United States Drug Patent 10,335,452: Scope, Claim Map, and US Patent Landscape (Terlipressin in HRS-1 With SIRS-Pattern Triage)
US Drug Patent 10,335,452 covers patient-identification and treatment-selection methods that determine whether a person with type 1 hepatorenal syndrome (HRS-1) or impaired renal function associated with liver disease is likely to respond to terlipressin, based on a SIRS-like triad and the exclusion of overt sepsis/septic shock/uncontrolled infection. The claims are method-only, with treatment directed by an algorithm that selectively administers terlipressin and excludes non-eligible patients (and sometimes assigns alternative treatment).
What does US 10,335,452 claim in plain technical terms? (Core method of selecting terlipressin responders)
Claim 1: HRS-1 responder triage using “2 of 3” SIRS criteria + sepsis exclusion
Claim 1 is a closed-loop selection method:
- Identify a plurality of patients as having HRS-1.
- For a first patient, determine the patient exhibits at least two of three criteria associated with systemic inflammation (SIRS-pattern):
- (i) WBC <4,000 or >12,000 cells/mm3
- (ii) heart rate >90 BPM
- (iii) either:
- PaCO2 <32 mmHg, or
- HCO3 <23 mmol/L
- Determine the first patient does not have:
- overt sepsis
- septic shock
- uncontrolled infection
- If the first patient meets 2 of 3 and has no overt sepsis/septic shock/uncontrolled infection, conclude HRS-1 is likely to respond to terlipressin.
- Administer terlipressin at an amount effective to treat HRS-1.
- For a second patient, determine the second patient:
- exhibits only one or none of the three criteria or has overt sepsis/septic shock/uncontrolled infection
- Conclude HRS-1 is unlikely to respond to terlipressin and exclude the second patient from terlipressin.
- For a third patient with overt sepsis/septic shock/uncontrolled infection, exclude from terlipressin.
Claims 15-20: Same triage logic extended to “impaired renal function associated with liver disease”
Claim 15 generalizes the selection method to:
- end-stage liver disease with impaired renal function
- triage based on:
- (i) WBC <4,000 or >12,000
- (ii) heart rate >90
- (iii) either:
- PaCO2 <32, or
- HCO3 <23, or
- tachypnea >20 breaths/min
- then selecting a first patient likely to improve renal function with terlipressin
- and excluding second/third patients not meeting criteria or with overt sepsis/septic shock/uncontrolled infection.
How narrow is the independent claim scope? (Key structural limitations that define infringement boundaries)
1) “2 of 3” requirement is mandatory
Both independent claim families require that the treated “first patient” meets at least two of three criteria.
- WBC is either extreme: <4,000 or >12,000 cells/mm3
- HR is >90 BPM
- criterion (iii) is conditional:
- Claim 1: PaCO2 <32 OR HCO3 <23
- Claim 15: PaCO2 <32 OR HCO3 <23 OR tachypnea >20
If a clinician treats a patient with HRS-1/renal impairment without documenting the patient meets 2 of 3, claim 1 and claim 15 coverage does not attach as written.
2) Sepsis/septic shock/uncontrolled infection exclusion is explicit
The method requires determination that the first patient:
- does not have overt sepsis, septic shock, or uncontrolled infection
And the method requires exclusion of at least two other categories:
- second patient with fewer than two criteria OR any of the overt infection states
- third patient with overt sepsis/septic shock/uncontrolled infection
That exclusion logic matters because it frames this as a treatment-selection algorithm, not a general therapeutic dosing claim.
3) Terlipressin is the only therapeutic in the selection conclusion
The algorithm’s endpoint is a decision that HRS-1/renal function is likely to respond, followed by administering terlipressin to the first patient.
Dependent claims permit another therapy for the excluded patient (claim 2 and claim 17), which reinforces that the patent is about when terlipressin is chosen, not about substituting another drug in the eligible arm.
What are the material dependent claim “dials” that broaden or narrow coverage?
A. Criterion (iii) bicarbonate cut-offs (HCO3)
- Claim 3: criterion (iii) is HCO3 <23 mmol/L
- Claim 4: criterion (iii) is HCO3 <21 mmol/L
- Claim 18: criterion (iii) is HCO3 <23 mmol/L
- Claim 19: criterion (iii) is HCO3 <21 mmol/L
These add specificity. Practically, they create “sub-classes” where an accused method must use the bicarbonate threshold stated.
B. Treatment amounts and administration duration
- Claim 5: 2.0 mg to 12.0 mg/day for 1 to 28 days
- Claim 6: 0.5 mg to 2.0 mg every 4 to 6 hours
- Claim 22: terlipressin dose over 4 to 6 hours: about 0.5 mg to 2.0 mg
- Claim 24: terlipressin dose does not exceed 4.0 mg per 24 hours
- Claim 23: continuous IV drip
These dosing claims are dependent. A method that uses the same selection logic but different dosing could fall outside dependent coverage even if independent selection steps are met.
C. Serum creatinine response-guided continuation/discontinuation
Claims 7-10 and 25-28 create a monitoring-and-stop/go cadence:
- Claim 7: determine if the patient shows a serum creatinine reduction during initial 1 to 4 days
- Claim 8: discontinue if no reduction in initial 1 to 4 days
- Claim 9: continue additional 3 to 12 days if reduction occurs
- Claim 10: treatment produces decrease in serum creatinine to ≤1.5 mg/dL
- Claim 25: baseline serum creatinine within 2 days prior, test at least once within 4 days after starting to see decrease vs baseline
- Claim 26: continue if decreased vs baseline; discontinue if not
- Claim 27: if decreased, continue an additional 3 to 8 days
- Claim 28: after treatment, creatinine tested and found ≤1.5 mg/dL
This monitoring package is the second major pillar of the patent’s practical scope: clinicians that follow an early response algorithm consistent with these time windows and stop rules are more likely to fit the claims.
D. Albumin co-administration cap
- Claim 11: treat with up to 100 g per day albumin for each day terlipressin is administered
This is a dependent add-on. It can become relevant when providers implement a combined regimen that includes albumin at or below that daily cap.
E. Complicating-factor reversal theory and mortality window
- Claim 12: terlipressin provides reversal of one or more complicating factors
- Claim 13: complicating factor includes splanchnic vasodilation
- Claim 14: reversal reduces mortality from associated complication within a 90 day window starting with administering terlipressin
These claims tie mechanistic outcomes (reversal) to clinical endpoints, but they remain dependent on claim 12’s premise, and they rely on what “complicating factors” are proven/recorded in the clinical method.
F. Sepsis exclusions used to drive alternative treatment assignment
- Claim 2: ineligible (second patient) receives a treatment other than terlipressin
- Claim 17: same for claim 15’s second patient
- Claim 20: third patient with overt sepsis/septic shock/uncontrolled infection excluded from terlipressin
These steps can expand practical infringement risk where protocols explicitly assign alternative management rather than simply withholding terlipressin.
G. Patient sub-population: Child-Pugh B or C
- Claim 21: patients have cirrhosis with Child-Pugh B or C
This is a dependent limitation. If an accused protocol applies the algorithm to earlier Child-Pugh stages (A), it may fall outside this dependent sub-scope.
What “scope” does the patent actually cover operationally? (Decision tree)
If the clinician’s workflow matches the following sequence, it is within the claim architecture:
- Diagnosis: HRS-1 (claim 1) or end-stage liver disease + impaired renal function (claim 15).
- Inflammation pattern test: WBC + HR + (PaCO2 or HCO3 or tachypnea for claim 15).
- Eligibility:
- first patient has at least 2 of 3 inflammation criteria
- and has no overt sepsis/septic shock/uncontrolled infection
- Treatment selection:
- administer terlipressin to the first patient
- exclude patients who fail (2 of 3) or who have overt sepsis/septic shock/uncontrolled infection
- Response monitoring (dependent):
- creatinine baseline and early reassessment in 1-4 days (and/or within 4 days)
- stop/go rules based on decrease vs baseline
- continuation windows 3-12 days (or 3-8 days depending on which dependent claim is asserted)
- Optional add-ons (dependent):
- albumin up to 100 g/day
- dosing schedules with specified mg and max mg/24h
- mechanistic outcome framing (splanchnic vasodilation and 90-day mortality reduction)
Patent landscape: what this likely blocks in the US (strategic freedom vs lock-in)
The claims are framed around:
- a patient stratification algorithm using objective inflammation markers
- an exclusion algorithm tied to infection severity
- a terlipressin selection and monitoring regimen
This design is intended to capture a broad clinical playbook while leaving room for:
- other therapies in non-eligible patients (dependent claims explicitly contemplate them)
- additional supportive care beyond albumin (not claimed as required, except by claim 11)
- dosing variations (but dependent claims include specific dosing windows that tighten coverage if matched)
Practical enforcement posture
- Highest-probability enforcement targets protocols that:
- use WBC/HR and PaCO2/HCO3 (or tachypnea) as a triad
- explicitly select terlipressin only for patients meeting 2 of 3
- explicitly exclude overt sepsis/septic shock/uncontrolled infection
- implement early creatinine response stopping rules within 1-4 days
- Lower-probability enforcement where protocols:
- do not use the 2-of-3 structure
- do not exclude overt sepsis/septic shock/uncontrolled infection
- use different early response endpoints/time windows than those specified
- apply different bicarbonate thresholds (for dependent claims 3/4/18/19) or different dosing beyond dependent claim constraints
Landscape implication for competitors
Any US product profile, label strategy, or investigator-led protocol that aims to broaden terlipressin use beyond the claimed decision logic risks creating a direct method claim overlap, particularly if trial protocols collect and apply the same triad and sepsis exclusion and use early creatinine response rules.
Claim inventory: a structured map of independent vs dependent claim content
| Claim type |
Claim numbers |
Scope focus |
Locking limitations |
| Independent |
1 |
Treat HRS-1; select terlipressin responders using 2-of-3 SIRS-pattern + no overt sepsis/septic shock/uncontrolled infection; exclude others |
HRS-1; criteria (i) WBC extreme, (ii) HR >90, (iii) PaCO2<32 or HCO3<23; exclude non-eligible |
| Dependent |
2-14 |
Expand protocol detail around non-terlipressin for excluded patients, criterion (iii) thresholds, dosing, early creatinine stop/go, creatinine targets, albumin limit, complicating factor reversal, mortality window |
HCO3 thresholds; dose windows; monitoring windows; albumin cap; splanchnic vasodilation; 90-day mortality |
| Independent |
15 |
Increase effectiveness of terlipressin in impaired renal function with end-stage liver disease; similar selection logic; includes tachypnea in criterion (iii) |
Renal impairment population; triad includes tachypnea >20 |
| Dependent |
16-28 |
Monitoring during treatment, non-terlipressin for excluded, HCO3 thresholds, sepsis exclusion for third patient, Child-Pugh B/C, dosing modes and maxima, baseline creatinine testing and continuation windows, creatinine endpoint ≤1.5 |
Time windows; Child-Pugh; dosing maxima; continuous IV; creatinine stop/go |
Key takeaways
- US 10,335,452 is a clinical decision method patent centered on terlipressin patient selection for HRS-1 and related impaired renal function in end-stage liver disease using an objective 2-of-3 SIRS-pattern triad (WBC extremes, HR >90, PaCO2/HCO3 or tachypnea) plus explicit exclusion of overt sepsis/septic shock/uncontrolled infection.
- The claims are structured so that independent coverage rests on the triage algorithm and exclusion logic; dependent claims add operational detail on dosing, administration mode, albumin cap, and early creatinine response stop/go rules within specific time windows.
- Protocols that mirror the triad (including the specified thresholds) and the sepsis exclusion and use early creatinine reduction to stop or continue are most exposed; protocols that deviate from the 2-of-3 structure, the infection exclusion, the time windows, or the specified dependent thresholds/doses reduce direct overlap with these dependent layers.
FAQs
1) What is the single most important eligibility gate in claim 1?
Meeting at least two of the three SIRS-pattern criteria and having no overt sepsis, septic shock, or uncontrolled infection.
2) Does claim 15 include tachypnea as an alternative to PaCO2 or HCO3?
Yes. In claim 15, criterion (iii) can be tachypnea >20 breaths/min in addition to PaCO2 <32 and HCO3 <23.
3) What are the early response time windows tied to stopping terlipressin?
Claim 7/8 ties it to the initial 1 to 4 days; claim 25/26 ties it to testing at least once within four days after starting, relative to baseline.
4) What serum creatinine endpoint appears in the patent?
Multiple claims use ≤1.5 mg/dL after treatment (claims 10 and 28), plus reduction vs baseline as a stop/go trigger (claims 7-9 and 25-27).
5) Is albumin required for the core independent method?
No. Albumin is addressed in a dependent claim only: up to 100 g/day during terlipressin therapy (claim 11).
References
[1] United States Patent US 10,335,452, “Method of treating hepatorenal syndrome,” claims 1-28 (provided claim set).
