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 Amendments
Applicant’s amendments to the claims of May 14, 2026, in response to the Office Action of February 18, 2026 are acknowledged.
Response to Arguments
The examiner finds Applicant’s arguments that the Jung reference does not teach the combination but rather teaches the claimed agents independently to be persuasive. The rejection, as written, is based on the use of icaritin and quercetin as independent agents each known for treating the claimed subject population. The examiner notes that Applicant’s arguments and allegations of unexpected results of the combination are addressed below.
As an initial matter, even if unexpected results were properly shown, they are not commensurate in scope with the claims because not a single claim requires a 5:1 ratio and a concentration. For example, a ratio of 5:1 includes 0.5 and 0.1 μM amounts. This is inarguably not shown to be synergistic. Further, Applicant’s declaration shows that at concentrations of 50:10, 75:15, and 100:20 (I:Q) each of which are 5:1 ratios yield a cell viability is approximately 60-80% which is below the argued synergistic 98%. See Figure 2. A combination if not synergistic when providing 60% cell viability when each agent alone is shown to provide for approximately 50% cell viability independently.
Claim 1 is directed to any combination with a ratio of 1-5:1 quercetin to icaritin, including a ratio of 1:1. (2) Claim 16 includes a 5:1 ratio with no concentration claimed and therefore is inclusive of concentrations shown in Figure 2 wherein the combination yields a total of 60% cell viability. Finally, (3) claim 17 provides for a ratio, including 5:6 icaritin to quercetin. Data and allegations for this ratio are not taught.
Thus, there is no claim that is commensurate in scope with the alleged showing. For purposes of expediting prosecution on the merits, the examiner responds below to Applicant’s arguments and use of the Colby Equation.
The Colby Formulation and Allegations of Unexpected Results:
The examiner notes that Applicant’s arguments provide a less than additive effect to show a synergy of a combination of two agents, icaritin and quercetin, each of which are known to potently treat the claimed liver symptoms/conditions. As such, Applicant has provided the Colby Formula in an allegation to show unexpected results. The showing is based on a single ratio of 5:1 at specific μM concentrations wherein icaritin- 50.8% and quercetin- 47.9% would provide for an additive benefit of 98.7%. Applicant argues that the Colby Formula predicts 73.5% and thus, the calculated 98.3% benefit should be considered an unexpected synergy.
The examiner responds below while noting that this explanation is to further prosecution if the claims were to be amended to be commensurate with the present allegations.
Kevin Tamm, “Distinguishing a Patent Over the Prior Art with Unexpected Synergistic Results,” Managing Editor, University of Cincinnati Law Review, April 15, 2013 explains:
To show synergy, the applicant must prove the invention exhibits more than mere additive effects. The effectiveness of the combination should be shown vs. the individual components, and the effectiveness also should be shown over what the closest cited prior art suggests. In Ex Parte Quadranti, 25 U.S.P.Q.2d 1071, (Bd. Pat. App. & Interf. May 22, 1992), the Board found evidence of unexpected synergy to be unpersuasive stating:
[G]eneralizations such as the Colby formula[4] are not particularly useful in determining whether synergism has been demonstrated, since the formula inherently results in expectation of less than additive effect for combination of herbicides, since there is no evidence that such approach is considered valid by significant number of ordinarily skilled workers in relevant area of technology, and since it could be reasonably argued that in most cases, additive or better than additive results could be expected for combination of herbicides. (emphasis added).
Corte et al., “Assessment of Assertions of Synergy as a Basis for Inventive Step in Compositions Comprising Mixtures,” https://information.patentepi.org/issue-1-2019/assessment-of-assertions-of-synergy.html (date accessed- August 14, 2026) explains the following. Based on the well-known “Colby” method, the predicted response for a mixture of two agents each giving 60% response is 60 + 60 - 60×60/100 = 84%. But suppose S1 and S2 were actually the same substance; under this scenario, S1 at 200g + S2 at 200g is nothing other than the same substance at 400g, and the likely response to this “mixture” is entirely dependent on the slope of the dose response relationship for the substance in question. With a fairly steep slope as shown in Figure 1a, the likely response to the mixture would be around 92%, which is somewhat bigger than the response predicted using the Colby method and thus implies that the substance in question is synergistic with itself.
To properly evaluate whether the Colby method can predict a synergy requires accounting for the slope and dose response curves for the claimed agents. The problem with the Colby method is that it can work when evaluating substances that have similar or the same modes of action, such that one would expect a dilution of the other agent and so a synergy may be recognized when less than additive effects are noted.
To further elucidate why a slope of effect is required to show a synergy, the examiner refers to: Levine, “Review and recommendations on criteria to evaluate the relevance of pesticide interaction data for ecological risk assessments,” Chemosphere, Volume 209, October 2018, pages 124-136. Levine explains with almost identical numbers used by Applicant how a synergy for the same agents can be shown or not shown. Levine states on page 126, 2nd full par:
As an example, for two components each exerting 50% response, the response addition model would predict a combined effect of 75% and the concentration addition model would predict, for two equipotent molecules exposed at their EC50 and a Hill slope of one, a 67% effect. However, for two components with steeper logistic slopes of two and five, one would predict an 80% and 96% effect, respectively. Note, a Hill slope of one on an arithmetic concentration scale equals a Hill slope of five on a log concentration scale.
This example shows that an identical combination can have entirely different results for a synergy calculation depending on the slope of the dose response curve.
In this case, Applicant argues that icaritin maintain cell viability of 50.8% and quercetin of 47.9% (almost identical to the example above) and argues that the combination yielded cell viability of 98.3%. This is similar to the predicted 96% in the above example. However, cell viability in Figure 2 appears reach a maximum with a numerous combinations. Figure 2 does not provide any dose response curve. Rather, only single data points for each agent are shown individually.
As noted in the conclusion of the previous Office Action, 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.
Status of the Claims
Claims 11 and 15-17 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 and 15-17 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
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.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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