Details for Patent: 9,326,966

Which drugs does patent 9,326,966 protect, and when does it expire?

Patent 9,326,966 protects RAVICTI and is included in one NDA.

This patent has thirty-four patent family members in twenty-four countries.

Summary for Patent: 9,326,966

Title:	Methods of therapeutic monitoring of nitrogen scavenging drugs
Abstract:	The present disclosure provides methods for evaluating daily ammonia exposure based on a single fasting ammonia blood level measurement, as well as methods that utilize this technique to adjust the dosage of a nitrogen scavenging drug, determine whether to administer a nitrogen scavenging drug, and treat nitrogen retention disorders.
Inventor(s):	Bruce SCHARSCHMIDT, Masoud Mokhtarani
Assignee:	Horizon Therapeutics US Holding LLC
Application Number:	US14/958,259
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,326,966
Patent Claim Types: see list of patent claims	Use; Delivery;

US Patent 9,326,966 (Method for Titrating Glyceryl Tri-[4-Phenylbutyrate] Dosage in Urea Cycle Disorders Based on Fasting Ammonia) Scope, Claims, and Landscape

US Patent 9,326,966 is directed to a dose-titration algorithm for glyceryl tri-[4-phenylbutyrate] (listed reference name in the claims as HPN-100) in patients with urea cycle disorders, using fasting plasma ammonia (and in a broader dependent claim using urinary PAGN) to decide whether to increase an initial dose. The independent claim establishes a decision rule tied to an “upper limit of normal” (ULN) plasma ammonia range of 26–64 μmol/L and increases the dose if the fasting ammonia is > half the ULN. Dependent claims narrow ULN ranges (32–38; 34–36), specify oral dosing, and add an iterative protocol. A separate independent claim covers a BSA-calculated initial dose with subsequent dose adjustment using urinary PAGN and/or fasting plasma ammonia.

What patents protect US 9,326,966’s urea cycle dosing algorithm and how broad is the claim scope?

Core protected concept: use of measured fasting plasma ammonia (and optionally urinary PAGN) to guide whether to increase glyceryl tri-[4-phenylbutyrate] dosing in urea cycle disorder patients, with explicit numeric thresholds.

Independent claim 1: fasting ammonia threshold with ULN range (26–64 μmol/L)

Claim 1 recites a method with these elements:

1. Population/condition
   • Subject with a urea cycle disorder.
2. Prior administration
   • Subject has previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate].
3. Measurement and comparison
   • Measure fasting plasma ammonia.
   • Compare fasting ammonia to the ULN for plasma ammonia.
4. Adjustment trigger
   • Administer adjusted dosage that is greater than the initial dosage if fasting ammonia is greater than half the ULN.
5. ULN numeric constraint
   • ULN is in the range 26–64 μmol/L.

Scope implications

• This is not a claim to a molecule formulation alone. It is an acute algorithm: measure, compare, then dose-increase decision.
• The decision threshold is normalized to the lab’s ULN, but the lab ULN is constrained to 26–64 μmol/L, making the claim both:
  • cross-lab adaptable (because it keys to ULN rather than a fixed ammonia cutpoint), and
  • numerically bounded (a lab ULN outside 26–64 μmol/L would likely fall outside the literal ULN limitation).
• The claim requires the subject’s fasting ammonia be > 0.5×ULN to increase dose. If treatment increases dose under lower values, that could be outside this claim’s literal limitation.

Dependent claims 2–3: tightening the ULN to specific ranges

• Claim 2: ULN 32–38 μmol/L
• Claim 3: ULN 34–36 μmol/L

Scope implications

• These depend on claim 1, so they keep all other elements, but narrow the numeric ULN range. If a competing protocol uses a different ULN range than those specified, it may avoid the dependent claims while still potentially implicating claim 1 (depending on the exact ULN used).

Claim 4: iterative repeating protocol until fasting ammonia ≤ half ULN

• Repeating steps (a) to (c) until fasting plasma ammonia is at or below half ULN.

Scope implications

• This adds a treatment course behavior: repeated dose increases/adjustments until a target threshold is met.
• It creates a stronger infringement narrative for protocols that continue titration rather than a one-time adjustment.

Claims 5, 8, 11, 14, 15: oral administration requirement

These claims specify oral dosing for the adjusted dosage (and for the initial/subsequent doses in claim 12).

Scope implications

• If a competitor administers glyceryl tri-[4-phenylbutyrate] non-orally (e.g., via a different route not satisfying the “oral” limitation), that could be a literal avoidance point. In practice, HPN-100 is typically oral in this therapeutic context, but the claim language creates a clear claim boundary.

Independent claim 6/9 structure: pediatric and adult variants

Claims 6 and 9 are essentially the same algorithmic steps, but explicitly limited to:

• pediatric subjects (claim 6), and
• adult subjects (claim 9).

Scope implications

• This is a typical strategy to ensure enforceability across demographic labeling. The algorithm is the same: adjust dose upward if fasting ammonia exceeds half ULN, with ULN defined identically through the dependency chain to claim 1 (as written in your excerpt).

Claim 12: BSA-based initial dosing with urinary PAGN and/or fasting ammonia guided escalation

Claim 12 recites:

1. Initial effective dosage calculated based on body surface area (BSA)
2. Measurement of urinary PAGN and/or fasting plasma ammonia to decide whether to change dosage
3. Subsequent effective dosage either same or increased
4. Increased dosage is calculated based on urinary PAGN and/or fasting plasma ammonia

Scope implications

• Claim 12 ties dosing to BSA for the initial effective dose. That is a meaningful limitation versus regimens that start with flat dosing or other scaling metrics.
• The dose-change decision uses PAGN (urinary metabolite related to phenylbutyrate therapy) and/or fasting ammonia, broadening the measurement basis beyond ammonia alone.
• Unlike claim 1, claim 12 as presented does not include the explicit ULN range and “> half ULN” trigger in the excerpted independent wording. It is instead “change dosage” and “increased dosage … calculated based on urinary PAGN and/or fasting plasma ammonia.”

Claim 13: repeat dosing steps until fasting ammonia ≤ half ULN

Claim 13 adds iteration and ties back to the half-ULN target concept.

Overall read: what is the “claim spine” of 9,326,966?

• The patent locks onto titration logic rather than composition-of-matter.
• It protects a normalized escalation rule: “increase when fasting ammonia exceeds half the lab ULN,” with ULN bounded to 26–64 μmol/L (and narrower dependent embodiments).
• It also protects body-surface-area initial dosing paired with subsequent adjustment using urinary PAGN and/or fasting ammonia.

How many claim “hooks” does the patent have for infringement, and what design-arounds are most plausible?

Claim hooks that are easiest to satisfy

1. Use of glyceryl tri-[4-phenylbutyrate] in urea cycle disorder.
2. A documented initial dosage, followed by subsequent adjustment.
3. Use of fasting plasma ammonia as a titration metric.
4. Dose increase triggered when fasting ammonia is > half ULN, where ULN falls within 26–64 μmol/L.
5. Use of oral administration (where the asserted claim is a dependent oral claim).

Design-around levers based on the claim text you provided

1. Break the “> half ULN” criterion
   • If dose increases occur only when fasting ammonia exceeds a different threshold (e.g., >0.7×ULN) and the clinician does not increase when ammonia is between 0.5×ULN and that higher threshold, claim 1 may be avoided.
2. Change the ULN parameterization
   • Claim 1 requires ULN in 26–64 μmol/L. A protocol that relies on a lab-defined ULN outside that range could avoid literal compliance with claim 1’s ULN limitation. (In practice, many clinical chemistry references may still land within this band.)
3. Avoid BSA-calculated initial dosing
   • Claim 12 requires initial dosing calculated on body surface area. A regimen that starts with a different calculation metric could reduce exposure to claim 12.
4. Avoid urinary PAGN-driven decisions where claim 12 is asserted
   • If a competitor’s regimen uses only fasting plasma ammonia and never uses urinary PAGN, it could still potentially fall within “and/or” language in claim 12. But the “calculated based on urinary PAGN and/or fasting plasma ammonia” framing gives litigators room to argue whether PAGN is used to calculate increases, depending on how “calculated” is operationalized.

What formulations, delivery systems, or manufacturing IP does 9,326,966 cover?

Based on the claim text you provided, 9,326,966 is not a composition claim focused on:

• specific salt forms,
• particle size,
• release profiles,
• excipient systems, or
• manufacturing steps.

It is a method-of-treatment with a dosing regimen. Any formulation- or manufacturing-only IP would sit in separate patents, typically in earlier generations of HPN-100 portfolios.

Where does 9,326,966 sit in the HPN-100/IP lifecycle versus competing urea cycle disorder therapies?

Competitive technology context

HPN-100 (glycerol tri-[4-phenylbutyrate]) is used in urea cycle disorders as an ammonia-scavenging phenylbutyrate prodrug strategy. Competitive and related products often include:

• sodium phenylacetate/phenylacetate combinations,
• other ammonia scavenging or alternative nitrogen management approaches, and
• other dosing/titration methods for phenylbutyrate-based therapy.

Litigation relevance

For dosing-regimen patents, infringement typically hinges on:

• how clinicians follow labeling,
• how clinical trials are run (protocol-based dose adjustments),
• whether generic or biosimilar entrants (or label expansions) trigger the claimed algorithm through their own prescribing information or trial protocols.

In US litigation, such patents often become leverage points in settlement to change label language or trial titration procedures.

What does the numeric structure imply for patent strength and enforceability?

Strength drivers

• The claims have specific numeric features:
  • ULN range 26–64 μmol/L,
  • escalation trigger > half ULN,
  • narrower dependent ULN ranges 32–38 and 34–36.
• The methodology is operational:
  • fasting plasma ammonia measurement,
  • comparison to ULN,
  • dose increase decision rule,
  • optional iteration until meeting a stopping threshold.

Numeric precision can reduce interpretive ambiguity and can make it easier to prove infringement through chart review and lab value documentation.

Fragility drivers

• If the field standard of care shifts to different titration metrics or thresholds, the patent’s practical reach can narrow.
• If the competitor’s protocol uses different ammonia reference ranges or different target definitions, defenses can be framed around the ULN limitation and “> half” trigger.

What Orange Book status would 9,326,966 have, and why does it matter?

US dosing-regimen patents tied to a specific drug are commonly listed in the Orange Book only when they are associated with an approved NDA/BLA and meet listing rules. Whether 9,326,966 is listed for HPN-100 depends on Orange Book data, which is not provided in your prompt. Without that, you cannot treat 9,326,966 as automatically connected to:

• patent expiry-driven generic timing, or
• Paragraph IV certification workflows.

What generic entry risks exist for urea cycle phenylbutyrate products under a dosing-regimen patent?

A dosing-regimen patent generally does not stop a product from being manufactured and marketed if the generic label does not induce the patented method, or if clinicians are not guided to follow the patented steps. Risk typically arises when:

• the generic product is approved with prescribing language that drives titration consistent with the claims,
• the generic is used in clinical settings where physicians follow titration protocols matching the patent’s algorithm, or
• the patentee can tie infringement to training materials, controlled access protocols, or trial protocols.

What settlement or litigation pattern would be expected for a dosing-titration algorithm?

For regimen patents like this, typical negotiated outcomes include:

• label changes clarifying when dose escalation is or is not recommended based on ammonia values,
• changes to clinical trial titration schedules,
• carve-outs for certain patient subsets or target thresholds,
• timing-based settlements that align with when the claims expire.

Without the patent’s litigation docket history in your input, no case-specific dates can be stated.

Key claim-by-claim scope map (based on your excerpt)

Claim	Patient subset	Trigger metric	Escalation rule	Threshold specificity	Route limitation	Iteration
1	UCD subject (general)	Fasting plasma ammonia vs ULN	Increase dose if fasting ammonia > 0.5×ULN	ULN 26–64 μmol/L	Not limited in claim 1	Not limited
2	Depends on 1	Same	Same	ULN 32–38 μmol/L	Not in 2	Not in 2
3	Depends on 1	Same	Same	ULN 34–36 μmol/L	Not in 3	Not in 3
4	Depends on 1	Same	Continue titration until fasting ammonia ≤ 0.5×ULN	Uses “half ULN”	Not limited	Yes
5	Depends on 1	Same	Same	Same	Oral	Not limited
6	Pediatric	Same	Same	ULN bounded via claim 1 chain	Not limited in claim 6	Not in 6
7	Depends on 6	Same	Continue until ≤ 0.5×ULN	Half-ULN stopping	Not limited	Yes
8	Depends on 6	Same	Same	Same	Oral	Not limited
9	Adult	Same	Same	ULN bounded via claim 1 chain	Not limited in 9	Not limited
10	Depends on 9	Same	Continue until ≤ 0.5×ULN	Half-ULN stopping	Not limited	Yes
11	Depends on 9	Same	Same	Same	Oral	Not limited
12	General patient	Urinary PAGN and/or fasting ammonia	Subsequent dose same or increased; increase is calculated based on PAGN and/or ammonia	No explicit ULN range in excerpt	Initial/subsequent oral in 12 as written (“wherein… is administered orally”)	Not in 12
13	Depends on 12	Same, includes fasting ammonia target	Repeat until ≤ 0.5×ULN	Half-ULN stopping	Not limited	Yes
14	Depends on 12	Same	Same	Same	Oral initial	Not limited
15	Depends on 12	Same	Same	Same	Oral subsequent	Not limited

Timeline and expiration analysis: what are the exclusivity dates for US 9,326,966?

Not computable from the information provided. The patent’s filing date, priority date(s), prosecution history, and terminal disclaimer status are required to compute the expiration date and any PTA-based adjustments.

Key Takeaways

• US 9,326,966 is a method-of-treatment dosing algorithm for glyceryl tri-[4-phenylbutyrate] (HPN-100) in urea cycle disorders.
• The principal escalation rule is: increase dose when fasting plasma ammonia exceeds half of the lab ULN, with ULN limited to 26–64 μmol/L.
• Dependent claims narrow ULN to 32–38 and 34–36 μmol/L, add an iterative titration protocol, and require oral dosing in certain claim sets.
• A separate independent claim protects a regimen that starts with a BSA-calculated initial dose and uses urinary PAGN and/or fasting plasma ammonia to decide whether to keep or increase subsequent dosing.
• Infringement risk concentrates where clinical practice, labeling, or study protocols follow these exact numeric and procedural steps.

FAQs

1. Can increasing HPN-100 dose when fasting ammonia is below half ULN avoid infringement of claim 1?
2. Does claim 12 require urinary PAGN measurement, or is fasting plasma ammonia alone sufficient?
3. How do the ULN ranges in claims 2 and 3 affect design-around strategies by changing lab reference ranges?
4. If a protocol uses BSA only for initial dosing but then adjusts based solely on PAGN, does it still fall within claim 12?
5. What changes to titration cadence (one-time adjustment vs repeated adjustments) affect exposure to claim 4 or claim 13?

Drugs Protected by US Patent 9,326,966

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Horizon Therap Us	RAVICTI	glycerol phenylbutyrate	LIQUID;ORAL	203284-001	Feb 1, 2013	AA	RX	Yes	Yes						TREATMENT OF A UREA CYCLE DISORDER

International Family Members for US Patent 9,326,966

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2012316750
Australia	2017251691
Brazil	112014007357
Canada	2850391
Chile	2014000783
China	104039358