United States Patent 7,326,708: Scope, Claims, and Patent Landscape for a Dihydrogenphosphate Salt of a Dihydro[1,2,4]triazolo[4,3-a]pyrazine-Based Butan-2-amine
What does US 7,326,708 protect?
US 7,326,708 protects a specific dihydrogenphosphate salt (and hydrates and crystal forms) of a defined small-molecule base with a highly fluorinated, heterocyclic core, plus related formulation and Type 2 diabetes (T2D) use claims, and process claims for preparing the salt and a crystalline monohydrate.
The claim set is structured as a classic salt-and-form patent:
- Core compound identity: a dihydrogenphosphate salt of a defined amine base (structural formula I).
- Stereochemical coverage: explicit (R) and (S) chiral variants (structural formulas II and III).
- Solid-state definition: monohydrate plus XRD, solid-state NMR, DSC, and TGA signatures to lock down a particular crystalline form.
- Use: administering the salt for T2D.
- Manufacturing: contacting 1 equivalent of the base with about 1 equivalent phosphoric acid under defined conditions; crystallizing at 25°C from isopropanol/water with water content above 6.8 wt% to obtain the crystalline monohydrate.
What is the exact chemical scope of the active salt claims?
Claim 1 anchors the scope:
Claim 1 (core protection)
- Product claim: “A dihydrogenphosphate salt” of:
- **4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine”
- Also covers: “or a hydrate thereof”
- This is the broadest product claim in the provided set.
Claim 2 and Claims 4-8 (stereochemistry + monohydrate + XRD locking)
- Claim 2: the salt of claim 1 with (R) configuration at the marked chiral center (structural formula II).
- Claim 4: a crystalline monohydrate version (the structural-form anchor).
- Claims 5-8: additional identity controls via X-ray powder diffraction (XRPD) d-spacings and a figure:
- Claim 5: d-spacings 7.42, 5.48, 3.96 Å
- Claim 6: d-spacings 6.30, 4.75, 4.48 Å
- Claim 7: d-spacings 5.85, 5.21, 3.52 Å
- Claim 8: XRPD pattern “of FIG. 1”
- Net effect: the patent focuses not only on “phosphate salt + monohydrate,” but on a specific crystalline material whose key diffraction features are defined numerically and visually.
Claims 3 (S stereochemistry)
- Claim 3: the same salt scaffold but with (S) configuration (structural formula III).
Claims 9-11 (solid-state carbon-13 CPMAS NMR signature)
- Claim 9: solid-state ^13C CPMAS NMR signals at 169.1, 120.8, 46.5 ppm
- Claim 10: further signals at 159.0, 150.9, 40.7 ppm
- Claim 11: spectrum “of FIG. 2”
These claims tighten enforceability by tying the crystalline monohydrate to an experimentally reproducible solid-state spectroscopic fingerprint.
Claims 12-14 (solid-state fluorine-19 MAS NMR signature)
- Claim 12: solid-state ^19F MAS NMR signals at −64.5, −114.7, −136.3, −146.2 ppm
- Claim 13: further signals at −96.5, −104.4, −106.3, −154.5 ppm
- Claim 14: spectrum “of FIG. 3”
Because the molecule is highly fluorinated, ^19F MAS is often sensitive to solid-state environments; this makes the signature claims more determinative than for less-fluorinated analogs.
Claims 15-16 (thermal behavior)
- Claim 15: TGA curve “of FIG. 4”
- Claim 16: DSC curve “of FIG. 5”
This typically acts as further crystal-form confirmation rather than a standalone distinguishing feature. In litigation or validity work, DSC/TGA plots can be used to argue form identity when XRPD alone is contested.
What does the medical-use scope cover?
Claim 17-18 (pharmaceutical compositions)
- Claim 17: composition with a therapeutically effective amount of the salt according to claim 2 plus pharmaceutically acceptable carriers.
- Claim 18: composition with a therapeutically effective amount of the salt according to claim 4 plus carriers.
This draws a line between:
- (R)-specific salt compositions (claim 17)
- The crystalline monohydrate compositions (claim 18)
Claims 19-20 (method of treatment)
- Claim 19: method for treating Type 2 diabetes by administering a therapeutically effective amount of the salt according to claim 2 or a hydrate thereof.
- Claim 20: method for treating Type 2 diabetes by administering the salt according to claim 4.
Net: the method claims are tied to the same salt/form identities as the product claims.
What does the patent protect in manufacturing and scale-up?
Two process claim layers are present.
Claims 21-22 (salt preparation by phosphoric acid formation)
- Claim 21: process for preparing the salt of claim 2:
- Contact 1 equivalent of the (2R)-amine base:
- (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
- with about 1 equivalent phosphoric acid
- in an organic solvent or aqueous organic solvent
- at 25–100°C
- Claim 22: organic solvent is a C1-C5 linear or branched alkanol.
This is relatively broad from a chemistry-process standpoint: it covers a general acid salt formation window with modest solvent constraints.
Claims 23-24 (the crystalline monohydrate)
- Claim 23: the phosphate salt “prepared according to claim 21.”
- Claim 24: process to prepare the crystalline monohydrate:
- (a) crystallize the dihydrogenphosphate salt of structural formula (II) at 25°C
- from a mixture of isopropanol and water
- with water concentration above 6.8 wt%
- (b) recover solid phase
- (c) remove solvent
Claim 24 is the most operationally restrictive part: monohydrate form is tied to a particular solvent system and a quantitative water-content threshold at a fixed temperature.
How broad are these claims in practice? (Claim-by-claim enforceability map)
Below is a business-useful scope stratification.
Tier 1: Broad product (but still structurally specific)
- Claim 1: dihydrogenphosphate salt of the exact amine scaffold, including hydrate.
- Enforced against: making/using/selling that exact salt scaffold (and hydrates) regardless of specific crystal form, assuming hydrate falls within scope.
Tier 2: Stereochemistry restricted but still chemical-salt level
- Claim 2: (R) configuration salt.
- Claim 3: (S) configuration salt.
- These claims can matter if a generic or follow-on drug uses an enantiomerically pure API with a specific configuration.
Tier 3: Crystalline monohydrate form with multi-modal solid-state identifiers
- Claim 4: crystalline monohydrate.
- Claims 5-8: XRPD d-spacings and figure pattern.
- Claims 9-11: ^13C CPMAS NMR signals and figure.
- Claims 12-14: ^19F MAS NMR signals and figure.
- Claims 15-16: TGA and DSC curves and figures.
This tier is where generic risk becomes form-dependent. A competitor can aim to:
- avoid the monohydrate form (make a different hydrate, solvated form, or anhydrous form), or
- produce material that differs in XRPD and/or NMR signatures enough to argue non-infringement.
Tier 4: Use claims tied to the same forms
- Claims 19-20: T2D administration of claim-2 salt/hydrate and claim-4 monohydrate.
The method claims track the same “form identity” as the product claims.
Tier 5: Manufacturing claims that track both general salt formation and a monohydrate crystallization window
- Claims 21-22: general acid salt formation.
- Claim 24: monohydrate crystallization at 25°C in isopropanol/water with water > 6.8 wt%.
If a manufacturer uses different solvent ratios, different temperature, or different acid equivalents, they may try to avoid the specific process claim routes.
What would likely sit around US 7,326,708 in a patent landscape?
Without pulling external documents, the most defensible landscape inference is structural: US 7,326,708 is a salt/form + use + process family member. In most modern small-molecule programs, this sits downstream of:
- claims on the base drug substance (the amine core),
- earlier enabling disclosures or formation methods,
- then later solid-state form patents (salts, hydrates, solvates) to protect manufacturability and lifecycle.
Landscape blocks to expect (typical for this type of claim set)
- Drug substance patents on the core 4-oxo-… butan-2-amine scaffold and/or the heterocycle.
- Chiral or enantiomer patents (or the base composition patents) that cover (R) versus (S) variants.
- Salt formation patents (phosphates and other acids), typically including dihydrogenphosphate and sometimes multiple counterions.
- Solid-state form patents (crystalline monohydrate, other hydrates, solvates).
- Formulation and method-of-use patents linking the salt form to therapeutic indication (here, T2D).
- Manufacturing parameter patents that lock the crystallization conditions.
Claim scope compared to typical generic design-around options
This patent’s differentiator is the combination of:
- stoichiometric salt chemistry (dihydrogenphosphate),
- enantiomer specificity (claim 2),
- and crystal-form identity using XRPD + solid-state NMR + thermal curves (claims 4-16).
Likely design-around axes
- Counterion change: use a different phosphate species or a different salt form entirely. Claim 1 is specifically “dihydrogenphosphate salt.”
- Hydrate change: use an anhydrous form or a different hydrate. Claim 4 is “crystalline monohydrate.”
- Form change via crystallization conditions: the monohydrate in claim 24 is defined by crystallization from isopropanol/water at 25°C with water > 6.8 wt%. Shifting these parameters may create a different form.
- Enantiomer switch: the provided claim set includes both (R) and (S) salt variants (claims 2 and 3). If a generic uses only one enantiomer, it may still land within the other claim if it matches.
Practical diligence targets for investors or R&D
For assessing freedom-to-operate or the strength of this patent as a blocking right, the key technical questions map directly to claim language:
- Is the exact dihydrogenphosphate counterion used? (Claim 1)
- Is the product crystalline monohydrate? (Claim 4)
- Do the XRPD d-spacings match the listed sets? (Claims 5-8)
- Do solid-state NMR fingerprints match?
- ^13C CPMAS signals (claims 9-11)
- ^19F MAS signals (claims 12-14)
- Do DSC/TGA match the claimed figures? (claims 15-16)
- Does the manufacturing process match claim 24’s quantitative monohydrate crystallization window? (water > 6.8 wt%, isopropanol/water, 25°C)
Key Takeaways
- US 7,326,708 protects a specific dihydrogenphosphate salt of a defined fluorinated, heterocyclic amine scaffold, with explicit coverage of (R) and (S) forms.
- The patent’s enforceability strength concentrates on a crystalline monohydrate defined by XRPD d-spacings, solid-state ^13C/^19F NMR signal lists, and DSC/TGA curves.
- Therapeutic and commercial scope includes pharmaceutical compositions and T2D treatment methods tied to the salt and monohydrate identities.
- Process protection includes both general acid salt formation (phosphoric acid with ~1 equivalent at 25–100°C) and a more restrictive crystalline monohydrate crystallization method (isopropanol/water at 25°C with water > 6.8 wt%).
FAQs
1) Does claim 1 already cover the crystalline monohydrate?
Yes. Claim 1 covers the dihydrogenphosphate salt and “a hydrate thereof.” Claim 4 further narrows to a specific “crystalline monohydrate” with additional identity features.
2) What is the most litigation-relevant part: XRPD, NMR, or thermal data?
XRPD is usually the primary solid-form discriminator because claims 5-8 define d-spacings. NMR (claims 9-14) and DSC/TGA (claims 15-16) add independent identity constraints.
3) Can a competitor avoid infringement by using a different hydrate?
The cleanest path is to avoid the specific “crystalline monohydrate” defined by claim 4 and its associated XRPD/NMR signatures. A different hydrate or solvated form is an expected design-around axis.
4) Are method-of-treatment claims broader than the product claims?
They track the product/form identities closely: claim 19 ties to the claim 2 salt (and hydrate thereof), while claim 20 ties to the claim 4 crystalline monohydrate.
5) Does claim 24 require water above 6.8 wt%?
Yes. Claim 24 requires isopropanol/water crystallization at 25°C with water concentration above 6.8 weight percent.
References
[1] User-provided claim text for US 7,326,708 (claims 1-24).
