Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This office action is in response to applicant’s communication filed on 3/4/24.
Claims 1-7 are pending in this application and are being examined in this Office Action.
Priority
The applicant claims benefit as follows:
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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.
Claims 1-7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1, 4 and 5 are indefinite because the claims recite the compound "4-chloro-2-(hydroxyimino)-N-(2-methylphenyl)acetamide," and this name does not agree with the structure drawn in the same claim, as shown below:
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The name places a chloro group at the 4-position of the acetamide chain and places no chloro group on the aryl ring. An acetamide has only two carbon atoms. There is no 4-position. The name is therefore impossible.
The structure drawn in equations (3) and (4) is instead N-(4-chloro-2-methylphenyl)-2-(hydroxyimino)acetamide. The chloro group is on the aryl ring, para to the amide nitrogen.
Because the name and the structure are directed to different compounds, the metes and bounds of the claims are unclear. For purposes of examination, the drawn structure is given controlling weight.
Claim 2 is indefinite because acetic acid and acetic anhydride are recited both as the acylation agent and as the solvent. Claim 2 then recites a molar ratio of o-toluidine to the acylation agent of 1:0.9 to 1:1.5 and a molar ratio of o-toluidine to the solvent of 1:3 to 1:7. When acetic acid or acetic anhydride is the only species present, one species is both the acylation agent and the solvent, and the two ratios cannot both be evaluated. Applicant's Example 1 uses 107 g of o-toluidine and 210 g of acetic acid and nothing else, a ratio of 1:3.50, which falls outside 1:0.9 to 1:1.5 and inside 1:3 to 1:7. Appropriate correction is required. (Specification, paragraph [0090])
Reference to applicant’s specification refers to applicant’s PGPub: US 20250002447
Claim 6 is indefinite because "to obtain the fifth reaction system" lacks antecedent basis. The fifth reaction system is first recited here using the definite article.
Claim 7 is indefinite because "to obtain the sixth reaction system" lacks antecedent basis, for the same reason given for claim 6.
Claims 2-7 are also rejected as depending from a rejected base claim. Appropriate correction is required.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same.
Claims 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to make and use the invention.
The matter at issue is the third step of claim 1. That step converts 4-chloro-2-methylacetanilide to N-(4-chloro-2-methylphenyl)-2-(hydroxyimino)acetamide using an oximation agent. Claim 4 limits the oximation agent to methyl, ethyl, n-butyl, isopropyl, isoamyl and n-amyl nitrite. See reaction from claim 1 below.
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The following evidence is relied upon:1. Touster ("The Nitrosation of Aliphatic Carbon Atoms," Organic Reactions, Vol. 7, Chapter 6, John Wiley & Sons, 1953, pages 327-377).2. Marvel et al. ("Isatin," Organic Syntheses, Vol. 5, 1925, page 71; Organic Syntheses Collective Volume 1, 1941, pages 327-330).3. Sythana et al. (WO 2022064454, pub date March 31, 2022, the US English equivalent US 20230339906, pub date Oct. 26, 2023, is used herein).4. Chen et al. (WO 2021086957, pub date May 6, 2021, the US English equivalent US 20220242837, pub date Aug. 4, 2022, is used herein).The factors set out in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), are addressed below. See MPEP 2164.01(a).(1) The breadth of the claims
Claim 1 recites "an oximation agent." Claim 1 recites no reagent, solvent, additive, catalyst, temperature or time for the third step. Claim 4 does recite nitrites, solvents, molar ratio ranges, and temperature ranges. (2) The nature of the invention
The invention is a six step process. The third step is a carbon-hydrogen functionalization at the carbon alpha to an amide carbonyl. 4-Chloro-2-methylacetanilide is a simple secondary acetamide. Its only alpha hydrogens are those of the acetyl methyl group. The step replaces two of those hydrogens with =N-OH. See reaction for the third step below.
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(3) The state of the prior art
Touster teaches that replacement of a hydrogen on an aliphatic carbon requires an electron-attracting group next to the carbon to be nitrosated. Touster teaches that monoketones are readily converted to alpha-oximino ketones. Touster further teaches that monoesters having no other activating group do not undergo the reaction at all. (Touster, page 328, first paragraph)
An amide carbonyl activates the adjacent carbon less than an ester carbonyl does. The acetyl methyl group of 4-chloro-2-methylacetanilide therefore falls outside the class of substrates Touster identifies as reactive.
Also the art prepares this same class of compound by other routes. Marvel et al. builds the alpha-oximino carbon in from chloral hydrate and hydroxylamine hydrochloride, and then cyclizes the product in sulfuric acid to isatin. (Marvel et al., pages 327-328, first scheme and "Procedure")
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Chen et al. makes the alpha-oximino anilide from o-toluidine, hydrochloric acid, chloral hydrate, hydroxylamine sulfate and sodium sulfate in water at 55-60 degrees C. (Chen et al., paragraph [0625])
Sythana et al. makes the identical claimed oxime from the alpha-chlorinated acetamide, 2-chloro-N-(4-chloro-2-methylphenyl)acetamide, using hydroxylamine hydrochloride and N,N-diisopropylethylamine in 2-propanol at 78 degrees C, and reports 1H-NMR and MS for the product. (Sythana et al., paragraphs [0287]-[0288]) See reaction below.
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Where Sythana et al. uses an alkyl nitrite, the substrate is not an acetanilide. Sythana et al. first reacts the aniline of formula (II) with a malonate ester to obtain the compound of formula (IVc). (Sythana et al., paragraph [0182]) Sythana et al. then converts the compound of formula (IVc) to the compound of formula (IVd) using sodium nitrite in the presence of an acid, or using methyl nitrite, ethyl nitrite or another alkyl nitrite. (Sythana et al., paragraph [0183]) The methylene of formula (IVc) lies between an amide carbonyl and an ester carbonyl. That methylene carries the activation Touster requires.
No reference of record applies an alkyl nitrite to the acetyl methyl group of an acetanilide.(4) The level of one of ordinary skill in the art
One of ordinary skill in this art holds an advanced degree in chemistry, or years of experience in industrial chemistry. That level of skill is high. A high level of skill does not supply a transformation that the art teaches does not occur on this class of substrate. See MPEP 2164.05(b).(5) The level of predictability in the art
Synthetic organic chemistry is an unpredictable art. Touster states that monoesters with no further activation do not react at all. (Touster, page 328, first paragraph) The result for a less activated amide is therefore not predictable from what the specification discloses.(6) The amount of direction or guidance presented
The specification states the step and gives conditions for it. Example 1 bubbles methyl nitrite into 37.5 g of the acetanilide in 200 mL of water at 5-10 degrees C for 5 hours. Example 2 adds 16.8 g of ethyl nitrite to 34.7 g of the acetanilide in 200 mL of water at 5-10 degrees C for 7 hours. (Specification, paragraphs [0092] and [0101])
Nothing in these conditions addresses the activation that Touster teaches is required. The specification does not state how the acetyl methyl group is made to react.
The disclosed sequence is also internally inconsistent. The fourth step requires 5-chloro-7-methylisatin. The chloro group of that compound sits on the aromatic ring. If the second step chlorinates the ring, as drawn in equation (2), then the acetyl methyl group entering the third step is unactivated. If instead the second step chlorinates the alpha carbon, then the third step would proceed as Sythana et al. teaches at paragraph [0287], but the ring would carry no chloro group and the fourth step could not give 5-chloro-7-methylisatin. The specification does not state which product the second step forms.(7) The existence of working examples
The specification gives two examples of the third step. (Specification, paragraphs [0092] and [0101])
Working examples are not required, and their absence would not by itself support this rejection. See MPEP 2164.02. The point here is narrower. Neither example characterizes the product, e.g. melting point, NMR spectrum, IR spectrum, a mass spectrum or an elemental analysis for the product. Where the art teaches that the reaction does not occur on this class of substrate, an example that reports only a mass and a purity value does not establish that the recited compound was obtained.(8) The quantity of experimentation necessary
One skilled in the art would first have to determine whether an alkyl nitrite reacts with the acetyl methyl group of 4-chloro-2-methylacetanilide at all. If a product forms, that person would then have to identify it. Only then could conditions be established across the reagents, solvents, ratios and temperatures of claims 1 and 4. That is research, not routine optimization.Conclusion:
On balance the Wands factors weigh against enablement. Undue experimentation would be required to practice the third step of claim 1. Claims 1-7 each require that step.
Where a specification contains a statement that the examiner has reason to doubt, applicant must come forward with evidence. In re Marzocchi, 439 F.2d 220 (CCPA 1971); MPEP 2164.04.
Applicant may overcome this rejection by submitting, under 37 CFR 1.132, NMR, mass spectral and melting point data for the product of the third step, together with the conditions actually used. Data showing the aromatic substitution pattern of the product of the second step would also be responsive.
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 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 of this title, 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 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sythana et al. (WO 2022064454, pub date March 31, 2022, the US English equivalent US 20230339906, pub date Oct. 26, 2023, is used herein), in view of Framroze (US 10981868, pub date Apr. 20, 2021), further in view of Chenevert et al. ("Chloration de l'acetanilide et de la benzanilide en presence des cyclodextrines et de l'amylose," Can. J. Chem. 1987, 65, 307-310) (the English Translation is used herein), and further in view of Chen et al. (WO 2021086957, pub date May 6, 2021, the US English equivalent US 20220242837, pub date Aug. 4, 2022, is used herein).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Sythana et al. teaches a process for preparing anthranilic amides used to make the anthranilic diamide insecticides, including chlorantraniliprole. Sythana et al. teaches that the process runs from a substituted aniline through the acylated aniline, the alpha-oximino anilide, the isatin and the isatoic anhydride to the anthranilic amide. Sythana et al. teaches that the preferred product carries methyl at R1, hydrogen at R2, chloro at R3, methyl at R4a and hydrogen at R4b, which is 2-amino-5-chloro-N,3-dimethylbenzamide, the compound of applicant's claim 1. (Sythana et al., paragraphs [0002]-[0003], [0011], [0088]-[0103], [0250] and [0252]-[0259], see schemes below)
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Sythana et al. teaches acylating o-toluidine. Sythana et al. adds 590 g of o-toluidine and triethylamine to dichlorethane, adds the acyl chloride at 0-10 degrees C, stirs 4 hours at 25-30 degrees C, adds water, and filters, water-washes and dries the precipitated anilide. Sythana et al. thus teaches the same acylation operation, order of addition and workup recited in applicant's claims 1 and 2. (Sythana et al., paragraph [0293], see scheme below)
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Sythana et al. teaches chlorinating the anilide on the aromatic ring, para to the amide nitrogen. Sythana et al. adds 37% hydrochloric acid and 30% aqueous hydrogen peroxide to the anilide in acetic acid at 15 degrees C and stirs at 25-30 degrees C for 15 hours. Sythana et al. also adds sulfuryl chloride in dichlorethane at 0 degrees C and stirs at 25 degrees C for 12 hours. Both give the 4-chloro anilide. (Sythana et al., paragraphs [0279] and [0282], see scheme below)
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Sythana et al. teaches installing the hydroxyimino group at the alpha carbon of the anilide using a nitrite reagent such as sodium nitrite in the presence of an acid, or an organic nitrite such as methyl nitrite or ethyl nitrite or another alkyl nitrite in the presence of a solvent. (Sythana et al., paragraph [0183])
Sythana et al. teaches using a nitrite reagent to install the hydroxyimino group at the carbon alpha to an anilide carbonyl. Sythana et al. reacts the aniline of formula (II) with a malonate ester to obtain the compound of formula (IVc). Sythana et al. then reacts the compound of formula (IVc) with sodium nitrite in the presence of an acid such as hydrochloric acid, or with an organic nitrite such as methyl nitrite or ethyl nitrite or another alkyl nitrite in the presence of a solvent, to obtain the compound of formula (IVd). (Sythana et al., paragraphs [0182]-[0183], see scheme below)
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Sythana et al. teaches the cyclization of the fourth step on the identical substrate. Sythana et al. adds 25 g (118 mmol) of N-(4-chloro-2-methylphenyl)-2-(hydroxyimino)acetamide portion-wise at 0-10 degrees C to ethylene dichloride and 81 g (826 mmol) of sulphuric acid, a molar ratio of 1:7.0, stirs 16 hours at 20-25 degrees C, quenches into ice cold water, filters and dries the precipitate, and obtains 20.7 g (106 mmol) of 5-chloro-7-methylindoline-2,3-dione, which is 5-chloro-7-methylisatin. Sythana et al. further teaches that sulphuric acid is the most suitable acid for this conversion. (Sythana et al., paragraphs [0231] and [0298], see scheme below)
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Sythana et al. teaches the oxidation of the fifth step on the identical substrate. Sythana et al. adds aqueous hydrogen peroxide drop wise to 61.3 g (314 mmol) of 5-chloro-7-methylindoline-2,3-dione in N-methylpyrrolidone, stirs at 45 degrees C, cools, filters, washes with water and dries, and obtains 56.4 g (266 mmol) of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione, which is 5-chloro-7-methylisatoic anhydride. (Sythana et al., paragraph [0382], see scheme below)
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Sythana et al. teaches the ring opening of the sixth step on the identical substrate. Sythana et al. adds an amine to 2.00 g (8.84 mmol) of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione in acetonitrile at 15-20 degrees C, a molar ratio of 1:1.2, heats to 70 degrees C, quenches with water, and recovers the 2-amino-5-chloro-3-methylbenzamide. (Sythana et al., paragraph [0394], see scheme below)
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Sythana et al. further teaches the reagents and solvents recited in the dependent claims. Sythana et al. teaches halogenating reagents including HX, sulfuryl chloride, chlorine, sodium hypochlorite, N-halosuccinimides, PX3 and PX5. Sythana et al. teaches oxidizing agents including hydrogen peroxide, oxone, peracetic acid and hypohalogenous acids. Sythana et al. teaches reaction solvents including methanol, ethanol, dichloromethane, dichloroethane, chlorobenzene, acetic acid and water. Sythana et al. teaches alcohol solvents for the oxime formation step. Sythana et al. teaches ethyl acetate and methyl acetate for the isatoic anhydride ring opening step. (Sythana et al., paragraphs [0224], [0225], [0232], [0233], [0234] and [0237])
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Sythana et al. teaches every step of claim 1 and the same target compound. Sythana et al. is deficient in the sense that Sythana et al. acylates o-toluidine with an acyl chloride and does not expressly recite acetic acid or acetic anhydride as the acylation agent, and therefore does not expressly recite o-methylacetanilide or 4-chloro-2-methylacetanilide as intermediates. Sythana et al. is further deficient in the sense that the substrate of paragraph [0183] is the malonate ester anilide of formula (IVc), and not the 4-chloro-2-methylacetanilide recited in the third step of claim 1.
Framroze cures this deficiency. Framroze is directed to the same intermediate, 5-chloro-7-methylindoline-2,3-dione, and states that it is an intermediate in the manufacture of chlorantraniliprole. Framroze teaches that this intermediate may be made by two routes, namely chlorination of N-(2-methylphenyl)acetamide followed by cyclization, or cyclization first followed by chlorination of the isatin. (Framroze, column 1, lines 17-39)
Framroze performs the second step of claim 1 on the identical substrate. Framroze dissolves 70 g of N-(o-tolyl)acetamide, which is o-methylacetanilide, in 300 mL of acetic acid, cools to 25 degrees C, purges 50 g of chlorine gas into the mass, heats to reflux for 2 hours, distills off the acetic acid and quenches with water, and obtains 25 g of N-(4-chloro-2-methylphenyl)acetamide, which is 4-chloro-2-methylacetanilide. The charge of 70 g of substrate (0.469 mol) and 50 g of chlorine (0.705 mol) is a molar ratio of about 1:1.5. (Framroze, column 3, lines 30-51, example 1, see scheme below)
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Framroze also teaches the cyclization conditions of claim 5. Framroze reacts 0.1 mole of 2-hydroxyimino-N-(o-tolyl)acetamide with 0.4 mole of concentrated sulphuric acid at 50-60 degrees C, a molar ratio of 1:4, and claims sulfuric acid of 18M to 18.4M concentration, which is about 95 to 98 weight percent. (Framroze, column 5, lines 5-59; claims 1, 2 and 5, example 4, see scheme below)
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Chenevert et al. also cures this deficiency. Chenevert et al. teaches that authentic samples of the 2-chloro and 4-chloro acetanilides were prepared by acetylation of the corresponding chloroanilines with acetic anhydride. (Chenevert et al., page 7, first paragraph)
Chenevert et al. further teaches the ring chlorination of an N-arylacetamide with chlorine. Chenevert et al. passes a stream of excess chlorine through the acetamide in water for one hour. Chenevert et al. reports 100 percent conversion of acetanilide and a product recovery above 90 percent, and an ortho to para ratio of 49:51 with no additive and 10:90 with alpha-cyclodextrin. Chenevert et al. teaches that the ortho positions are masked and that the chlorine reacts at the para position. (Chenevert et al., page 2, Table 1, first and second compounds; page 7, 3rd paragraph)
Sythana et al. is further deficient in the sense that its worked ring opening example uses tert-butylamine and does not expressly recite monomethylamine or an aqueous solution of monomethylamine as recited in claims 1 and 7.
Chen et al. cures this deficiency. Chen et al. prepares the identical final compound. Chen et al. charges 10.0 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione and 100.0 g of ethyl acetate to a reactor, bubbles gaseous methanamine through the mixture at room temperature, extracts with water and removes the solvent, and obtains 8.5 g of 2-amino-5-chloro-N,3-dimethylbenzamide. Chen et al. further teaches that the alkylamine is methylamine, and teaches solvents including acetonitrile, dichloroethane, methanol, ethanol and ethyl acetate, and a reaction temperature of about 0 to about 100 degrees C. (Chen et al., paragraphs [0261]-[0263], [0265]-[0266] and [0629])
Chen et al. also teaches the oxidation of the fifth step on the identical substrate. Chen et al. charges 18.0 g of 5-chloro-7-methylindoline-2,3-dione, 100.0 g of acetic acid and 1.0 g of sulfuric acid, controls the temperature at 60-65 degrees C, adds 13.0 g of 30% hydrogen peroxide solution drop wise, charges water, and filters, water-washes and dries the cake to obtain 14.6 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. The charge of 18.0 g of isatin (0.092 mol) and 13.0 g of 30% hydrogen peroxide (0.115 mol) is a molar ratio of 1:1.25. Chen et al. further teaches oxidation agents including hydrogen peroxide, peroxyacetic acid, chromium trioxide, potassium permanganate, sodium hypochlorite and potassium peroxymonosulfate. (Chen et al., paragraphs [0149] and [0628])
Chen et al. also teaches the cyclization of the fourth step. Chen et al. charges the alpha-oximino anilide by portions to sulfuric acid, controls the temperature between 60 and 65 degrees C, cools, adds the mixture to ice water, stirs, filters, water-washes and dries the cake to obtain the isatin. (Chen et al., paragraph [0626])
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Therefore, it would be prima facie obvious to one of ordinary skill in the art at the time of the invention to carry out the Sythana et al. process from o-methylacetanilide, that is, to acylate o-toluidine with acetic acid or acetic anhydride as taught by Chenevert et al., to ring chlorinate the resulting o-methylacetanilide as taught by Framroze and Chenevert et al., to install the hydroxyimino group with an alkyl nitrite as taught by Sythana et al., and to complete the sequence with aqueous monomethylamine as taught by Chen et al., and thereby obtain 2-amino-5-chloro-N,3-dimethylbenzamide.
The order of the steps is taught by Sythana et al. itself. Sythana et al. chlorinates the anilide before cyclization and then carries the ring chlorinated material through the oxime, the isatin, the isatoic anhydride and the amine step to the claimed product. No rearrangement of the prior art sequence is required.
With regard to the third step of claim 1, the route requires that the hydroxyimino group be installed at the carbon alpha to the anilide carbonyl before the sulfuric acid cyclization of the fourth step. Sythana et al. identifies two reagent classes for installing that group at that position, namely an alkali metal nitrite with an acid, and an alkyl nitrite including methyl nitrite and ethyl nitrite. (Sythana et al., paragraph [0183]) Selecting an alkyl nitrite from those two identified classes is a choice from a finite number of identified, predictable solutions. The alkyl nitrites of claim 4 are members of the class Sythana et al. names.
Substituting the acetanilide for the chloroacetanilide of Sythana et al. is the substitution of one known acylation product of o-toluidine for another with a predictable result. Framroze teaches that the acetanilide undergoes the same para ring chlorination with chlorine in acetic acid, and Chenevert et al. teaches that N-arylacetamides are chlorinated on the ring by chlorine at the para position with complete conversion.
One of ordinary skill in the art would have been motivated to make this combination because Sythana et al. seeks a simple, efficient and industrially economical process for these intermediates, and because Framroze teaches that chlorinating the isatin instead gives poor regioselectivity that requires expensive fractional distillation for purification. (Sythana et al., paragraph [0007]; Framroze, column 2, lines 20-35)
With regard to claim 1, step 1, Sythana et al. teaches acylating o-toluidine and Chenevert et al. teaches acetylating an aniline with acetic anhydride. Framroze further shows that o-methylacetanilide was a known and available starting material, using 70 g of it in its Example 1. Thus obtaining o-methylacetanilide from o-toluidine and an acylation agent would have been obvious. (Sythana et al., paragraph [0293]; Chenevert et al., page 7; Framroze, column 3, lines 43-51)
With regard to claim 1, step 2, Framroze chlorinates o-methylacetanilide with chlorine gas in acetic acid and obtains 4-chloro-2-methylacetanilide. Sythana et al. performs the same ring chlorination on the anilide with hydrogen peroxide and hydrochloric acid, and with sulfuryl chloride. Chenevert et al. confirms that the chlorine goes to the para position. Thus step 2 would have been obvious. (Framroze, column 3, lines 43-51; Sythana et al., paragraphs [0279] and [0282]; Chenevert et al., page 7, Table 1)
With regard to claim 1, step 3, Sythana et al. teaches converting the alpha carbon of the anilide to the hydroxyimino group with an organic nitrite such as methyl nitrite or ethyl nitrite or another alkyl nitrite, and Sythana et al. makes the identical claimed oxime, N-(4-chloro-2-methylphenyl)-2-(hydroxyimino)acetamide. Thus selecting an alkyl nitrite as the oximation agent for this step would have been obvious. (Sythana et al., paragraphs [0183] and [0287])
With regard to claim 1, step 4, Sythana et al. cyclizes the identical oxime with sulphuric acid and obtains 5-chloro-7-methylisatin. Chen et al. and Framroze teach the same cyclization with sulfuric acid. Thus step 4 would have been obvious. (Sythana et al., paragraph [0298]; Chen et al., paragraph [0626]; Framroze, column 5, lines 43-59)
With regard to claim 1, step 5, Sythana et al. and Chen et al. each oxidize 5-chloro-7-methylisatin with hydrogen peroxide and obtain 5-chloro-7-methylisatoic anhydride. Thus step 5 would have been obvious. (Sythana et al., paragraph [0382]; Chen et al., paragraph [0628])
With regard to claim 1, step 6, Chen et al. reacts 5-chloro-7-methylisatoic anhydride with methylamine and obtains 2-amino-5-chloro-N,3-dimethylbenzamide. Sythana et al. performs the same ring opening with an amine. Thus step 6 would have been obvious. (Chen et al., paragraph [0629]; Sythana et al., paragraph [0394])
With regard to claim 2, Sythana et al. adds the acylating agent to the amine in solvent under stirring, reacts, adds water, and filters, water-washes and dries the product, and works at 0-10 degrees C and then 25-30 degrees C, which falls within the claimed range of -10 to 135 degrees C. Sythana et al. uses 4573 mmol of o-toluidine and 5259 mmol of acylating agent, a molar ratio of 1:1.15, which falls within the claimed range of 1:0.9 to 1:1.5. Chenevert et al. teaches acetic anhydride as the acylation agent. Sythana et al. teaches dichloromethane, dichloroethane and xylene as acylation solvents. The claimed molar ratio of o-toluidine to solvent is a result effective variable that one of ordinary skill in the art would optimize by routine experimentation, and applicant shows no criticality, since neither working example falls within the claimed range. (Sythana et al., paragraphs [0233] and [0293]; Chenevert et al., page 7; Specification, paragraphs [0090] and [0099])
With regard to claim 3, Framroze adds chlorine gas, a recited chlorination agent, to o-methylacetanilide in acetic acid, a recited solvent, at a molar ratio of about 1:1.5, which is within the claimed range of 1:1.1 to 1:1.5, and then cools, filters and dries the product. Sythana et al. teaches hydrogen peroxide with hydrochloric acid and sulfuryl chloride, also recited chlorination agents, and works at 15 to 30 degrees C, which falls within the claimed range of -10 to 105 degrees C. Sythana et al. further teaches methanol, ethanol, dichloromethane, dichloroethane, chlorobenzene, acetic acid and water as reaction solvents. The claimed molar ratio of substrate to solvent is a result effective variable that one of ordinary skill in the art would optimize by routine experimentation, and applicant shows no criticality, since neither working example falls within the claimed range. (Framroze, column 3, lines 43-51; Sythana et al., paragraphs [0224], [0232], [0279] and [0282]; Specification, paragraphs [0091] and [0100])
With regard to claim 4, Sythana et al. teaches methyl nitrite and ethyl nitrite, both recited oximation agents, and teaches methanol and ethanol among the solvents for the oxime forming step, both recited solvents. Sythana et al. also adds the nitrite reagent to the stirred substrate solution and then filters and dries the precipitated oxime. The claimed molar ratios and the claimed temperature range of -10 to 115 degrees C are result effective variables that one of ordinary skill in the art would optimize by routine experimentation, and applicant shows no criticality, since neither working example falls within the claimed substrate to solvent range. (Sythana et al., paragraphs [0183], [0234] and [0305]; Specification, paragraphs [0092] and [0101])
With regard to claim 5, Sythana et al. adds the oxime portion-wise to stirred sulphuric acid at a molar ratio of 1:7.0, quenches into ice cold water and filters and dries the isatin. Framroze uses a molar ratio of 1:4 and 18M to 18.4M sulfuric acid, which is about 95 to 98 weight percent, at 50-60 degrees C. Chen et al. works at 60-65 degrees C and cools, filters, water-washes and dries the cake. Each ratio falls within the claimed range of 1:3 to 1:30, each acid concentration falls within the claimed range of 75 to 98 weight percent, and each temperature falls within the claimed range of 20 to 115 degrees C. (Sythana et al., paragraph [0298]; Framroze, column 5, lines 43-59 and claims 2 and 5; Chen et al., paragraph [0626])
With regard to claim 6, Chen et al. adds hydrogen peroxide, a recited oxidation agent, drop wise to the stirred isatin solution at 60-65 degrees C, then cools, filters, water-washes and oven-dries the anhydride. The charge corresponds to a molar ratio of 1:1.25, which falls within the claimed range of 1:1.1 to 1:2.1, and the temperature falls within the claimed range of -10 to 110 degrees C. Sythana et al. likewise adds aqueous hydrogen peroxide drop wise and then cools, filters, water-washes and dries. Chen et al. and Sythana et al. further teach the recited oxidation agents peroxyacetic acid, chromium trioxide, potassium permanganate, sodium hypochlorite and potassium peroxymonosulfate. (Chen et al., paragraphs [0149] and [0628]; Sythana et al., paragraphs [0225] and [0382])
With regard to claim 7, Chen et al. reacts the anhydride with methylamine in ethyl acetate, a recited solvent, at room temperature, which falls within the claimed range of -10 to 110 degrees C, and then works the mixture up with water. Chen et al. further teaches methanol, ethanol, dichloroethane and acetonitrile as solvents for this step, all recited solvents. Sythana et al. uses a molar ratio of anhydride to amine of 1:1.2, which falls within the claimed range of 1:1.1 to 1:3.1, and filters, washes and dries the product. Chen et al. and Sythana et al. do not expressly recite a 10 to 40 weight percent aqueous solution of monomethylamine added drop wise. However, the concentration of the amine solution and its rate of addition are result effective variables that one of ordinary skill in the art would optimize by routine experimentation, and applicant shows no criticality, since applicant's Example 1 uses a molar ratio of 1:1.06, which falls outside the claimed range. (Chen et al., paragraphs [0263] and [0629]; Sythana et al., paragraph [0394]; Specification, paragraph [0095])
Note that an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). The substitution of acetic anhydride for an acyl chloride, and the selection of a known chlorination agent, oxidation agent, amine, solvent and reaction temperature, are predictable modifications of a known reaction sequence.
Conclusion
No claim is allowed.
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/JENNIFER C SAWYER/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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