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, 4, 11, and 13 were amended and claims 2 and 5 were canceled in the response filed 9/8/2025. Claims 1, 3, 4, and 6-13 are currently pending and under examination.
Drawings
The drawings were received on 9/8/2025. These drawings are acceptable. Therefore, the objection to the drawings on p. 2-3 of the OA dated 6/16/2025 is withdrawn.
Claim Objections
The amendments filed 9/8/2025 are persuasive to overcome almost all of the objections of record on p. 3-4 of the OA dated 6/16/2025. Therefore, unless the objection is repeated below it is withdrawn.
Claim 1 is objected to because of the following informalities:
In line 2 of the definition of variable X in claim 1, the limitation “a salts” should be deleted and replaced by “a salt”.
Appropriate correction is required.
Additionally, in claim 13, line 4, the Examiner suggests deleting the limitation “the reaction vessel” and replacing it with –the microreactor—to be consistent with the language used throughout the claims.
Modified Claim Rejections - 35 USC § 112-Necessitated by Amendment
The amendments filed 9/8/2025 are persuasive to overcome the 35 USC 112(b) and 35 USC 112(d) rejections of record on p. 4-5 of the OA dated 6/16/2025. Therefore, the rejections are withdrawn. However, the amendment to claim 13 has introduced a new indefiniteness issue into the claim.
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.
Claim 13 is 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.
Claim 13, previously an independent claim, was amended to depend from claim 1 and the final two lines of claim 13 recite: “permitting reaction of the ethyl acetate, hydroxylamine salt or the equivalent and base in the microreactor unit to form acetohydroxamic acid.” The issue is with the phrase “or the equivalent” with respect to the hydroxylamine salt. Though the phrase is explicitly recited on p. 5 and 12, lines 1-6, of the specification as filed, claim 1 does not recite this limitation. Therefore, there appears to be a lack of antecedent basis for the limitation. Nor it is clear what an “equivalent” to the hydroxylamine salt encompasses as there are no examples or discussion in the specification as filed.
Modified Claim Rejections - 35 USC § 103-Necessitated by Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. See p. 5-14 of the OA dated 6/16/2025 fr the rejection of record. The rejection of claim 13 has been modified to address the amendments filed 9/8/2025.
Claim(s) 1 and 6-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (CN 103922968A, published on 7/16/2014, of record in the IDS filed on 5/17/2022) in view of Riva (“Efficient Continuous Flow Synthesis of Hydroxamic Acids and Suberoylanilide Hydroxamic Acid Preparation” J. Org. Chem. 2009 (74), p. 3540, including Supporting Information p. S1-S13, of record). Liu is not in English and there is no English equivalent available, therefore a machine generated translation is provided.
Applicant Claims
Applicant claims a continuous process for reacting an alkyl ester with a hydroxylamine salt in the presence of a base in a microreactor to produce a hydroxamic acid according to the following scheme:
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. Each of the alkyl ester, hydroxylamine salt, and the base are fed to the microreactor through separate lines and reacted.
Determining the Scope and Content of the Prior Art (MPEP §2141.01)
Liu discloses a method for the preparation of hydroxamic acids and salts thereof. See abstract. Liu teaches that the process comprises reacting a methanolic solution of an organic carboxylic acid methyl ester of formula (1) or (2) with hydroxylamine or a salt thereof, in the presence of alkaline (base) to produce the corresponding hydroxamic acid salts of formula (3) or (4), which can then be acidified to obtain the hydroxamic acids of formula (5) or (6). See claims. The process of Liu corresponds to the following Examiner drafted reaction scheme:
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+ MeOH + alkaline + NH2-OH [Wingdings font/0xE0]
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[Wingdings font/0xE0]
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.
In the compounds of formula (1), (3), and (5) and Liu, R is a C5-C21 alkane (alkyl) group and variable M in the (5) includes potassium and sodium. See claims. Thus, the compounds of formula (1) of Liu correspond to the claimed alkyl ester wherein instant R is a C5-C21 alkyl and R1 is methyl, a C1 alkyl and the compounds of formula (5) of Liu correspond to the instantly claimed aliphatic hydroxamic acid products (claim 1) wherein R is as above. Hexyl acetate, an instant alkyl ester wherein R1 is methyl and R is hexyl (C6 alkyl) is exemplified in working example 4. Also see discussion of “preferred methyl organic carboxylates” on p. 2 of the translation.
The hydroxylamine salt of Liu corresponds to the claimed hydroxylamine salt of formula NH2-OH·X, wherein X is HCl (hydroxylamine hydrochloride) or H2SO4 (hydroxylamine sulfate). See preferred hydroxylamine salts on p. 2 of the translation. Hydroxylamine hydrochloride is exemplified in the working examples and in claim 3. Thus, the X represents salts with inorganic acids in Liu (claims 1 and 6).
The base of Liu corresponds to the claimed base, and includes sodium hydroxide and potassium hydroxide (claims 1 and 7). See claim 2, examples, and discussion of the bases in the lower half of p. 2 of the translation.
Riva teaches an efficient continuous flow synthesis of hydroxamic acids according to the following scheme:
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. See abstract.
The process of Riva is analogous to the process of Liu, wherein an ester is reacted with hydroxylamine (NH2OH) in the presence of a sodium methoxide (MeONa, a base) in methanol to produce the corresponding hydroxamic acids. In Table 3 on p. 3451, Riva teaches that the process is predictable for both aromatic (compounds above wherein R is an aromatic group) and aliphatic (compounds above wherein R is an aliphatic group) methyl esters (wherein R’ of the ester compound is methyl, a C1 alkyl).
In the experimental sections on p. 3543 and p. S3-S7, Riva teaches a 0.5M solution of the ester (1 eq) and 50% aqueous hydroxylamine (10 eq) in MeOH (reagent stock bottle A) and a 0.5 M solution of MeONa (1 eq) in MeOH (reagent stock bottle B) are each transferred continuously and simultaneously to a microreactor, through an automated injection system, to produce the corresponding hydroxamic acid products. The microreactor is described as a poly(tetrafluoroethylene) (PTFE-see p. S1) tubing and is shown as being coiled/looped in the abstract (claim 8). Also see Fig. 3, element 16, of the instant drawings, which is described as a “looped” microreactor on p. 14 of the specification as filed.
Riva further teaches that continuous flow chemistry processes are known to have numerous advantages over batch processes, including “precise control of variables such as temperature, pressure, concentration, residence time, and heat transfer. All of these aspects significantly affect the reaction outcome, improving yield and selectivity.5 Moreover, the possibility of carrying out reactions in superheated solvents allows novel
thermal regimes previously inaccessible within conventional apparatus.6 By rapid and efficient heat dispersion, large exotherms can be minimized, producing safer and more selective processes.” See abstract and first paragraph on p. 3540.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.02-03)
Regarding claim 1, Liu does not explicitly teach that the hydroxamic production process can be carried out by continuously charging a) a solution of the alkyl ester, b) a solution of the hydroxylamine salt and c) a solution of the base to a microreactor through three separate lines.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Liu and Riva to arrive at the instantly claimed process with a reasonable expectation of success before the effective filing date of the claimed invention. A person of ordinary skill would have been motivated to carry out the process of Liu in a continuous microreactor because Riva teaches that flow microreactors are known in the art for facilitating analogous reactions between esters and hydroxylamine in the presence of base. Riva additionally teaches that there are numerous safety and efficiency advantages that are associated with flow chemistry as compared to batch processes. Carrying out the reaction of Liu in the continuous microreactor system of Riva will predictably produce hydroxamic acids according to the claimed process with increased efficiency. Also see MPEP 2143(B) and MPEP 2144.04(V)(E).
Regarding the requirement that each of the alkyl ester, the hydroxylamine salt, and the base is charged continuously through independent lines to the microreactor in claim 1, Riva teaches that the ester and hydroxylamine reactants are pre-mixed and fed continuously to the microreactor in a first line while the base is simultaneously fed to the microreactor in a second line. Liu, in the examples, teaches that the hydroxylamine salt and base are first mixed and then that the alkyl ester is added to the first mixture. Both Liu and Riva teach that the reaction requires heat. While neither Liu or Riva, explicitly teach that the three reactants are added in three separate lines to a microreactor, both Liu and Riva teach that all three reactants and heat are required to initiate the claimed reaction. Therefore, the order of combining the reactants does not appear to be critical and the selection of any order of mixing ingredients and/or performing process steps is prima facie obvious. See MPEP 2144.04(IV)(C).
Regarding claims 9-12, Liu teaches that the batchwise reactions are carried out at a temperature between 45-55°C for 3-5 hours and produce hydroxamic acids in yields ≥95%. See examples, in particular example 4, and discussion of preferred reaction conditions near the end of p. 2 of the translation. Liu is silent regarding the pressure of the reaction; however, the reaction procedure of the examples indicates that the reaction is carried out at ambient pressure (about 1 bar) as no special measures to increase or decrease the pressure inside the reaction vessel are required. Therefore, Liu teaches that the reaction temperature, pressure, and yields fall within the claimed ranges. Also see MPEP 2144.05.
As discussed above, Riva teaches that known benefits of converting batch reactions to continuous processes in microreactors include the ability to more precisely control reaction variables, including temperature, pressure, and residence time, which result in higher yields, selectivities, and purities. Riva teaches in Table 1 on p. 3541 that analogous reactions to that of Liu can be carried out at residence time of 5 or 30 minutes, both of which fall within the claimed range. See MPEP 2144.05.
Further regarding claim 12, Riva teaches in Table 2 on p. 3541, that the conversion of the reaction is increased by 20% by switching from batch conditions to the described flow system. As Liu already teaches high yields and purities when carrying out the claimed reaction under batch conditions, then if the same process were made continuous using the flow system of Riva, then even higher yields and purity levels would be expected based on the disclosure of Riva. Also see MPEP 2144.05(II).
Claim(s) 3-4 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (CN 103922968A, published on 7/16/2014, of record in the IDS filed on 5/17/2022) in view of Riva (“Efficient Continuous Flow Synthesis of Hydroxamic Acids and Suberoylanilide Hydroxamic Acid Preparation” J. Org. Chem. 2009 (74), p. 3540, including Supporting Information p. S1-S13, of record), as applied to claims 1 and 6-12 above, and further in view of Fushida (CN1384097A, published on 12/11/2002, and including a machine generated English language translation, of record).
Applicant Claims
Applicant claims the process of claim 1, wherein the hydroxamic acid produced is acetohydroxamic acid, a compound wherein R and R1 are both methyl, C1 alkyl, in claims 3 and 13.
Applicant further claims the process of claim 1, where the alkyl ester is one of the claimed lower alkyl esters of claim 4 or the ethyl acetate of claim 13.
Determining the Scope and Content of the Prior Art (MPEP §2141.01)
Liu teaches a genus of esters of formula (1) which overlap with those claimed, wherein R is C5-C21 alkyl and R1 is methyl, a C1 alkyl.
Fushida is directed to a process for preparing acetohydroxamic acid, the compound of instant claim 3. See abstract and claims. Fushida teaches that acetohydroxamic acid is obtained in an analogous process to those of Liu and Riva, wherein methyl acetate, an instant alkyl ester of claim 4 wherein R and R1 are both methyl (C1 alkyl), is reacted with hydroxylamine hydrochloride (NH2-OH·HCl) in the presence of an alkali base (NaOH or KOH) and methanol or ethanol. See claims and examples. Fushida further teaches that acetohydroxamic has wide application in various fields of animal husbandry, agriculture, medicine, and environmental protection and can promote the development of various related industries. See final sentence of abstract.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.02-03)
Liu does not explicitly teach the use of one of the alkyl esters of claim 4 or the production of the acetohydroxamic acid of claim 3.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Liu, Riva, and Fushida to arrive at the instantly claimed process with a reasonable expectation of success before the effective filing date of the claimed invention. A person of ordinary skill would have been motivated to substitute the methyl acetate alkyl ester of Fushida into the combined process of Liu and Riva to produce acetohydroxamic acid because Fushida teaches that acetohydroxamic acid is a valuable commercial product. Further, the process of Fushida is analogous to the combined process of Liu and Riva such that there is more than a reasonable expectation of success of obtaining acetohydroxamic acid from methyl acetate from the combined process of Liu, Riva, and Fushida.
Further regarding the ethyl acetate alkyl ester of claim 13 (wherein R is Me and R1 is Et, a C2 alkyl), it would have been prima facie obvious to substitute the methyl acetate alkyl ester of the combined process of Liu, Riva, and Fushida, for the ethyl acetate alkyl ester because it is a one-carbon homolog of the methyl acetate alkyl ester and the two are presumed to possess substantially identical properties. See MPEP 2144.09. Therefore, replacing one lower alkyl ester with another would predictably produce the same product with a reasonable expectation of success. See MPEP 2144.07 and MPEP 2143(B).
Applicant Arguments on p. 5-11 of the response filed 9/8/2025
The Applicant argues that the present continuous flow process is beneficial over the traditional batch vessels for at least the following reasons:
Mass and heat transfer can be significantly improved by decreasing reactor size;
Fewer transport limitations can be offered by the feasibility and device flexibility of continuous flow synthesis;
Yield and selectivity can be improved due to the precise control of reaction variables such as temperature, pressure and residence time; and
Scale-up of continuous flow synthesis is readily achieved by simply increasing the number of reactors or their sizes.
The Applicant then refers to Table 1 of p. 26 of the specification as filed. The Applicant argues that yield up to 98% can be achieved when the reaction is conducted at 90C and pressure is set up to 4-5 bar in a continuous flow microreactor. Applicant argues it is also observed that the amounts of certain impurities formed during synthesis of aliphatic hydroxamic acid reduced drastically, leading to high purity and high yield of the aliphatic hydroxamic acid synthesized in continuous flow system according to the present invention.
The Applicant then argues that the claimed method is distinct from Liu because Liu’s method teaches agitating. The Applicant further argues that since Liu teaches a work-up comprising distillation, cooling, and addition of vitriol (sulfuric acid) that the process does not read on that claimed because the instant process does not require those steps.
The Applicant argues that though Riva discloses continuous flow synthesis of hydroxamic acids in a microreactor using esters, hydroxylamine, and base with reactants charged in different lines that Riva does not compensate for the deficiencies of Liu. The Applicant argues that Riva only teaches simultaneously charging two streams to the microreactor; one containing a premix of the alkyl ester and hydroxylamine (referred to as reagent stock bottle A in Riva) and one containing the base (referred to as reagent stock bottle B in Riva). The Applicant argues Riva does not teach or suggest three feed streams. The Applicant argues that the three streams is not a “mere procedural nuance, but a substantive difference in reactor design and process control”. The Applicant cites the alleged unexpected advantages of a three-feed configuration and generally refers to the specification and examples therein to support the argument.
The Applicant also argues that Riva only teaches the use of a PTFE continuous microreactor and the instant claimed encompass a broader range of microreactors which provides additional flexibility and potential process optimization that is not contemplated by Riva. The Applicant further argues that the scope of reactants in the present claims is also broader than that disclosed in Riva.
Examiner Response
The Applicant’s arguments have been fully considered but are not persuasive. Regarding the advantages of the claimed continuous process, these are all well-known and expected in the art. For example, see Riva p. 3540. Therefore, if the batch process of Liu were carried out under continuous conditions, then all of these advantages would be expected.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). With respect to the “agitating” of Liu, if the process of Liu and Riva were combined then the “agitating” would be replaced by the continuous mixing claimed. Further, it is not clear what scope the Applicant is attributing to the word “agitating”. According to Merriam Webster (“agitate” https://www.merriam-webster.com/dictionary/agitate, downloaded 10/6/2025), “agitate” means “to move with an irregular, rapid, or violent action”. Therefore, this definition would also appear to apply to a continuous process. Further still, even assuming that the Applicant is trying to limit the definition of “agitate” to stirring, it is noted that claim 8 explicitly recites that the process can be carried out in a continuous stirred tank reactor (CSTR). Therefore, this argument is not persuasive.
Regarding the work-up of Liu, firstly, the Examiner notes that the instant process recites open-ended “comprising” language such that extra steps or reagents may be included in the claimed process even if they are not explicitly recited, including the conditions of Liu. See MPEP 2111.04. Additionally, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a specific work-up or isolation of the aliphatic hydroxamic acid) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Therefore, the conditions of Liu fall within the scope of the claimed process.
Furthermore, neither Riva, Liu, nor their combination have to teach every possible embodiment of the claimed invention to fall within the scope of the claimed method. If only one embodiment is rendered obvious then the whole process is rendered prima facie obvious. See genus-species discussions in MPEP 2131.02 and MPEP 2144.08.
Regarding the use of three separate charging lines in the claimed process, as discussed in the rejection:
“Regarding the requirement that each of the alkyl ester, the hydroxylamine salt, and the base is charged continuously through independent lines to the microreactor in claim 1, Riva teaches that the ester and hydroxylamine reactants are pre-mixed and fed continuously to the microreactor in a first line while the base is simultaneously fed to the microreactor in a second line. Liu, in the examples, teaches that the hydroxylamine salt and base are first mixed and then that the alkyl ester is added to the first mixture. Both Liu and Riva teach that the reaction requires heat. While neither Liu or Riva, explicitly teach that the three reactants are added in three separate lines to a microreactor, both Liu and Riva teach that all three reactants and heat are required to initiate the claimed reaction. Therefore, the order of combining the reactants does not appear to be critical and the selection of any order of mixing ingredients and/or performing process steps is prima facie obvious. See MPEP 2144.04(IV)(C).”
If a prima facie case of obviousness is established, the burden shifts to the applicant to come forward with arguments and/or evidence to rebut the prima facie case. See, e.g., In re Dillon, 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc). MPEP 2145. The only objective evidence cited by the Applicant is experimental Table 1. As discussed above, all of the generic advantages that the Applicant attributes to the claimed process are predictable when batch reactions are converted to continuous reactions in microreactors. Experimental Table 1 does not appear to vary the order of addition of the alkyl eater, hydroxylamine salt, and base in any examples. Nor is there evidence that “independent and precise control over the flow rate, concentration, and timing of each reactant entering the microreactor” provides significantly different results if three feed lines are used vs. two. It is further noted that though three feed lines are employed, the instant Figures teach that all three lines are fed to the same point and the reaction requires heat to begin. Therefore, the Office does not see any evidence that the use of three feed lines is “a substantive difference” which provides unexpected results.
Also see MPEP 2145: “Evidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339.” “Additionally, the evidence must be reasonably commensurate in scope with the claimed invention. See, e.g., In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990); In re Grasselli, 713 F.2d 731, 743, 218 USPQ 769, 777 (Fed. Cir. 1983)”.
Therefore, the claims remain rejected for the reasons of record.
Conclusion
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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/AMY C BONAPARTE/ Primary Examiner, Art Unit 1692