Scope and claims dissection and US patent landscape for US Patent 9,493,582 (alkylated cyclodextrin purification using phosphate-free activated carbon and low-conductivity endpoints)
What is US 9,493,582 about, and what do its claims actually cover?
US 9,493,582 is directed to a purification process for producing an alkylated cyclodextrin composition with tightly controlled impurity carryover. The controlling novelty is the combination of (i) staged separation steps to remove “unwanted components” while leaving “drug-degrading impurities” in solution, followed by (ii) treatment with phosphate-free activated carbon until a conductivity endpoint is reached, producing the purified alkylated cyclodextrin with low phosphate and low chloride and with low UV absorbance consistent with reduced degradants/color bodies.
Claim architecture (what is broad vs. what is narrow)
Core independent claim: Claim 1 (process). It covers:
- Start: mixing a cyclodextrin with an alkylating agent to form a reaction milieu containing:
- alkylated cyclodextrin
- unwanted components
- drug-degrading impurities
- Step (b): one or more separations chosen from:
- ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, dialysis
to remove unwanted components and form a partially purified solution containing alkylated cyclodextrin and drug-degrading impurities
- Step (c): treatment with phosphate-free activated carbon having a residual conductivity of 10 μS or less, then producing the alkylated cyclodextrin
- No explicit endpoint requirement in Claim 1 other than the carbon’s residual conductivity attribute and the defined treatment.
Product claims: Claims 26 and 27–44 (composition).
- Claim 26 is a “product prepared by” Claim 1.
- Claim 27 and its dependent claims define composition parameters:
- average degree of substitution (DS): 2 to 9
- phosphate: < 500 ppm
- chloride: ≤ 0.07% (w/w) (with tightening in dependents)
- UV absorbance thresholds (multiple wavelength/concentration/path-length combinations)
- Claims 33–35 and 42–44 anchor the chemical identity to sulfoalkyl ether cyclodextrins (Formula II), including sulfobutyl ether cyclodextrin embodiments.
Formulation claims: Claims 45–49
- Pharmaceutical composition comprising:
- the cyclodextrin composition of Claim 27
- an active pharmaceutical agent
- Claim 46 limits actives to “chloride sensitive active agent” list (bortezomib, disulfiram, epigallocatchin-3-gallate, salinosporamide A, carfilzomib) and Claim 47 specifies carfilzomib.
The “fences” that likely define infringement risk
Across the estate, the claims repeatedly constrain four measurable attributes:
- Phosphate: <500 ppm (and tightened to <200 ppm and even lower by dependent formulations).
- Chloride: ≤0.07% (and tightened to ≤0.05%, plus “no detectable levels” by charged aerosol detection).
- Conductivity / activated carbon requirement: phosphate-free activated carbon with residual conductivity ≤10 μS, and dependent claims tighten the process to ≤9 μS and ≤8 μS.
- UV absorbance: low absorbance at defined wavelength ranges and defined assay concentration and path length, including language tying absorbance “due to drug degrading agent” or “color forming agent.”
What are the independent claims, and how broad are they compared with dependent claim narrowing?
Independent Claim 1 (process)
Claim 1 is the main capture mechanism. It is broad on:
- the type of cyclodextrin (not fully limited in Claim 1; later dependents restrict to specific sulfoalkyl ether cyclodextrins),
- the alkylation reaction concept (generic alkylating agent),
- the class of separations used (a selectable list),
- the existence of drug-degrading impurities in the partially purified solution stage,
- the composition result language (“producing the alkylated cyclodextrin”) without imposing an explicit final phosphate/chloride/UV value in Claim 1.
It is narrow on the sequencing and the carbon attribute:
- the carbon must be phosphate-free, and
- it must have a residual conductivity ≤10 μS (and dependents tighten).
Key dependent process claim tighteners
- Claim 4/5: residual conductivity ≤9 μS and ≤8 μS (tightening).
- Claims 2/3: phosphate <500 ppm and <125 ppm (tightening).
- Claims 6–8: chloride <0.5% (w/w), then 0.1%, then ≤0.05% (w/w).
- Claims 9–11: DS range constraints (2–9; 4.5–7.5; 6–7.5).
- Claims 12–19: UV absorbance thresholds:
- at 245–270 nm and/or 320–350 nm,
- at specific concentrations (300 mg/mL or 500 mg/mL) and a 1 cm path length,
- with absorbance thresholds 1 A.U. and 0.5 A.U.
- Claims 14/18: ties absorbance to drug-degrading agent or color forming agent.
- Claims 20–21: carbon washing detail to reach the endpoint residual conductivity in (c), using solvent wash or water wash until conductivity matches.
Claim 22–23 chemical identity restriction
- Claim 22 specifies alkylated cyclodextrin as a sulfoalkyl ether cyclodextrin of Formula (II):
- p = 4, 5, or 6
- R1 is either hydroxyl or sulfonated alkylene ether substituents with pharmaceutically acceptable cations
- at least one R1 is OH and at least one R1 is the sulfoalkyl ether.
- Claim 23 sets R1 subset:
- alkylene is C4 (O-(C4 alkylene)-SO3−-T)
- T is Na+.
Independent composition claim (Claim 27)
Claim 27 is the main product capture. It requires all of:
- DS 2 to 9
- phosphate <500 ppm
- chloride ≤0.07% (w/w)
- UV absorbance <1 A.U. at 245–270 nm, at 300 mg/mL, 1 cm path length
This is materially narrower than Claim 1 because it fixes measurable attributes. Dependent claims then tighten:
- Claim 28: absorbance ≤0.5 A.U.
- Claim 29: absorbance ≤0.2 A.U.
- Claim 31: absorbance ≤0.5 A.U. but uses 500 mg/mL at 245–270 nm.
- Multiple wavelength variants: Claim 36 and dependents shift to 320–350 nm.
Identity anchoring within product claims
- Claim 33: sulfoalkyl ether cyclodextrin Formula (II) with p = 4–6 and sulfonated ether substituents, plus requirement of at least one OH.
- Claim 35: explicitly sulfobutyl ether cyclodextrin.
- Claims 34, 42–44 similarly narrow the substituent pattern and the cation (Na+).
Pharmaceutical composition scope (Claim 45)
Claim 45 is limited to:
- the Claim 27 alkylated cyclodextrin composition
- plus an “active pharmaceutical agent”
Claim 46 then limits to a “chloride sensitive active agent” list, and Claim 47 specifies carfilzomib. Claim 48/49 replicate the same concept for the process of Claim 25 (process with active agent).
What do the conductivity and “phosphate-free activated carbon” limitations mean for claim construction?
Claim 1’s key functional/structural limitation is the activated carbon:
- phosphate-free
- having a residual conductivity of 10 μS or less
Dependent claims tighten the process residual conductivity to:
- ≤9 μS (Claim 4)
- ≤8 μS (Claim 5)
Claims 20 and 21 specify a washing approach to reach that residual conductivity:
- solvent wash until eluted solvent reaches residual conductivity endpoint
- or water wash until eluted water reaches the endpoint
From an infringement perspective, the claim is likely to be enforced on the property of the activated carbon used (residual conductivity after washing) and the sequence (phosphate-free activated carbon treatment at the defined stage).
What impurity ceilings (phosphate/chloride) and UV limits define the product?
Phosphate
- Process: Claim 2 (<500 ppm) and Claim 3 (<125 ppm)
- Product: Claim 27 requires <500 ppm
- Additional product tightener: Claim 53 (<200 ppm) and mirrored process/composition dependents (Claim 50 and Claim 56/59/62)
Chloride
- Process: Claim 6 (<0.5% w/w), Claim 7 (0.1% w/w), Claim 8 (≤0.05% w/w)
- Product: Claim 27 (≤0.07% w/w)
- Product tightener:
- Claim 54 (≤0.05% w/w)
- “No detectable levels” by charged aerosol detection in Claims 55, 58, 61, 64
UV absorbance (multi-wavelength, multi-loading assay)
The claims specify:
- wavelength bands:
- 245–270 nm (Claims 12–13, 15, 29, 31, 38, 40 and dependents)
- 320–350 nm (Claims 16–17, 19, 37, 40 and dependents)
- concentration and path length:
- aqueous solution containing 300 mg/mL, 1 cm path length (many dependents)
- aqueous solution containing 500 mg/mL, 1 cm path length (some dependents)
- thresholds:
- <1 A.U.
- ≤0.5 A.U.
- ≤0.2 A.U. (Claim 29 and Claim 38)
- causation language:
- absorbance due to drug-degrading agent (Claim 14) or color forming agent (Claim 18) and mirrored variations in composition claims.
Which cyclodextrin chemistries are covered? What is Formula (II)?
The chemical scope is broadened in Claim 1 but becomes explicit in Claims 22, 33, 42, and 43.
Sulfoalkyl ether cyclodextrin (Formula II)
Claims define:
- p = 4, 5, or 6
- R1 at each occurrence is independently:
- OH, or
- O-(C2–C6 alkylene)-SO3−-T
- T is a pharmaceutically acceptable cation
- at least one R1 is OH and at least one R1 is sulfoalkyl ether.
Dependent limitations narrow:
- Claim 23: R1 includes O-(C4 alkylene)-SO3−-T with T = Na+ at each occurrence.
- Claim 34, 43 mirror cation/specification.
- Claim 35 and 44 identify the compound as sulfobutyl ether cyclodextrin.
Practically, this anchors the family to specific sulfonated ether substituted cyclodextrin structures, likely used as chloride/impurity scavenging or stabilization excipients.
What pharmaceutical use scope is claimed, and why “chloride sensitive active agent” matters?
Claim 45 onward links the excipient/product to use in formulations where chloride content can impact stability or performance.
Covered actives (explicit list)
- bortezomib
- disulfiram
- epigallocatechin-3-gallate
- salinosporamide A
- carfilzomib
Claim 47 and Claim 49: carfilzomib.
For freedom-to-operate, the combination of:
- the specific excipient composition parameters (Claim 27),
- plus the chloride-sensitive active agent limitation,
- plus the same impurity control strategy,
creates a formulation-specific infringement pathway even if generic cyclodextrin chemistry is otherwise known.
What is the likely competitive patent landscape around US 9,493,582, based on claim themes?
Without the external record, the US bibliographic data, prosecution history, citing/cited patents, and whether there are related continuations cannot be enumerated. This analysis therefore focuses on the landscape implied by the claim’s differentiators and the common technical competitors in cyclodextrin purification and impurity-controlled excipients.
Landscape clusters implied by claim elements
-
Alkylated/sulfoalkyl ether cyclodextrin preparation
- Process and composition claims for sulfonated ether substituted cyclodextrins (DS-controlled, p-controlled).
- Competitors typically claim:
- specific alkylation agents,
- purification workflows,
- and DS range definitions for reproducible pharmacological performance.
-
Impurity control: phosphate and chloride
- A separate sub-genre targets:
- minimizing phosphate carryover (especially from alkylation neutralizations, buffers, or reagents),
- and minimizing chloride (from quenchers, salts, reagents, or downstream precipitation/neutralization).
- Those patents often claim:
- washing, ion exchange, membrane steps,
- or particular filter/carbon conditioning.
-
Conductivity endpoint conditioning
- The “residual conductivity ≤10 μS” with phosphate-free activated carbon is a distinct signature.
- Competitors may claim similar “washed adsorbent” approaches but with different endpoint metrics or different adsorbent chemistries.
-
UV/vis absorbance as a degradant/color proxy
- The claim uses assay conditions as product quality attributes.
- That typically spawns:
- tighter specification patents,
- degradant identification patents,
- and analytical-method dependent claims.
-
Formulation for chloride-sensitive actives
- The “chloride sensitive active agent” list and carfilzomib pin the formulation risk to stability-driven impurity tolerances.
- Competitors may counter with:
- alternative excipient systems,
- different chloride management strategies,
- or use of different cyclodextrin chemistries not meeting the DS/phosphate/chloride/UV envelope.
Where design-arounds are most plausible within this claim set
Claim 1’s modular structure means a counterparty could aim to avoid one of three enforcement axes:
- Avoid the carbon property: use phosphate-containing carbon, or carbon treated to a different conductivity endpoint, or a different adsorption/finishing method not “phosphate-free activated carbon” with residual conductivity ≤10 μS.
- Avoid the separation sequence requirement: ensure the “partially purified solution” still contains unwanted components or avoid the specific stage definitions used in the claim.
- Avoid the product specs: exceed chloride/phosphate ceilings or exceed UV absorbance thresholds.
Because dependent claims lock many of these attributes, a design-around must usually move beyond a single parameter tweak.
What would an Orange Book-style status or FDA regulatory risk assessment look like for this patent type?
The patent is about an excipient/purification product and formulation compositions rather than a directly administered drug substance. That means regulatory linkage typically occurs via:
- listed inactive ingredient/excipient references in relevant drug applications,
- and any drug substance/drug product specifications relying on this excipient’s impurity control.
However, no specific FDA listing, Orange Book entry, application number, or referenced drug product can be asserted from the provided claim text alone.
What is the practical enforcement reach of the claims (process vs. composition vs. formulation)?
Strongest direct infringement vectors
- Process infringement: if a manufacturer produces the alkylated cyclodextrin using:
- the staged separation approach,
- and phosphate-free activated carbon with residual conductivity at or below the claimed threshold,
and the process inherently results in the claimed product envelope.
- Composition infringement: if the manufacturer sells or uses an alkylated cyclodextrin composition meeting:
- DS 2–9,
- phosphate <500 ppm (and possibly <125 ppm),
- chloride ≤0.07% and/or ≤0.05%,
- UV absorbance limits as measured under the claimed assay conditions.
- Formulation infringement: if a drug product includes:
- the claimed excipient composition, and
- the explicitly identified chloride-sensitive active agents (with carfilzomib singled out).
Potential indirect infringement vectors
- If a supplier sells the cyclodextrin meeting the composition claim limits to a formulators for carfilzomib or other listed actives, the product claim may be the dominant legal lever.
What “claim map” can be drawn from the limitations?
Claim 1 to product parameter mapping
- Step (a) and (b): establishes that drug-degrading impurities are present in partially purified solution after removing unwanted components.
- Step (c): phosphate-free activated carbon with residual conductivity endpoint drives removal of degradants and/or color bodies, enabling UV absorbance and impurity specs in downstream product.
Composition claims parameter mapping
- DS range defines degree of substitution and likely performance solubility/complexation profile.
- Phosphate ceiling defines suppression of phosphate-derived impurities.
- Chloride ceiling defines stabilization for chloride-sensitive actives and/or prevents degradation pathways.
- UV absorbance limits define quality and degradant reduction.
- Formula II constraints define the cyclodextrin’s chemical identity.
Key Takeaways
- US 9,493,582 is an alkylated cyclodextrin purification and specification patent anchored on phosphate-free activated carbon with a residual conductivity ≤10 μS endpoint, following staged separations that remove “unwanted components” but leave “drug-degrading impurities” for carbon treatment.
- Process Claim 1 is broad on separation modality but narrow on adsorbent property and sequencing; it becomes product-specific through dependent claims tying phosphate/chloride/UV to the treated cyclodextrin.
- Composition claims (notably Claim 27) are tight: DS 2–9, phosphate <500 ppm, chloride ≤0.07% (and dependents ≤0.05% and “no detectable chloride”), plus specific UV/vis absorbance thresholds at defined wavelengths, concentrations, and a 1 cm path length.
- Chemical identity is explicitly limited in later dependents to sulfoalkyl ether cyclodextrins (Formula II) including sulfobutyl ether cyclodextrin with defined substituent patterns and, in dependents, Na+.
- Formulation claims tie the excipient to chloride-sensitive actives, including a specific subset and carfilzomib.
FAQs
1) What measurement endpoints drive infringement for US 9,493,582?
Residual conductivity of the phosphate-free activated carbon (≤10 μS in Claim 1; ≤9 μS and ≤8 μS in dependents) and product specs including phosphate (<500 ppm; <125 ppm in dependents), chloride (≤0.07% with tighter limits and “no detectable” charged aerosol detection), and UV/vis absorbance thresholds at specified wavelengths and assay conditions.
2) Can a different separation method avoid Claim 1?
Likely only if it falls outside the listed separations in Claim 1 or disrupts the claimed staging logic (unwanted components removed to produce a partially purified solution containing drug-degrading impurities) while also avoiding the carbon property limitation.
3) Are product claims easier to enforce than process claims?
Composition claims are enforcement-ready because they rest on measurable attributes (phosphate/chloride/UV absorbance) and defined chemical identity constraints in dependents.
4) Does the patent require that absorbance be caused by a specific degradant?
Some dependent claims state absorbance is due to drug-degrading agent or color forming agent, but the main composition constraints still require the absorbance thresholds at defined conditions.
5) Which marketed drug families are most at risk under the formulation claims?
Carfilzomib is singled out, alongside a defined list of chloride-sensitive actives (bortezomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, carfilzomib).
References
- US 9,493,582 (provided claims text by user).
