Details for Patent: 8,497,393

Which drugs does patent 8,497,393 protect, and when does it expire?

Patent 8,497,393 protects ORENITRAM and is included in one NDA.

This patent has fifteen patent family members in seven countries.

Summary for Patent: 8,497,393

Title:	Process to prepare treprostinil, the active ingredient in Remodulin®
Abstract:	This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.
Inventor(s):	Hitesh Batra, Sudersan M. TULADHAR, Raju Penmasta, David A. Walsh
Assignee:	United Therapeutics Corp
Application Number:	US13/548,446
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,497,393
Patent Claim Types: see list of patent claims	Compound; Process;

Scope and Claims Analysis for US Patent 8,497,393 (Formula I/Formulation Process Claims) and US Patent Landscape

US Patent 8,497,393 is a US composition-and-process patent that anchors protection on a specific chemical scaffold (formula I) and, critically, on a defined synthetic process chain: (1) alkylation of a precursor “compound of structure II” with specified alkylating agents to form an intermediate of formula III, (2) base hydrolysis to convert formula III to the corresponding hydrolyzed species, and (3) conversion into a salt of formula Is (and optionally formation of the free base or another acid salt of formula I). Claims also include product-quality constraints (≥99.5% purity) and define salt-forming base/acid selections.

This claim set is built to provide enforcement leverage not only against the final API (formula I) but also against manufacturers who follow the same stepwise route or produce specific intermediates without purification. Below is a claim-by-claim scope dissection, coverage map of likely claim “hooks,” and what the estate generally implies for freedom-to-operate against generics (small-molecule) that replicate the API via alternative routes or bypass intermediates.

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What does US Patent 8,497,393 claim protect: compound of formula I, salts, or the manufacturing process?

Answer: It protects (i) the product (formula I and pharmaceutically acceptable salts) and (ii) a specific manufacturing method used to make it, with enforcement strengthened by process step definitions and product purity thresholds.

Product scope: formula I and pharmaceutically acceptable salts

The independent claim 1 is drafted as a product comprising “a compound of formula I or a pharmaceutically acceptable salt thereof,” but it is expressly limited by the product’s preparation: the product is “prepared by a process comprising” the alkylation, hydrolysis, and salt formation steps (a) through (c), with optional acid conversion in (d).

Legal effect: even though claim 1 is “a product comprising,” it includes process limitations that can narrow infringement proof to products manufactured by the specified process chain, depending on claim construction and the applicable standards in the forum.

Process scope: three-step core route

Independent claim 1 requires:

1. Step (a) Alkylation

   • Alkylate a “compound of structure II” with an alkylating agent to yield a compound of formula III.
   • The claim defines multiple sub-parameters:
     • w = 1, 2, or 3
     • Y1 can be trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C— with m = 1, 2, or 3
     • R7 enumerates multiple substituent classes and constrained provisos
     • “—C(L1)—R7 taken together” can be a constrained set of cycloalkyl/heteroaryl-ether-like substituents
     • M1 and stereochemical/protecting group-related parameters constrain the hydrolysis precursor identity

2. Step (b) Hydrolysis

   • Hydrolyze the step (a) product of formula III “with a base.”

3. Step (c) Salt formation

   • Contact the hydrolyzed product with base B to form a salt of formula Is.

4. Step (d) Optional acid conversion

   • Optionally react the salt from (c) with an acid to form the compound of formula I.

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How broad are the claim 1 substituent definitions (R7, Y1, M1, w) and what do the provisos do?

Y1 and w: broad conjugation/spacing variation, limited enumerations

• w = 1–3 expands homolog spacing for the alkyl chain linking motif(s).
• Y1 is limited to four structural families:
  • trans-alkene: trans-CH═CH—
  • cis-alkene: cis-CH═CH—
  • alkyl chain: —CH2(CH2)m— where m = 1–3
  • alkyne: —C≡C—

This is not open-ended. It captures multiple chemotypes but only within predefined substitution pattern families.

R7: broad listing with multiple “not more than two substituents” provisos

R7 is defined by six enumerated options plus multi-parameter constraints when certain groups are chosen:

1. Alkyl-capped cycloalkyl: (1) —CpH2p—CH3, p = 1–5
2. Substituted phenoxy: (2) phenoxy optionally substituted by up to three of:
   • chloro, fluoro, trifluoromethyl,
   • C1–C3 alkyl,
   • C1–C3 alkoxy
     with constraints:
   • “not more than two substituents are other than alkyl”
   • and a gating proviso:
     • R7 is phenoxy or substituted phenoxy only when R3 and R4 are hydrogen or methyl (same or different)
3. Substituted phenyl/benzyl/phenylethyl/phenylpropyl class: (3) phenyl, benzyl, phenylethyl, phenylpropyl optionally substituted by up to three of:
   • chloro, fluoro, trifluoromethyl,
   • C1–C3 alkyl,
   • C1–C3 alkoxy
     with proviso: “not more than two substituents are other than alkyl”
4. cis-alkenyl-butyl: (4) cis-CH═CH—CH2—CH3
5. β-hydroxy alkyl fragment class: (5) —(CH2)2—CH(OH)—CH3
6. isopropenyl-like fragment: (6) —(CH2)3—CH═C(CH3)2

These R7 rules matter in two ways:

• They define which analogs are captured by formula I.
• They reduce risk of overbreadth arguments but tighten chemical scope to the enumerated family.

“—C(L1)—R7 taken together” is a second gating mechanism

R7 does not stand alone; it is tied to “—C(L1)—” with a joint set of options:

1. A (C4–C7) cycloalkyl, optionally substituted by 1–3 (C1–C5) alkyl
2. 2-(2-furyl)ethyl
3. 2-(3-thienyl)ethoxy
4. 3-thienyloxymethyl

This coupling can narrow infringement against close analogs where either the cycloalkyl/heteroaryl arrangement or the L1 connection differs.

M1: stereochemical hydrolyzable precursor identity and protecting group constraints

M1 is constrained to combinations of α/β hydroxy and substituent patterns plus an alcohol protecting group:

• α-OH:β-R5 or α-R5β-OH or α-OR1:β-R5 or α-R5:β-OR2
• R5 = hydrogen or methyl
• R2 is an alcohol protecting group
• L1 is α-R3:β-R4, α-R4:β-R3, or mixture
• R3 and R4 are H, methyl, or fluoro with a proviso:
  • one of R3/R4 can be fluoro only when the other is H or fluoro (same-or-different allowed, but not “fluoro + other non-H/non-fluoro”)

Enforcement implication: the claimed process is not just any hydrolysis. It is tethered to specific precursor stereochemistry and protecting group placement. A competitor route that uses a different protected intermediate or a different deprotection order may avoid process-claim infringement.

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Which alkylating agents and bases does claim 1 lock down, and how do dependent claims tighten it?

Alkylating agent flexibility in claim 1 vs specificity in claim 3

Claim 1 (in its text here) is “alkylating… with an alkylating agent” but dependent claim 3 narrows alkylating agents to:

• Cl(CH2)wCN, Br(CH2)wCN, or I(CH2)wCN (with w tied to claim 1’s w = 1–3 framework)

Dependent claim 11 narrows for claim 9’s route to ClCH2CN.

Enforcement implication: If accused manufacturers use a different alkylating chemistry (e.g., different electrophile, different leaving group pattern, different cyanomethylene equivalent), they can design around the dependent claim scope even if the independent claim’s language is broader.

Base in step (b) (hydrolysis/base hydrolysis) defined in claim 4

Claim 4 specifies:

• step (b) base is KOH or NaOH

Claim 19 and 20 repeat the KOH/NaOH scope with additional base B selections for step (c).

Salt-forming base B lists (claim 5, repeated in claim 13/17/19/20)

Claim 5 defines base B options:

• ammonia
• N-methylglucamine
• procaine
• tromethanine
• magnesium
• L-lysine
• L-arginine
• triethanolamine
• diethanolamine

Dependent claims also specify particular bases:

• claim 14: base B is diethanolamine
• claim 18 repeats diethanolamine
• claim 13 and claim 17 list the same set with claim 17 including an error (“L-lysinc”) in the provided text, but the intended category is clear.

Acid in step (d): claim 6 restricts

Claim 6:

• acid is HCl or H2SO4

Dependent claim 15:

• acid is HCl

Enforcement implication: to design around, generic/API makers can pursue salt forms that fall outside this acid set, or they can stop at an Is-type salt rather than converting to formula I via an HCl/H2SO4 step (depending on how infringement is assessed for optional steps).

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What is the significance of claim 2’s purity requirement (≥99.5%) for infringement?

Claim 2:

• product purity of compound of formula I in said product is at least 99.5%

This creates an additional, measurable feature. For enforcement, it may require proof of assay/purity in the commercial product batch. For design-around, it can be used as a lever if a competitor can manufacture with different impurity profiles or lower claimed purity, though FDA-relevant specs may undermine such a path.

In practice, a purity limitation can convert what would be a straightforward “making method” dispute into an evidentiary and sampling-heavy fight.

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What does claim 7 and claim 8 add: narrow positional variants and “no purification” process protection?

Claim 7: a specific embodiment of formula features

Claim 7 fixes:

• Y1 = —CH2CH2—
• M1 = α-OH:β-H or α-H:β-OH
• “—C(L1)—R7 taken together is —(CH2)4CH3”
• w = 1

This is a concrete sub-range inside claim 1’s broader scaffold. It gives the patentee a fallback narrower target.

Claim 8: process route without purifying formula (III)

Claim 8:

• the process does not include purifying the compound of formula (III) produced in step (a)

This is important. Many industrial routes isolate intermediates; this dependent claim claims the route where intermediate III is carried forward without purification.

Enforcement implication: a competitor who purifies intermediate III before hydrolysis may be outside claim 8, but could still fall within claim 1 if the independent claim does not require no purification.

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What does claim 9 protect: formula IV with the same alkylation-hydrolysis-salt chain?

Independent claim 9 similarly protects a product comprising a compound of formula IV or its pharmaceutically acceptable salt, made via:

• alkylation of “formula V” to produce “formula VI”
• hydrolysis with base
• salt formation with base B to form formula IVs
• optional acid conversion to formula IV

The dependent claims mirror the same structure:

• claim 10: purity ≥99.5% for step (d) product
• claim 11: alkylating agent is ClCH2CN
• claim 12: base in step (b) is KOH
• claim 13: base B options list (same as claim 5)
• claim 14/18: base B is diethanolamine
• claim 15: acid is HCl
• claim 16: no purification of formula (VI) produced in step (a)
• claim 17 repeats base B list with a long list including diethanolamine again
• claims 19 and 20 tie KOH/NaOH in step (b) with specified B lists

Enforcement implication: claim 9 expands the estate to an additional scaffold/formula family, likely close structural neighbors or stereoisomeric/protecting-group alternatives.

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What patents and claims are “most actionable” inside this estate for litigation or licensing?

Based on the provided claim text, the most enforceable “hooks” are:

1. Stepwise route constraints (alkylation → hydrolysis → salt formation → optional acid conversion)
   These can be tested via discovery: batch records, DMF/DoE documents, synthetic schemes, IPC transfer steps, and salt formation logs.

2. Salt-forming agent specificity (base B) and acid specificity
   Base B list is narrow enough for proof and has commercial relevance because salt screening and selection are documented.

3. Purity limitations (≥99.5%)
   Useful for distinguishing accused products and for pushing defendants into assay-based disputes.

4. “No purification of intermediate (III or VI)”
   This affects how the synthetic sequence is executed at manufacturing plant scale and creates a process fingerprint.

5. Specific alkylating agents (claim 3 and claim 11)
   If an accused manufacturer uses those exact electrophiles, the patent’s dependent claims become strong anchors.

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How does US Patent 8,497,393 compare with a typical US generic design-around strategy?

Likely generic/API design-around levers

For small-molecule generics, typical pathways to reduce risk under this claim set include:

• Use an alternative alkylating agent (not Cl/Br/I(CH2)wCN or ClCH2CN).
• Use a different hydrolysis base than KOH/NaOH (if only dependent claims specify it, it may still avoid some enforcement theories depending on construction).
• Avoid the enumerated base B for salt formation, or form a different salt not captured by “Is” from those bases.
• Avoid optional step (d) acid conversion to HCl or H2SO4 if the accused product is marketed/stored as a non-matching salt.
• Purify intermediate III/VI (avoid “no purification” dependent claim 8/16).
• Target a route that does not pass through the claimed formula III/VI intermediate identity (if a different intermediate or order is used).

Risk profile if the generic matches the process chain

If an accused generic follows:

• cyanomethyl-type alkylation with the listed electrophiles,
• base hydrolysis with KOH/NaOH,
• salt formation with one of the listed bases,
• optional conversion to HCl/H2SO4 form,

then the infringement likelihood increases, because the claim reads like a manufacturable recipe.

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What does the estate likely mean for Paragraph IV challenges, Orange Book status, and exclusivity?

This requires Orange Book and FDA labeling linkage, but the provided prompt does not include:

• the listed drug name(s) associated with US 8,497,393,
• the Orange Book active ingredient entries,
• the expiration dates listed by FDA,
• any granted exclusivities (e.g., 5-year NCE, 3-year new clinical investigation, patent term adjustment, or pediatric extension).

Because the filing is not provided, no litigation timing or Paragraph IV framework can be deterministically mapped to this specific patent from the information given here.

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US patent landscape: how to structure a search for related filings and continuation coverage (within this claim family)

The patent’s internal claim design suggests a family pattern common in process-protection portfolios:

• dependent claims lock down specific alkylating agents, base choices, acids, purity, and whether intermediates are purified;
• independent claims cover at least two formula families (formula I/formula Is and formula IV/formula IVs).

A complete US landscape build for this family would usually include:

• continuations/divisionals with overlapping process language,
• separate claims directed to salts (Is/IVs), polymorphs, and intermediates,
• related foreign filings with corresponding scope.

However, the prompt asks for “detailed analysis of the scope and claims and patent landscape” for US 8,497,393 specifically. That landscape analysis cannot be produced from the claim text alone without the patent publication identifiers, assignee, priority data, and citation tree.

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Key Takeaways

• US 8,497,393 is structured to protect formula I APIs and salts using a three-step process fingerprint: defined alkylation to formula III, base hydrolysis, then salt formation with one of a specified set of bases (B), with optional acid conversion to HCl or H2SO4 forms.
• The claim language contains multiple gating provisos (R7 substitution limits, conditional phenoxy eligibility, and joint “C(L1)-R7” restrictions), which narrows chemical scope but increases confidence that an accused product must match a specific scaffold configuration.
• Dependent claims provide high-evidence enforcement levers: ≥99.5% purity, narrow alkylating agents (Cl/Br/I(CH2)wCN and ClCH2CN), KOH/NaOH hydrolysis base, explicit salt-forming bases, and “no purification of intermediate” execution (carry-forward without purifying formula III or VI).
• For design-around, the most direct routes are to deviate from the alkylation chemistry, salt-forming base, acid conversion step, or intermediate handling (purification vs carry-forward); alternative synthetic intermediates also reduce match to formula III/VI process constraints.

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FAQs

1. Do process-limited product claims like claim 1 require proving the defendant used the exact alkylation-to-salt route?
2. Which dependent claims in US 8,497,393 are best suited for evidentiary proof from batch records (alkylating agent, bases, acids, and purification steps)?
3. How do the “not more than two substituents are other than alkyl” provisos for phenoxy/phenyl substituents affect infringement against analogs?
4. Does claim 8 (no purification of intermediate III) matter if the accused manufacturer can show purity and correct final salt but purifies intermediates?
5. If a generic produces an Is-type salt but does not perform optional step (d), can claim 1 still be asserted based on the final commercial form?

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References

1. US Patent 8,497,393 (claim set and text provided in prompt).

Drugs Protected by US Patent 8,497,393

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
United Therap	ORENITRAM	treprostinil diolamine	TABLET, EXTENDED RELEASE;ORAL	203496-002	Dec 20, 2013		RX	Yes	No	8,497,393			Y	Y
United Therap	ORENITRAM	treprostinil diolamine	TABLET, EXTENDED RELEASE;ORAL	203496-003	Dec 20, 2013		RX	Yes	Yes	8,497,393			Y	Y
United Therap	ORENITRAM	treprostinil diolamine	TABLET, EXTENDED RELEASE;ORAL	203496-004	Dec 20, 2013		RX	Yes	No	8,497,393			Y	Y

International Family Members for US Patent 8,497,393

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2710205
China	101903324
China	103274926
European Patent Office	2252570
European Patent Office	3287434