Scope, Claims, and US Patent Landscape for US Patent 10,603,384 (Hydroxypropyl-β-cyclodextrin IV formulation of (4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-ylacetic acid)
US 10,603,384 is a US composition-of-matter and formulation-and-process patent centered on an IV drug product comprising (4S)-substituted quinazoline acetic acid (and salts/solvates), specifically complexed or solubilized with hydroxypropyl-β-cyclodextrin in the presence of NaOH and NaCl at near-neutral to mildly basic pH (7.0–8.5). The claims extend beyond the liquid to include lyophilized solids produced from that liquid, and include treatment claims for cytomegalovirus infection with IV dosing ranges. The claim set is tightly conditioned by excipient identity (hydroxypropyl-β-cyclodextrin), quantitative ratios (equivalents and g/100 mL ranges), pH, NaOH/NaCl presence, and stability requirements for specific “stable liquid” embodiments.
Because the question provided only the claims text and not the patent document’s bibliographic metadata (title, filing/priority dates, issuance date, assignee, and claim construction record) and not the full US prosecution history, FDA/Orange Book listings, or related family members, a complete, jurisdictional, date-specific “landscape” cannot be produced to a litigation-grade standard.
What is the protected active compound in US 10,603,384?
Answer: The claims cover a specific enantiomeric quinazoline acetic acid: the (S)-configuration at the carbon in position 4 of the dihydroquinazoline core, expressed as the (4S) isomer in multiple dependent claims, plus pharmaceutically acceptable salts and solvates.
What exact chemical identity is recited?
The operative recitation appears in multiple places as:
- {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid
- with the ring carbon in position 4 having (S)-configuration
- plus salts, solvates, and solvates of salts
Dependent claim 31/37/44 narrows the compound identity explicitly to:
- {(4S)-8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
How broad is “salt/solvate” coverage?
The wording is broad on paper for salts and solvates because it includes:
- “a salt thereof”
- “a solvate thereof”
- “a solvate of a salt thereof”
However, any real-world scope depends on whether particular salts/solvates were actually enabled and supported in the specification and examples. The claim language itself covers the category.
What formulations are claimed (core composition claims 1, 40, 41, 42)?
Answer: An IV-ready aqueous composition containing the (4S) quinazoline acetic acid at 0.5–2.5 g per 100 mL, hydroxypropyl-β-cyclodextrin at 10–30 g per 100 mL, with NaOH and NaCl, and pH 7.0–8.5, plus excipient equivalents limits.
Claim 1: baseline IV composition with strict excipient/pH/alkali conditions
Key quantitative constraints (from claim 1):
- Compound (4S): 0.5 to 2.5 g per 100 mL
- Hydroxypropyl-β-cyclodextrin: 10.0 to 30.0 g per 100 mL
- NaOH present (and NaCl)
- pH: 7.0 to 8.5
- IV-suitable form
Claim 40: similar but with additional “equivalents” constraints
Claim 40 adds a condition:
- Hydroxypropyl-β-cyclodextrin present in 1 to 10 equivalents relative to compound
- NaOH present in up to 2.0 equivalents relative to compound
It also repeats the g/100 mL ranges and pH band.
Claim 41 and claim 42: stable liquid compositions (time-temperature potency retention)
Claim 41 adds a stability framing:
- Stored at 2–8°C, 25°C, or 40°C for at least two weeks
- Retains minimum proportion >90% compound in solution
Claim 42 adds a dilution/reconstitution stability requirement:
- After dilution/reconstitution to 0.8–10 mg/mL for infusion at 2–8°C
- Retains >90% in solution for at least four hours
This is a common litigation hinge: stability claims can block “work-alike” products even if initial composition falls inside the ranges, if the accused product fails the retention specification.
How do the dependent claims narrow the excipient and NaOH/NaCl ranges?
Answer: The claim set materially narrows the NaOH level and hydroxypropyl-β-cyclodextrin equivalents with multiple dependent claims, creating a lattice of quantitative embodiments.
NaOH quantitative limitations (dependent claims 12, 24, 27–30, 35–36)
- Claim 12: up to 0.0–350 mg NaOH per 100 mL
- Claim 24: up to 2.0 equivalents NaOH relative to compound
- Claim 27/28: excipient 2–7 equivalents and NaOH up to 2.0 equivalents
- Claim 29: excipient 2.5–5 equivalents and NaOH 0.5–1.5 equivalents
- Claim 30: excipient 2.5–5 equivalents and NaOH 0.75–0.9 equivalents
Hydroxypropyl-β-cyclodextrin equivalents (dependent claims 9–11, 10, 25–26, 33–38)
- Claim 10: excipient 2–5 equivalents
- Claim 11: excipient 1–10 equivalents
- Claim 25: excipient 2–5 equivalents
- Claim 26: excipient 2.5–4.5 equivalents
- Claim 27–28: excipient 2–7 equivalents
- Claim 29–30: excipient 2.5–5 equivalents
- Claim 33–36: specifically with defined hydroxypropyl-β-cyclodextrin substitution level
- Claim 32: average 5 hydroxypropyl groups per cyclodextrin molecule
- Claims 33–36: excipient equivalents 2–5, 2.5–4.5, 2.5–5 with NaOH sub-ranges
NaOH/cyclodextrin coupling
The dependent claims repeatedly couple:
- excipient equivalents range
- to a corresponding NaOH equivalents band
That coupling increases the number of enforceable “specific embodiments” and reduces easy “design-around” by changing only pH/alkali while keeping everything else constant.
What buffer, sugar, and pH constraints are claimed?
Buffer
- Claim 2: composition includes at least one buffer
- Claim 3: buffers are phosphate, tris, or citrate
Buffers are not optional in claim 1, but they are part of dependent coverage, which can matter if an accused formulation includes one of these buffers.
Sugar/excipients
- Claim 4: at least one sugar
- Claim 5: sugar candidates include glucose, sucrose, lactose, maltose, trehalose, sorbitol, mannitol
Again, this is dependent coverage; a competing product without a named sugar may avoid those dependent claim embodiments.
pH
- Claim 1: pH 7.0–8.5
- Claim 8: pH 7.5–8.5
The narrower pH band can matter in claim charting, particularly if the accused pH is just below 7.5 or just above 8.5.
What is claimed about concentration limits (mg/mL upper bounds)?
- Claim 6: amount of compound up to 100 mg/mL
- Claim 7: amount of compound up to 50 mg/mL
These dependents create additional fences for accused concentrations within the broader g/100 mL bounds.
What solids are protected: lyophilized product and stability pathway?
Answer: The patent explicitly covers a solid dosage form made by lyophilizing the liquid composition.
- Claim 14: “A solid pharmaceutical composition produced by lyophilizing a pharmaceutical preparation according to claim 1.”
This ties solid product coverage to the exact liquid starting composition, not just to “the same drug” in general.
What manufacturing methods are claimed (sterile filtering, pH adjustment, sterile fill, optional heat sterilization, lyophilization)?
Answer: US 10,603,384 claims multiple process routes for preparing the formulation, with steps that are often practical and thus relevant to “process patent” litigation.
Method claim 15: sequential dissolving, pH adjustment, sterile filtering, fill, optional heat sterilization
Claim 15 requires:
- Dissolve hydroxypropyl-β-cyclodextrin in water
- Add the compound (4S) to form the solution
- Optionally add sugar and/or buffer
- Adjust pH to target
- Sterile-filter and fill
- Optionally heat sterilize
Method claim 16: lyophilization to obtain solid
- “further comprising lyophilizing said final solution”
Method claim 17: split solutions and mixed pH adjustment
Claim 17 breaks the process into:
- First solution pH adjustment
- Second solution with sugar/buffer dissolution and optional pH adjustment
- Mixing, then sterile-filter and fill
Method claim 18: add compound to aqueous NaOH solution; add water; add cyclodextrin and NaCl
This route:
- Adds the compound (4S) to aqueous NaOH
- Adds water/suspension
- Adds hydroxypropyl-β-cyclodextrin and NaCl
- Sterile-filter and fill
- Optional heat sterilization
If an accused process uses a different order, design-around may exist for process claims, but product claims still control if the final formulation falls within the composition claim parameters.
What treatment indications and dosing are claimed?
Answer: The patent includes method-of-use claims for cytomegalovirus infection treated by administering the claimed IV composition, including explicit IV dose ranges per kg.
Claims 19–22: cytomegalovirus infection treatment
- Claim 19: method for treatment of cytomegalovirus infection
- Claim 20: human cytomegalovirus (HCMV)
- Claim 21: IV dosing provides 0.001 to 10 mg/kg
- Claim 22: IV dosing provides 0.01 to 5 mg/kg
Claim 23: combating cytomegalovirus infections in human or animal
A broader “combating” framing extends beyond human-specific wording.
These are important because a formulation patent plus use claims can block an ANDA applicant from arguing “no medical use infringement” if the product is administered for the claimed purpose.
How is claim scope segmented across composition vs stable solution vs process vs use?
Answer: US 10,603,384 has four enforceable “layers,” each with different design-around paths.
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Composition (liquid IV) layer
- Controlled by specific compound identity, enantiomer configuration, excipient identity, concentration windows, NaOH/NaCl presence, and pH band (7.0–8.5).
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Stable liquid layer
- Controlled by storage and post-dilution potency retention thresholds (>90% after set times at set temperatures).
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Solid layer
- Lyophilized solid produced from the claimed liquid composition.
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Process and use layers
- Manufacturing steps with sterile filtration and pH adjustment.
- Cytomegalovirus infection treatment with IV dose ranges.
A competitor seeking to avoid infringement typically must escape all relevant layers implicated by their product and intended use, not only one set of claim elements.
Which elements are most likely to drive infringement analyses? (high-salience claim limitations)
Answer: The following limitations are most likely to be litigated as “hard” claim elements rather than easily substitutable variables.
- Hydroxypropyl-β-cyclodextrin as the cyclodextrin excipient (not other cyclodextrins or polymers)
- Specific quantitative ranges
- 0.5–2.5 g/100 mL compound
- 10–30 g/100 mL hydroxypropyl-β-cyclodextrin
- pH band
- 7.0–8.5; narrower 7.5–8.5 dependent
- NaOH and NaCl presence, plus NaOH equivalence bands (0.5–2.0 equivalents; narrower dependent sub-ranges)
- (4S)/(S) configuration requirement
- This is a key chemical scope constraint in enantiomeric cases.
- Stability performance thresholds for the stable liquid claims
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90% retention after two weeks at 2–8°C/25°C/40°C and/or >90% after at least four hours post dilution at 2–8°C
US patent landscape: what can be stated from the provided claims alone?
Answer: With only the claims text and no bibliographic or family information, the patent landscape can be analyzed only at the “within-claim” level, not across competing US patents, related compositions, or co-pending continuations in the family.
Within-claim architecture suggests likely related patent categories in the same family
Even without confirming family members, the claim draft indicates that the applicant pursued:
- Drug substance scope (the (4S) compound plus salts/solvates)
- Formulation development focused on cyclodextrin solubilization at near-neutral pH using NaOH/NaCl
- Stability profiling to secure enforceable stable liquid coverage
- Solid conversion via lyophilization of the specific liquid composition
- Operational/process protection via sterile filtration and pH adjustment steps
- Method-of-use for cytomegalovirus infection with IV dosing
In practice, portfolios around this type of IV cyclodextrin formulation typically also include adjacent patents on:
- preparation of the active pharmaceutical ingredient (API) and its polymorphs/solvates
- additional excipient ratios and pH points
- alternate buffers/sugars
- device-specific fill volumes or dilution schemes
But those cannot be enumerated without external patent-family data.
Key claim-to-competitive product “design-around” vectors (product-level)
Answer: Based on claim elements, design-around attempts typically focus on at least one of these high-salience constraints.
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Excipient identity switch
- Replace hydroxypropyl-β-cyclodextrin with another solubilizer or cyclodextrin (e.g., methyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, or non-cyclodextrin polymers). This is the cleanest escape from dependent claim coverage that hard-codes hydroxypropyl-β-cyclodextrin.
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pH outside 7.0–8.5 or outside 7.5–8.5
- Target pH just below 7.0 or above 8.5, or avoid the dependent band.
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NaOH/NaCl absence or NaOH equivalence out of range
- If the formulation does not contain NaOH or contains it outside the equivalents bands, it may fall outside multiple dependent embodiments. Independent claim 1 requires NaOH and NaCl “further comprises”; that element is likely to be strictly construed.
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Concentration windows
- Operate outside 0.5–2.5 g/100 mL compound and/or 10–30 g/100 mL hydroxypropyl-β-cyclodextrin.
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Stability performance
- Even if composition matches the claimed formulation, stable-liquid claims 41–42 can be avoided by achieving <90% retention under the specified conditions. That is a test-and-evidence barrier for challengers.
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Dosing regimen and patient population
- Use claims 19–23 can be avoided by not using the claimed IV composition for the claimed cytomegalovirus treatment. In practice, however, labeling and clinical practice matter.
Key Takeaways
- US 10,603,384 is structurally a near-neutral, NaOH/NaCl-containing IV aqueous formulation patent for a specific (4S) quinazoline acetic acid API, using hydroxypropyl-β-cyclodextrin at defined concentration bands.
- The claim set expands protection to lyophilized solids derived from the claimed liquid.
- Method claims protect sterile preparation and pH adjustment workflows, including routes that add the drug to aqueous NaOH and then incorporate hydroxypropyl-β-cyclodextrin and NaCl.
- The patent includes cytomegalovirus method-of-use claims with IV dosing ranges (0.001–10 mg/kg and 0.01–5 mg/kg).
- The enforceability pressure points are pH, cyclodextrin identity, NaOH/NaCl presence and NaOH equivalents, concentration windows, and stability retention thresholds (>90%) after set storage and post-dilution conditions.
FAQs
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Does US 10,603,384 cover other cyclodextrins besides hydroxypropyl-β-cyclodextrin?
The composition claims require hydroxypropyl-β-cyclodextrin; other cyclodextrins are not encompassed by the explicit excipient language.
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Is lyophilized solid coverage limited to lyophilizing the specific claimed liquid composition?
Yes. Claim 14 ties solid product coverage to lyophilizing a pharmaceutical preparation according to claim 1.
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What stability conditions are recited for the stable liquid claims?
Claim 41 uses two-week storage at 2–8°C, 25°C, or 40°C with >90% retention. Claim 42 adds a dilution/reconstitution condition with >90% retention for at least four hours at 2–8°C.
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Can a different buffer avoid infringement of the buffer-dependent claims?
Buffer claims are dependent (claims 2–3) and specific to phosphate/tris/citrate; a product without those buffers may avoid dependent claim embodiments but not necessarily the independent composition claim.
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Do the treatment claims require HCMV specifically?
Claim 20 specifies HCMV as a dependent narrowing, but claim 19 broadly covers cytomegalovirus infection; claim 23 covers human or animal cytomegalovirus treatment.
References
- United States Patent 10,603,384 (claims text provided by user).
