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 .
Response to Arguments
Applicant argues that the secondary references teach antioxidant activity as a mode of action rather than PPAR gamma and AMPK activation. Applicant argues this to be different.
The examiner notes that the prior art clearly recognizes the claimed agent as a PPAR gamma agonist. For example, Wu teaches: The use of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone as peroxisome proliferator-activated receptor gamma (PPAR gamma ) excitant.
Similarly, Lee teaches 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone to be a AMPK activator and inhibition of apoptosis of vascular cells.
Thus, the claimed core scaffold is known to activate both PPAR gamma and AMPK.
Applicant’s argument hinges on the claimed compound working through these mechanisms rather than as an antioxidant, which is predictable in view of the addition of fluorine to a claimed scaffold. However, the examiner notes that it is Applicant’s contention and not an assumption by the examiner that antioxidant potential was the alleged unexpected result. Applicant’s statement in their Remarks of February 5, 2026, at the bottom of page 2 explains:
PNG
media_image1.png
89
660
media_image1.png
Greyscale
The examiner notes that antioxidant potential is also capable of positively impacting metabolic disorders as claimed.
As evidenced by Mohammadian et al., “The Role of Antioxidants in the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review,” Antioxidants 2024, 13(7), 797, metabolic conditions can be treated with antioxidants. For example, in metabolic dysfunction-associated fatty liver disease, antioxidant therapy was shown to be effective. “In total, 31.1% of human studies used natural antioxidants, 53.3% used synthetic antioxidants, and 15.5% used both natural and synthetic antioxidants. In human-based studies, natural antioxidants showed 100% efficacy in the treatment of MAFLD, while synthetic antioxidants showed effective results in only 91% of the investigations.”
In this case, the claimed scaffold is able to be a PPAR gamma and AMPK agonist, as well as an antioxidant that can treat metabolic conditions. As Applicant argued, the claimed compounds are also antioxidants.
Applicant argues that the cited references teach a structurally different scaffold as the claims require a methoxy group and two methyl groups on the “A” ring.
The examiner notes that multiple primary references cited teach the claimed scaffold.
Furthermore and as previously noted, Bist teaches inhibitory effects on ROS of fluorinated chalcones. Bist establishes a concrete structure activity relationship and fluorinated chalcones act as radical scavengers, anti-diabetic agents, and anti-inflammatory agents.
PNG
media_image2.png
480
589
media_image2.png
Greyscale
The secondary references 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.
The examiner also notes on page 7 of the Specification that the claimed agents are taught to be able to treat claimed conditions through modes of action that include “exhibiting an antioxidant effect.” See p7, lines 3-6.
Thus, the examiner believes that a prima facie showing is established that the claimed scaffold, which is taught to treat claimed conditions can be substituted with a fluorine to increase the antioxidant effect of substituted chalcones and chalcone derivatives as shown. While there is no guarantee that such substitution would work better, there is a reasonable expectation of success that it would be efficacious and that it would be a more potent antioxidant. The examiner also notes that the compounds cited by the prior art remain included in the genus of claim 1.
Applicant argues that Patani does not necessarily mean that activity will be improved.
The examiner notes that Patani provides a motivation to fluorinate a chalcone compound. The burden is not on the examiner to show that the prior art establishes unexpected results. Any allegation of unexpected results must be shown and established by Applicant as compared to the closest prior art and any showing must actually be unexpected.
The cited references teach: “The fluorinated chalcones were found to be more potent antioxidants than their hydroxyl counterparts.” See 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.
In view of these teachings and the state of the art, unexpected results have not been established. Even if they were, claim 1 remains directed to the specific compound taught by the prior art. Halogenation is expected to increase potential to treat metabolic conditions. Fluorine is a preferred halogen for such purpose.
A prima facie showing is therefore established. Unexpected results are not shown as the inclusion of fluorine to a claimed chalcone compound is expected to increase diabetic potential, antioxidant potential, and anti-inflammatory potential. A rejection is set forth below.
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).
PNG
media_image2.png
480
589
media_image2.png
Greyscale
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.
PNG
media_image3.png
523
589
media_image3.png
Greyscale
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
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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. 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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JARED BARSKY/Primary Examiner, Art Unit 1628
Prosecution Insights