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 .
Status of Claims
Claims 1, 2, 5, 7-9, 12, 15-17, 19, 21-23, 27-28, 36, and 41 are pending.
Response to Arguments / Amendment
Applicant's arguments and the declaration of inventor Dr. Mark Dobish filed 2/6/2026 have been fully considered but they are not persuasive.
Applicant argues that the high level of selectivity of the claimed method is unexpected and thus nonobvious. Applicant points to the discussion in the declaration regarding Dialer’s 4:1 ratio of 4,6-DBO : undesired compounds while the claimed invention allegedly “obtain greater than 9:1 ratio, and as much as 20:1, of 4,6-DBO to undesired brominated compounds” as shown in Table 10 from Example 9 of the specification.
This argument is not persuasive because the alleged unexpected results are not commensurate in scope with the claims – i.e., under various conditions that are within the scope of the claims, it appears that such ratios of 9:1 would not be obtained. For example, in Table 10 of the specification 79.2% was 4,6-DBO : 20.7% other brominated products which is a ratio of 3.8 : 1. Such ratios are what one of ordinary skill in the art would expect in view of the evidence of record.
Applicant also argues that Song’s halogenation is primarily mono-halogenation and that Song would not suggest to one of ordinary skill in the art that olivetol would be expected to be dibrominated due to the limited examples 8d and 8e which would not provide insight to selectivity because of the substrate’s symmetry.
This argument is not persuasive because one of ordinary skill in the art would know that the dibromination would occur in view of the teaching of both Dialer having the same reactant and product with different conditions than the claims and Song have the same conditions and reagents but slightly different substrates than the claimed invention. In view of the teaching of the cited art, one of ordinary skill in the art would have applied their knowledge and experience and recognized that using Song’s conditions would reasonably be expected to result in the dibromination product as in the instant claims. Furthermore, Song cites to Majetich et al. (J. Org. Chem. 1997, 62, 4321-4326) wherein is taught selective dibromination of 15 and 18 under elevated temperature as depicted below:
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(p. 4323: “warm HBr, DMSO, and AcOH produces dibromide 17 in good yield (cf. 15 f 16), whereas bromine in conditions C and D gave a mixture of bromides 16 and 17. Likewise, bromination of p-cresol or aniline using the standard conditions at room temperature gives exclusively the monobrominated product, whereas the same reactions at elevated temperatures result in nearly quantitative yields of dibromide”). Thus, one of ordinary skill in the art would have had a significant expectation of success that like Majetich’s 15 and 16, treating olivetol with HBr and DMSO under elevated temperature would also be successful in selective dibromination.
Applicant argues that one of ordinary skill in the art would not expect an improvement in forming 4,6-DBO using the technique of Song as supported by the declaration.
This argument is not persuasive because as shown by Song in Scheme 8:
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Song teaches that dihalogenation is controlled by adjusting the ratio of HX and the temperature (p. 2888: “Notably, the mono- and dihalogenation could be efficiently controlled by only adjusting the dosage of HX (X = Br, I) and DMSO (Scheme 8). For example, diiodinated or dibrominated arenes 8 were obtained in high yields with 2 equiv of HX. Compared to the previous reports on the adjustment of monoand dihalogenation by the reaction time or reaction temperature, 6c,11 [Majetich] the present strategy shows higher selectivity.”). Furthermore, as taught by Majetich compounds 17 and 20 were produced in good or quantitative yields which are also analogous to the claimed invention. Thus, the evidence of record supports the conclusion that one of ordinary skill in the art would have had a reasonable expectation in light of the prior art that olivetol would be similarly dibrominated to 4,6-DBO with high selectivity.
Contrary to the applicant’s arguments the halogenation pattern does not occur unexpectedly. One having ordinary skill in the art would know that the substituent groups on an arene compound affect both the reactivity and orientation in an electrophilic aromatic substitution reaction, such as the halogenation reaction. The skilled artisan would know that the substituent groups influence the orientation of attack by the incoming electrophile. As in the instant claimed invention, Dialer et al. disclose a method for halogenating olivetol. Olivetol is an arene compound having OH groups meta to each other at positions 1 and 5 and a pentyl group at position 3. Both the OH and alkyl groups are ortho-para directors. However, due to steric hindrance, the hydroxyl groups being meta to each other and the OH groups being stronger directing (activating) groups than the alkyl groups, the ordinary skilled artisan would reasonably expect to predominantly obtain the 4,6-DBO upon halogenation of olivetol over any of the other possible halogenation products. In particular, since the ordinary skilled artisan would recognize that substitution does not occur to an appreciable extent between meta substituents if another position is open.
Applicant’s arguments that one having ordinary skill in the art would not expect the teachings of Song to be limited only to the specific arenes utilized in the examples disclosed in Song are also not persuasive. One of ordinary skill in the art would reasonably expect the teachings of Song to be applicable to any arene capable of undergoing halogenation including dihydroxy arenes, including the olivetol disclosed by Dialer. In particular, since Song discloses that the high halide-atom economy, broad substrate scope, easy accessibility, and low cost of aqueous HX and DMSO make this strategy extremely attractive in the development of efficient approaches to aryl bromides and iodides and the mild and simple conditions are amenable to late-stage functionalization of natural products (column 1, paragraph 2 on page 2887 and column 1, paragraph 1 on page 2889). Further, as discussed above, due to steric hindrance, the hydroxyl groups being meta to each other and the OH groups being stronger directing (activating) groups than the alkyl groups, the ordinary skilled artisan would reasonably expect to predominantly obtain the 4,6-DBO upon halogenation of olivetol over 2-DBO; 4-MBO; 2,4 DBO or 2,4,6-TBO. Further, Song disclose that stoichiometric DMSO and HX is sufficient for full conversion of the arenes. The slow generation of X2 in situ is crucial for highly regioselective halogenation of arenes (last 4 lines in column 2 on page 2888). Thus, one having ordinary skill in the art would reasonably expect that the halogenating reagents used in Song would be suitable for replacing the halogenating reagents in Dialer. In particular, since Song et al. disclose that the DMSO/HX system is an efficient and practical system for inexpensive bromination and iodination of arenes (abstract). The skilled artisan would have further been motivated to utilize the DMSO/HX system of Song in place of the bromine, chlorine or iodide halogenating agents of Dialer et al. in order to avoid the limitations: (1) X2 are hazardous, toxic, and corrosive reagents; (2) Halide-atom economy is below 50% with HX as the byproduct: (3) sometimes, the undesirable byproducts are uncontrollable that Song et al. disclose accompany the current dominant industrial approach to aryl bromides and iodides, namely the halogenation of arenes with X2 (X is Br or I), as taught by Dialer et al.
For the above reasons, the rejection of claims 1, 2, 5, 7-9, 12, 15-17, 19, 21-23, 27-28, 36, and 41 under 35 U.S.C. 103 as being unpatentable over Dialer et al. (US 2018/0319763 A1) alone or in view of SONG, et al., ("Efficient and Practical Oxidative Bromination and lodination of Arenes and Heteroarenes with DMSO and Hydrogen Halide: A Mild Protocol for Late-State Functionalization", Org. Lett., 17:2886-2889, (2015)) is maintained.
Claim Rejections - 35 USC § 103
Claims 1, 2, 5, 7-9, 12, 15-17, 19, 21-23, 27-28, 36, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Dialer et al. (US 2018/0319763 A1) alone or in view of SONG, et al., ("Efficient and Practical Oxidative Bromination and lodination of Arenes and Heteroarenes with DMSO and Hydrogen Halide: A Mild Protocol for Late-State Functionalization", Org. Lett., 17:2886-2889, (2015)) and Majetich et al. (J. Org. Chem. 1997, 62, 4321-4326).
Regarding claim 1, Dialer et al. disclose a method of preparing a compound of Formula I:
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wherein, R1 is a straight chain C3 or C5 alkyl; and R2 and R3 are each independently selected from a group consisting of halogen, the method comprising: contacting a compound of Formula I’ having a structure:
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wherein, R1’ is a straight chain C3 or C5 alkyl; and R2’ and R3’ are each independently selected from the group consisting of hydrogen wherein, the compound of Formula I is prepared (paragraphs 0234-0238, 0265-0269 and 0279-0283 and Figures 5-7). Dialer teaches the reaction temperature can be adjusted including within the claim scope ([0128]: “The reaction mixture can be held at … , 30° C., 40° C., 50° C. …. or about −0° C. to about 50° C.”; [0155]).
Regarding claim 5, Dialer et al. disclose the method of claim 1, wherein R1 and R1’ are the same and each is selected from the group consisting of straight propyl and pentyl (paragraphs 0237 and 0268).
Regarding claim 8, Dialer et al. disclose the method of claim 1, wherein the compound of Formula I is a compound having a structure:
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wherein R1 and R1’ are the same (paragraph 0237).
Regarding claim 9, Dialer et al. disclose the method of claim 8, wherein R1 and R1’ are each selected from the group consisting of straight propyl (paragraph 0237).
Regarding claim 15, Dialer et al. disclose the method of claim 1, wherein the compound of Formula I’ is selectively di-halogenated in the 4 and 6 positions (paragraphs 0237 and 0268).
Regarding claim 16, Dialer et al. disclose the method of claim 15, wherein the 4,6-di-halogenated compound of Formula I, wherein each of R1 and R2 is halogen is prepared at a ratio of from about 25:1 to about 34:1 relative to the 2,4-dihalogenated impurity compound (paragraphs 0234-0238 and 0265-0269).
Regarding claim 17, Dialer et al. disclose the method of claim 1, wherein prior to said contacting, the compound of Formula I’ is contacted with a first solvent to form a mixture (paragraphs 0235 and 0269).
Regarding claim 21, Dialer et al. disclose the method of claim 17, wherein the solvent is present from about 9.7 vol to about 16.1 vol (paragraphs 0235 and 0269).
Regarding claim 27, Dialer et al. disclose a method of preparing a compound of Formula I:
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wherein, R1 is a straight chain C3 or C5 alkyl; and R2 and R3 are each halogen, the method comprising: selectively halogenating at the 4- and 6- positions by contacting a compound of Formula I’ having a structure:
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wherein, R1’ is a straight C3 or C5 alkyl; and R2’ and R3’ are each hydrogen; with a first solvent to form a mixture, the compound of Formula I is prepared (paragraphs 0234-0238 and 0265-0269).
Regarding claim 28, Dialer et al. disclose the method of claim 27, wherein the compound of Formula I is present at a ratio of at least 10:1 relative to a mono-halogenated, tri-halogenated or 2,4-dihalogenated compound (paragraphs 0235-0238 and 0265-0269).
Regarding claim 36, Dialer et al. disclose the method of claim 27, wherein R1’ is propyl or pentyl, and the compound of Formula I is selected from the group consisting of:
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(paragraphs 0235-0238).
Dialer et al. disclose the claimed method as described above. Dialer et al. differ from the claimed method in that Dialer et al. utilize bromine, chlorine or iodide as the halogenating agent instead of HX, wherein X is a halide. In particular, Dialer et al. do not disclose wherein HX is selected from HBr, HCl, HI, and HF as required in claim 2.
Further, the method of Dialer et al. is not carried out in the presence of an organic sulfoxide wherein, the contacting is at a temperature from about 30 °C to about 55 °C.
Song et al. disclose a process for the inexpensive bromination and iodination of arenes by using readily available dimethyl sulfoxide and HX, wherein X is Br or I (abstract). The contacting is at a temperature within the claimed range (Scheme 1 d on page 2886; Scheme 2: 35 ºC). Song et al. disclose that the current dominant industrial approach to aryl bromides and iodides is the halogenation of arenes with X2, wherein X is Br or I, which suffers from obvious limitations: (1) X2 are hazardous, toxic, and corrosive reagents; (2) Halide-atom economy is below 50% with HX as the byproduct: (3) sometimes, the undesirable byproducts are uncontrollable (column 1 on page 2886). It is disclosed that hydrogen halides (HX), the byproduct of X2-based halogenations, are readily available, inexpensive, and easy to store and transport. Song et al. disclose a simple and practical bromination and iodination of arenes as well as various heteroarenes with stoichiometric aqueous HX (X=Br, I) and DMSO performed in EtOAc. The high halide-atom economy, broad substrate scope, easy accessibility and low cost of aqueous HX and DMSO make this strategy extremely attractive in the development of efficient approaches to aryl bromides and iodides (column 1, first full paragraph on page 2887). Song et al. disclose the heteroaromatic halogenations are very important because they are ubiquitous in modern medicinal chemistry. Therefore, the development of new approaches to heteroaromatic halides has always drawn chemists attention (column 2, paragraph 2 on page 2887). Song et al. disclose that the DMSO/HX system is effective as a versatile protocol for the synthesis of aryl halides and a mild method for late-stage modification of natural products (conclusion on page 2889). Regarding the claim amendment to narrow the temperature of reaction to 30 to 55 C, Song teaches that the temperature is a results effective variable through demonstrating how the yield increased by adjusting the temperature (p. 2887, 2888: “adjustment of mono and dihalogenation by the reaction time or reaction temperature”) and as was done by Song, such variables are routinely optimized in chemical synthesis.
Song cites to Majetich et al. (J. Org. Chem. 1997, 62, 4321-4326) wherein is taught selective dibromination of 15 and 18 under elevated temperature as depicted below:
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(p. 4323: “warm HBr, DMSO, and AcOH produces dibromide 17 in good yield (cf. 15 f 16), whereas bromine in conditions C and D gave a mixture of bromides 16 and 17. Likewise, bromination of p-cresol or aniline using the standard conditions at room temperature gives exclusively the monobrominated product, whereas the same reactions at elevated temperatures result in nearly quantitative yields of dibromide”). Majetich also teaches the dibromination occurs upon heating (p. 4323: “Given the mildness of our bromination procedure, it was not surprising that only monobromination occurs at room temperature, while a second bromine is introduced upon heating.”).
One having ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious that the halogenations of Dialer et al. could be carried out utilizing stoichiometric aqueous HX (X=Br, I) and DMSO in EtOAc, as taught by Song et al., since Song et al. disclose that the DMSO/HX system is effective as a versatile protocol for the synthesis of aryl halides and a mild method for late-stage modification of natural products. The skilled artisan would have further been motivated to utilize the DMSO/HX system of Song in place of the bromine, chlorine or iodide halogenating agents of Dialer et al. in order to avoid the limitations: (1) X2 are hazardous, toxic, and corrosive reagents; (2) Halide-atom economy is below 50% with HX as the byproduct: (3) sometimes, the undesirable byproducts are uncontrollable that Song et al. disclose accompany the current dominant industrial approach to aryl bromides and iodides, namely the halogenation of arenes with X2 (X is Br or I), as taught by Dialer et al. In addition, one of ordinary skill in the art would have had a significant expectation of success due to Majetich’s success with dibromination of 15 and 16 with HBr and DMSO under elevated temperature would also be successful in selective dibromination of olivetol. Furthermore, one of ordinary skill in the art would have considered routine the optimization of well-known results effective variables including reaction temperature in optimization of the conditions to improve yield.
Regarding claim 7, Dialer et al. disclose the method of claim 1, but differs from claim 7 in that it is not disclosed wherein R1 and R1’ are the same and each is selected from the group consisting of a branched chain C1-12 alkyl having one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve carbon atoms.
Song et al. disclose a simple and practical bromination and iodination of arenes as well as various heteroarenes with stoichiometric aqueous HX (X=Br, I) and DMSO performed in EtOAc. The high halide-atom economy, broad substrate scope, easy accessibility and low cost of aqueous HX and DMSO make this strategy extremely attractive in the development of efficient approaches to aryl bromides and iodides (column 1, first full paragraph on page 2887).
One having ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious that the halogenation method taught by Song et al. could be utilized for halogenating compounds wherein R1 and R1’ are the same and each is selected from the group consisting of a branched chain C1-12 alkyl having one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve carbon atoms, since Song et al. disclose that the DMSO/HX system has broad substrate scope. The ordinary skilled artisan would have been motivated to utilize the system because its high halide-atom economy, easy accessibility and low cost.
Regarding claim 12, Dialer et al. in view of Song et al. disclose the method of claim 9, but differs from the instant claim 12 in that Dialer et al. in view of Song et al. do not disclose wherein the compound of Formula I is a compound having a structure:
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wherein said compound has a purity above about 93A% by HPLC. However, Dialer al. disclose an analogous compounds wherein the two bromines are replaced with chlorines (paragraph 0265-0269). Further, Dialer et al. and Song et al. teach that bromine and chlorine are interchangeable (paragraph 0155 of Dialer et al. and column 1, first full paragraph on page 2887 of Song et al.).
Thus, one having ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious that the claimed compound of formula 2a could be made utilizing the DMSO/HX system of Song et al. in a similar manner as it would to make compound 6 and compound 11 of Dialer et al.
Regarding claim 19, Dialer et al. disclose the method of claim 17, but fails to disclose wherein the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, and acetone.
Song et al. disclose a simple and practical bromination and iodination of arenes as well as various heteroarenes with stoichiometric aqueous HX (X=Br, I) and DMSO performed in EtOAc (column 1, first full paragraph on page 2887).
One having ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to utilizing the DMSO/HX system in EtOAc as taught by Song et al. to make compound 6 and compound 11 of Dialer et al., since Song et al. has shown that this system is effective as a versatile protocol for the synthesis of aryl halides and a mild method for late-stage modification of natural products.
Regarding claim 22, Dialer et al. in view of Song et al. disclose the method of claim 1, wherein the organic sulfoxide is present in an amount of about 2.0 equiv to about 3.0 equiv (Scheme 1d, eq 4 on page 2886 and Scheme 8 on page 2888).
Regarding claim 23, Dialer et al. in view of Song et al. disclose the method of claim 22, wherein the HX is present in an amount from about 2.0 equiv to about 3.0 equiv. (Scheme 1d, eq 4 on page 2886 and Scheme 8 on page 2888).
Regarding claim 41, Dialer et al. in view of Song et al. disclose the method of claim 1 or 27, wherein said organic sulfoxide is of the general formula:
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wherein, Ra and Rb are each independently selected from the group consisting of alkyl (Scheme 1d, eq 4 on page 2886 and Scheme 8 on page 2888).
Conclusion
No claim allowed.
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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