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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 22, 2026, has been entered.
Response to Arguments
The examiner has considered Applicant’s arguments and allegations of unexpected results. Applicant’s arguments and allegations are responded to below.
Applicant argues that obviousness required more than a proposition that two agents can individually treat liver fibrosis.
The examiner notes that the prior art teaches each agent works independently and together, and provides a ratio of components in a cell viability assay that is consistent with that claimed.
More specifically, the prior art teaches that icaritin can induce cell death in activated HSCs and ameliorate the progress of hepatic fibrosis in a concentration and time-dependent manner. See Abstract. The IC50 was 12.83 μM at 48 hours. Further, quercetin dramatically ameliorated liver inflammation, fibrosis, and inhibited HSCs activation.” As such, the use of quercetin and icaritin to treat fibrosis, e.g., with the claimed agents is established by the prior art. Further, a specific mechanism of action by which these agents do so is taught.
More importantly, Jung teaches on page 479 in paragraph 1 that “The MTT assay revealed that icaritin (10-30 μM) and quercetin (30 μM) significantly reduced cytotoxic effect of AA+iron (Fig 4B). Additionally, Figure B shown below indicates that the efficacy shown as a percentage of cell viability is established as optimal the concentration of icaritin is in the range of 3-10 μM and quercetin is 30 μM. This includes claimed ratios of approximately 6:30, 10:30, and 30:30 I:Q (i.e., the breadth of claimed ratios).
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Statistical significance is shown at the higher concentration of 30 micromolar for quercetin and at least as low as 10 micromolar icaritin. Jung also teaches that in the HepG2 cell viability assay, the compounds when used alone had no effect. Thus, the combination yields a synergy.
As such, the examiner cannot conclude that unexpected results are shown in view of the cited prior art because Jung an instance in which quercetin needs to be at a higher dose than icaritin by 1-5 times to achieves a maximum efficacy in a cell viability assay. As such, it is unclear how this constitutes an unexpected result. The examiner also notes that a ratio of 1:5 is likely to work only when the ratio also corresponds to a minimum concentration of each component claimed.
Status of the Claims
Claims 11, 15, and 16 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 11, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Jung et al., Epimedium koreanum Ameliorates Oxidative Stress-Mediated Liver Injury by Activating Nuclear Factor Erythroid 2-Related Factor 2,” The American Journal of Chinese Medicine, Vol. 46, No. 2, 469-488 (February 13, 2018) (cited in ISR of 12/29/2022), in view of Li et al., The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice,” Front. Pharmacol., 08 February 2018, and in view of Li et al., “Icaritin induces cell death in activated hepatic stellate cells through mitochondrial activated apoptosis and ameliorates the development of liver fibrosis in rats,” Journal of Ethnopharmacology, Volume 137, Issue 1, 1 September 2011, Pages 714-723.
Jung teaches when Nrf2 is deleted, hepatitis and fibrosis are more severe. Nrf2 activation protects cells from oxidative stress caused by various liver injuries. See p470, 2nd par. Oxidative stress causes hepatitis, fibrosis, and other conditions and is a strategy to ameliorate acute and chronic liver conditions. See p470, 1st par. Jung teaches icaritin and quercetin were both found to have HepG2 protective effects and pretreatment ameliorated CCL4-mediated damage by preventing increases in aspartate aminotransferase, hepatic parenchyma degeneration, and inflammatory cell infiltration. See Abstract. EKE is shown to be an anti-oxidant in vivo and in vitro. Figure 4 explains that icaritin and quercetin protect cells from oxidative stress via Nrf2 activation. Icaritin and quercetin at concentrations of 10-30 μM promoted transactivation of Nrf2. See p485, 1st par. The findings indicate an ability to treat a diverse group of oxidative stress mediated disorders. See p485, final par. Each of 10-30 μM worked. Also see p479, 1st par.
Thus, Jung teaches the claimed agents for treating fibrosis and hepatitis, among others.
Li et al., The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice,” Front. Pharmacol., 08 February 2018, teaches: “Our results showed that quercetin dramatically ameliorated liver inflammation, fibrosis, and inhibited HSCs activation.” Abstract. “Taken together, our data indicated that quercetin attenuated CCl4- induced liver inflammation and fibrosis in mice through inhibiting macrophages infiltration and modulating M1 macrophages polarization via targeting Notch1 pathway. Hence, quercetin holds promise as potential therapeutic agent for human fibrotic liver disease.”
Li et al., “Icaritin induces cell death in activated hepatic stellate cells through mitochondrial activated apoptosis and ameliorates the development of liver fibrosis in rats,” Journal of Ethnopharmacology, Volume 137, Issue 1, 1 September 2011, Pages 714-723. Li teaches icaritin can induce cell death in activated HSCs and ameliorate the progress of hepatic fibrosis and is a promising drug candidate for treating liver fibrosis. It did so in a concentration and time-dependent manner. See Abstract. The IC50 was 12.83 μM at 48 hours.
Thus, icaritin and quercetin are taught to independently treat liver fibrosis through different and complementary mechanisms of action. For example, quercetin inhibited HSC activation and icaritin induces cell death in activated HSCs in a dose dependent manner. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In this case, Jung teaches EKE which comprises icaritin and quercetin to mitigate inflammation. It does not teach the claimed broad ratio of components. However, if the alleged unexpected result in the combination claimed, this combination is taught and present in EKE. Alternatively, if the alleged unexpected limitation is the ratio of icaritin to quercetin, the examiner notes that such ratio has not been shown to be critical for the breadth of the claimed range.
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 treat a subject with fibrosis or hepatitis with the claimed agents because they are taught to independently treat the same. Further, one would use these agents together because they have separate and complimentary mechanisms of action. As such, there is a reasonable and predictable expectation of success in treating the claimed subject with the claimed agents at an optimizable ratio and dosage. A person of ordinary skill can optimize two known result-effective variables through nothing more than routine experimentation. As such, a prima facie showing is established and while offered, a sufficient showing of unexpected results has not been made.
As such, claims 11, 15 and 16 are rejected.
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