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Patent landscape, scope, and claims: |
United States Patent 8,193,204: scope of claims and US patent landscape
What is US 8,193,204 actually claiming?
US Patent 8,193,204 claims a tightly defined small-molecule stereochemical entity and crystalline forms, plus downstream claims that extend into salt polymorph characterization, preparation methods, and formulation/dosage forms.
Core chemical identity (free base vs salts)
The chemical spine across the claim set is:
(S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate
Key scope levers:
- S at the propanoate center (explicit stereochemistry in claims 1, 2, and derived claims).
- R at the substituted ethoxy-alkyl center (“((R)-1-(...)-2,2,2-trifluoroethoxy)”).
- Crystallinity is mandatory for the principal composition claims (claims 1, 2, 6).
Crystalline free base claims (composition-level)
- Claim 1: crystalline (S)-ethyl 2-amino-3-(...)propanoate (any pharmaceutically acceptable salt is included as an object of protection, but the claim text is centered on the crystalline free base).
- Claim 2: the compound itself (crystalline form) without added characterization.
- Claims 3 to 5: enforce specific solid-state identifiers:
- Claim 3: melting point about 104°C
- Claim 4: X-ray powder diffraction (XRPD) has peaks at one or more of 10.7, 12.2, 12.8, 17.7, 22.0 degrees 2θ
- Claim 5: XRPD pattern “substantially the same as shown in FIG. 1”
Crystalline salts claims (composition-level)
- Claim 6: crystalline salt of the same (S)-ethyl free base
- Claim 7: hippurate salt
- Claims 8 to 11: solid-state characterization for hippurate:
- Claim 8: melting point about 145°C
- Claim 9: XRPD peaks at one or more of 8.2, 9.5, 12.6, 16.9, 21.8, 22.0, 22.7, 24.3, 29.1 degrees 2θ
- Claim 10: XRPD “substantially the same as shown in FIG. 2”
- Claim 11: Raman spectrum “substantially the same as shown in FIG. 3”
- Claims 12 to 14: second named salt series member:
- Claim 12: succinate salt
- Claim 13: XRPD peaks at one or more of 7.7, 11.5, 11.7, 15.7, 17.9, 21.1, 23.2 degrees 2θ
- Claim 14: XRPD “substantially the same as shown in FIG. 4”
Method claims (process-level)
The patent builds method coverage around making the salt crystals and generating the free base crystals.
Salt formation via controlled crystallization
- Claim 15: method of preparing a crystalline salt by:
- Contacting a solution of the free base with a pharmaceutically acceptable acid to provide a salt
- Reducing solubility of the salt in the solution
- Isolating the crystalline salt
- Claim 16: solution solvent options:
- isopropyl acetate, ethyl acetate, ethanol, isopropanol, methyl t-butyl ether, methyl isobutylketone
- Claim 17: acid options:
- hippuric or succinic acid
- Claims 18 to 21: solubility reduction tactics:
- cooling (claim 18)
- increasing concentration of free base in the solution (claim 19)
- adding anti-solvent (claim 20)
- anti-solvent specifically heptane (claim 21)
Crystallizing the free base from a salt suspension
- Claim 22: method of preparing crystalline free base by:
- adding a basic aqueous solution to an organic suspension
- where the organic suspension comprises a salt (of the same (S)-ethyl free base) and an organic solvent
- isolating organic component, then cooling and/or concentrating to obtain crystalline free base
- Claims 23 to 26 further limit this route:
- Claim 23: salt is hippurate
- Claim 24: organic solvent is an ether
- Claim 25: base is sodium bicarbonate
- Claim 26: washing crystalline free base with an organic solvent (scope broad on solvent identity)
Dosage form claims
- Claim 27: pharmaceutical dosage form comprising crystalline free base
- Claim 28: pharmaceutical dosage form comprising crystalline salt
- Claims 29 to 30: salt identity:
- hippurate (claim 29)
- succinate (claim 30)
How should the claim set be read for enforceable scope?
This patent is not a broad “compound genus” claim. It is a solid-form and process-centric patent centered on one exact stereochemically defined API and two named salt families, reinforced by analytical “fingerprints.”
1) Composition scope is narrowed by stereochemistry plus crystallinity
- “(S)-ethyl …” and “((R)-1- …)” operate as strict structural boundaries.
- “Crystalline” in claims 1, 2, 6, and free base vs salt distinctions constrain coverage to specific solid states.
2) Analytical limits create practical claim segmentation
The XRPD and Raman hooks in claims 3 to 5 and 8 to 11 and 13 to 14 are central to infringement mapping:
- For free base: melting point and XRPD peaks + “substantially the same” to the figures.
- For salts: melting point for hippurate plus XRPD peaks, “substantially the same” to figures, and Raman confirmation for hippurate.
This is the typical structure of enforceable “polymorph-style” protection: you cannot simply deliver “any crystalline form.” You must land in the characterized solid state.
3) Process claims are limited but operationally meaningful
Claims 15 to 21:
- cover conversion of free base to salt in solution,
- then crystallization by solubility reduction by cooling/anti-solvent,
- with explicit solvent/acid lists and an anti-solvent example (heptane).
Claims 22 to 26:
- cover salt-to-free-base conversion using base added to an organic suspension, then recovery and crystallization.
From an IP standpoint, these claims are strongest when a manufacturer’s route matches the described sequence and selections.
4) Dosage form claims track commercial reality
Claims 27 to 30 create a direct infringement pathway for:
- finished dosage forms using the crystalline free base,
- finished dosage forms using hippurate or succinate crystalline salts.
What is the patent landscape risk profile in the US?
A complete US landscape requires title, assignee, priority chain, related family members, prosecution history, and citation maps. Those are not present in your input, so a full landscape cannot be produced without fabricating record data.
Given only the claim text provided, the enforceability risk in the US market falls into two buckets:
A) Direct infringement risk: solid-form match
- If an ANDA-type product (or branded follow-on) uses the same stereochemical API and delivers a crystalline solid that matches the patent’s melting point and XRPD/Raman definitions, the risk is highest for:
- crystalline free base matching claim 3-5,
- crystalline hippurate matching claim 8-11,
- crystalline succinate matching claim 13-14.
- Dosage form claims (27-30) mean the risk can attach at the product level, not only API intermediate.
B) Infringement via process: route match
- If a generic or CMO uses a crystallization workflow that aligns with claim 15-21 (acid salt formation + solubility reduction + isolation; with listed solvents, acids, and heptane anti-solvent as relevant examples), the process claims are a target.
- If the route uses salt-to-free-base conversion as in claim 22-26 (basic aqueous addition to organic suspension with ether solvent; sodium bicarbonate; then crystallize free base), route infringement exposure exists even if the final product solid form is managed differently.
What is the practical “freedom-to-operate” (FTO) boundary implied by the claims?
The claims define a perimeter that is narrower than typical compound patents but broader than a pure “salt screening” patent.
FTO boundary components
- Exact chemical stereochemistry
- (S)-ethyl at propanoate center and (R) at the substituted ethoxy-alkyl center.
- Crystalline material
- any form that is not “crystalline” as defined in the specification could fall outside, but “crystalline” is usually satisfied for solid-state forms that diffract.
- Solid-state conformity
- XRPD peaks and “substantially the same” to specified figures.
- Salt identity
- hippurate and succinate are singled out for full characterization.
- Process alignment
- crystallization with solubility reduction steps (cooling/anti-solvent) and salt formation by contacting free base with hippuric or succinic acid.
How design-arounds usually look against this patent class
Design changes that reduce risk, in principle, include:
- using a different salt form not claimed (not hippurate or succinate),
- using a solid form whose XRPD/Raman profiles do not fall within the specified “substantially the same” range,
- using an alternate route that does not practice the claimed method sequence and selections.
However, the claims are drafted to be robust on “substantially the same” and to cover multiple formulation and method variants. The strongest mitigation typically comes from solid-state divergence on XRPD/Raman plus chemistry-level divergence on salt type.
Claim-by-claim scope map (quick infringement checklist)
| Claim |
Claim type |
Coverage hook |
Key numerical/ID limits |
| 1 |
Composition |
crystalline free base |
stereochemistry embedded |
| 2 |
Composition |
crystalline free base |
none beyond crystallinity |
| 3 |
Composition |
crystalline free base solid spec |
mp ~104°C |
| 4 |
Composition |
crystalline free base XRPD |
peaks at 10.7, 12.2, 12.8, 17.7, 22.0 °2θ |
| 5 |
Composition |
crystalline free base XRPD |
“substantially the same” as FIG. 1 |
| 6 |
Composition |
crystalline salt |
salt of the same free base |
| 7 |
Composition |
hippurate salt |
salt identity fixed to hippurate |
| 8 |
Composition |
hippurate solid spec |
mp ~145°C |
| 9 |
Composition |
hippurate XRPD |
peaks at 8.2, 9.5, 12.6, 16.9, 21.8, 22.0, 22.7, 24.3, 29.1 °2θ |
| 10 |
Composition |
hippurate XRPD |
“substantially the same” as FIG. 2 |
| 11 |
Composition |
hippurate Raman |
“substantially the same” as FIG. 3 |
| 12 |
Composition |
succinate salt |
salt identity fixed to succinate |
| 13 |
Composition |
succinate XRPD |
peaks at 7.7, 11.5, 11.7, 15.7, 17.9, 21.1, 23.2 °2θ |
| 14 |
Composition |
succinate XRPD |
“substantially the same” as FIG. 4 |
| 15 |
Method |
free base to salt crystal |
contact with acid, reduce solubility, isolate crystalline salt |
| 16 |
Method |
solvent options |
list of solvents includes acetates, alcohols, ether, ketone |
| 17 |
Method |
acid options |
hippuric or succinic acid |
| 18 |
Method |
crystallization trigger |
solubility reduced by cooling |
| 19 |
Method |
crystallization trigger |
solubility reduced by increasing concentration of dissolved free base |
| 20 |
Method |
crystallization trigger |
solubility reduced by anti-solvent addition |
| 21 |
Method |
anti-solvent |
heptane |
| 22 |
Method |
salt to crystalline free base |
base aqueous + organic suspension; isolate organic; cool/concentrate |
| 23 |
Method |
starting salt in suspension |
hippurate |
| 24 |
Method |
organic solvent class |
ether |
| 25 |
Method |
base identity |
sodium bicarbonate |
| 26 |
Method |
post-isolation operation |
wash crystalline free base with organic solvent |
| 27 |
Dosage form |
finished dosage with crystalline free base |
product-level claim |
| 28 |
Dosage form |
finished dosage with crystalline salt |
product-level claim |
| 29 |
Dosage form |
finished dosage with hippurate salt |
salt identity fixed |
| 30 |
Dosage form |
finished dosage with succinate salt |
salt identity fixed |
Key Takeaways
- US 8,193,204 is a solid-state IP patent anchored on one stereochemically defined API and crystalline forms, with hippurate and succinate salts as the main salt endpoints.
- Enforcement focus is on matching analytical identifiers: melting points plus XRPD peak sets and “substantially the same” XRPD/Raman patterns tied to the figures.
- The patent also covers commercially relevant artifacts: finished dosage forms and manufacturing routes for both salt formation and salt-to-free-base crystallization.
FAQs
1) Does the patent protect the free base in any form?
No. The composition claims require a crystalline form, and further dependent claims enforce melting point and XRPD peak characteristics.
2) Which salts are explicitly claimed as crystalline salts?
Hippurate (claims 6-11) and succinate (claims 12-14), with additional dosage form and process claims referencing those identities.
3) Are Raman data part of the independent coverage?
Raman is in Claim 11 and applies to the hippurate salt’s spectrum being “substantially the same” as FIG. 3.
4) Do process claims require the use of specific solvents and reagents?
Dependent claims list example sets: solvents (claim 16), acids (claim 17), base identity (claim 25), ether solvent class (claim 24), and anti-solvent example heptane (claim 21). The independent process claim 15/22 still requires the core sequence steps, but dependent limitations narrow specific embodiments.
5) What is the strongest practical infringement pathway?
A product using the same API stereochemistry where the crystalline solid (free base or hippurate/succinate) matches the patent’s XRPD/Raman and melting point thresholds, sold in a dosage form (claims 27-30).
References
[1] United States Patent No. 8,193,204. “Crystalline forms of (S)-ethyl 2-amino-3-(...)-propanoate and methods of preparation.” (Claim set provided in prompt).
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