DETAILED ACTION
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 .
Status of the Claims
The amendment filed on 08/25/2025 has been entered. Claim 1 has been amended. Thus claims 1-20 are currently pending and are under examination.
Withdrawn Rejection
Claim 1 has been amended to recite “2-methytetrahydrofuran” in the solution of 2-chloroethylisocyanate. Jaman (Jaman, Z. et al. “Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions” Org. Process Res. Dev. 2019, 23, 334−341 and Supporting information pages S1-S31; cited in PTO-892 05/23/2025) uses a different solvent in the solution of 2-chloroethylisocyanate, THF, and thus the 103 rejection over Jaman has been withdrawn.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 7-16 and 20 are newly rejected under 35 U.S.C. 103 as being unpatentable over Jaman (Jaman, Z. et al. “Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions” Org. Process Res. Dev. 2019, 23, 334−341 and Supporting information pages S1-S31; cited in PTO-892 05/23/2025) in view of Aycock (Aycock, D. F. “Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions” Organic Process Research & Development 2007, 11, 156-159).
Regarding claim 1, Jaman teaches a process for making lomustine is provided comprising: (i) treating a solution of 2-chloroethylisocyanate in THF with a solution of cyclohexylamine with continuous-flow pumps in flow reactors to form a combined solution, (ii) adding H2O with a continuous flow-pump to the combined solution to form a liquid-organic phase solution, (iii) extracting the organic phase from the solution, and (iv) treating the organic phase with a solution of TBN (t-butyl nitrite) with a continuous flow pump in a flow reactor to form a lomustine solution (S16-S17).
Regarding claim 2, the combined solution in Jaman is pumped into a coiled flow reactor (Fig. 6).
Regarding 3, wherein the organic phase in step (iv) is pumped into a coiled flow reactor (Fig 6).
Regarding claims 4-5 and 7, Jaman teaches that the reactions were monitored by TLC and ESI-MS (S17) and in the TLC monitoring, lomustine was visualized under shortwave UV light (230 nm) (S21).
Regarding claims 8 and 10, the process further comprises an additional extraction of the organic phase with water to further purify the lomustine solution after step (iv) (S21).
Regarding claims 11-12, Jaman teaches crystallizing lomustine solution through batch crystallization (S21).
Ascertaining the Differences between the Claimed Invention and the Prior Art:
Regarding claim 1:
Jaman fails to teach that water of step (ii) is a deionized water. However, the use of deionized water in a chemical reaction process is a common practice to a skilled artisan due to its purity comprising only of hydrogen and oxygen without the presence of all other minerals and ions, thus making it the ideal water to use in experiments to achieve reliable data. A skilled artisan would thus have been motivated to use deionized water in step (ii) and for extraction purposes of step (iii).
Furthermore, while Jaman teaches the use of a solution of 2-chloroethylisocyanate in THF, the reference fails to teach or suggest a solution of 2-chloroethylisocyanate in 2-methyltetrahydrofuran (2-MeTHF hereinafter). The deficiency is however cured by Aycock.
Aycock teaches 2-MeTHF as being an aprotic ether solvent that, while being a strong Lewis base like THF, is only partially miscible with water while THF is completely water miscible and causes problems in water quenching steps (page 156, 1st col.). The reference goes on to list the superior properties of 2-MeTHF, such as it is derived from renewable resources, has low impurities with less than 300 ppm water, and has moderate b.pt. and m.pt. (page 156, 2nd col.). Furthermore, Aycock teaches that 2-MeTHF is a very effective solvent for extracting polar compounds from water mixtures. Thus, since Jaman teaches a water workup by (ii) adding H2O with a continuous flow-pump to the combined solution to form a liquid-organic phase solution, (iii) extracting the organic phase from the solution, a skilled artisan would have been motivated to use 2-MeTHF of Aycock in place of THF in the process of Jaman with a reasonable expectation of success in extracting the organic compound from water more effectively than Jaman.
Regarding claim 9, Jaman fails to teach that the water in the additional extraction is a deionized water, but as indicated above, a skilled artisan would have been motivated to use it due to its purity. Furthermore, the reference fails to teach that water for additional extraction is delivered via pump. However, differences in mode of delivering/adding extraction solvent used for extraction would not alter the function of the solvent. As such, delivering water via a pump as instantly claimed or via other modes, the water would still be used as extractant.
Regarding claims 13-14, Jaman teaches the use of petroleum ether for recrystallizing lomustine but fails combining lomustine and petroleum ether via a pump. However, differences in mode of combining the aforementioned, including via pump, would not alter the final outcome, and lomustine would still be crystallized. Furthermore, the recrystallization would necessarily have to be conducted in an apparatus.
Regarding claims 15-16, the reference fails to teach removing the solvent to make crystals, and wherein the solvent is removed by drying. However, such steps are a common practice to a skilled artisan after the recrystallization step, in which the crystals are collected from the solvents and dried to remove the remaining solvents.
Regarding claim 20, as indicated above, the recrystallization process in Jaman occurs through a batch process (S21) but fails to teach recrystallization through the continuous mode. However, in view of MPEP § 2144.04, making the operation continuous from a batch process, is one of the examples directed to various common practices which the court has held normally require only ordinary skill in the art and hence are considered routine expedients. As such, the continuous process is prima facie obvious in view of Jaman’s batch process.
It would thus have been prima facie obvious to a skilled artisan before the effective filing date of the instant invention to conduct a process for making lomustine is provided comprising: (i) treating a solution of 2-chloroethylisocyanate in 2-methyltetrahydrofuran with a solution of cyclohexylamine with continuous-flow pumps in flow reactors to form a combined solution, (ii) adding deionized water with a continuous flow-pump to the combined solution to form a liquid-organic phase solution, (iii) extracting the organic phase from the solution, and (iv) treating the organic phase with a solution of t-butyl nitrite with a continuous flow pump in a flow reactor to form a lomustine solution in view of the teachings of Jaman and Aycock.
Claim 6 is newly rejected under 35 U.S.C. 103 as being unpatentable over Jaman (Jaman, Z. et al. “Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions” Org. Process Res. Dev. 2019, 23, 334−341 and Supporting information pages S1-S31; cited in PTO-892 05/23/2025) in view of Aycock (Aycock, D. F. “Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions” Organic Process Research & Development 2007, 11, 156-159) as applied to claims 1-5, 7-16 and 20 above, and further in view of Anton Paar (“Raman Spectroscopy Applications” Nov. 10, 2019).
The teachings of Jaman and Aycock have been set forth above.
Regarding claim 6, while Jaman teaches TLC monitoring and that lomustine is visualized under shortwave UV light, the reference fails to teach or suggest monitoring via a Raman spectrometer. However, Anton Parr teaches that Raman Spectroscopy is an optical measurement technique which analyzes the inelastic scattered light from the sample material and one of its applications is to monitor chemical reaction. Accordingly, a skilled artisan would use the teachings of Anton Parr in the process of Jaman with a reasonable expectation of success in monitoring the formation of Jaman’s lomustine.
It would thus have been prima facie obvious to a skilled artisan before the effective filing date of the instant invention to conduct a process for making lomustine is provided comprising: (i) treating a solution of 2-chloroethylisocyanate in 2-methyltetrahydrofuran with a solution of cyclohexylamine with continuous-flow pumps in flow reactors to form a combined solution, (ii) adding deionized water with a continuous flow-pump to the combined solution to form a liquid-organic phase solution, (iii) extracting the organic phase from the solution, and (iv) treating the organic phase with a solution of t-butyl nitrite with a continuous flow pump in a flow reactor to form a lomustine solution, wherein the process the process is monitored by a Raman spectrometer in view of the teachings of Jaman, Aycock and Anton Parr.
Claims 17-19 are newly rejected under 35 U.S.C. 103 as being unpatentable over Jaman (Jaman, Z. et al. “Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions” Org. Process Res. Dev. 2019, 23, 334−341 and Supporting information pages S1-S31; cited in PTO-892 05/23/2025) in view of Aycock (Aycock, D. F. “Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions” Organic Process Research & Development 2007, 11, 156-159) as applied to claims 1-5, 7-16 and 20 above, and further in view of Gordon (Gordon, K. et al. “Investigating Crystallinity Using Low-Frequency Raman Spectroscopy: Applications in Pharmaceutical Analysis” Feb. 1, 2017).
The teachings of Jaman and Aycock have been set forth above.
Regarding claims 17-19, while Jaman teaches recrystallization of lomustine, the reference fails to teach or suggest monitoring the recrystallization by one or more analytical instruments (claim 17), wherein at least one analytical instrument is a Raman spectrometer (claim 18) or an x-ray powder diffractometer (claim 19). However, the deficiencies are cured by Gordon.
Gordon teaches that crystallinity is an important factor when producing pharmaceuticals because it directly affects the bioavailability of the drug. Furthermore, Gordon details the importance of crystallinity for the pharmaceutical agents:
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Thus, Gordon teaches the importance and the process of monitoring crystallinity using Raman spectrometry and XRD.
Jaman teaches that lomustine, a widely used anticancer agent, is a highly lipophilic alkylating agent that produces chloroethyl carbenium ions and carbamylating intermediates in vivo (1st col., pg. 334), thus making it an important pharmaceutical agent.
Accordingly, a skilled artisan would have been motivated to monitor Jaman’s recrystallization of lomustine using Gordon’s Raman spectrometry and XRD to ensure the crystalline form of lomustine is formed.
It would thus have been prima facie obvious to a skilled artisan before the effective filing date of the instant invention to conduct a process for making lomustine is provided comprising: (i) treating a solution of 2-chloroethylisocyanate in 2-methyltetrahydrofuran with a solution of cyclohexylamine with continuous-flow pumps in flow reactors to form a combined solution, (ii) adding deionized water with a continuous flow-pump to the combined solution to form a liquid-organic phase solution, (iii) extracting the organic phase from the solution, and (iv) treating the organic phase with a solution of t-butyl nitrite with a continuous flow pump in a flow reactor to form a lomustine solution, wherein the process further comprises crystallizing lomustine solution, wherein the crystallization is monitored by one or more analytical instruments, wherein at least one analytical instrument is a Raman spectrometer, wherein at least one analytical instrument is an x-ray powder diffractometer in view of the teachings of Jaman, Aycock and Gordon.
Conclusion
Claims 1-20 are rejected and no claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MEDHANIT W BAHTA/Primary Examiner, Art Unit 1692