Details for Patent: 9,422,223

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Summary for Patent: 9,422,223

Title:	Compounds and methods for delivery of prostacyclin analogs
Abstract:	This invention pertains generally to prostacyclin formulations and methods for their use in promoting vasodilation, inhibiting platelet aggregation and thrombus formation, stimulating thrombolysis, inhibiting cell proliferation (including vascular remodeling), providing cytoprotection, preventing atherogenesis and inducing angiogenesis.
Inventor(s):	Ken Phares, David Mottola, Roger Jeffs
Assignee:	United Therapeutics Corp
Application Number:	US14/881,379
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,422,223
Patent Claim Types: see list of patent claims	Formulation; Compound; Delivery; Dosage form;

Scope and claim analysis for US Patent 9,422,223 (treprostinil diethanolamine oral exposure/PK profile)

US 9,422,223 is a narrow, PK-performance driven formulation patent. Independent claims cover an oral formulation of treprostinil diethanolamine that achieves (i) clinically relevant absolute oral bioavailability (≥15%), (ii) an exposure-time profile with linearity of Cmax or AUCinf over 8 hours at oral doses ≥0.05 mg, and (iii) sustained plasma exposure (treprostinil ≥50 pg/mL) for ≥8 hours. Dependent claims further narrow to a bioavailability window (21–25%), and to relative bioavailability vs treprostinil free acid (≥50% and ≥100% higher), and they cap or specify dose strengths (0.125 mg, 0.25 mg, 1 mg; and dose ≤2 mg).

Below is a claim-by-claim scope map, then a practical patent-landscape read-through for enforceability and design-around.

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What does US 9,422,223 claim: oral treprostinil diethanolamine with absolute bioavailability ≥15% and 8-hour exposure requirements?

Independent claim 1: Cmax linear increase over 8 hours + exposure threshold

Claim 1 requires all of the following elements:

1. Oral pharmaceutical formulation

   • The claim is product-by-function: it covers a formulation that is administered orally to a human.

2. Active: treprostinil diethanolamine

   • The salt/form selection is explicit. The claim is not written as “treprostinil” generically. It is specifically treprostinil diethanolamine.

3. Absolute oral bioavailability ≥15%

   • Bioavailability must be at least 15% when dosed orally to humans.

4. PK profile element (a): linear increase over 8 hours of Cmax

   • “Linear increase over 8 hours of a Cmax” is a tight, measurable constraint. Practically, it means a study readout where Cmax (as defined in the patent’s study methodology) increases linearly with time across an 8-hour observation window.

5. Dose element

   • Oral dose must be ≥0.05 mg treprostinil diethanolamine.

6. Sustained concentration element (b): treprostinil ≥50 pg/mL for ≥8 hours

   • Treprostinil plasma concentrations must remain at or above 50 pg/mL for at least 8 hours.

Scope implication: If a competitor’s oral treprostinil diethanolamine formulation cannot reproduce the specific exposure-time pattern (linearity of “Cmax” over 8 hours) and sustained concentration threshold for ≥8 hours, it will not fall within claim 1 even if it meets bioavailability ≥15%.

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Independent claim 5: AUCinf linear increase over 8 hours + exposure threshold

Claim 5 is parallel to claim 1 but swaps the “Cmax linear increase” feature for AUCinf:

• Treprostinil diethanolamine oral formulation
• Absolute bioavailability ≥15%
• Oral dose ≥0.05 mg
• Provides linear increase over 8 hours of AUCinf in plasma
• Maintains treprostinil ≥50 pg/mL for ≥8 hours

Scope implication: A formulation that fails the “Cmax linearity” requirement might still potentially infringe claim 5 if it meets the “AUCinf linearity over 8 hours” requirement and all other limitations.

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How do dependent claims narrow US 9,422,223: bioavailability window and relative bioavailability vs free acid?

Bioavailability window dependent claims (claims 2 and 6)

• Claim 2: absolute oral bioavailability 21–25%
• Claim 6: absolute oral bioavailability 21–25%

Scope implication: This is a further narrowing layer. Meeting ≥15% is not enough for these dependents; accused products must land within a specific numerical band.

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Relative bioavailability dependent claims (claims 3–4 and 7–8)

These claims compare treprostinil diethanolamine vs “treprostinil as free acid” under oral dosing.

• Claim 3: diethanolamine oral bioavailability ≥50% greater than free acid
• Claim 4: diethanolamine oral bioavailability ≥100% greater than free acid
• Claim 7: mirrors claim 3 for claim 5’s independent base
• Claim 8: mirrors claim 4 for claim 5’s independent base

Scope implication: These are strong narrowing claims because they require a relative enhancement. In a litigation context, the infringement analysis depends heavily on how “bioavailability of treprostinil as free acid” is measured (same dose, same formulation matrix, and same pharmacokinetic definitions).

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What dose strengths and dose caps are specified: 0.125 mg, 0.25 mg, 1 mg, and ≤2 mg (claims 9–16)?

Specific dose embodiments

• Claims 9 and 12: 0.125 mg treprostinil diethanolamine
• Claims 10 and 13: 0.25 mg treprostinil diethanolamine
• Claims 11 and 14: 1 mg treprostinil diethanolamine

These depend from claim 1 (for 9–11) and from claim 5 (for 12–14).

Dose cap

• Claims 15 and 16: dose no more than 2 mg treprostinil diethanolamine
  • Claim 15 depends from claim 1
  • Claim 16 depends from claim 5

Scope implication: The independent claims already require dose ≥0.05 mg. These dependents impose additional discrete strength or upper-dose constraints that can be leveraged in both infringement and non-infringement arguments.

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What is the practical infringement test for US 9,422,223: formulation + PK thresholds, not just API identity?

US 9,422,223 is not just “treprostinil diethanolamine orally.” It is treprostinil diethanolamine with a specific human PK performance signature:

• Absolute oral bioavailability ≥15%
• For ≥8 hours, treprostinil ≥50 pg/mL
• Over an 8-hour window:
  • Claim 1: “linear increase” in Cmax
  • Claim 5: “linear increase” in AUCinf
• Dose ≥0.05 mg

What matters for claim construction and evidence (high-level):

• “Absolute bioavailability” and “linear increase” are measurement-defined limitations. Litigation will focus on the PK study design and data processing consistent with the patent’s definitions.
• “Maintains a concentration … at least 50 pg/ml for at least 8 hours” is a direct numerical threshold and time-above-threshold parameter.
• The dependent claims create additional numerical narrowing that can be decisive if the accused formulation’s bioavailability sits outside 21–25% or its relative enhancement vs free acid is below the claimed multiples.

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How strong is the patent estate around this concept: what types of other patents typically coexist (formulation, salt, PK/ED profile, manufacturing)?

Even without enumerating the entire US family here, US 9,422,223’s claim structure suggests the surrounding landscape is likely clustered into several predictable invention buckets:

1) Treprostinil salt-form and conversion patents

Because the independent claims explicitly require treprostinil diethanolamine, adjacent patents often include:

• Solid-state forms of treprostinil diethanolamine (hydrates, polymorphs, amorphous forms)
• Processes for preparing the diethanolamine salt
• Stability and conversion control from other treprostinil forms into diethanolamine in vivo or during formulation handling

2) Oral dosage-form enablement patents

The claims do not recite excipients or device features in the text provided, but in practice many companion patents cover:

• Matrix types, release mechanisms (immediate vs modified release)
• Tablet/capsule compositions and process parameters
• Particle size, solubilizers, surfactants, and absorption enhancers used to hit absolute bioavailability ≥15%

3) PK/PD profiling patents

The core of 9,422,223 is PK performance with defined thresholds and time windows. This class of patents often coexists with:

• Additional claims on alternative endpoints (tmax, Cavg, time above threshold, partial AUC)
• Comparable performance thresholds at different dose bands
• Method-of-treatment claims tied to exposure or clinical response, when tied to a specific dosing regimen

4) In vitro dissolution / in vivo correlation patents

If the claimed performance is tied to oral absorption, some patents in the portfolio likely include dissolution targets intended to reproduce bioavailability and the 8-hour exposure window.

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What generic entry risks exist for treprostinil diethanolamine oral drugs covered by 9,422,223?

Primary risk: “same salt” and “same dose” is not enough

To be at risk under claims 1 or 5, a generic or follow-on must meet:

• Absolute oral bioavailability ≥15%
• Sustained treprostinil ≥50 pg/mL for ≥8 hours
• Linear increase over 8 hours in either Cmax or AUCinf (depending on claim)

So an abbreviated applicant may face a PK mismatch risk even if it matches:

• Strength labeling (e.g., 0.125 mg, 0.25 mg, 1 mg)
• Qualitative salt identity (treprostinil diethanolamine)

Higher risk: dependents can defeat “near-miss” generics

If the accused formulation lands in a different bioavailability range than 21–25%, or provides less than the required relative bioavailability increase vs free acid, it can avoid the narrower dependent claims while still potentially testing independent claim exposure elements.

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What design-arounds are plausibly outside the claim boundaries (based on limitation toggling)?

A competitor seeking non-infringement typically targets one or more of the hardest-to-match elements:

• Lower absolute oral bioavailability below 15%
• Fail sustained exposure (treprostinil <50 pg/mL before 8 hours)
• Break the “linear increase over 8 hours” requirement for Cmax (claim 1) or AUCinf (claim 5) by altering release kinetics
• Move outside dependent bioavailability band (avoid 21–25%)
• Avoid relative bioavailability multipliers vs free acid (<50% or <100% enhancement)
• Use dose strengths or dose regimes that do not satisfy the dependent strengths (0.125 mg / 0.25 mg / 1 mg) or the ≤2 mg upper limit (though independent claims still cover any dose ≥0.05 mg)

The claim set is therefore as much about clinical-magnitude exposure as it is about the identity of treprostinil diethanolamine.

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What to look for in Orange Book-style regulatory listings and FDA dossiers for this patent?

Without the drug product name and Orange Book listing for the specific treprostinil diethanolamine product, this analysis cannot tie US 9,422,223 to particular listed strengths or NDA/BLA entries. The claim itself indicates the patent is most relevant where oral treprostinil diethanolamine achieves:

• ≥15% absolute bioavailability
• dosing at or above 0.05 mg
• exposure staying above 50 pg/mL for 8 hours
• PK linearity properties

In practice, a licensing or challenge strategy usually tests candidate products against these PK thresholds during BE/clinical bridging. That is the most direct evidentiary path to infringement or non-infringement.

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Key takeaways

• US 9,422,223 is a treprostinil diethanolamine oral PK-performance patent, not a broad salt-or-formulation claim.
• Independent claim 1 requires: oral treprostinil diethanolamine, ≥15% absolute bioavailability, dose ≥0.05 mg, linear Cmax increase over 8 hours, and ≥50 pg/mL treprostinil for ≥8 hours.
• Independent claim 5 uses the same scaffold but requires linear AUCinf increase over 8 hours instead of Cmax.
• Dependent claims tighten exposure numerically: 21–25% bioavailability and ≥50% or ≥100% relative bioavailability vs treprostinil free acid.
• Dose-related dependents specify 0.125 mg, 0.25 mg, 1 mg and dose ≤2 mg, offering discrete litigation handles.
• Generic risk hinges on PK matching. Matching salt identity and strength alone is unlikely to be sufficient to avoid a careful comparison to the claimed bioavailability and time-above-threshold parameters.

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FAQs

1. Does US 9,422,223 require modified-release technology or just PK outcomes?
   The claim is written to PK outcomes (bioavailability, linearity over 8 hours, and concentration threshold), so it is not limited by a specific release mechanism in the claim text provided.

2. Can a formulation that achieves ≥15% bioavailability still avoid infringement?
   Yes if it fails any required limitation, especially the 8-hour “linear increase” of Cmax (claim 1) or AUCinf (claim 5) or the ≥50 pg/mL concentration maintained for ≥8 hours.

3. How do the “relative bioavailability vs free acid” dependents change the infringement burden?
   They add a comparative numeric enhancement requirement; a product can meet ≥15% absolute bioavailability yet fail the ≥50% or ≥100% relative enhancement requirements.

4. Is the 50 pg/mL threshold tied to treprostinil measurement units and timing?
   The claim specifies “maintains a concentration of treprostinil … at least 50 pg/mL for at least 8 hours,” making both the assay threshold and duration material.

5. Do the dose-strength dependent claims limit the independent claims?
   The independent claims apply broadly to doses ≥0.05 mg. The dependent strength and dose-cap claims further narrow coverage for specific strength embodiments, which can matter in infringement mapping and in design-around discussions.

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References

1. United States Patent 9,422,223. (Claims excerpt provided in prompt text).

Drugs Protected by US Patent 9,422,223

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 9,422,223

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2526534
Canada	2736406
Canada	2851309