Details for Patent: 7,544,713

Summary for Patent: 7,544,713

Title:	Compounds and methods for delivery of prostacyclin analogs
Abstract:	This invention pertains generally to prostacyclin analogs 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. Generally, the compounds and methods of the present invention increase the oral bioavailability and circulating concentrations of treprostinil when administered orally. Compounds of the present invention have the following formula:
Inventor(s):	Ken Phares, David Mottola
Assignee:	United Therapeutics Corp
Application Number:	US11/603,116
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,544,713
Patent Claim Types: see list of patent claims	Use; Delivery;

Executive summary: U.S. Patent 7,544,713 is directed to oral small-molecule treatment regimens for pulmonary hypertension and peripheral vascular indications using a “compound of Structure II” with a tightly constrained substitution framework on R1, R2, and R3 (non-trivial requirement that R1, R2, and R3 are not all H), plus claim dependent coverage for oral bioavailability advantages vs treprostinil, optional P-glycoprotein inhibition, and specific solid-state/physical-parameter product forms (melting point and XRPD). The independent claim scope is method-centric (treating via oral administration) and is built to capture both formulated/chemical variation (prodrug-like groups such as phosphate and amino-acid ester substituents) and administration strategies (co-dosing with P-gp inhibitors; salt/enantiomer coverage).

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What is U.S. Patent 7,544,713 and what does it claim for oral pulmonary hypertension therapy?

Featured snippet answer: U.S. 7,544,713 claims methods of treating pulmonary hypertension by orally administering a pharmaceutically effective amount of a compound of Structure II with defined substituent ranges (R1 includes alkyl/arylalkyl/glycolamide ester-forming groups; R2/R3 include H, phosphate, and amino-acid/protein ester-forming groups), with a constraint that R1, R2, and R3 are not all H, plus dependent coverage for higher oral bioavailability than treprostinil, P-gp inhibitor co-administration, and solid-state attributes for certain embodiments.

Core legal claim architecture

The claim set you provided shows a common structure:

1. Independent method claims (pulmonary hypertension) using oral administration of a Structure II compound.
2. Dependent claims narrowing substituents (R1 variants; amino-acid/phosphate patterns).
3. Performance/PK-oriented dependent claims (bioavailability relative to treprostinil).
4. Co-therapy dependent claims (P-gp inhibitors).
5. Solid-state dependent claims for the compound (melting point; XRPD peak position).
6. Second independent expansion for peripheral vascular disease and multiple mechanistic endpoints, still via oral administration of the same Structure II chemistry.

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How broad is the “Structure II” substituent scope in claim 1 (R1, R2, R3) and what boundary conditions matter?

Featured snippet answer: Claim 1 covers an oral pulmonary hypertension method using a Structure II compound where R1 can be H or substituted/unsubstituted alkyl or arylalkyl or a glycolamide-ester-forming substituent, and R2/R3 can be H, phosphate, or amino-acid/protein ester-forming substituents, with a prohibitory proviso that not all of R1, R2, R3 are H. It also covers enantiomers and pharmaceutically acceptable salts.

Claim 1 substituent ranges (directly from your text)

R1 is independently selected from:

• H
• substituted and unsubstituted alkyl groups
• arylalkyl groups
• groups wherein OR1 form a substituted or unsubstituted glycolamide ester

R2 and R3 are independently selected from:

• H
• phosphate
• groups wherein OR2 and OR3 form esters of amino acids or proteins

Critical boundary condition:

• “with the proviso that all of R1, R2 and R3 are not H”

Practical impact for infringement mapping

1. Not-all-H proviso is the key limiting condition. A design that yields the same “Structure II” scaffold but effectively makes R1=H and R2=H and R3=H would fall outside claim 1.
2. Choice flexibility is high because:
   • each of R1, R2, R3 is “independently selected” within broad lists; and
   • claim 1 already includes “H” for each position, so a large number of specific analogs still satisfy the proviso by having at least one non-H element (phosphate or an amino-acid ester group; or a glycolamide ester form on R1; or non-H on R1).

Salt and enantiomer coverage

Claim 1 explicitly includes:

• “enantiomers thereof”
• “pharmaceutically acceptable salt”

That matters for both chemical design-around and claim capture for common clinical variants.

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Which dependent claims narrow R1, and how much chemical design space do they still leave?

R1 when it is glycolamide-ester-forming (claims 2–4)

• Claim 2: if OR1 forms a glycolamide ester, then
  • R1 is —CH2CONR4R5
  • R4/R5 independently are H, OH, alkyl, —(CH2)mCH3 (m=0–4), —CH2OH, —CH2(CH2)nOH (n=0–4)
• Claim 3: R1 is C1–C4 alkyl
• Claim 4: R1 is methyl/ethyl/propyl/butyl

Effect:

• Claims 3–4 narrow R1 to simple alkyls.
• Claim 2 covers a larger class but with a specific glycolamide motif for R1.

R1 when it is benzyl (claims 5–6)

• Claim 5: R1 is a substituted or unsubstituted benzyl group
• Claim 6: R1 is —CH3 or —CH2C6H5

Effect:

• This is narrower and can be leveraged to argue non-infringement for non-benzyl R1 analogs; however, it is dependent, so it only matters for embodiments that fall within claim 5–6.

R4/R5 restriction (claim 7)

• Claim 7: R4 and R5 independently are H, OH, —CH3, or —CH2CH2OH

Effect:

• Additional narrowing inside the glycolamide branch.

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How do claims 8–15 constrain R2 and R3 patterns (phosphate vs amino-acid esters)?

Featured snippet answer: Dependent claims specify combinations of H, phosphate, and amino-acid (dipeptide to tetrapeptide) ester-forming substituents at R2 and/or R3, including limits like “only one of R2 or R3 is phosphate” and specific amino-acid targets like glycine or alanine.

Pattern-based narrowing

• Claim 8: one or both of R2 and R3 are H
• Claim 9: if not H, then R2/R3 are independently phosphate or amino-acid/protein ester groups, covering esters of:
  • amino acids
  • dipeptides
  • tripeptides
  • tetrapeptides
• Claim 10: only one of R2 or R3 is phosphate
• Claim 11: R2 and R3 are amino-acid ester groups
• Claim 12: one or both are esters of glycine or alanine
• Claim 13: one of R1 is H
• Claim 14: one of R1 and R2 is H
• Claim 15: R2 is H (and depends on claim 14)

Effect on coverage:

• The dependent claims make it easier to prove infringement if a commercial product uses (for example) phosphate only on one position or uses glycine/alanine esters.
• From a validity/design-around perspective, these dependent limitations can be used to argue that certain analogs fall outside those narrower embodiments, while still leaving claim 1 potentially asserted for the broader class.

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What is the bioavailability scope vs treprostinil in claims 16–18, and how is it likely to be litigated?

Featured snippet answer: Claims 16–18 add a performance requirement: the oral Structure II compound must have oral bioavailability greater than treprostinil, including thresholds of at least 50% greater and at least 100% greater.

Claim language (as provided)

• Claim 16: oral bioavailability of compound is > treprostinil
• Claim 17: ≥ 50% greater
• Claim 18: ≥ 100% greater

Litigation significance

These “relative bioavailability” limitations can become the focal point for:

• expert-driven pharmacokinetic proof (Cmax/AUC-based metrics depend on how the specification defines “oral bioavailability”)
• comparative study design (species, fed/fasted, formulation, dosing, analytical methods)
• data availability: whether the accused formulation matches the tested compound form.

From a patent landscape standpoint, they also create a class of “strong evidence” infringement theories when the developer has published comparative PK results.

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How do P-glycoprotein inhibitor co-administration claims (19–22) expand method coverage?

Featured snippet answer: Claims 19–22 broaden infringement by adding a co-therapy option: orally administered P-glycoprotein (P-gp) inhibitor administered simultaneously with, prior to, or orally/IV, alongside the oral Structure II compound.

Claim set

• Claim 19: method further comprises administering pharmaceutically effective amount of P-gp inhibitor
• Claim 20: simultaneous with compound of Structure II
• Claim 21: prior to compound administration
• Claim 22: inhibitor administered orally or intravenously

Practical implications

1. Regimen flexibility: infringement can be triggered by sequencing (simultaneous vs prior) and delivery route (oral or IV).
2. Design-around: avoiding P-gp inhibitor co-administration may reduce exposure for the P-gp-specific dependent claims, but not necessarily for the base claim 1/23 method coverage.

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What do claims 23–26 add: peripheral vascular disease indications and specific solid-state characteristics?

Peripheral vascular disease / pleiotropic mechanistic language (claim 26 context via claim 23 and 26)

• Claim 23: method of treating pulmonary hypertension by oral administration (note: your text shows claim 23 is pulmonary hypertension; claim 26 then addresses peripheral vascular disease).
• Claim 26: method of treating peripheral vascular disease and a list of pharmacodynamic outcomes:
  • promoting vasodilation
  • inhibiting platelet aggregation and thrombus formation
  • stimulating thrombolysis
  • inhibiting cell proliferation
  • providing cytoprotection
  • preventing atherogenesis
  • inducing angiogenesis

Still uses “orally administering… a pharmaceutically effective amount of a compound of structure II” with the same R1/R2/R3 constraints.

Effect:
The indication expansion can increase licensing leverage and litigation surface because multiple off-label/label-like mechanistic endpoints can be framed within the same independent method claim structure (depending on whether the claim is interpreted as requiring “treating peripheral vascular disease” specifically or whether downstream physician use arguments attempt to map endpoints).

Solid-state dependent constraints (claims 24–25)

• Claim 24: compound melts at about 107°C
• Claim 25: XRPD peak at about 17.2 degrees 2θ

Effect:

• These claims tend to attach to specific polymorphs/solid forms or formulations with a defined crystalline structure.
• For generics or reformulated products, solid-state characterization (DSC/melting point; XRPD) becomes central.

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How many “distinct invention routes” does U.S. 7,544,713 cover, based on the claim set you provided?

From the wording you shared, the patent is effectively built from at least five separable claim “routes”:

1. Base chemical-method route: oral treating pulmonary hypertension with Structure II, flexible substituents (claim 1).
2. Substituent-structure route: dependent refinement of R1/R2/R3 combinations (claims 2–15).
3. Oral PK/performance route: relative oral bioavailability versus treprostinil (claims 16–18).
4. Regimen route: P-gp inhibitor co-administration sequencing/route (claims 19–22).
5. Product/solid-state route: specific melting point and XRPD peak (claims 24–25), plus indication expansion to peripheral vascular disease outcomes (claim 26).

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What does the claim language imply about the underlying drug concept (prodrug-like phosphate/amino-acid esters and glycolamide esters)?

Even without the explicit Structure II drawing, the substituent definitions signal a design that likely:

• uses phosphate and amino-acid ester groups at R2/R3, consistent with prodrug strategies for oral absorption; and/or
• uses glycolamide ester functionality at R1.

The presence of P-gp inhibitor dependent claims and the explicit comparison to treprostinil indicate the patent is written around oral bioavailability barriers (absorption and/or efflux), aiming to improve the oral PK profile.

This combination is consistent with a patent strategy that attempts to capture both:

• the chemical scaffold variations that enable improved oral exposure; and
• the clinical administration strategy to realize that exposure.

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Patent landscape for U.S. 7,544,713: what is likely claim-adjacent and how does it affect freedom-to-operate?

You did not provide:

• the patent’s specification text,
• the identity of “compound of structure II” (actual chemical name),
• the assignee,
• the publication number(s) (US pregrant, PCT publication),
• related family members,
• or any Orange Book / litigation context.

Without those, no accurate, source-cited landscape can be produced. This response therefore limits itself to claim-constructed landscape mechanics: the patent’s claim features identify what adjacent patent categories and infringement proof elements will dominate a landscape review.

Claim-constructed adjacent categories companies typically face

1. Core scaffold patents (covering Structure II chemistry more generally)
2. Prodrug/ester-form substitution patents (phosphate vs amino-acid ester permutations)
3. Oral formulation patents (solid form, excipients, amorphous vs crystalline)
4. Crystalline form patents (matching melting point and XRPD peaks)
5. PK strategy patents (bioavailability enhancements relative to treprostinil)
6. Transporter modulation patents (P-gp inhibition combinations)

Because 7,544,713 already asserts method-of-use plus physical form parameters, it increases the likelihood that a challenge will split along:

• chemical identity (Structure II match),
• solid-state match,
• and comparative oral bioavailability proof.

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Key Takeaways

• U.S. 7,544,713 is a method-of-treatment patent for oral pulmonary hypertension (and peripheral vascular disease) using a Structure II compound defined by broad but constrained substituent lists on R1, R2, R3 with the key proviso that not all R1, R2, R3 are H.
• Dependent claims narrow:
  • R1 into alkyl (including C1–C4), benzyl variants, and a glycolamide ester-forming motif.
  • R2/R3 into patterns including phosphate vs amino-acid/peptide esters (including glycine/alanine).
• The claim set includes oral bioavailability advantage limitations vs treprostinil (greater than; ≥50% greater; ≥100% greater).
• It adds P-gp inhibitor co-administration coverage with sequencing and route flexibility (oral or IV).
• It includes solid-state dependent limitations (melting point ~107°C; XRPD peak ~17.2° 2θ), which can be decisive for product-form infringement and invalidity strategies targeting polymorph definitions.
• Indication and mechanistic language broadens the potential commercial and litigation footprint beyond pulmonary hypertension.

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FAQs

1. Does claim 1 require P-glycoprotein inhibitor co-administration?
   No. P-gp inhibitor appears in dependent claims (19–22).

2. Can a product avoid infringement by removing phosphate or amino-acid ester groups?
   Claim 1 still permits R1 non-H choices and allows H at R2/R3; only the “not all H” proviso constrains the combination.

3. How do claims 16–18 change the infringement standard compared with ordinary method claims?
   They add a comparative oral bioavailability threshold versus treprostinil, requiring PK evidence tied to the tested dosing/form.

4. Do the melting point and XRPD claims target the active ingredient or a formulation?
   The dependent claims reference the compound’s physical properties (melting point; XRPD peak), typically aligning with specific solid-state forms of the active.

5. What is the practical significance of “enantiomers” and “pharmaceutically acceptable salts” in claim 1?
   It expands coverage to stereoisomeric variants and salt forms of the Structure II compound, limiting common product-design carveouts.

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References

No external sources were cited because the prompt supplied only the claim text and did not provide bibliographic identifiers, assignee, specification, prosecution history, Orange Book listings, or litigation records.

Drugs Protected by US Patent 7,544,713

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 7,544,713

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2526534
Canada	2736406
Canada	2851309
Canada	2959852
China	100558351
China	101265226