Notice of 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 Applicants’ Amendment and Remarks filed on 10/28/2025 in which claims 10, 15-19, 23-25 and 31 are cancelled and claims 1, 11 and 26 are amended. No claims are newly added.
Claims 1, 2, 4, 6, 8, 9, 11, 12, 14 and 26 are pending in the instant application and are examined on the merits herein.
Priority
The application is a continuation of application 17/011838, now US 11,642,360, filed on 9/3/2020, which claims benefit to provisional application US 62/895292 filed on 9/3/2019.
Withdrawn Rejections
All rejection(s) of record for claim(s) 10, 15-19, 23-25 and 31 is/are hereby withdrawn due to the cancellation of said claim(s) rendering said rejection(s) moot.
Applicant’s amendment, filed on 10/28/2025, with respect to the rejection of: Claims 1, 2, 4, 6, 8 and 9 under 35 U.S.C. 103(a) as being unpatentable over Hughes et al. (Rev. Food Sci. Nut., 2017) in view of Ishikawa et al. (Phytomed., 2006) and Lee et al. (J. Food Sci., 2010);
Claims 11, 12 under 35 U.S.C. 103(a) as being unpatentable over Hughes et al. (Rev. Food Sci. Nutr., 2017) in view of Martinez et al. (Pharm. Biochem. Behav., 2010);
Claim 14 under 35 U.S.C. 103(a) as being unpatentable over Hughes/Martinez, as applied in claim 11, further in view of Ishikawa et al. (Phytomed., 2006); and
Claim 26 under 35 U.S.C. 103(a) as being unpatentable over Hughes/Martinez, further in view of Possemiers et al. (WO 2013186220 A1), has been fully considered and is persuasive. None of the cited prior art, either alone or in combination, teach the claimed ratio of flavone:flavanone. The rejections are hereby withdrawn.
Rejections Necessitated by Amendment
The following are new ground(s) or modified rejections necessitated by Applicants' amendment, filed on 10/28/2025, wherein instant independent claims 1 and 11 are amended to alter the breadth and scope of the claim, wherein the remaining pending claims depend from said independent claims. Therefore, new grounds of rejection have been made or rejections from the previous Office Action have been modified.
New Grounds of Rejection
Claim Rejections - 35 USC § 112(b)
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 26 is rejected for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 26 depends from canceled claim 15, which renders the metes and bounds of claim 26 unclear.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1, 2, 4, 6, 8 and 9 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hughes et al. (Rev. Food Sci. Nut., 2017, IDS) in view of Ishikawa et al. (Phytomed., 2006, reference of record) and Lee et al. (J. Food Sci., 2010, reference of record), further in view of Birbara et al. (US 2012/0213842 A1, PTO-892).
Hughes et al. disclose that apigenin (4’, 5, 7-trihydroxyflavone) reduces the onset and severity of arthritis in treated collagen-induced arthritis (CIA) mice (p. 19; Figure 4). Furthermore, Hughes et al. disclose that histopathology confirmed that apigenin exerted an anti-arthritic effect in adjuvant-induced arthritis (AIA ) rats; reducing inflammation scores, inflammatory cell infiltration, cartilage damage, synovial edema and cellular damage in the hind paw (pp.19-20). Also, Hughes et al. disclose that several other studies have shown a reduction in arthritis scores in adjuvant-induced arthritis (AIA ) rats treated with hesperidin. Additionally, hesperidin reduced both paw swelling and arthritic clinical scores in rats with adjuvant-carrageenan induced arthritis. Bone destruction, vascular proliferation, synovial hyperplasia and inflammatory cell infiltration were attenuated in hesperidin treated AIA animals. Pathological changes in joint structure, splenic histology, and inflammation scoring were reduced in hesperidin treated AIA rats. The proliferation of synoviocytes taken from AIA rats was inhibited with hesperidin. A few other studies have also confirmed hesperidin induced apoptosis in synovial fibroblasts, obtained from RA patients, stimulated with TNF-α (p. 18). Hughes further discloses that dietary flavonoids have been reported to control joint inflammation and alleviate arthritis symptoms in both human rheumatoid arthritis (RA) and animal models of arthritis (Abstract). Furthermore, Hughes discloses that typical features of rheumatoid arthritis (RA) are symmetrical inflammation in the small joints of the hands, wrists, and feet, and though any synovial joint may be involved at any point of the disease RA often begins subtly with symptoms of joint pain and stiffness associated with swelling over the joint area (pp. 4-5). In addition, Hughes et al. disclose that flavonoids including hesperidin and apigenin modulates rheumatoid arthritis (RA) pathogenesis (p. 51; Table 2). This implies or suggest that hesperidin and apigenin can be used to reduce or treat joint inflammation such as joint inflammation associated to rheumatoid arthritis (RA).
Hughes et al. does not exemplify co-administering apigenin and hesperidin. Hughes also does not teach the ratio of apigenin:hesperidin.
Ishikawa et al. discloses that among flavanoids studied, apigenin was particularly effective in inhibition of COX-2 protein expression. (p. 312, Col. 2; Figure 2) Ishikawa also discloses that apigenin inhibited PGE2 production and COX-2 expression extremely. (p. 315, Col. 2) Ishikawa concludes that the observed results explain the efficacy of flavanoids as anti-inflammatory compounds. (Abstract)
Lee et al. discloses that hesperidin was among the most potent COX-2 inhibitors studied. (Table 6) Lee also discloses that the expression of COX-2 is a key element in the pathophysiology of several inflammatory disorders, and its regulation differs between cell types. COX-2 is expressed during inflammatory disease in many cells, including fibroblasts and macrophages, and mediates the release of large quantities of proinflammatory PGs at the site of inflammation. COX-2 and NO represent key regulatory molecules in the inflammatory process in RA. (p. H216, Col. 2)
Birbara et al discloses preparing flavonoid compositions for use in treating arthritis. (Claim 39; ¶0059) Birbara exemplifies compositions comprising apigenin and hesperidin, in a ratio of 1:1. (Tables IX, XV) Birbara also teaches that apigenin may be present in the composition at 5-10 wt%. (¶0126)
It would have been obvious to one having ordinary skill in the art, at the time of the effective filing date, to decrease joint inflammation caused by or associated with rheumatoid arthritis (RA) by administering to a subject a composition comprising hesperidin and apigenin, that both inhibit cyclooxygenase-2 (COX-2) as taught by Ishikawa and Lee, thereby arriving at the instant invention. One having ordinary skill in the art would have been motivated co-administer hesperidin and apigenin, to decrease joint inflammation caused by or associated with rheumatoid arthritis (RA) because Hughes teaches that both apigenin and hesperidin are known individually to treat or modulate RA by acting as anti-inflammatory agents. In co-administering apigenin and hesperidin, one would expect to reap the aggregate additive benefits of each flavanoid individually in effectively treating joint inflammation in RA.
It would have been further obvious to look to Birbara for guidance on art recognized amounts and ratios for apigenin and hesperidin, because Hughes does not provide specific guidance on amounts and ratios. Absent specific guidance, it is within the purview of one of ordinary skill in the art to seek guidance from analogous art. With respect to the ranges of amounts claimed, said ranges overlap that of the prior art. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). (MPEP § 2144.05(I)) Moreover, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (MPEP § 2144.05(II)) “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
It should be noted that it is obvious to expect that the inhibition of COX-2 which implies the decrease in expression would involve the decrease in concentration of COX-2. Furthermore, with respect to claim 4, the administration of apigenin would be expected to inhibit COX-2 expression simultaneously with inhibiting PGE2 production, as taught by Ishikawa. With respect to claims 8 and 9, the limitations regarding ROS modulation or arachidonic acid metabolism modulation, these limitations are not accorded patentable weight because of the inseparable connection between an administered composition and the mechanism of action within the subject to which the composition is administered. The active method step in the instant claim is administering the flavanoid composition whereas the ROS modulation or arachidonic acid metabolism modulation are effects which will necessarily occur and do not delineate a manipulative difference between the instant method and the method of the prior art. Therefore, because the combined prior art teaches the same active step to administer the same composition, the properties applicant discloses and/or claims are necessarily present. Ex parte Novitski, 26 USPQ2d 1389 (Bd. Pat. App. & Inter. 1993). See also MPEP § 2112.02.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art
Claims 11, 12 and 26 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hughes et al. (Rev. Food Sci. Nutr., 2017, IDS) in view of Martinez et al. (Pharm. Biochem. Behav., 2010, reference of record), further in view of Birbara et al. (US 2012/0213842 A1, reference of record).
Hughes et al. disclose that apigenin (4’, 5, 7-trihydroxyflavone) reduces the onset and severity of arthritis in treated collagen-induced arthritis (CIA) mice (p. 19; Figure 4). Furthermore, Hughes et al. disclose that histopathology confirmed that apigenin exerted an anti-arthritic effect in adjuvant-induced arthritis (AIA ) rats; reducing inflammation scores, inflammatory cell infiltration, cartilage damage, synovial edema and cellular damage in the hind paw (pp.19-20). Also, Hughes et al. disclose that several other studies have shown a reduction in arthritis scores in adjuvant-induced arthritis (AIA ) rats treated with hesperidin. Additionally, hesperidin reduced both paw swelling and arthritic clinical scores in rats with adjuvant-carrageenan induced arthritis. Bone destruction, vascular proliferation, synovial hyperplasia and inflammatory cell infiltration were attenuated in hesperidin treated AIA animals. Pathological changes in joint structure, splenic histology, and inflammation scoring were reduced in hesperidin treated AIA rats. The proliferation of synoviocytes taken from AIA rats was inhibited with hesperidin. A few other studies have also confirmed hesperidin induced apoptosis in synovial fibroblasts, obtained from RA patients, stimulated with TNF-α (p. 18). Hughes further discloses that dietary flavonoids have been reported to control joint inflammation and alleviate arthritis symptoms in both human rheumatoid arthritis (RA) and animal models of arthritis (Abstract). Furthermore, Hughes discloses that typical features of rheumatoid arthritis (RA) are symmetrical inflammation in the small joints of the hands, wrists, and feet, and though any synovial joint may be involved at any point of the disease RA often begins subtly with symptoms of joint pain and stiffness associated with swelling over the joint area (pp. 4-5). In addition, Hughes et al. disclose that flavonoids including hesperidin and apigenin modulates rheumatoid arthritis (RA) pathogenesis (p. 51; Table 2). This implies or suggest that hesperidin and apigenin can be used to reduce or treat joint inflammation such as joint inflammation associated to rheumatoid arthritis (RA).
Hughes et al. does not teach co-administering apigenin and hesperidin. Hughes also does not teach the ratio of apigenin:hesperidin.
Martinez et al. discloses that hesperidin has been identified as the primary active agent in plant extracts known to have anti-nociceptive and anti-inflammatory effects in subjects with RA and osteoarthritis, where the antinociceptive response of the hesperidin involves the participation of TRPV1 receptors.(p. 687, Col. 2; p. 688, Col. 2)
Birbara et al discloses preparing flavonoid compositions for use in treating arthritis. (Claim 39; ¶0059) Birbara exemplifies compositions comprising apigenin and hesperidin, in a ratio of 1:1. (Tables IX, XV) Birbara also teaches that apigenin may be present in the composition at 5-10 wt%. (¶0126)
It would have been obvious to one having ordinary skill in the art, at the time of the effective filing date, to decrease joint inflammation caused by or associated with rheumatoid arthritis (RA) by administering to a subject a composition comprising hesperidin and apigenin, where hesperidin acts as an antagonist for TRPV1 receptors, as taught by Martinez, thereby arriving at the instant invention. One having ordinary skill in the art would have been motivated co-administer hesperidin and apigenin, to decrease joint inflammation caused by or associated with rheumatoid arthritis (RA) because Hughes teaches that both apigenin and hesperidin are known individually to treat or modulate RA by acting as anti-inflammatory agents. In co-administering apigenin and hesperidin, one would expect to reap the aggregate additive benefits of each flavanoid individually in effectively treating joint inflammation in RA.
It would have been further obvious to look to Birbara for guidance on art recognized amounts and ratios for apigenin and hesperidin, because Hughes does not provide specific guidance on amounts and ratios. Absent specific guidance, it is within the purview of one of ordinary skill in the art to seek guidance from analogous art. With respect to the ranges of amounts claimed, said ranges overlap that of the prior art. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). (MPEP § 2144.05(I)) Moreover, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (MPEP § 2144.05(II)) “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Claim 14 is rejected under 35 U.S.C. 103(a) as being unpatentable over Hughes/Martinez/Birbara, as applied in claim 11, further in view of Ishikawa et al. (Phytomed., 2006, reference of record).
The disclosure of Hughes/Martinez/Birbara is referenced as discussed above. The combined prior art does not disclose that modulation of PGE2 signaling.
Ishikawa et al. discloses that among flavanoids studied, apigenin was particularly effective in inhibition of COX-2 protein expression. (p. 312, Col. 2; Figure 2) Ishikawa also discloses that apigenin inhibited PGE2 production and COX-2 expression extremely. (p. 315, Col. 2) Ishikawa concludes that the observed results explain the efficacy of flavanoids as anti-inflammatory compounds. (Abstract)
It would have been obvious to one having ordinary skill in the art, at the time of the effective filing date, that the administration of apigenin, in the method of Hughes/Martinez, would be expected to inhibit PGE2 production, because Ishikawa teaches that apigenin inhibited PGE2 production.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Maintained Rejection
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1, 2, 4, 6, 8, 9, 11, 12, 14 and 26 of the instant application are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9 of US 11,642,360. Although the conflicting claims are not identical, they are not patentably distinct from each other because: The method of ‘360 anticipates the instant method.
Response to Arguments
Applicants’ response with respect to the double patenting rejections over US 11,642,360, has been fully considered.
Applicant responds to the double patenting rejections that the rejection is moot in view of the filing of the terminal disclaimer on 10/28/2025. Applicants’ argument is not persuasive because the terminal disclaimer was disapproved on 10/30/2025. The rejection is still deemed proper and maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new and/or modified 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 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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALE R MILLER whose telephone number is (571) 272-6146. The examiner can normally be reached on M-F 7:00 AM – 3:30 PM EST.
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/DALE R MILLER/Primary Examiner, Art Unit 1693