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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 25, 2026, has been entered.
Response to Arguments
Applicant’s argument is that there are unexpected results associated with fluorinated compounds. Applicant argues that the compound with a fluorine in place of a hydrogen provides a superior antioxidant efficacy.
The examiner notes that he will address unexpected results below in light of 6 references that each teach and provide an expectation of enhanced antioxidant potential by incorporating a fluorine or halogen in a chalcone compound.
The examiner refers to the following references to show what would be expected to a POSA for a number of different chalcone compounds.
Padhye et al., Fluorinated 2’ hydroxychalcones as garcinol analogs with enhanced antioxidant and anticancer activities,” Bioorganic and Medicinal Chemistry Letters 20 (2010) 5818-5821.
Padhye teaches, “The fluorinated chalcones were found to be more potent antioxidants than their hydroxyl counterparts.” Abstract. Further, fluorine derivatives are more potent SOD scavengers due to their higher metabolic stability of the C-F bond. See p5820.
Mathew et al., Development of fluorinated methoxylated chalcones as selective
monoamine oxidase-B inhibitors: Synthesis, biochemistry and molecular
docking studies,” Bioorganic Chemistry 62 (2015) 22-29.
Mathew teaches all fluorinate chalcones exhibited good activity towards MAO-B in the submicromolar range. See p26, 1st par. Substitution of CF3 and fluorine both enhanced MAO-B potencies. The presence of CF3 or fluorine on the ring of chalcones are stabilized and are expected to enhance the interactions of MAO-B inhibitory potencies. See p29, 1st full par.
Hasan et al., “SYNTHESIS OF NEW FLUORINATED CHALCONE DERIVATIVE WITH ANTI-INFLAMMATORY ACTIVITY,” International Journal of Pharmacy and Pharmaceutical Sciences Vol 4, Suppl 5, 2012.
Hasan teaches fluorinated chalcone derivates were synthesized with potent anti-inflammatory activity. Beneficial changes in chalcone molecules from introduction of a fluorine atom in the molecule is thought to derive from physiochemical property alterations. See p433, final par.
Bist et al., “Inhibition of LPS-stimulated ROS production by fluorinated and hydroxylated chalcones in RAW 264.7 macrophages with structure-activity relationship study,” Bioorganic and Medicinal Chemistry Letters 27 (2017) 1205-1209.
Bist teaches and evaluates inhibitory effects on ROS of fluorinated chalcones, e.g. Chalcone derivatives were formulated with fluorine in each position of R3-R7 claimed. See Scheme 1, p1206. A concrete structure-activity relationship was observed according to the positions of substitutions of the hydroxyl and fluorinated groups. Bist also noted that hydroxylated chalcones are reported to have activity as radical scavengers, anti-diabetic agents, and anti-inflammatory agents, e.g.
Prabhakar et al., “Antioxidant studies on monosubstituted chalcone derivatives - understanding substituent effects,” Pak. J. Pharm. Sci., Vol.29, No.1, January 2016, pp.165-171.
Prabhakar teaches chalcones possess good antioxidant properties. These trends correlated with anti-inflammatory activity. All derivatives with a single exception showed improved antioxidant profiles compared to an unsubstituted parent compound. “Also, halogenated chalcones have been known to possess a stronger antioxidant potential than their non halogenated counterparts with bromine and fluorine derivatives preferred over that of chlorine substituents (Isaac et al., 2012).” P.166, 1st full par.
Isaac et al., “Halogen Substituted Chalcone as Potential Antioxidants: An In Vitro Study,” Advanced Science, Engineering and Medicine Vol. 4, pp. 499-505, 2012.
Isaac teaches chalcones are natural products used as free radical scavengers and NO scavengers, e.g. Examples were tested using substitutions of H, F, Cl, and Br. In different positions on a chalcone. Examples from Figure 2 are shown below.
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“All these halogenated chalcones were found to possess considerable level of antioxidant activity.” Conclusion.
Overall, the examiner notes the following. The claims explicitly include a compound with a single fluorine or other halogen substitution at one of positions R3-R7. Moreover, the closest prior art includes a claimed compound of claim 2 wherein a single difference is the incorporation of a fluorine for a hydrogen, or a chlorine atom for a hydrogen.
Substitution of a fluorine for a hydrogen atom is a known bioisosteric substitution, generically. This has been established as taught by Patani. Applicant traversed the obviousness of record rejection by providing a showing that a fluorine atom in a single position increased antioxidant of the chalcone derivative. One requirement for a showing of unexpected results is that the results are unexpected. In this particular case, and as shown by the above by 6 separate references, the halogenation, including fluorination of a chalcone compound of different core chalcone scaffolds, is expected to increase antioxidant potential of the molecule as it has predictably done. As such, while enhanced activity may be shown, it is not clear how this enhanced activity is unexpected. As such, a prima facie showing is established and the proffered unexpected results do not yet appear to established unexpected results.
Status of the Claims
Claims 1 and 2 are pending and examined.
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.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over CN101259118 (published September 10, 2008), in view of Patani et al., “Bioisosterism: A Rational Approach in Drug Design,” Chem Rev 1996, 96, 3147-3176, and in view of Prabhakar et al., “Antioxidant studies on monosubstituted chalcone derivatives - understanding substituent effects,” Pak. J. Pharm. Sci., Vol.29, No.1, January 2016, pp.165-171, and Isaac et al., “Halogen Substituted Chalcone as Potential Antioxidants: An In Vitro Study,” Advanced Science, Engineering and Medicine Vol. 4, pp. 499-505, 2012, and Padhye et al., Fluorinated 2’ hydroxychalcones as garcinol analogs with enhanced antioxidant and anticancer activities,” Bioorganic and Medicinal Chemistry Letters 20 (2010) 5818-5821.
Wu teaches:
The use of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone as peroxisome proliferator-activated receptor gamma (PPAR gamma ) excitant.
Antidiabetic; Anorectic; Antilipemic.
USE - The 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone is used as PPAR gamma excitant, useful for treating type II diabetes, adiposity and hyperlipemia (claimed).
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The sole difference between the above compound and that of chemical formula 2 of instant claim 2 is the inclusion of a single fluorine atom on a phenyl ring as claimed.
Patani teaches the substitution of a hydrogen by fluorine is one of the most commonly employed isosteric replacements that are often employed. In multiple instances there is no change is the efficacy of the compound, as shown in Figures 1 and 2. Using bioisosteric replacements is common in drug design to find drugs that elicit similar biological activity based on common physiochemical properties. See par. 3148. Patani concludes the section by explaining: “Thus, the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are
maintained.” See p3150, 1st full par.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of Wu and Patani. One would be motivated to do so because Wu teaches a claimed compound for a claimed use. While the compound taught by Wu is not identical because it has a single fluorine replacing a single hydrogen atom. However, Patani explains that rational drug design commonly employs bioisosteric replacements and there are many examples in which such substitution works. One of the most employed substitutions is a fluorine for a hydrogen. As such, there is a reasonable and predictable expectation of success in using the compound taught by Wu with a fluorine atom substituted for a hydrogen atom in view of Patani.
Further, Prabhakar, Isaac, and Padhye teach the following:
“The fluorinated chalcones were found to be more potent antioxidants than their hydroxyl counterparts.” Abstract. Further, fluorine derivatives are more potent SOD scavengers due to their higher metabolic stability of the C-F bond. “Also, halogenated chalcones have been known to possess a stronger antioxidant potential than their non halogenated counterparts with bromine and fluorine derivatives preferred over that of chlorine substituents (Isaac et al., 2012).” With reference to compounds substituted in the R5 equivalent position, among others, it is noted: “All these halogenated chalcones were found to possess considerable level of antioxidant activity.” Conclusion. As such, there is a reasonable and predictable expectation that halogenated and fluorinated chalcones will have enhanced antioxidant potential.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al., KR2013112980 (dated October 15, 2013), in view of Patani et al., “Bioisosterism: A Rational Approach in Drug Design,” Chem Rev 1996, 96, 3147-3176, and in view of Prabhakar et al., “Antioxidant studies on monosubstituted chalcone derivatives - understanding substituent effects,” Pak. J. Pharm. Sci., Vol.29, No.1, January 2016, pp.165-171, and Isaac et al., “Halogen Substituted Chalcone as Potential Antioxidants: An In Vitro Study,” Advanced Science, Engineering and Medicine Vol. 4, pp. 499-505, 2012, and Padhye et al., Fluorinated 2’ hydroxychalcones as garcinol analogs with enhanced antioxidant and anticancer activities,” Bioorganic and Medicinal Chemistry Letters 20 (2010) 5818-5821.
Lee teaches composition for preventing and treating atherosclerosis by AMPK activation and inhibition of apoptosis of vascular cells. See below Abstract from STN.
The title compn. for preventing and treating atherosclerosis, comprises Cleistocalyx operculatus ext. or compds. e.g. 7-hydroxy-5-methoxy-6,8-dimethylisoflavone, 5,7-dihydroxy-6,8-dimethyldihydroflavonol, 2,7-dihydroxy-5-methoxy-6,8-dimethylflavanone, 4,2',4'-trihydroxy-6'-methoxy-3',5'-dimethylchalcone, 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone, 7-hydroxy-5-methoxy-6,8-dimethylfavanone, 2',4'-dihydroxy-3'-methyl-6'-methoxychalcone, 6-formyl-8-methyl-7-O-methylpinocembrin, (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone, 5,7-dihydroxy-6,8-dimethylfavanone or 2,2',4'-trihydroxy-6'-methoxy-3',5'-dimethylchalcone. The Cleistocalyx operculatus ext. is obtained by extg. with a solvent comprising water and/or C1-4 alc. The ext. is Et acetate fractions of Cleistocalyx operculatus ext. The ext. increases adenosine monophosphate-activated protein kinase (AMPK) activity. A food compn. for improving or preventing atherosclerosis , comprising Cleistocalyx operculatus ext., is disclosed. The compn. shows excellent AMPK activation and inhibition of apoptosis of vascular cells.
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The sole difference between the above compound and that of chemical formula 2 of instant claim 2 is the inclusion of a single fluorine atom on a phenyl ring as claimed.
Patani teaches the substitution of a hydrogen by fluorine is one of the most commonly employed isosteric replacements that are often employed. In multiple instances there is no change is the efficacy of the compound, as shown in Figures 1 and 2. Using bioisosteric replacements is common in drug design to find drugs that elicit similar biological activity based on common physiochemical properties. See par. 3148. Patani concludes the section by explaining: “Thus, the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are
maintained.” See p3150, 1st full par.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of Lee and Patani. One would be motivated to do so because Lee teaches a claimed compound for a claimed use. While the compound taught by Lee is not identical because it has a single fluorine replacing a single hydrogen atom. However, Patani explains that rational drug design commonly employs bioisosteric replacements and there are many examples in which such substitution works. One of the most employed substitutions is a fluorine for a hydrogen. As such, there is a reasonable and predictable expectation of success in using the compound taught by Lee with a fluorine atom substituted for a hydrogen atom in view of Patani.
Further, Prabhakar, Isaac, and Padhye teach the following:
“The fluorinated chalcones were found to be more potent antioxidants than their hydroxyl counterparts.” Abstract. Further, fluorine derivatives are more potent SOD scavengers due to their higher metabolic stability of the C-F bond. “Also, halogenated chalcones have been known to possess a stronger antioxidant potential than their non halogenated counterparts with bromine and fluorine derivatives preferred over that of chlorine substituents (Isaac et al., 2012).” With reference to compounds substituted in the R5 equivalent position, among others, it is noted: “All these halogenated chalcones were found to possess considerable level of antioxidant activity.” Conclusion. As such, there is a reasonable and predictable expectation that halogenated and fluorinated chalcones will have enhanced antioxidant potential.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628