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
1. This application is a 371 of PCT/CN2020/125753 11/02/2020. FOREIGN APPLICATIONS: CHINA 201911082204.3 11/07/2019 and CHINA 202010045084.6 01/16/2020.
Claims 1, 5-9, 11-13, 15-16 are pending.
Request for Continued Examination
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 16, 2025 has been entered.
Response to Arguments/Amendments
3. The rejection of claim(s) 1, 5, 8, and 15-16 under 35 U.S.C. 103 as being unpatentable over Meazza WO 2004056785 A2 in view of Jeschke AND Wang is maintained. Applicant’s arguments of December 16, 2025 have been fully considered but are not persuasive. Applicants’ representative argues that one of the most relevant compounds, compound 156, from Meazza has been compared to the compounds of the instant claims in the Table 8 of the specification [reproduced on pages 2-3 of the response]. Compound 1-2 differs from compound 1561 only by a fluorine atom:
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The additional compounds have other structural features, making them incomparable to compound 156, for example compound I-55 has the following structure:
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.
This is quite distinct and the oxime ester above is not directly comparable. Compound 1-164 in Meazza is also directly comparable to compound 1-1, however there is no data for this comparison. Regardless the comparison of claimed compound 1-2 to Meazza compound 1-156 is a fair comparison. According to the arguments there is “much better herbicidal activity”. There is an explanation on page 65 as to what the numbers in Table 8 mean.
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Unfortunately, these are expected results since according to Wang, “[I]n most cases, substituting electron-withdrawing lipophilic groups at 2-position of phenyl ring, are favorable to activity, with fluorine atom gives superior result”. The magnitude of the expected increase in Wang is revealed in Table 1 and 2, comparing examples 8a to 5a, 8b to 5b, 8c to 5c, 8d to 5d, and 8e to 5e.
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In all cases the 2-fluoro compounds resulted in compounds that were more effective inhibitors at lower concentrations. The Ki was calculated for the compound 5a, 5b, 5c, 5d, 5e as 4.9nM, 24 nM, 1.7nM, 6.5nM. 4.3 nM and 7.6 nM, while the non-fluorinated congeners 8a, 8b, 8c, 8d, and 8e have Ki of 50nM, 33 nM, 60 nM, 41 nM, and 85 nM, respectively. Generally fluorination gave around an order of magnitude increase in potency. Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989).
Applicants’ representative argues that there is no reason for site selection2 of the 2-position for fluorination. As explained in the rejection fluorine was suggested as the X1 group in a genus of 2 choices H or halogen.
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The site selected for halogenation (X1), shown above in the Meazza genus as put forth in the rejection, was already selected. The genus of halogens includes F, Cl, Br, I and At. Astatine has never been used in agrochemical commerce since it is rare and all isotopes are highly radioactive, with the longest-lived (At-210) having a half-life of about 8.1 hours. This leaves a genus of four halogens, however iodine substituted compounds are less common compared to F or Cl compounds due to the cost of synthesis and the lower stability of the aryl-iodine bond compared to other halogens. This is an option of at most four alternatives to hydrogen at this site, and excluding iodine leaves only three. The F as a substituent for X1 was not prophetic in Meazza. Meazza exemplifies a number of compounds with the X1 as F and X3 as Cl. 3-{5-[(5-tert-butyl-1,3,4-oxadiazol-2-yl)methoxy]-4-chloro-2-fluorophenyl}-1 methyl-6- (trifluoromethyl)-2 ,4 (1H,3H)-pyrimidinedione (Compound No 6.) (2E)-4-{2-chloro-4- fluoro-5-[1,2,3,6-tetrahydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]phenoxy}-3-methoxybut-2-enoate (Compound No 2.) were two of the three compounds in Table 1 which bear this pattern.
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The site selection of X1 as F is taught without even considering the teaching in Wang. Wang explains that “in most cases, substituting electron-withdrawing lipophilic groups at 2-position of phenyl ring, are favorable to activity, with fluorine atom gives superior result;”. Wang is not concerned with general fluorination, but is specifically concerned with compounds acting on the same target of Meazza, Protoporphyrinogen oxidase (PPO, EC 1.3.3.4). Wang refers to this pattern as “classical” and for the compounds Wang prepared fluorination increased potency:
It was found that when other substituents were kept the same, fluorosubstituted compounds (5a−f) always displayed significantly enhanced herbicidal potency than their corresponding hydrogen, chlorine, and bromine substituted analogs 8, 6, and 7, respectively (F > H > Cl > Br). Therefore, we can conclude that for the SAR of 2-position of the phenyl ring of the new N-isoxazolinylphenyltriazinones also conform to classical SARs of the N-phenyl heterocycles. [Wang page 12386 col. 1]
At the time the invention was made the “classical SARs” of these compounds was that fluorination of the 2-position, the difference between the prior art and the instant claims, “significantly enhanced herbicidal potency”. Against this backdrop applicants’ representative now submits a new reference, Crews US 5,610,120, which is said to show that chlorination not fluorination is preferred in a series of 1-cyclohexene-1,2-dicarboximido substituted halophenyl-2,4,6- trioxo-s-triazines. According to the argument, Methyl 3-[5-(1-cyclohexene-1,2-dicarboximido)-2,4-difluorophenyl]-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate, compound 1,
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, is more potent than compound 10 which is difluorinated:
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While there are some differences in potency the compounds are both active, with differences only in degree not kind. Unfortunately, Crews does not isolate the exact change upon going from Meazza to the claimed compound, i.e. the case where the 4-position is chlorinated and the 2 position is H, which is then fluorinated, but has a situation where an already difluorinated compound has one F is swapped for chlorine. As best as can be understood, Crews does not isolate an H to F modification, however it is possible to reach a different conclusion based upon Crews that substantiates the factual finding in the office action. Crews shows that mixed F/Cl substitution on the phenyl ring increases potency. Taken to its logical conclusion, modifying Meazza in the manner taught by Crews, i.e. selecting F as the second halogen when the compound was already chlorinated, would also lead to the claimed compounds with an expectation of increased potency. Meazza has this type of pattern in two of the three Table 1 compounds tested. Regardless it is always possible that there are exceptions to the rule, the established “classical SARs”. Wang speaks of the strong consistency with regard to the 2-position SAR, finding that the new compounds he prepared share the same “classical SARs” of other protoporphyrinogen oxidase inhibitors with heterocyclic moiety attached to a phenyl ring. Wang describes the results as “in most cases”, finding that “substituting electron-withdrawing lipophilic groups at 2-position of phenyl ring, are favorable to activity, with fluorine atom gives superior result”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
4. Claim(s) 1, 3-5, 8, 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Meazza WO 2004056785 A2 (cited on the IDS) in view of Jeschke “The Unique Role of Fluorine in the Design of Active Ingredients for Modern Crop Protection” ChemBioChem 2004, 5, 570 – 589 AND Wang “Discovery of Novel N‑Isoxazolinylphenyltriazinones as Promising Protoporphyrinogen IX Oxidase Inhibitors” J. Agric. Food Chem. 2019, 67, 12382−12392, published October 21, 2019 (cited on the IDS). The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Meazza teaches the compounds of the instant claims that have the same utility and compositions. On page 2 a genus is disclosed, which is essentially that of the instant claims:
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The X3 group as Q2 being equivalent to the thiazole with the carbonyl containing group where is Q2 is thiazol-2-yl, thiazol-4-yl or thiazol-5-ul as defined on page 8 line 6. The thiazole being substituted with various carbonyl groups listed on page 9 such as “C2-C6 alkoxycarbonyl or C2-C6 haloalkoxycarbonyl, C2-C7 alkenyloxycarbonyl or C3-C7 alkynyloxycarbonyl” A number of example compounds supporting this genus are disclosed including
ethyl 2-{2-chloro-5-[1,2,3,6-tetrahydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]phenyl}-1,3-thiazole-4-carboxylate (Compound No 156}, on page 75
methyl 2-{2-chloro-5-[1,2,3,6-tetrahydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]phenyl}-1,3- thiazole-4-carboxylate (Compound No 164); on page 76
ethyl 2-{2-chloro-5-[1,2,3,6-tetrahydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]phenyl}-4-methyl-1,3-thiazole-5-carboxylate on page 103 (Compound No. 131)
These compounds are shown below:
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The F was not prophetic, Meazza exemplifies compounds with the X1 as F and X2 as Cl. Meazza teaches compounds with the 2-Chloro-4-Fluoro substitution including thiazoles:
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And 3-{5-[(5-tert-butyl-1,3,4-oxadiazol-2-yl)methoxy]-4-chloro-2-fluorophenyl}-1 methyl-6- (trifluoromethyl)-2 ,4 (1H,3H)-pyrimidinedione (Compound No 6.) (2E)-4-{2-chloro-4- fluoro-5-[1,2,3,6-tetrahydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]phenoxy}-3-methoxybut-2-enoate (Compound No 2.), two of the three compounds in Table 1 which bear this pattern.
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Ascertainment of the difference between the prior art and the claims
The prior art differs only semantically from the genus of claim 1. The species above differ by the presence of a fluorine atom on the phenyl ring in the 2-position. Compound 2-2 in claim 5 is the fluorinated analog of compound 156 shown above.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to use analogs of those of Meazza to produce the instant invention. Fluorine was suggested as the X1 group in a genus of 2 choices H or halogen. Jeschke discusses fluorination of agrochemicals generally, which was known to improve the properties of herbicides.3 Within this narrow field, the change of H to F in this exact position was known to give superior results as shown by Wang. “Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitory herbicides are among the most widely used herbicides in crop fields around the world.” [Wang Page 12382 col. 1] “Studies have shown that for inhibitors with heterocyclic moiety attached to a phenyl ring, in most cases, substituting electron-withdrawing lipophilic groups at 2-position of phenyl ring, are favorable to activity, with fluorine atom gives superior result; placing substituents at 3-position can decrease activity; installing electron-withdrawing lipophilic groups at 4-position are favorable to activity, with chlorine atom shows the best biological activity; a variety of functional groups (including five- or six-membered ring systems) are acceptable for activity at 5-position, the substituents at this position have a great impact on crop selectivity and overall herbicidal activity.17” [Emphasis added, Wang page 12383 col. 1].
The magnitude of the expected increase in Wang is revealed in Table 1 and 2, comparing examples 8a to 5a, 8b to 5b, 8c to 5c, 8d to 5d, and 8e to 5e.
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In all cases the 2-fluoro compounds resulted in compounds that were more effective inhibitors at lower concentrations. The Ki was calculated for the compound 5a, 5b, 5c, 5d, 5e as 4.9nM, 24 nM, 1.7nM, 6.5nM. 4.3 nM and 7.6 nM, while the non-fluorinated congeners 8a, 8b, 8c, 8d, and 8e have Ki of 50nM, 33 nM, 60 nM, 41 nM, and 85 nM, respectively. Generally fluorination gave around an order of magnitude increase in potency.
The experienced organic chemist, who would make applicants' compounds, would be motivated to prepare these analogs based on the expectation that the fluorinated compoudns would have increased potency and upon the routine nature of such experimentation in the art of agrochemistry. These compounds have the same properties as those of the prior art as protoporphyrinogen oxidase (PPO) inhibitory herbicides. Considering that the claimed compounds have the same structure as Meazza and Meazza offers a very limited number of alternatives (hydrogen or halogen), the activity would be expected to be enhanced just the same as the known “classical SARs” of other compounds of this class upon fluorination. A person of ordinary skill would have known how to synthesize the claimed compound, and the structural and/or functional result can reasonably have been predicted. Expected results are evidence of obviousness.
Conclusion
5. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 Applicants’ representative explains that control compound A is “exactly compound 156 in Meazza”, which is defined on page 67 at ¶ [0157].
2 Applicants’ representative introduced the term “pointer” in the Response to Non-Final rejection of August 7, 2025 on page 5 as describing the site selection of fluorination. The examiner used this term in subsequent replies, but now adopts the term site selection.
3 Jeschke gives a number of motivations to fluorinate, on page 52: “The importance of fluorine in commercial products can be attributed to the well-known physicochemical effects arising from the introduction of fluorine and fluorinated substituents into biologically active molecules. The so-called “fluorine factor” described in the literature several years ago stems from the unique combination of properties associated with the fluorine atom itself.” “[T]he small size of the fluorine atom (1.47 Å) is a unique characteristic and its van der Waals radius is similar to that of hydrogen (1.20 Å), therefore, a fluorine atom can mimic a hydrogen atom….” Additional effects on lipophilicity, and other compound attributes are discussed. “Numerous key physical properties of molecules that are important for agricultural uses, like soil behavior, toxicology, systemicity, solubility, volatility, polarity, as well as penetration and so forth, can be influenced or enhanced by fluorine and fluorine containing substituents.” Jesche provides various case studies of fluorination in the agrochemical art including herbicides under 5. “Herbicides containing fluorine.”