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 Amendment
Applicant’s remarks and amendments filed 11/3/2025, in response to the non-final rejection mailed 8/7/2025, are acknowledged and have been fully considered. Applicant’s amendment to the claims is acknowledged. This listing of the claims replaces all prior versions and listings of the claims. Claims 20-24 remain withdrawn as being directed to a non-elected invention. Claims 13, 15-17, 19, and 25-26 are pending and have been examined on the merits.
Response to Arguments
Applicant’s remarks, on page 5 of the reply filed 11/3/2025, with respect to the objections to the specification have been fully considered. The objections to the specification have been withdrawn in response to the claim amendment.
Any previous rejection or objection not mentioned herein is withdrawn.
Applicant’s arguments, see pages 6-8 (section III.) of the remarks, with respect to the rejection of claim 17 under 35 U.S.C. § 112(a) for lack of enablement for the full claim scope- have been fully considered and are persuasive in light of the amendments to the claim.
Regarding the previous rejections of claims 13, 15-17, and 19 under 35 U.S.C. § 103 as being obvious over the combined teachings of Jin et al. (CN-110302380-A, of record), Coombs et al. (Cancer letters 380, 2 (2016), of record) and Lee et al. (European Food Research and Technology 244 (2018), of record), Applicant’s arguments on pages 8-12, section IV, of the remarks filed 11/3/2025 have been fully considered and are persuasive in light of the amendments to the claim.
However, upon further consideration, new grounds of rejection are presented herein, as necessitated by Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 103
(Modified as necessitated by amendments)
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 13, 15-17, 19, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al. (CN-110302380-A, of record) in view of Coombs et al. (Cancer letters 380, no. 2 (2016): 424-433, of record), Lee, S. J., et al. (“Inhibitory effects of IL-6-induced STAT3 activation of bio-active compounds derived from Salvia plebeia R. Br.” Process Biochemistry, 51, 12 (2016): 2222-2229), and Johnson et al. (“Targeting the IL-6/JAK/STAT3 signaling axis in cancer.” Nature reviews. Clinical oncology vol. 15,4 (2018): 234-248. doi:10.1038/nrclinonc.2018.8).
Jin et al. pertains to the use and administration of Salvia plebeia water extract as a sensitizer for inhibiting colorectal cancer, wherein the extract has demonstrated effects on tumor growth and cancer proliferation (Abstract; Fig. 1). Jin teaches that the herb Salvia plebeia, used in traditional Chinese medicine, has known antibacterial, anti-inflammatory, antioxidant, and antiviral functions (page 2 of the translation, under “Background”). Jin teaches obtaining a “water extract of salvia plebeian” (i.e. an aqueous extract) and applying the extract to a subject, in particular to a tumor-bearing mouse model (page 2-3 of the translation, steps 1-4 therein). Jin teaches that the application of the herb extract, in combination with other cancer therapies, is effective for preventing tumor growth (see Example 1 and see page 6 of the translation which states: “The present invention further develops the [Salvia plebeia] extract in application of use for inhibiting colorectal cancer… the experiment result shows that the invention comprises obvious restraining effect for colorectal cancer growth, proliferation”).
Thus, Jin teaches a method comprising administering a composition comprising a Salvia plebeia extract as an effective component to a subject having a disorder of cancer, including colorectal cancer.
However, Jin does not explicitly teach the administering of an ethanolic extract that results in immune checkpoint inhibition and that the associated immune checkpoint inhibition (blockade) pathway is caused by PD-L1/PD-1.
Coombs et al. is a research article drawn to the application of the naturally-occurring flavone apigenin – stated to be found in a variety of plants - on the activity and expression of programmed death-ligand 1 (PD-L1). Coombs states that: “The present investigation focuses on the effect of the phytochemical apigenin on inducible and constitutive PD-L1 expression by mammary carcinoma cells. We provide evidence that apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by BC cells may allow T-cells to mount an anti-tumor immune response” (page 425, left col, top paragraph; pg. 426, right col; and also Fig. 1 and Fig. 4). Coombs also teaches that “Apigenin has been extensively studied for its direct inhibitory effects on the growth of cancer cells [35–39]; however, to our knowledge, the present investigation is the first to provide evidence of a potential role for apigenin in enhancing a T cell-mediated antitumor immune response against BC cells by targeting the PD-L1/ PD-1 checkpoint, which is considered a promising target for immunotherapy [17].” (see page 429, first paragraph under Discussion). Coombs demonstrates that application of apigenin abrogates the inhibitory effect of PD-L1-expressing BC cells on T cell proliferation (Fig. 7). Coombs also demonstrates that luteolin, a metabolite of apigenin, has a similar effect on the expression of PD-L1 (Fig. 5; pg. 426, right col). Coombs thus teaches that apigenin, and luteolin, has the potential to increase the vulnerability of cancer cells to T cell-mediated anti-tumor immune responses (Abstract, Title).
Lee et al. (Process Biochemistry, 2016) pertains to the characterization of bio-active compounds derived from Salvia plebeia R.Br, and their effects on the immune modulating pathway mediated by IL-6 and STAT3 (Title, Abstract). Lee teaches that an ethanol extract of the aerial parts of Salvia plebeia R.Br. (SPRB) showed a significant inhibitory effect on IL-6-induced STAT3 expression and that 22 known compounds were determined in the ethanolic extract, and included apigenin (1), luteolin (2), and hispidulin (5), among others (see Fig. 2, Table 1; and pg. 2226, right col, section 3.1.). Lee teaches that the compounds were extracted with 95% EtOH (300 L) at 70 ◦C for 5 h using an equipped extractor (pg. 2223, left col, Section 2.3). Lee concludes that several of the chemicals were identified as effective inhibitors of IL-6-mediated STAT3 activation and, thus, promising drug targets for several diseases such as cancer and inflammatory pathologies (pg. 2228, right col).
Johnson et al, a review article, teaches that in the tumour microenvironment, IL-6, JAK, and STAT3 signaling promotes the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumor immune response (Abstract, and Key points on pg. 235). Johnson states that “inhibition of IL-6/JAK/STAT3 signaling will be useful in combating the various adverse inflammatory effects resulting from treatment with immune-checkpoint inhibitors. Moreover, pre-clinical evidence is emerging that inhibition of IL-6/ JAK/STAT3 signaling might augment the antitumor efficacy of immune-checkpoint inhibitors” (pg. 244, left col). Further Johnson teaches that previous studies support that inhibition of IL-6/JAK/STAT3 signaling downregulates PD-1 and/or PD-L1 expression (pg. 244, left col, last paragraph), and experimental data suggests that co-targeting of IL-6 and PD-L1 leads to enhanced inhibition of tumour growth (pg. 244, right col, first paragraph).
Therefore, before the effective filing date of the claimed invention, to one of ordinary skill in the art it would have been prima facie obvious to administer, as an effective component, an extract of Salvia plebeia to a subject to treat a cancer, as taught in Jin, wherein the Salvia plebeia extract is an ethanolic extract as taught in Lee (Process Biochemistry) for the predictable result of inhibiting both the IL-6/STAT3 pathway and the PD1/PD-L1 immune checkpoint, as suggested by the combination of Coombs, Lee (Process Biochemistry), and Johnson.
One of ordinary skill in the art would have been motivated by the teachings of Coombs, to apply to cancer cells a natural product containing the compounds apigenin and its metabolite luteolin for the known benefit of inhibiting the PD1/PD-L1 regulated immune checkpoint. Lee teaches that ethanolic Salvia plebeia extracts contain both apigenin and luteolin, and provide an inhibitory effect on the pro-tumor IL-6/STAT3/JAK pathway. Jin demonstrates the usefulness of administration of a similar, aqueous, polar Salvia plebeia extract as an adjuvant therapy in cancer subjects. Therefore, one would have been motivated by the combined knowledge of the cited art to administer to a subject with a cancer, in need of immune checkpoint inhibition (i.e. a subject undergoing a simultaneous immunotherapy or similar treatment), a composition having an effective amount of an ethanolic Salvia plebeia extract to regulate PD-L1 activity and the IL-6/STAT3 pathway in the cancer environment.
The substitution of the ethanol of extract of Lee for the water-based extract of Salvia plebeia taught in Jin would have been a matter of simple substitution of one known component for another, with a predictable result, according to the teachings of Lee and Johnson. One having ordinary skill in the art would predict that the combination would yield the useful result of inhibiting the immune checkpoint pathway- thus increasing the activity of immune cells such as T-cells targeting the cancer cells- while also providing the advantage of modulating the IL-6/STAT3 signaling, thus providing additional anti-inflammatory and anti-cancer cell proliferation activity, as suggested in the teachings of Johnson and Lee.
Regarding claim 15, the combination of Coombs and Lee teaches that the Salvia plebeia ethanol extract contains apigenin and luteolin, which are compounds that target the PD1/PD-L1 pathway by reducing the expression of the PD-L1 receptor protein in a targeted cancer cell as demonstrated in Coombs. Thus, it would have been predictable to one of skill in the art that a treatment with an ethanolic S. plebeia extract would target PD-L1 or PD-1.
Similarly, the amended claim 17 requires that the Salvia plebeia extract is produced using ethanol, the administrating inhibits PD-l/PD-L1 binding thus activating T-cells, and that the disorder is a cancer. These limitations are found obvious for all of the reasons described above. The ethanolic extract of Lee inherently possess the useful compounds and activities taught in Cooms and Lee, and thus, the administering of the ethanolic extract would predictable treat a cancer by inhibiting the PD-l/PD-L1 immune checkpoint, including the activation of T-cells, as would be recognized by one of ordinary skill in the art (also discussed in Johnson pg. 244).
Further, the PD-l/PD-L1 binding-inhibiting activities of the ethanol extract amount to inherent properties of a known compound, in particular the ethanolic extract of Lee, and administering such an extract, for ultimately the desired purpose of treating cancer taught in Jin, would have been prima facie obvious. See MPEP § 2141.01: In re Papesch, 315 F.2d 381, 391, 137 USPQ 43, 51 (CCPA 1963)... "From the standpoint of patent law, a compound and all its properties are inseparable.", and also MPEP § 2144.09. VII. “If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc)”). In the instant case, administration of an ethanolic S. plebeia extract to treat tumors would have been obvious, and the activity of the compounds in the extract to block the PD-1/PD-L1 interaction and activate T-cells would have followed, as suggested in the cited art.
Regarding claims 16 and 19, the cancer cells demonstrated in Jin et al. for treatment with a Salvia plebeia extract include colorectal cancer cells, e.g. cells from colon cancer. Coombs pertains to the use of the flavones apigenin and luteolin on breast cancer cells. One of ordinary skill in the art would have been motivated to administer a Salvia plebeia extract having these immune checkpoint inhibiting compounds to at least one of these types of cancer cells. Further, any cancer cell wherein the targeting of PD-L1 activity is desired would have been similarly obvious selections, as evidenced by the teachings of Johnson et al. concerning PD-L1 inhibitors. Claims 25 and 26 limit the treatment to cancers of the colon and/or lungs, which is also found obvious over the combination of art discussed above, for the same reasons.
There would have been a reasonable expectation of success as the use of S. plebeia extracts with anti-inflammatory activity to treat tumors is taught in Jin, and a S. plebeia ethanol extract would have the predictable activity of inhibiting the immune checkpoint pathway by affecting the PD-1/PD-L1 and IL-6/STAT3 pathways, as set forth by the combination of Coombs, Lee, and Johnson. From the teachings of the applied reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at and performing the claimed method wherein an ethanolic S. plebeia extract is applied to treat a cancer including the function of inhibiting the PD-L1/PD-1 immune checkpoint.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments concerning the prior rejection under 35 U.S.C. § 103, as so far as they relate to the teachings relied upon in the modified rejections have been fully considered.
As an initial matter, ethanol extractions of S. plebeia are known in the art, as taught at least in Lee et al. (2016), and applied above in the modified grounds of rejection. Further, the enrichment of pharmacology useful compounds in an ethanol-based extract of S. plebeia, including various flavonoids as discussed by the Applicant, is taught in Lee et al. (2016) which also describes the presence of the component compounds apigenin and luteolin, taught in Coombs to be useful for inhibiting a PD-L1 mediated checkpoint.
In response to Applicant’s arguments that the mechanistic limitations of claim 17 distinguishes the instant invention from that of Coombs, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). MPEP § 2144.09.VII. states that “If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc)”). In this case, the ethanolic extract taught in Lee (2016) appears to be substantially the same as that which is instantly claimed, and the application thereof would result in the same mechanistic effect on the PD-1/PD-L1 blockade.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, regardless of the mechanism, the application of S. plebeia extracts for treating immune-related diseases including cancer is known in the art, and the selection of an ethanolic extraction (or any similar polar extraction) method would be a matter of judicious selection to one of ordinary skill.
Applicant’s argument that there is a lack of motivation and lack of a reasonable expectation of success (on pg. 10) is not persuasive, as the reasoning to combine the teachings of the cited art has been derived from evidence on the record, provided from the relevant art.
There would have been a reasonable expectation of success as similar plant extracts have previously been shown to have success in treating cancers, as evidenced in Jin. The selection of a water extract, methanol extract or ethanol extract would have been a matter of judicious selection to one skilled in the art. The test for obviousness is not that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
The argument pertaining to the differences in methanol and ethanol extraction profiles (see pages 10-11) is rendered moot by the newly presented teachings of Lee (2016).
Regarding the Applicant’s argument of unpredictability and unexpected results, the evidence cited by the Applicant is not supportive of their argument. The teachings of the prior art cited above and the findings of the Applicant both support that application of a S. plebeia extract leads to increased T-cell proliferation (i.e. through either the reduction in expression of PD-L1 or the blocking of its binding), and the reduction of tumor burden. These are findings that would logically flow from the teachings of the prior art. The Applicant has not provided any particular evidence that the water-based extract of Jin, nor the methanolic extracts in the previously cited references, would not achieve the same results as that which is instantly claimed. The discovery of a mechanism through which the immune checkpoint inhibition is achieved is immaterial on the patentability of the claimed invention, when the differences would have otherwise been obvious. The argued effects on the PD-1/PD-L1 pathway would have been intrinsically present in other ethanol extracts of S. plebeia, which are clearly known to the art.
Even if the claimed extract is not identical to the referenced ethanolic extract of S. plebeia and its effects, with regard to some yet unidentified characteristics, the differences between that which is claimed and that which is disclosed is so slight that the referenced composition is likely to inherently possess the same characteristics of the claimed composition, particularly in view of the similar characteristics which they have been shown to share and by the functions of the component materials (e.g. apigenin and luteolin, among others) inherently present in each and which functions are inclusive of those appreciated in the instant disclosure as being present (see MPEP 2112.02 at Ex parte Novitski, in reference to reference-silent functioning of biological materials providing anticipation of the functions based upon the material itself, noting the reference of “Dart” therein did not appreciate the claimed function but still anticipated the function based on the inherent function of the material, and that the Applicant’s disclosure appreciating the function upon usage thereof as further evidence of the presence of the function).
Citation of Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Rho et al. (US PGPub No. 20150174186), pertains to a pharmaceutical composition for preventing or treating STAT3-mediated diseases, comprising an Salvia plebeia R. Br. ethanol extract or fraction thereof as an active ingredient, and to a method for treating STAT3-mediated diseases, comprising a step of injecting the composition into an individual suspected of having a STAT3-mediated disease (Abstract, Title, [0040]).
Xia et al. (CN 109998012; an English language translation of which is also provided) is drawn to a Salvia Plebeia flavone extraction method comprising extracting the plant material in ethanol (Abstract, Claim 1).
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new 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 nonprovisional extension fee (37 CFR 1.17(a)) 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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/A.T.M./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
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