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, 3, 4, 6-8, 12, and 13 are pending.
Maintained Claim Rejections - 35 USC § 103
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. 2-15 of the OA dated 2/24/2026 for the rejections of record.
Claim(s) 1, 6-8, and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (CN103922968A, published on 7/16/2014, of record in the IDS filed on 5/17/2022, including machine translation) 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) and Voros (“Formation of Aromatic Amidoximes with Hydroxylamine using Microreactor Technology” Org. Process. Res. Dev. 2012, p. 1717).
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 at a residence time of reactants in the microreactor from about 30 seconds to 1 hour, at a temperature from about 50 to about 120°C, and at a pressure greater than 1 bar.
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.
Voros is directed to a continuous flow process for the formation of aromatic amidoximes with hydroxylamine using microreactor technology. See abstract. In the introduction section, Voros teaches the same known benefits of microreactors as those already described in Riva. Specifically, highly efficient mixing properties combined with superheat heat exchange ability with a high surface to volume ratio which allows for running highly exothermic and hazardous reactions in a safe manner. See first paragraph on p. 1717. On p. 1718, column 1, Voros discusses hydroxylamine as a reactant. Voros states “Hydroxylamine (HA) is a widely used reagent in the research of semiconductors, apart from its use in the chemical and pharmaceutical industries. HA is classified as a
corrosive substance (Class 8) by the United Nations (UN) recommendations on the transport of dangerous goods (12th ed.). HA itself is a crystalline material with a highly explosive property. Its water solution above a concentration of 70% is also very explosive. HA is also considered to be toxic and from the point of view of process safety a problematic reagent that is mainly available in a stable salt form or, recently in water solution, as bulk material containing stabilizing agents. Water solutions of HA are very advantageous from a chemical engineering point of view, but they need very cautious handling and storage due to their thermal instability and catalytic decomposition potential, which are well described in the literature”.
Voros then teaches that microreactors can mitigate the safety hazards associated with hydroxylamine. Voros teaches the reaction of nitrile derivatives with hydroxylamine under elevated pressure in two microreactor systems. Schemes 4 and 5 on p. 1720 teach the scope of the condensation reaction and Tables 2-4 on p. 1720-1721 teach that the reactions were carried out under an elevated temperature (100 or 125°C) and under an elevated pressure (20 bar) in the Labtrix S1 microreactor of Figure 4 on p. 1721. Tables 5-7 on p. 1720-1721 teach the reaction under elevated temperature (100 or 125°C) and pressure (2.5-3 bar) in a Corning LF reactor of Fig. 5-6 on p. 1721-1722. Voros teaches that high yields of the desired amidoxime compounds (both via HPLC and isolated yields) are obtained in both microreactor systems operated under elevated temperature and pressure when hydroxylamine is used as a reactant. The microreactors of Voros are also shown to comprise separate inlets for the introductions of reactants and a back pressure regular (BPR) to regular the elevated pressure in the reactor. Also see “Reactions in the Microreactor” section on p. 1725.
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. Nor does Liu explicitly teach a residence time of reactants in the microreactor from about 30 seconds to 1 hour, at a temperature from about 50 to about 120°C, and at a pressure greater than 1 bar.
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 Voros 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. A person of ordinary skill would have been further motivated to use a continuous flow reactor in the process of Liu and Riva because Voros teaches that the unstable and toxic hydroxylamine reactant of Liu and Riva is stable in continuous flow reactions under elevated temperatures and pressures. Therefore, carrying out the reaction of Liu in the continuous microreactor as taught by Riva and Voros will predictably produce hydroxamic acids according to the claimed process with increased efficiency and safety. 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) .It is additionally noted that Riva and Voros teach the at the microreactors can have several separate inlets such that the skilled artisan could easily modify any known microreactor to include three inlets.
Regarding the residence time and temperature of the reaction, 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% (claim 12). 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 and yield fall within the ranges in claims 1 and 12. Riva additionally teaches that the reaction in the microreactors are carried out in the range of 50-70°C, which falls within the claimed range. See Table 1 on p. 3541. 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.
Regarding the pressure of the reaction, both Liu and Riva teach ambient pressure (about 1 bar). This pressure appears to overlap with the claimed range of “pressure greater than 1 bar” because ambient pressure can include values just below and above 1 bar and the claim does not specify how far about 1 bar the pressure has to be. Riva explicitly teaches that the pressure of the reaction can be precisely controlled using a microreactor and that temperatures which are too high can cause by-product formation. See paragraph bridging col. 1-2 on p. 3540 and second paragraph in col. 1 on p. 3541. Voros teaches the same known benefits of microreactors as those already described in Riva. Specifically, highly efficient mixing properties combined with superheat heat exchange ability with a high surface to volume ratio which allows for running highly exothermic and hazardous reactions in a safe manner. Voros further teaches that hydroxylamine can be used safely in a microreactor under elevated temperatures and pressures and the microreactors are equipped with back pressure regulators to control the pressure of the reaction. Therefore, the skilled artisan would also find it prima facie obvious to optimize the reaction temperatures and pressures of the reaction system. It is known that increasing the severity of reaction conditions (increasing reaction temperature and pressure) can affect the residence time and purity of the reaction. Therefore, the skilled artisan could predictably increase the pressure of the reaction while decreasing the temperature of the reaction to safely and effectively further investigate the optimization of the reaction with a reasonable expectation of success. Also 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) and Voros (“Formation of Aromatic Amidoximes with Hydroxylamine using Microreactor Technology” Org. Process. Res. Dev. 2012, p. 1717), as applied to claims 1, 6-8, and 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, Voros 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, Riva, and Voros 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, Riva, and Voros 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, Voros, 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).
Response to Applicant Arguments on p. 2-5 of the response filed on 5/26/2026:
Applicant argues:
“The asserted combination does not teach or suggest the specifically claimed
continuous microreactor process in which (1) an alkyl ester, (2) a solution containing a hydroxylamine salt or equivalent, and (3) a base solution are each charged in continuous flow through first, second, and third lines, respectively, and reacted at a pressure greater than 1 bar. The Office action acknowledges that Liu does not expressly teach this three-line continuous microreactor configuration or the claimed operating pressure. The rejection therefore depends on importing a generalized flow reactor concept from Riva and a generalized teaching of elevated pressure from Voros, without an articulated reason why a person of ordinary skill would have reconstructed the batch hydroxylamine salt chemistry of Liu into the claimed three-stream design.
Liu teaches a materially different process. Liu describes adding alkali into a methanol solution of hydroxylamine salt under stirring, then adding an organic methyl carboxylate and reacting for 2-6 hours at 30-70°C. See Liu, Claim 1. Liu's examples likewise use batch sequencing, including adding sodium hydroxide in portions to hydroxylamine hydrochloride in methanol, reacting hydroxylamine hydrochloride with sodium hydroxide, removing NaCl by filtration, and then mixing the filtrate with methyl octanoate. See Liu, Comparative Example 1. This is not continuous metering of three independent streams into a microreactor.
Rather, Liu teaches that hydroxylamine salt and base are handled together before ester addition, with salt byproduct management occurring before the ester reaction. That teaching does not suggest separately and continuously feeding hydroxylamine salt and base into a microreactor while expecting rapid hydroxamic acid formation within the claimed residence time window.
Riva does not cure that deficiency. Riva does disclose continuous flow hydroxamic acid synthesis, but its reagent arrangement is different from claim 1.
Specifically, Riva has under the "General Reaction Procedure for the Synthesis of Hydroxamic Acids" heading, "Reagent stock bottle A: ester (1 equiv); 50% aq hydroxylamine (10 equiv), 0.5 M solution in MeOH" and "Reagent stock bottle B: MeONa (1 eq), 0.5 M solution in MeOH." Riva, p. 3543, 1St, col (emphasis added for readability).
Riva further states that "[a] mixture of la [methylbenzoate] (0.5 M in MeOH) and
hydroxylamine (1:10 ratio) was simultaneously pumped into the flow reactor with a solution of MeONa." Riva, p. 3540, 2nd col. Thus, Riva premixes ester with free hydroxylamine and separately feeds sodium methoxide as a second stream. Riva does not teach a separate continuous stream containing hydroxylamine salt, and does not teach a separate third continuous base stream.
The statement in the Office action that the "order of combining the reactants does not appear to be critical" does not supply the missing reason to modify the art. Office action, p. 10. Claim 1 is not directed merely to a different order of adding known ingredients to a batch vessel. It requires a specific continuous microreactor feed design with separate continuous feeds of the ester, hydroxylamine salt or equivalent, and base solution through independent lines, under defined residence time, temperature, and pressure conditions. The batch processing of Liu and the two-stream free hydroxylamine process of Riva are not interchangeable with that design.
The Office action does not identify evidence that a skilled artisan would have been motivated to redesign Riva's two-feed system into a three-feed hydroxylamine salt and base system, with the attendant ionic byproducts and compatibility considerations arising from continuous salt and base contact, while still expecting successful conversion of the ester to hydroxamic acid at the claimed short residence times. Under M.P.E.P. § 2143, obviousness requires an articulated reasoning with some rational underpinning to support the legal conclusion. The general proposition that microreactors may have multiple inlets does not explain why the claimed three-stream hydroxylamine salt process would have been selected.
In addition, the pressure limitation is an independent deficiency in the cited references. Claim 1 requires operation "at a pressure greater than 1 bar." Liu is silent as to positive pressure control and describes conventional stirred batch operation. The hydroxamic acid flow process of Riva likewise does not disclose operating the reaction at a pressure greater than 1 bar. The Office action's position that "ambient pressure" appears to overlap a pressure greater than 1 bar is not a sufficient factual basis for obviousness. The claim affirmatively excludes 1 bar, and neither Liu nor Riva teaches deliberately pressurizing their corresponding processes above 1 bar.
Voros does not remedy this defect. Voros concerns the "formation of aromatic amidoximes with hydroxylamine using microreactor technology," not formation of hydroxamic acids from alkyl esters using hydroxylamine salt and base. Voros, Title. Voros reacts aromatic nitriles with a 50% hydroxylamine solution. The "Reactions in the Microreactor" section explains that the system was maintained at 20 bar back pressure "in order to prevent the reactants and solvent system from boiling when temperatures above the atmospheric boiling point were employed." Voros, p. 1725, 1St col. Consequently, this section and the tables in Voros show elevated pressure in a different nitrile to amidoxime reaction system. They do not provide a reason to impose a pressure greater than 1 bar on the hydroxamic acid chemistries of Liu and Riva.
Accordingly, the combination of Liu, Riva, and Voros fails to teach or suggest at least the three-stream hydroxylamine salt microreactor process operated at a pressure greater than 1 bar as required by independent claim 1.”
The Applicant’s arguments have been fully considered but are not persuasive. Applicant argues that Liu and Riva are materially different from the claimed process because they do not explicitly teach separately charging a) an alkyl ester through a first line of a microreactor unit in continuous flow; b) a solution containing a hydroxylamine or an equivalent thereof through a second line of a microreactor unit in continuous flow; and c) charging a base solution through a third line of the microreactor unit, in a continuous flow. In response, 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 inventive examples, teaches that the hydroxylamine salt and base are first mixed and then that the alkyl ester is added to the first mixture. Applicant cites the conditions of the comparative example 1 in the arguments. 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). It is additionally noted that Riva and Voros teach the at the microreactors can have several separate inlets such that the skilled artisan could easily modify any known microreactor to include three inlets.
Thus, Liu and Riva are teaching the same overall reaction as that claimed, with a different order of adding/mixing ingredients/reactants. The reaction of Liu and Riva is further taught to require heat to proceed (which is also required in the instant claims). Therefore, based on the teachings of Liu and Riva, a person of ordinary skill in the art would expect that any order of mixing the claimed reactants will predictably result in a process for producing a hydroxamic acid, especially if all three are mixed in the absence of the heat required for the reaction to proceed. Further, as taught by Riva and Voros, teach 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. Specifically, Voros teaches that highly efficient mixing properties combined with superheat heat exchange ability with a high surface to volume ratio which allows for running highly exothermic and hazardous reactions in a safe manner, including those comprising hydroxylamine. The motivation to modify the order of addition is that selection of any order of mixing ingredients and/or performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04(IV)(C). Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.)
As discussed above, due to the requirement of the heat for the reaction to proceed and the excellent and predictable process control of microreactors, changing the order of mixing the ingredients will not produce unexpected results. Further, there is no objective evidence in the specification as filed that the order of adding reactants and/or number of inlets to the microreactor, is critical. The Applicant generally argues that “the attendant ionic byproducts and compatibility considerations arising from continuous salt and base contact, while still expecting successful conversion of the ester to hydroxamine acid at the claimed short residence times” is unpredictable, however, there is no objective evidence to support this assertion. Further, all of the same byproducts will be present in the reactor once all three are mixed, therefore it is not clear how the claimed order of addition imparts patentability to the claimed invention. Also see MPEP 2145(I): Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
Regarding the claimed pressure, both Liu and Riva teach ambient pressure (about 1 bar). This pressure appears to overlap with the claimed range of “pressure greater than 1 bar” because ambient pressure can include values just below and above 1 bar and the claim does not specify how far above 1 bar the pressure has to be (for example 1 atm = 1.01325 bar, which falls within the claimed range). Furthermore, the skilled artisan would also find it prima facie obvious to optimize the reaction temperatures and pressures of the reaction system. It is known that increasing the severity of reaction conditions (increasing reaction temperature and pressure) can affect the residence time and purity of the reaction. Therefore, the skilled artisan could predictably increase the pressure of the reaction while decreasing the temperature of the reaction to safely and effectively further investigate the optimization of the reaction with a reasonable expectation of success. Also see MPEP 2144.05.
This is further underscored by the teachings of Voros, which is cited to explicitly teach that hydroxylamine, an unstable and toxic reagent, can be safely subjected to reactions at elevated temperature and pressure to produce products in greater than 90% isolated yield and close to 100% purity by HPLC. Voros teaches that the reaction is safe, efficient, and effective because of all of the known benefits of microreactors which are argued by the Applicant and explicitly taught by Riva and Voros. Voros further teaches that back pressure regulators are well-known in the art for maintaining elevated pressure in microreactor systems. Therefore, the Examiner respectfully disagrees with the Applicant’s arguments that operation at elevated pressure is not routine in flow systems.
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). Voros is cited not to teach the specifics of the claimed reaction, which are taught by the combination of Liu and Riva, but to teach that microreactors are known to be compatible with hydroxylamine. Thus, carrying out the known reaction of Liu and Riva in a microreactor will be predictable.
Applicant further argues that Fushida does not cure the alleged deficiencies of Liu, Riva, and Voros. However, this is not persuasive for the reasons cited above.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY C BONAPARTE whose telephone number is (571)272-7307. The examiner can normally be reached 11-7.
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/AMY C BONAPARTE/Primary Examiner, Art Unit 1692
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