but multiple dependent claims impose narrower size distribution and sieve retention/pass-through thresholds. Avoiding those dependent ranges can reduce risk if dependents are asserted.
3) Are capsule design elements material to claim 1 scope?
Claim 1 specifies administration in a capsule to fasted healthy subjects at 600 mg free cysteamine base and includes PK requirements under that scenario. Claim 19 additionally requires a capsule shell enclosing the beads.
4) Is the PK requirement absolute or expressed as ranges?
It is expressed as mean windows. Claim 1 requires mean Cmax in 2.3 ± 0.6 mg/L and mean AUC(0-inf_D) in 0.84 ± 0.19 min*mg/L/mg, with alternate “80% to 125%” windows.
5) What tests most often determine whether the formulation matches the claimed ranges?
Based on the claim language: bead size distribution via sieving/mesh, enteric dissolution onset and gastric acid resistance via dissolution testing in 0.1N HCl and buffered pH conditions, enteric membrane load via formulation accounting, and verification of mean Cmax/AUC via clinical PK studies under the described dosing conditions.
References
[1] United States Patent Application / Patent No. 9,233,077, “Delayed-release cysteamine beads,” claims 1–23 (text as provided by user).
