United States Patent 7,799,777 (Crystalline Form B of Diazoxide:Choline Hydroxide)
A US patent centered on analytical-defined crystalline Form B of the diazoxide-based 1:1 salt with choline hydroxide, with protection spanning (i) the Form B solid state as defined by XRPD/NMR/IR signatures, (ii) multiple solvent-and-conditions processes to make Form B from diazoxide/choline hydroxide and from Form A, and (iii) pharmaceutical compositions containing Form B.
What does US patent 7,799,777 claim for diazoxide choline hydroxide salt crystalline Form B?
Answer: It claims a specific solid-state polymorph or crystalline form (Form B) of 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine dioxide:2-hydroxy-N,N,N-trimethyl ethanaminium (1:1), where the form is defined by XRPD “characteristic peaks”, NMR chemical shifts, and IR absorbances. It also claims processes that produce Form B using defined solvent systems and precipitation/crystallization steps, plus pharmaceutical compositions containing the Form B.
Core claim structure (what is protected)
- Product by analytical characterization (Form B crystal)
- Claims 1-7: crystalline Form B defined by:
- XRPD characteristic peaks at specified 2-theta values (Cu Kα, 40 kV, 40 mA).
- NMR characteristic chemical shifts (DMSO-d6).
- FTIR (IR) characteristic absorbances in cm−1.
- Processes to make Form B
- Claims 8-18: Form B produced from diazoxide + choline hydroxide using defined solvent suspensions (THF/2-MeTHF) and solvent-removal crystallization.
- Claims 12-18 (dependency set inside claim 12): extended solvent list (THF, 2-MeTHF, MeCN, MEK), with MTBE as co-solvent and precipitation harvesting.
- Claims 19-27: Form B produced from Form A or mixture (A+B) by re-crystallization using MeCN/i-AmOH with controlled cooling (fast/slow).
- Claims 24-27: alternative re-crystallization using IPA / t-AmOH / i-BuOH with slow cooling to room temperature.
- Claims 28-33: alternative solvent and co-solvent systems using MeOH/EtOH/IPA/MeCN with specified co-solvents (MTBE/EtOAc/IPAc/THF/c-hexane/heptane/toluene/dichloromethane/dioxane) and fast/slow cooling variants.
- Compositional and downstream product claims
- Claim 34: slurry conversion route from Form A (or A+B mixture) to slurry resulting in Form B substantially free of Form A.
- Claim 35-36: pharmaceutical composition claims.
What exactly is Form B “on paper” (analytical claim hooks)
XRPD-defined crystalline form (Claims 1-3)
- Claim 2 (approx. 2θ values): 10.3, 18.3, 20.6, 26.3 degrees (Cu Kα).
- Claim 3 (additional set of approx. 2θ values): 8.9, 12.0, 24.1, 24.5, 27.1, 28.9 degrees (Cu Kα).
NMR-defined crystalline form (Claims 4-6)
- Claim 5: chemical shifts approx. 2.05, 3.10, 3.40, 3.85 ppm (DMSO-d6).
- Claim 6: chemical shifts approx. 7.10, 7.30, 7.50 ppm (DMSO-d6).
IR-defined crystalline form (Claim 7)
- FTIR absorbances approx.: 3256, 2174, 2890, 1605, 1463, 1235 cm−1.
What is the immediate infringement risk category?
This patent is designed to catch:
- Any manufacturer or supplier that sells or uses Form B (product-by-form) meeting the XRPD/NMR/IR signature.
- Any process that falls within the enumerated solvent/co-solvent and crystallization conditions for generating Form B.
- Any formulation using Form B, via the pharmaceutical composition claims.
How broad are the XRPD, NMR, and IR limitations for Form B?
Answer: The claim language is “substantially as shown” plus specific peak/shift/absorbance sets, which usually gives a boundary defined by those characteristic values. In practice, the infringement question becomes whether an accused Form retains the claimed “characteristic” spectral pattern even if there are intensity variations, peak broadening, preferred orientation effects, or batch-to-batch differences.
XRPD breadth vs. precision
- Claim 2 and 3 pin down two different sets of 2θ peaks. Together they define a fingerprint spanning low-angle to higher-angle reflections.
- Because the claims give approximate degrees (not exact to decimal places in the text you provided), the legal scope generally tracks the “substantially as” framework and the ability to show that an accused material’s XRPD matches the claimed fingerprint.
NMR breadth vs. solvent and reporting choices
- NMR is constrained by solvent: DMSO-d6.
- Chemical shifts are given as approximate values, with two clusters (around ~2-4 ppm and ~7-7.5 ppm). This limits “designer polymorph” attempts that preserve only some chemical environment but not the same crystalline state.
IR breadth vs. instrumentation variability
- Claim 7 defines specific wavenumbers. FTIR peak positions can drift with instrument resolution and sample prep, but the discrete selection of peaks across the spectrum limits “near misses.”
What processes for making Form B from diazoxide and choline hydroxide are covered?
Answer: Claims 8-18 and the dependent claim chain capture multiple crystallization workflows using diazoxide suspended in defined solvents, then reacting with choline hydroxide in solution, heating, and crystallizing/precipitating under defined solvent/co-solvent ratios.
Process Claim 8: THF or 2-MeTHF suspension route
- Steps: suspend diazoxide in THF or 2-MeTHF, heat suspension, add choline hydroxide solution to diazoxide suspension, remove solvent to form Form B.
- Specific suspension ratios:
- If THF: ~1 g diazoxide per 3 mL THF to ~1 g per 8 mL THF.
- If 2-MeTHF: ~1 g diazoxide per 2 mL 2-MeTHF to ~1 g per 8 mL 2-MeTHF.
Process Claim 12: expanded solvent list and MTBE co-solvent precipitation
- Steps: suspend diazoxide in THF / 2-MeTHF / MeCN / MEK, add choline hydroxide solution, heat, add MTBE as co-solvent to form precipitate, harvest precipitate for Form B.
- If diazoxide suspended in:
- THF / 2-MeTHF / MeCN: ~1 g per 1 mL solvent to ~1 g per 8 mL solvent
- MEK: ~1 g per 4 mL MEK
- Dependency: choline hydroxide in MeOH (Claim 17).
Process risk implication
A generic “salt formation then isolate crystals” approach is not the target. The patent targets:
- Specific solvent systems (and in the expanded route, MTBE co-solvent),
- Specific concentration ranges (solvent-to-solute),
- Specific sequence: suspension, heating, addition of choline hydroxide solution, crystallization/precipitation, harvesting.
What processes convert Form A to Form B are covered?
Answer: Claims 19-34 capture multiple re-crystallization and slurry conversion routes starting from Form A (or A+B mixtures), using distinct solvent systems and cooling profiles to achieve Form B substantially free of Form A.
Process Claim 19: MeCN or isoamyl alcohol (i-AmOH) with cooling to precipitate
- Suspend Form A (or A+B mixture) in MeCN or i-AmOH.
- Heat, then cool to form precipitate, harvest precipitate yielding Form B substantially free of Form A.
- Cooling variants:
- fast cooling (Claim 20)
- slow cooling (Claim 21)
- Solvent choice:
- MeCN (Claim 22)
- i-AmOH (Claim 23)
Process Claim 24: IPA / t-AmOH / i-BuOH with slow cooling to room temperature
- Suspend Form A/A+B in IPA / t-AmOH / i-BuOH.
- Heat, then slow cool to room temperature.
- Harvest precipitate to obtain Form B substantially free of Form A.
- Solvent options:
- IPA (Claim 25)
- t-AmOH (Claim 26)
- i-BuOH (Claim 27)
Process Claim 28: MeOH or EtOH with extensive co-solvent menu and fast cooling
- Suspend Form A/A+B in MeOH or EtOH.
- Add co-solvent selected from: MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluene, CH2Cl2, dioxane.
- Heat, then fast cool to form precipitate.
- Harvest to obtain Form B substantially free of Form A.
- Co-solvent restriction when starting from MeOH (Claim 28 text): co-solvent limited to MTBE, EtOAc, IPAc, toluene, dioxane.
Process Claim 31: IPA or MeCN with co-solvent menu and slow cooling
- Suspend in MeOH IPA or MeCN (text indicates MeOH/IPA/MeCN variants; Claim 31 as provided lists IPA or MeCN).
- Add co-solvent selection from the same menu as Claim 28.
- Heat, then slow cooling.
- Harvest to obtain Form B substantially free of Form A.
Process Claim 34: slurry conversion
- Slurry Form A (or A+B mixture) in a solvent to generate a slurry comprising Form B substantially free of Form A.
Practical breadth of “conversion” claims
Even if a competitor starts with Form A, these claims can capture their downstream isolation steps if they are used to convert A → B using the specified solvent and thermal handling. This is a common enforcement approach against suppliers who provide an intermediate polymorph but then reprocess to target a marketed crystal form.
How do the pharmaceutical composition claims expand coverage?
Answer: Claims 35-36 extend protection beyond crystal manufacture to the finished dosage product made using Form B, and to compositions containing Form B generated by the claimed processes.
Claim 35: composition containing Form B of Claims 1-7
- Covers a pharmaceutical composition with an effective amount of the Form B crystalline salt defined by XRPD/NMR/IR (product-by-form).
Claim 36: composition containing Form B generated by Claims 8-34
- Covers compositions when Form B is produced by the claimed processes. This provides an alternative infringement route:
- Even if the accused product’s spectral identity is disputed, proof of the claimed manufacturing method can support infringement.
What is the patent landscape relevance for US 7,799,777?
Answer: Based on your claim set, US 7,799,777 is a solid-state patent built around analytical signatures and manufacturing routes for a specific polymorph/crystalline form. In enforcement and freedom-to-operate (FTO), it typically sits among other patents covering:
- The active ingredient (diazoxide),
- Salt formation and/or the diazoxide-choline salt chemistry,
- Polymorphs/crystalline forms (Form A vs Form B and potentially other forms),
- Formulation or process improvements around crystal isolation.
However, producing a complete landscape map (related patent numbers, family members, prosecution history, continuations, terminal disclaimers, and expiry dates) requires bibliographic and legal-record data not provided here. Without that, any quantified landscape would be incomplete.
What would a competing generic or follow-on sponsor need to show to avoid infringement?
Answer: A design-around can follow two tracks:
- Avoid Form B identity: ensure the marketed solid state does not meet the XRPD/NMR/IR “characteristic” sets (or does not qualify as “substantially as shown”).
- Avoid the claimed process routes: change solvent systems, co-solvent, concentration ranges, thermal steps (fast vs slow cooling where claimed), or the “substantially free of Form A” outcome when starting from Form A.
Because the claims are layered, competitors typically must address both:
- Their crystal form and
- Their manufacturing method.
Key clause-level observations for claim strength
Product-by-analytical claims (1-7)
- Strength driver: clear analytical fingerprint elements (XRPD, NMR, IR).
- Enforcement driver: if the accused Form B matches the claimed fingerprint, product-by-form claims often provide direct infringement paths.
Process claims (8-34)
- Strength driver: multiple solvent systems and defined concentration ratios and co-solvent strategies.
- Enforcement driver: process documentation from CDMOs, batch records, and validation reports can map to claim elements.
“Substantially free of form A”
- Strength driver: a functional purity limitation tied to polymorphic conversion. It is more enforceable when the patent record defines how “substantially free” is measured (typically XRPD quantitation), though that measurement method is not included in your excerpt.
Key takeaways
- US 7,799,777 protects crystalline Form B of a diazoxide:choline hydroxide 1:1 salt through analytical signatures: XRPD peak sets, DMSO-d6 NMR chemical shifts, and IR absorbance values.
- The patent also covers multiple manufacture routes for Form B:
- direct formation from diazoxide + choline hydroxide in specified solvents (THF/2-MeTHF and extended THF/2-MeTHF/MeCN/MEK with MTBE co-solvent),
- conversion from Form A (or A+B) via re-crystallization (MeCN/i-AmOH; IPA/t-AmOH/i-BuOH; MeOH/EtOH with co-solvents) and slurry conversion.
- Pharmaceutical composition claims bring Form B into finished dosage protection and provide an alternate infringement theory tied to whether Form B was made by the claimed processes.
FAQs
1) Do Claims 1-7 cover only “Form B” or also mixtures with Form A?
They are drafted as crystalline Form B. The inclusion of “substantially as shown” XRPD and other analytical descriptors means mixtures may still infringe if Form B is present in a way that satisfies the claimed “crystalline form B” identity as characterized.
2) Can a manufacturer avoid infringement by changing XRPD measurement settings?
The claims tie to Cu Kα with specified conditions in the text for at least the XRPD peak claims (Cu Kα, 40 kV, 40 mA). A credible avoidance strategy would need to show the material does not match the claimed characteristic peak pattern, not merely that testing is done differently.
3) Does “fast cooling” matter for infringement?
Yes for the dependent process claim variants that expressly require fast cooling versus slow cooling, because they narrow the process steps that are within the claim scope.
4) Are MTBE co-solvent choices required?
For the expanded diazoxide + choline hydroxide precipitation route (Claim 12), MTBE is specifically recited as the co-solvent for precipitation. Alternative co-solvent systems may fall outside that specific claim.
5) What is the strongest enforcement path: product or process?
For practical litigation strategy, product-by-analytical Form claims (1-7) are often strongest if the accused material can be matched to the XRPD/NMR/IR fingerprint. Process claims (8-34) become powerful when manufacturing records show solvent/cooling/co-solvent steps that match the claimed sequences.
References
[No external sources were provided or cited in the prompt.]
