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 .
Claim Status
Claims 1-15 are pending.
Claims 3-10 and 12-15 have been amended.
No claims have been cancelled.
Thus, claims 1-15 represent all claims currently under consideration.
Priority
Domestic Priority data as claimed by Applicant:
This application is a 371 of PCT/EP2022/067361 (06/24/2023)
Foreign Applications:
EUROPEAN PATENT OFFICE 2118410.8 (06/24/2021)
EUROPEAN PATENT OFFICE 21209660.6 (11/22/2021)
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claim 4 is objected to because of the following informalities:
In line 2, “wherein following step is performed after step D)” should read “the wherein following step is performed after step D):”
In line 3, “purifying compound” should read “purifying the compound”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11 and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 11 recites the broad recitation “chlorinating agent”, and the claim also recites “preferably thionyl chloride, oxalyl chloride, bis(trichloromethyl)carbonate, or phosgene” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 13 recites the limitation "after step G) or instead of step G)" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. The Examiner notes that if claim 13 were to be amended to depend upon claim 12 which recites “step G)”, this would cause an issue for the limitation “instead of step G)” recited in claim 13.
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, 6-7, 9, and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Weissman et al. (US 2018/0303925 A1; published 10-25-2018; IDS of 12-22-2023), in view of Fujiwara et al. (“Continuous-Flow Synthesis of Cationic Lipid SST-01 via Safe and Scalable Aerobic Oxidation and Reductive Amination”; Org. Process Res. Dev. 2020, 24, 1988-1995; published 07-22-2020) and Van Waes et al. (“Efficient and catalyst-free condensation of acid chlorides and alcohols using continuous flow”; Green Chem. 2012, 14, 2776-2779; published 08-31-2012).
Regarding claim 1, Weissman teaches compositions and methods for inducing an adaptive immune response in a subject, wherein the composition further comprises a lipid nanoparticle (LNP) (Abstract; claims 1 and 11, 0009).
Weissman further teaches in one embodiment, the LNP comprises a compound having one of the following structures (claim 17; 0046; Tables 1 and 3):
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These species reside within the genus of formula (I) of instant claim 1 when R1 is H; R2 is C6 alkyl; R3 is C8 alkyl; L is C4 alkylene (as in compounds I-5, III-3, and III-7) or C7 alkylene (as in compound I-6); P is C2 alkylene (as in compounds I-5 and I-6), C4 alkylene (as in compound III-3), or C5 alkylene (as in compound III-7); X is –NR4R5 wherein R4 and R5 are C1 alkyl (as in compounds I-5 and I-6), or –OH (as in compounds III-3 and III-7).
Example 6 of Weissman further teaches a synthesis of compound I-5 according to method B as follows:
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Regarding steps A) and B) of instant claim 1, Weissman teaches the following synthesis procedure. A solution of hexan-1,6-diol (10 g) in methylene chloride (40 mL) and tetrahydrofuran (20 mL) was treated with 2-hexyldecanoyl chloride (10 g) and triethylamine (10 mL). The solution was stirred for an hour and the solvent removed. The reaction mixture was suspended in hexane, filtered and the filtrate washed with water. The solvent was removed and the residue passed down a silica gel (50 g) column using hexane, followed by methylene chloride, as the eluent, yielding 6-(2′-hexyldecanoyloxy)hexan-1-ol as an oil (7.4 g) (General Reaction Scheme 2; Example 6, 0439 and 0573-0574). 2-Hexyldecanoyl chloride corresponds to acid chloride (II) of claim 1 when R1 is H, R2 is C6 alkyl, and R3 is C8 alkyl; hexan-1,6-diol corresponds to diol compound (III) of claim 1 when L is C4 alkylene; and 6-(2′-hexyldecanoyloxy)hexan-1-ol corresponds to the compound of formula (IV) of claim 1 wherein the R variables are as defined above.
Regarding steps C) and D) of instant claim 1, Weissman teaches the following synthesis procedure. The purified product (6-(2′-hexyldecanoyloxy)hexan-1-ol, 7.4 g) was dissolved in methylene chloride (50 mL) and treated with pyridinum chlorochromate (5.2 g) for two hours. Diethyl ether (200 mL) as added and the supernatant filtered through a silica gel bed. The solvent was removed from the filtrate and resultant oil passed down a silica gel (50 g) column using a ethyl acetate/hexane (0-5%) gradient. 6-(2′-Hexyldecanoyloxy)dodecanal (5.4 g) was recovered as an oil (0575). The skilled artisan would recognize pyridinum chlorochromate as an oxidizing agent. The compound 6-(2′-hexyldecanoyloxy)dodecanal corresponds to a compound of formula (V) of claim 1 wherein the R variables are as defined above .
Regarding steps E) and F) of instant claim 1, Weissman teaches the following synthesis procedure. A solution of the product (6-(2′-hexyldecanoyloxy)dodecanal, 4.9 g), acetic acid (0.33 g) and 2-N,N-dimethylaminoethylamine (0.40 g) in methylene chloride (20 mL) was treated with sodium triacetoxyborohydride (2.1 g) for two hours. The solution was washed with aqueous sodium hydroxide. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed. The residue was passed down a silica gel (50 g) column using a methanol/methylene chloride (0-8%) gradient to yield the desired product (1.4 g) as a colorless oil (0576). The skilled artisan would recognize sodium triacetoxyborohydride as a reducing agent. 2-N,N-Dimethylaminoethylamine corresponds to formula (VI) of claim 1 when P is C2 alkylene and X is –NR4R5 wherein R4 and R5 are C1 alkyl, and the final product compound I-5 from Example 6 of Weissman corresponds to a compound of formula (I) of claim 1, as detailed above.
Weissman does not teach (1) a continuous flow reactor process for producing a compound of formula (I); and (2) conducting the method steps A) and B) in the absence of a base. Instead, Weissman teaches a batch process for producing a compound of formula (I), and the esterification step from the acid chloride (i.e., 2-hexyldecanoyl chloride) and diol (i.e., hexan-1,6-diol) is performed in the presence of triethylamine base (Example 6, 0574).
Regarding point (1), Fujiwara teaches a continuous flow synthesis of cationic lipid SST-01 via safe and scalable aerobic oxidation and reductive amination method steps (Title; Abstract). The use of a continuous flow reactor results in a shorter total reaction time and an improved isolated yield in comparison with the corresponding batch process (page 1993; Table 4). In addition, Fujiwara teaches that intermediate purification is optional in the continuous flow process, and Fig. 5 of Fujiwara shows an embodiment wherein a continuous flow of a solution of alcohol 4 is combined with a continuous flow of an oxidizing agent (TEMPO), and the continuously produced aldehyde compound is subsequently combined with a continuous flow solution of Me4NBH(OAc)3 reducing agent and a continuous flow solution of amine for the reductive amination method step (page 1993; Table 4, footnote a; Fig. 5). Thus, the process of Fujiwara is analogous to the claimed invention in that it teaches a continuous flow synthesis of a cationic lipid comprising method steps consistent with step C) through E) of instant claim 1.
Further regarding point (1) and point (2), Van Waes teaches efficient and catalyst-free condensation of acid chlorides and alcohols using continuous flow, wherein different esters could be obtained with excellent conversions in very short reaction times (Title; Abstract; page 2776, Scheme 1).
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Of particular note, Van Waes teaches that performing the condensation of acid chlorides and alcohols under catalyst-free conditions has an important economical advantage because the costs for the catalyst, including base catalysts like E3N, are eliminated, purification becomes almost redundant, and the use of microreactor technology is inherently safer than batch technology because of the small internal volume and excellent heat transfer (page 2276; Col. 1, paragraph 1 and Col. 2, paragraph 2). Thus, the process of Van Waes is analogous to the claimed invention in that it teaches a continuous flow synthesis esterification method by providing a continuous flow of a solution comprising an acid chloride and an alcohol to continuously produce an ester compound in the absence of a base, in a manner consistent with the method steps A) and B) of instant claim 1.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the batch process of Weissman to incorporate the teachings of Fujiwara and Van Waes to pursue a continuous flow process with predictable advantages over the corresponding batch process with a reasonable expectation of success to arrive at the claimed invention. See MPEP § 2143(I)(A). The motivation to do so would predict the skilled artisan to pursue, with a reasonable expectation of success, a process with improved yields, shorter reaction times, an improved safety profile, and economical advantages (i.e., costs of base catalysts are eliminated and purification steps are optional), as described above. Furthermore, MPEP § 2144.04(V)(E) states that “a continuous operation would have been obvious in light of the batch process of the prior art.”
Regarding claims 6-7 and 9, Figure 5 of Fujiwara teaches a continuous flow reductive amination method step using a solution of Me4NBH(OAc)3 as the reducing agent in NMP solvent that is continuously combined with a solution of the amine (MeNH2) in methanol and a solution of the aldehyde starting material 5 in NMP using a cross-shaped mixer M5 to form the desired reductive amination product (page 1993; Figure 5 and Col. 1, paragraph 2). Methanol is a C1 alcohol, and the skilled artisan would recognize that NMP is an aprotic solvent, in a manner consistent with instant claim 7. In addition, Weissman teaches the use of sodium triacetoxyborohydride in the reductive amination method step (0576).
Regarding claim 10, Van Waes teaches that the continuous flow procedure was evaluated for acid chlorides and alcohols in solution, and compounds are introduced into the microreactor and mixed with a T-mixer or a SOR mixer, and both reagents were pumped through the microreactor to form the esterified product under continuous flow conditions (page 2776, Scheme 1; page 2777, Col. 2, paragraphs 4-6; page 2778, Table 2 and Col. 2, paragraph 3; page 2779, Col. 1, paragraph 2 and Table 4). When considering Weissman in view of Fujiwara and Van Waes, the skilled artisan would arrive at a continuous flow of a solution comprising hexyldecanoyl chloride and hexan-1,6-diol (Weissman; 0574) obtained through the combination of their respective individual solutions prior to mixing at the T-mixer or SOR mixer, and these compounds correspond to acid chloride (II) and diol compound (III) of the instant claim. Also see MPEP § 2144.04(IV)(C).
Regarding claim 11, Van Waes teaches that the continuous flow procedure was evaluated for acid chlorides and alcohols in solution, and compounds are introduced into the microreactor and mixed with a T-mixer or a SOR mixer, and both reagents were pumped through the microreactor to form the esterified product under continuous flow conditions (page 2776, Scheme 1; page 2777, Col. 2, paragraphs 4-6; page 2778, Table 2 and Col. 2, paragraph 3; page 2779, Col. 1, paragraph 2 and Table 4). When considering Weissman in view of Fujiwara and Van Waes, the skilled artisan would arrive at a continuous flow of a solution comprising hexyldecanoyl chloride and hexan-1,6-diol (Weissman; 0574), and these compounds correspond to acid chloride (II) and diol compound (III) of the instant claim.
Further regarding claim 11, Weissman teaches the preparation of an acid chloride derived from myristic acid by heating at 70 ºC in toluene in the presence of oxalyl chloride, or by heating at 60 ºC in benzene with DMF (1 drop) in the presence oxalyl chloride (0593 and 0595). The reaction temperatures of Weissman reside within the range recited in instant claim 11. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Weissman, Fujiwara, and Van Waes do not teach wherein the continuous flow of a solution comprising the acid chloride (II) is obtained from reacting a carboxylic acid of formula (VII) with a chlorinating agent in a continuous flow reactor, as recited in instant claim 11, the skilled artisan would be sufficiently motivated to arrive at a continuous flow reactor process for the acid chloride synthesis step to pursue, with a reasonable expectation of success, a process with improved yields, shorter reaction times, an improved safety profile, and economical advantages (i.e., costs of base catalysts are eliminated and purification steps are optional), as described above in the rejection of claim 1. See MPEP § 2143(I)(A). Furthermore, MPEP § 2144.04(V)(E) states that “a continuous operation would have been obvious in light of the batch process of the prior art.”
Regarding claim 12, Weismann teaches that after the reductive amination step, the solution was washed with aqueous sodium hydroxide. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed. The residue was passed down a silica gel (50 g) column using a methanol/methylene chloride (0-8%) gradient to yield the desired product (1.4 g) as a colorless oil (Example 6; 0576). In addition, Fujiwara teaches that following the two-step continuous flow process, for isolation of the product, the recovered mixture was diluted with heptane, washed successively with 1 M aqueous NaOH solution and saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The resultant mixture was concentrated under reduced pressure and purified by amino silica gel column chromatography (page 1994; Col. 1, paragraph 3 and Col. 2, paragraph 1).
Regarding claim 13, Weissman teaches that experiments were conducted to examine the effectiveness of various LNP formulations, as measured by the effective translation of the encapsulated mRNA, including LNPs comprising cationic lipids I-5, I-6, III-3, and III-7 (Example 5; 0572). In some embodiments, LNPs are included in a formulation comprising a nucleoside-modified RNA (0272). Weissman further teaches that the composition for inducing an adaptive immune response in a subject comprising at least one nucleoside-modified RNA encoding at least one antigen is encapsulated within the LNP, wherein the composition is a vaccine that may be formulated with an adjuvant (claims 1 and 11-13; 0008, 0054, 0150, 0204). Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier (0511).
Regarding claims 14-15, Weissman teaches the preparation of compound III-3 of the following structure (paragraphs 0046 and 0413; Table 3; claim 17):
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Compound III-3 of Weissman corresponds to the species of claims 14-15 when R1 is –(CH2)5–CH3, R2 is –(CH2)7–CH3, R3 is H, L is –(CH2)4–, P is is –(CH2)4–, and X is –OH.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Weissman et al. (US 2018/0303925 A1; published 10-25-2018; IDS of 12-22-2023), in view of Fujiwara et al. (“Continuous-Flow Synthesis of Cationic Lipid SST-01 via Safe and Scalable Aerobic Oxidation and Reductive Amination”; Org. Process Res. Dev. 2020, 24, 1988-1995; published 07-22-2020) and Van Waes et al. (“Efficient and catalyst-free condensation of acid chlorides and alcohols using continuous flow”; Green Chem. 2012, 14, 2776-2779; published 08-31-2012) as applied to claims 1, 6-7, 9-10, and 12-15 above, and further in view of Guarat et al. (US 2014/0343326 A1; published 11-20-2014) as evidenced by ChEBI database (page 1 of CHEBI:32145-sodium hypochlorite; pages 1-6; published 07-31-2020).
Regarding claim 2, Fujiwara teaches a continuous flow of a mixture comprising an organic solution of 0.1 equiv TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl), CuI, and NMI ligand in NMP solvent (page 1993, Figure 5; page 1994, Col. 2, Abbreviations section).
Weissman, Fujiwara, and Van Waes do not teach a mixture comprising an oxidizing agent of step C) is obtained by combining i) an aqueous solution comprising the oxidizing agent sodium hypochlorite, a base and an alkali metal bromide salt, and ii) an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound, as recited in instant claim 2.
However, Guarat teaches an improved process for fast catalyzed hypohalous oxidation of alcohol groups to aldehydes or ketones, wherein the process is carried out in the presence of a buffered oxidative hypohalous solution and a nitroxide oxidation catalyst within a microreactor (Title; Abstract; claim 1; 0002).
The main advantages of the process of Guarat are that (1) the oxidation reaction goes rapidly to completion, generally in less than 3 minutes and sometimes within seconds; (2) the process is efficient at room temperature and without a co-catalyst, although the use of co-catalysts are not totally excluded for carrying out the process; (3) reduced amounts of catalyst can be used; (4) the process can be carried out for selective oxidations; and (5) the process allows in-line monitoring of the pH to optimize the rate and yield of the reaction (0037 and 0069).
The Examples of Guarat teaches a first solution of 1-octanol and 0.05% (molar) of TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) dissolved in toluene, or 0.2% (molar) of TEMPO dissolved in dichloromethane as a first solution, and a solution of buffered bleach at a given pH is extemporaneously prepared, for example by diluting bleach with water and adding NaHCO3 stepwise to obtain a saturated solution, and the two solutions are pumped into the microreactor. In one embodiment, a third feed comprising a 0.7 M phosphate buffer solution is added for further pH control (Examples 1A and 1B; 0002, 0084, 0097-0100, 0104-0105). The skilled artisan would recognize that bleach is known to comprise sodium hypochlorite, as evidenced by the ChEBI database (page 1). Guarat further teaches that KBr may be used as a co-catalyst in the present invention for the purposes of accelerating the reaction (Example A; 0005 and 0083).
The process of Guarat is analogous to that of Fujiwara and the claimed invention because of their use of TEMPO-based oxidation methods for aliphatic alcohols in continuous flow reactors. Furthermore, the skilled artisan would recognize that the process of Guarat is metal-free and ligand-free (as opposed to Fujiwara who teaches the use of CuI and NMI ligand), and requires much less of the TEMPO catalyst (i.e., 0.05 mol%) than the process of Fujiwara (i.e., 0.1 equiv or 10 mol%).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified Weissman, Fujiwara, and Van Waes to substitute the oxidation reaction conditions of Fujiwara with the biphasic reaction conditions of Guarat to predictably pursue an oxidation method step that is metal-free and requires less TEMPO catalyst to arrive at the claimed invention with a reasonable expectation of success. See MPEP § 2143(I)(B). The motivation to do so would predict the skilled artisan to pursue, with a reasonable expectation of success, a process with improved efficiency and sustainability that does not rely on the use added metals and ligands and is effective with reduced amount of TEMPO catalyst, as described above.
Claims 3 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Weissman et al. (US 2018/0303925 A1; published 10-25-2018; IDS of 12-22-2023), in view of Fujiwara et al. (“Continuous-Flow Synthesis of Cationic Lipid SST-01 via Safe and Scalable Aerobic Oxidation and Reductive Amination”; Org. Process Res. Dev. 2020, 24, 1988-1995; published 07-22-2020) and Van Waes et al. (“Efficient and catalyst-free condensation of acid chlorides and alcohols using continuous flow”; Green Chem. 2012, 14, 2776-2779; published 08-31-2012), and Guarat et al. (US 2014/0343326 A1; published 11-20-2014) as applied to claim 2 above, and further in view of D. F. Aycock (“Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions”; Org. Process Res. Dev. 2007, 11, 156-159; published 12-06-2006).
Regarding claim 3, Guarat teaches every limitation of the instant claim with the exception of a solution of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in 2-methyl tetrahydrofuran. Instead, Guarat teaches the use of toluene or dichloromethane as the organic solvent in solution with TEMPO (Examples 1A and 1B; 0098 and 0104).
However, Aycock teaches that 2-methyltetrahydrofuran (MeTHF) is a commercially available solvent that is produced from renewable resources and is also a good substitute for highly regulated chlorinated solvents like dichloromethane in biphasic reactions because it has a moderate bp, is more resistant to reactions with nucleophiles like amines, and provides clean organic-water phase separations (Abstract; page 158, Col. 2, paragraphs 2 and 4). Aycock further teaches that MeTHF is a very effective solvent for extracting polar compounds from water mixtures that is superior to toluene (page 158, Col. 2, paragraphs 1-2; page 159, Col. 1, paragraph 1).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified Weissman, Fujiwara, Van Waes, and Guarat with the teachings of Aycock to substitute the dichloromethane or toluene solvent of Guarat with 2-methyl tetrahydrofuran as taught by Aycock to predictably pursue a process that utilizes a commercially available solvent produced from renewable resources and provides cleaner extraction properties to arrive at the claimed invention with a reasonable expectation of success. See MPEP § 2143(I)(B). The motivation to do so would predict the skilled artisan to pursue, with a reasonable expectation of success, a process that avoids highly regulated chlorinated solvents, utilizes a solvent sourced from renewable resources and therefore improves sustainability, and provides very effective and clean organic-water phase separations and polar compound extraction ability, as described above.
Regarding claim 8, when considering the combined process of modified Weissman, Fujiwara, Van Waes, Guarat , and Aycock, the continuous flow obtained from the reductive amination step E) is expected to comprise methanol from the reductive amination process of Fujiwara (page 1993; Figure 5) and 2-methyl tetrahydrofuran from the biphasic oxidation process of Guarat in view of Aycock, as detailed above.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Weissman et al. (US 2018/0303925 A1; published 10-25-2018; IDS of 12-22-2023), in view of Fujiwara et al. (“Continuous-Flow Synthesis of Cationic Lipid SST-01 via Safe and Scalable Aerobic Oxidation and Reductive Amination”; Org. Process Res. Dev. 2020, 24, 1988-1995; published 07-22-2020) and Van Waes et al. (“Efficient and catalyst-free condensation of acid chlorides and alcohols using continuous flow”; Green Chem. 2012, 14, 2776-2779; published 08-31-2012), and Guarat et al. (US 2014/0343326 A1; published 11-20-2014) as applied to claim 2 above, and further in view of Lebl et al. (“Continuous Flow Synthesis of Methyl Oximino Acetoacetate: Accessing Greener Purification Methods with Inline Liquid-Liquid Extraction and Membrane Separation Technology”; ACS Sustainable Chem. Eng. 2019, 7, 20088-20096; published 11-15-2019) as evidenced by De Paoli et al. (“How to define the right ambient temperature range for storage and distribution of pharmaceutical raw materials”; Biologicals 2021, 69, 66-69; published 12-17-2020).
Regarding claims 4-5, Weissman teaches the isolation and purification of (2′-Hexyldecanoyloxy)dodecanal, a compound that resides within the genus of formula (V) of instant claim 4, and the isolation and purification of 6-(2′-hexyldecanoyloxy)hexan-1-ol, a compound that resides within the genus of formula (IV) of instant claim 5 (Example 6, 0574-0575).
Weissman, Fujiwara, Van Waes, and Guarat do not explicitly teach the method step D’) of instant claim 4, or the method steps B1’), B2’), and B3’) of instant claim 5.
However, Lebl teaches compound purification via inline continuous liquid-liquid extraction (LLE) and phase separation using continuous membrane separation technology to selectively remove the organic phase from a biphasic stream (page, 20093, Col. 2, paragraph 2). The combination of microreactors for LLE with the microscale, membrane-based, continuous phase separators have advantages over traditional batch extraction processes, such as more precisely controlling the conditions and dramatically reducing the amounts of solvents and reagents during process optimization owing to their small internal volume. Integrating multiple chemical transformations in one telescoped continuous flow process can further decrease the required workload and material consumption during the workup step, and inline extraction and phase separation is crucial for the development of such telescoped sequences (page 20089, Col. 1, paragraphs 1-2; page, 20093, Col. 2, paragraph 2).
The process of Lebl is analogous to the process of Fujiwara and the claimed invention because they reside in the overlapping technical field of telescoped continuous flow processes. Thus, the skilled artisan would recognize from the teachings of Lebl that incorporating inline separation technology can improve the efficiency of a telescoped process by separating aqueous soluble impurities out from the main stream or remove excess reagents that may not be compatible with the subsequent reactive step. Furthermore, the skilled artisan would recognize that inline membrane-based, continuous phase separators method would be directly applicable to the biphasic continuous flow oxidation method of Guarat to remove aqueous soluble impurities prior to the subsequent reductive amination step.
Further regarding claim 5, Lebl teaches a continuous flow setup for the inline quench of acid and product extraction by a static mixer and liquid-liquid separator, wherein an aqueous solution of NaOH is combined with the organic product solution comprising acid under continuous flow to perform quenching and extraction method steps This system resulted in an integrated synthesis-inline purification protocol with an excellent process mass intensity (quantity of raw materials input/quantity of product output) of only 11.1 (page 20090, Scheme 3; page 20093; Col. 2, paragraphs 1-2; page 20094, Col. 1, paragraph 3). The skilled artisan would recognize that the process of Scheme 3 of Lebl is applicable to the continuous flow esterification method of Weissman, Fujiwara, Van Waes, and Guarat because the reaction output is expected to produce HCl as a byproduct (Van Waes; Abstract), such that its subsequent neutralization and product purification as taught by Lebl would predictably improve the results of the following biphasic oxidation step which takes place at a basic pH (Guarat; Examples 1A and 1B).
Although Lebl does not explicitly teach continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23 ºC, as recited in step B2’) of instant claim 5, the process of Lebl as described in Scheme 3 suggests that the neutralization takes place at or near room temperature, which is generally recognized as a temperature in the range of 20-25 ºC, as evidenced by De Paoli (page 67, Col. 1, USP42 definition). MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” Furthermore, Lebl teaches the ability to separate heat-sensitive compounds, and that inline neutralization of the acid excess with NaOH is assisted with real-time pH monitoring of the aqueous solution to optimize the flow rate of the quench solution (page 20088, Col. 1, paragraph 1; page 20091, Col. 2, paragraph 3). Thus, the skilled artisan would recognize that the reaction temperature of the neutralization reaction could be controlled through optimization of the flow rate of the quench solution, as taught by Lebl. See MPEP § 2144.05(II). Finally, the skilled artisan would recognize that the temperature of neutralization could be predictably performed at a lower temperature to mitigate any risks for exotherms, especially for the neutralization of a strong base (i.e., NaOH, as taught by Lebl) and a strong acid generated from the synthesis of acid chlorides (i.e., HCl, as taught by Van Waes).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the process of Weissman, Fujiwara, Van Waes, and Guarat to incorporate the teachings of Lebl to implement the method steps of D’), B1’), B2’), and B3’) to arrive the invention of claims 4-5 to pursue an improved telescoped continuous flow process that predictably removes aqueous soluble impurities or excess reagents out from the main stream with a reasonable expectation of success to arrive at the claimed invention. See MPEP § 2143(I)(A). The motivation to do so would predict the skilled artisan to pursue, with a reasonable expectation of success, a process with in an integrated synthesis-inline purification protocol that improves process mass intensity and decreases the required workload and material consumption during the workup step, as described above.
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success of arriving at the instantly claimed process. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Conclusion
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/D.R./Examiner, Art Unit 1692
/AMY C BONAPARTE/Primary Examiner, Art Unit 1692
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