United States Patent 11,504,365: Scope, Claims, and Patent Landscape for Tivozanib Dosing in Refractory Advanced RCC
US Drug Patent 11,504,365 claims a method of treating refractory advanced renal cell carcinoma (RCC) using a tivozanib hydrochloride oral dosing schedule that is adjusted based on hepatic impairment status, with an efficacy benchmark tied to progression-free survival (PFS).
What is the claim core and how does it narrow scope?
The patent’s scope is dominated by a single integrated dosing construct:
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Patient population
- Human subject with refractory advanced RCC
- Previously received at least two anti-cancer therapies
- At least one included a TKI (explicitly: at least one anti-cancer therapy included a tyrosine kinase inhibitor (TKI))
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Treatment structure
- “one or more treatment cycles consisting essentially of” a dosing pattern:
- 21 days on treatment
- 7 days off treatment
- Repeated in cycles
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Dose and schedule pivot based on hepatic impairment
- Baseline cycle dose:
- 1.5 mg tivozanib hydrochloride daily for 21 days, then 7 days without tivozanib
- Trigger event:
- “until the subject experiences moderate hepatic impairment”
- Post-trigger dose reduction:
- upon moderate hepatic impairment, reduce 1.5 mg to 1.0 mg (same 21-on / 7-off cycle structure)
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Efficacy requirement (only in claim 1)
- “thereby to achieve a progression free survival in the subject of at least 5 months”
The claim language “consisting essentially of” is a critical narrowing device: it permits limited adjuncts while preventing full freedom to add other substantial active agents into the cycle unless they do not materially change the claimed treatment essence.
What do independent claim 1 and claim 7 cover?
H2: What does claim 1 cover (baseline 1.5 mg then reduce to 1.0 mg upon moderate hepatic impairment)?
Claim 1 is the broadest enforceable dosing method because it starts at 1.5 mg and includes a dynamic adjustment to 1.0 mg after onset of moderate hepatic impairment, while setting a PFS bar.
Key elements:
- Indication/population: refractory advanced RCC; at least two prior therapies; at least one prior therapy included a TKI
- Dosing cycle:
- 21 days oral tivozanib 1.5 mg/day
- 7 days off
- Adjustment trigger: “until” the subject “experiences moderate hepatic impairment”
- Adjusted dose: reduce to 1.0 mg/day for subsequent cycles (same cycle pattern)
- Clinical outcome: “thereby to achieve” PFS ≥ 5 months
H2: What does claim 7 cover (1.0 mg from the start in moderate hepatic impairment)?
Claim 7 covers a distinct treatment pathway:
- Indication/population: refractory advanced RCC; at least two prior therapies; at least one prior therapy included a TKI
- Condition: the subject is experiencing moderate hepatic impairment (present during treatment)
- Cycle dosing (single fixed dose):
- 1.0 mg/day oral tivozanib for 21 days, then 7 days off
- No explicit PFS performance statement in claim 7 (unlike claim 1)
This creates two actionable method categories for infringement analysis:
- Start-at-1.5 mg then reduce to 1.0 mg when moderate hepatic impairment occurs (claim 1)
- Use 1.0 mg from the outset where moderate hepatic impairment exists (claim 7)
How do dependent claims expand or constrain scope?
H2: How do claims 2-6 and 8-12 define prior therapy configurations?
Dependent claims shape the prior-therapy context through additional limitations that align with common RCC treatment sequencing, particularly VEGF-targeted TKIs and immune checkpoint inhibitors.
Claim family elements
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Claims 2 and 8: prior therapies include:
- first line anti-cancer therapy
- second line anti-cancer therapy
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Claims 3 and 9: both first and second line include:
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Claims 4 and 10: first and second line include:
- VEGFR TKI therapy AND a PD-1 or PD-L1 inhibitor therapy
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Claims 5 and 11: first and second line include:
- VEGFR TKI therapy AND a systemic anti-cancer agent
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Claims 6 and 12: include patient stratification:
- IMDC risk score = favorable or intermediate prior to treatment
H2: What does this mean for infringement and design-around?
The dependent claims do not replace the core dosing method. They instead require additional patient-history features. Practically:
- If a competitor uses the same tivozanib dose cycling logic but targets a patient population that lacks the specified prior-therapy pattern, it may evade infringement of the dependent claims (but still risk exposure under claim 1/7 if the core limitations match).
- If a competitor uses a different dose adjustment rule (e.g., holds dosing rather than reducing from 1.5 mg to 1.0 mg, or uses a different threshold hepatic severity), it affects the core limitations used in claim 1/7.
What is the effective “method recipe” across the independent claims?
H2: Can the dosing protocol be reduced to a discrete operational recipe?
Yes. The claims encode a reproducible protocol.
| Feature |
Claim 1 |
Claim 7 |
| Disease/patient |
Refractory advanced RCC; ≥2 prior therapies; at least one prior therapy included a TKI |
Same |
| Hepatic impairment state |
Moderate hepatic impairment occurs during treatment (trigger) |
Moderate hepatic impairment is present during treatment |
| Cycle structure |
“consisting essentially of” 21 days on / 7 days off |
Same |
| Starting daily dose |
1.5 mg/day |
1.0 mg/day |
| Dose change rule |
Reduce from 1.5 mg to 1.0 mg after moderate hepatic impairment occurs |
No change; fixed 1.0 mg/day |
| Outcome clause |
PFS ≥ 5 months |
No PFS threshold stated |
How strong is the enforceable scope relative to alternatives?
H2: Where is the patent strongest?
The patent is strongest where actual prescribing matches all of the following simultaneously:
- Refractory advanced RCC after at least two prior therapies with TKI exposure in at least one prior line
- A 21-on / 7-off cycle structure
- Use of tivozanib at either:
- 1.5 mg/day initially then reduce to 1.0 mg/day after moderate hepatic impairment occurs (claim 1), or
- 1.0 mg/day in the setting of moderate hepatic impairment (claim 7)
- For claim 1: achievement of PFS ≥ 5 months
This is a relatively specific operational slice of RCC management.
H2: Where can competitors shift risk?
Risk shifts if any single core limitation is changed:
- Changing cycle pattern (e.g., different on/off schedule)
- Using a different dose reduction magnitude or different dose levels
- Using a different hepatic impairment threshold category
- Avoiding the required patient history (at least two therapies with TKI exposure)
- Not meeting the claim-1 PFS requirement (if the claim is asserted with outcome-focused enforcement)
Patent landscape: likely positioning and collision points
H2: What does the landscape imply about who is most exposed?
Given the claim set, the most exposed actors are those pursuing:
- Tivozanib for refractory advanced RCC
- Labeling or off-label protocols that incorporate:
- dose reduction to 1.0 mg/day in the setting of moderate hepatic impairment
- the specific 21-day on / 7-day off cycle framework
- Trials or regimens enrolling:
- RCC patients with multiple prior therapies and prior TKI exposure
Even without referencing other specific patents in this record, the practical collision points are dictated by the claim’s factual and dosing constraints:
- dosing protocol
- patient impairment category
- refractory setting with prior treatment history
- PFS performance statement (claim 1)
H2: Which claim features create the most likely “prior art” leverage?
From a landscape perspective, the patent is most vulnerable to novelty or obviousness arguments based on:
- Earlier published tivozanib dosing schedules using similar 21-on / 7-off cycles
- Earlier guidance describing dose adjustment in hepatic impairment for tivozanib (particularly where “moderate” hepatic impairment maps to a reduction aligned with 1.0 mg/day)
- Earlier clinical disclosures linking tivozanib dosing to PFS outcomes in refractory advanced RCC populations
The dependent claims also add posture likely designed to align with prior line sequencing (VEGFR TKI plus PD-1/PD-L1, or VEGFR TKI plus systemic agent) and IMDC risk stratification, which can be compared against earlier RCC treatment literature and study inclusion criteria.
Scope map: claim-by-claim “coverage grid”
H2: What combinations of patient history and therapy lines are explicitly covered?
The dependent claims add these specific combinations:
- At least two anti-cancer therapies with at least one TKI exposure (base)
- With explicit line structure:
- With explicit therapy content:
- VEGFR TKI + VEGFR TKI (claims 3 and 9)
- VEGFR TKI + PD-1/PD-L1 inhibitor (claims 4 and 10)
- VEGFR TKI + systemic anti-cancer agent (claims 5 and 11)
- With explicit risk stratification:
- IMDC favorable or intermediate (claims 6 and 12)
This creates a coverage grid where “dose protocol + refractory state + moderate hepatic impairment” is the anchor, and prior therapy pattern is the selector for dependent claims.
Key Takeaways
- US 11,504,365 protects a tivozanib dosing method in refractory advanced RCC patients with at least two prior therapies where at least one prior line includes a TKI.
- Claim 1 is defined by a 21-days-on / 7-days-off cycle using 1.5 mg/day, with a dose reduction to 1.0 mg/day upon onset of moderate hepatic impairment, and a PFS ≥ 5 months outcome clause.
- Claim 7 covers 1.0 mg/day tivozanib on the same 21-on / 7-off schedule where moderate hepatic impairment is already present.
- Dependent claims constrain scope by adding: first/second-line structure, VEGFR TKI and immune/systemic partner therapy patterns, and IMDC favorable/intermediate risk.
- The enforceable “collision surface” is narrow: it aligns tightly to tivozanib + hepatic impairment-adjusted dosing + refractory RCC + prior-treatment history + cycle structure.
FAQs
1) Does the patent cover starting at 1.0 mg without waiting for hepatic impairment to occur?
Yes. Claim 7 covers patients “experiencing moderate hepatic impairment” and uses 1.0 mg/day for 21 days followed by 7 days off.
2) Is the 21-day on / 7-day off schedule mandatory?
Yes. Both independent claims use cycles “consisting essentially of” that schedule.
3) Is a prior TKI therapy required even if the other therapy was not a TKI?
Yes. The base requirement is that at least one of the prior anti-cancer therapies included a TKI.
4) Which claim includes a progression-free survival performance requirement?
Claim 1 includes: PFS of at least 5 months.
5) Can the dependent claims be infringed without matching the exact first-line/second-line therapy composition?
No. Dependent claims add specific limitations on what first-line and second-line therapies include (VEGFR TKI alone, VEGFR TKI plus PD-1/PD-L1, or VEGFR TKI plus a systemic agent, plus optional IMDC favorable/intermediate risk).
References
[1] US Patent Application and claims text provided in the prompt for US Drug Patent 11,504,365.
