Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This office action is in reply to the application submitted on 27 September 2023. Claims 4, 10, and 14 are amended. Currently, claims 1-14 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 27 September 2023 was filed on the mailing date of the application on 27 September 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 7, 10-12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Sandnes et al. (A simple synthesis of the macrocycle 1,4,7,10-tetraazacyclododecane, Acta Chemica Scandinavica 1998, 52, 1402-1404), Sandnes et al. (Process for tetraazacycloalkane preparation, WO 1996/028432, IDS entered on date 27 September 2023), and Platzek et al. (Process for the production of cyclene, WO 2000/032581, IDS entered on date 27 September 2023) and further in view of Weisman and Reed (A new synthesis of cyclen (1,4,7,10-tetraazacyclododecane), J. Org. Chem. 1996, 61, 5186-5187, IDS entered on date 27 September 2023), Reed and Weisman (1,4,7,10-tetraazacyclododecane, Org. Syn. 2004, 10, 667, IDS entered on date 27 September 2023), and Argese et al. (Stereochemistry of the intermediates in the synthesis of 1,4,7,10-tetraazacyclododecane from triethylamine, glyoxal and diethyl oxolate, Tetrahedron 2006, 62, 6855-6861, IDS entered on date 27 September 2023).
Sandnes discloses the synthesis of decahydrodiimidazo[1,2-a:2’,1’-c]pyrazine from the reaction of aqueous solution of glyoxal (40%) with triethylenetetramine in ethanol at 20°C, lower than room temperature (25°C) for 12 hours with reported yields of 55% and 75%, giving the 5,5,6 tricyclic intermediate as the major product (scheme 1). Platzek performs this reaction at a 50 g scale, demonstrating scalability (example 1). Argese further characterizes this synthesis utilizing micellar electrokinetic chromatography, identifying several reaction features including 1) the generation of only the desired racemic 5,5,6 tricyclic pyrazine mixture after 30 minutes reaction time and 2) an isolated mixture comprised of 87.7% of the desired isomer (table 1). Indeed, while Sandnes doesn’t appear to meticulously track the reaction progression, Argese demonstrates that the desired intermediate is rapidly formed (30 minutes) and is the dominant isomer at completion. Sandnes does not, however, disclose the reduction of decahydrodiimidazo[1,2-a:2’,1’-c]pyrazine with a reducing agent selected from a group consisting of dialkyl aluminum hydride, trialkylamine alane complex, or mixtures thereof. Weisman and Reed rectify this deficiency by teaching this double reduction utilizing DIBALH, a well-known aluminum hydride reagent, in toluene, refluxed for 15 hours under atmospheric pressure, followed by treatment with NaF in water to give Cyclen in 83% yield, purified to >98% after sublimation, at a 5 g scale (scheme 1, procedure 1). The authors note that they do not foresee any difficulties to the scale up of this reaction. As such, it would have been prima facie obvious to a person of ordinary skill in the art, to combine the synthesis of the 5,5,6 tricyclic intermediate as disclosed by Sandnes, scaled-up by Platzek, and characterized by Argese, with the reduction and subsequent generation of Cylene by DIBALH as disclosed by Weisman and Reed in a process-appropriate, 2-pot reaction.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Sandnes, Platzek, Argese, and Weisman and Reed as applied to claims 1-2, 7, 10-12, and 14 above, and further in view of Branco et al. (The switching point between kinetic and thermodynamic control, Computers and Chemical Engineering 2019, 125, 606-611).
While Sandnes, Platzek, and Argese disclose the synthesis of decahydrodiimidazo[1,2-a:2’,1’-c]pyrazine, they do not disclose a temperature parameter range of 0°C to 10°C. Branco rectifies this by teaching the findings of Woodward and Baer in their study of fulvene with maleic anhydride, citing application of their thesis to the kinetic product, which Argese identifies the intermediate as, by controlling the reaction with lower temperatures and shorter reaction times (introduction). Argese negates the concern of the shorter reaction times by demonstrating that the desired kinetic intermediate is predominantly formed by the reaction conditions even at 20°C over 20 hours. As such, it would have been prima facie obvious, to a person of ordinary skill in the art, to take the classical teachings of organic chemistry and apply them, utilizing a lower temperature regime to further optimize the formation of the preferred 5,5,6 tricyclic intermediate.
Claims 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Sandnes, Platzek, Argese, and Weisman and Reed as applied to claims 1-2, 7, 10-12, and 14 above, and further in view of N. G. Anderson (Practical process research and development, 2nd Ed. Chapter 5, Elsevier Inc. 2012).
While Sandnes, Platzek, and Argese disclose the synthesis of decahydrodiimidazo[1,2-a:2’,1’-c]pyrazine, they do not disclose a process where the crude mixture of step (a) in claim 1 is fed into a distillation column along with a hydrocarbon solvent. The examples in the specification (e.g. Example 2), describe reducing the volume of the reaction mixture to 14 mL, then feeding the concentrated solution to a 5-trays distillation column containing 60 g of toluene with an attached Dean-Stark separator. Anderson explains this process of azeotrope distillation where miscible solvents ethanol and water are involved. Toluene is used as an “entrainer” that forms a ternary azeotrope, allowing the more efficient removal of water and ethanol as an azeotrope (boiling point 74.4°C) which can be collected by the Dean-Stark trap setup. As such, it would have been prima facie obvious, to a person of ordinary skill in the art, to utilize basic laboratory operations in the removal of residual solvents from the reaction mixture using azeotropic distillation to obtain the crude product.
Claim 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Sandnes, Platzek, Argese, and Weisman and Reed as applied to claims 1-2, 7, 10-12, and 14 above, and further in view of Park et al. (Composition comprising novel 5,6-dihydroergosterol glycoside derivative, WO2015156558A1, 2015) and Noon et al. (Reaction of diisobutylaluminum hydride with selected organic compounds containing representative functional groups, J. Org. Chem. 1985, 50, 2443-2450).
While Sandnes, Platzek, and Argese disclose the synthesis of decahydrodiimidazo[1,2-a:2’,1’-c]pyrazine intermediate and cyclen through reduction of the intermediate, they do not disclose reduction by DIBAL-H under elevated pressure and temperature from 120°C to 160°C and in a time period between 2-to-6 hours. Park teaches the application of DIBAL-H in the difficult reduction of ergosterol to 5,6-dihydroergosterol, which sees a singular olefin reduction of ergosterol’s diene. Their experimental conditions recite toluene as the solvent, performed within a sealed tube, and warmed to 140°C for 20 hours, to obtain 5,6-dihydroergosterol after workup and purification in 96% yield (exemplary form of the invention). As the boiling point of toluene is approximately 110°C, the pressure inside the sealed reaction vessel is necessarily elevated above 1 atmosphere. Additionally, though DIBAL-H is known to begin undergoing decomposition at and above 120°C, Park demonstrates that highly efficient reduction is a reasonable expectation under high temperature and long reaction times. Noon teaches a wide range of empirically derived reduction reactions parameters, including nitrogen containing compounds in toluene, at 0°C, exemplifying a number of reaction times from 0.5 hours to 48 hours (table X). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05. As such, it would have been prima facie obvious, to a person of ordinary skill in the art, to consider the broad reaction times as recited by Noon and the experimental example of ergosterol reduction by Park, combined with the knowledge that DIBAL-H will begin decomposition at high temperatures and extended reaction periods, to explore experimental parameters that would achieve a better outcome.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Sandnes, Platzek, Argese, and Weisman and Reed as applied to claims 1-2, 7, 10-12, and 14 above, and further in view of N. G. Anderson (Practical process research and development, 2nd Ed. Chapter 5, Elsevier Inc. 2012), Park et al. (Composition comprising novel 5,6-dihydroergosterol glycoside derivative, WO2015156558A1, 2015), and Noon et al. (Reaction of diisobutylaluminum hydride with selected organic compounds containing representative functional groups, J. Org. Chem. 1985, 50, 2443-2450).
While Sandnes, Platzek, and Argese disclose the synthesis of decahydrodiimidazo[1,2-a:2’,1’-c]pyrazine intermediate and cyclen through reduction of the intermediate, they do not disclose subjecting the crude intermediate to continuous distillation, to generate cyclen from the reduction of the intermediate using DIBAL-H under refluxing conditions in atmospheric condition or elevated temperatures of 120°C to 160°C in a 2-to-6-hour period. These deficiencies are addressed by Anderson, Park, and Noon who teach azeotropic distillation, high temperature reduction of ergosterol, and a diverse range of DIBAL-H reduction times for a variety of nitrogen-containing compounds, respectively. As such, it would have been prima facie obvious, to a person of ordinary skill in the art, to combine the teachings of classical organic chemistry and basic laboratory practices, to optimize the previously established synthesis of cyclen.
Conclusion
No claims are allowed.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622