DETAILED ACTION
This office action is in response to the Applicant’s filing dated November 13th, 2025.
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 .
Status of Claims
Claims 65, 93-96 and 129-136 are pending in the instant application. Acknowledgement is made of Applicant’s remarks and amendments filed on November 13th, 2025. Acknowledgment is made of Applicant’s amendment of claims 65 and 93-96; and cancelation of claims 87-88 and 137-140.
Claims 129-136 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 17th, 2025.
Priority
This application is a 371 of PCT/CN2021/084009 filed on March 30th, 2021; and claims benefit of foreign priority of CN202010249023.1 filed on March 31st, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Maintained Objections and/or Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 non-obviousness.
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 65 and 93-96 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (CN 106139151 A; citing English machine translation from Google Patents), cited in a previous Office action; in view of Leow et al (Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells. (2010), Invest New Drugs, 28, 766-782), cited in a previous Office action.
Regarding claim 65, Lu teaches method of treating tumors in mice comprising administering a compound doxorubicin/vitamin C palmitoyl ester (herein referred to as ascorbyl palmitate) nanoparticle group (addressing claim 65[a]); and further compared the efficacy of the compound nanoparticle group with ascorbyl palmitate nanoparticle group, a doxorubicin solution group, and a saline control group. Lu states, “The experimental results showed that compared with the normal saline group, the compound nanoparticle group, the vitamin C palmitoyl ester nanoparticle group, and the doxorubicin aqueous solution group all produced pharmacological effects, among which the compound nanoparticles had the strongest efficacy, followed by the vitamin C palmitoyl ester nanoparticle group, which was stronger than the doxorubicin aqueous solution group, indicating that the nanoparticle preparation has advantages; after administration, the weight changes of tumor-bearing mice in each group were not very obvious, indicating that the compound nanoparticles have less toxicity” (page 25, Experiment 3).
Lu does not teach PKF118-310 as the substance affecting the formation of a TCF/β-catenin complex, in combination with ascorbic acid or a derivative thereof.
Leow teaches the use of PKF118-310 (addressing claim 65[b]) to treat osteosarcoma cell lines, namely U2OS, SaOS-2 and HOS, with efficacy evaluation by MTT assays (page 771, right column, last paragraph). Leow further goes on to discuss PKF118-310’s efficacy, stating “Our results indicated that these osteosarcoma cells had relatively similar sensitivities to curcumin while PKF118-310 had the most potent anti-proliferative effect against U2OS cells. Furthermore, among the three cell lines, U2OS has been reported to be highly invasive” (page 772, left column, first paragraph). Leow further teaches, “PKF118-310 was able to significantly inhibit U2OS cell migration in a dose- and time-dependent manner. In parallel to its anti-migration effects, PKF118-310 treatment significantly reduced the invasive capacity of U2OS cells by 42.4±16.6% and 38.1±12.0% at 0.10 μM and 0.15 μM respectively (Fig. 4e). The anti-metastatic effects of PKF118-310 was observed at concentration ranges that are shown to inhibit downstream β-catenin/Tcf transcriptional activities (Fig. 2) as well as nuclear translocations of the β-catenin protein (Fig. 3) and were not a result of cell toxicity as U2OS cells did not exhibit significant growth inhibition at these concentrations as shown previously in Fig. 1c and d” (page 776, right column, first paragraph).
It would have been prima facie obvious to a person of ordinary skill in the art to combine the combine the ascorbyl palmitate taught by Lu with PKF118-310 compound of Leow in a method of treating osteosarcoma tumors. Lu teaches that ascorbyl palmitate enhances the anti-tumor efficacy and reduces toxicity of anti-tumor agents, including in nanoparticle formulations. Leow demonstrated the potent anti-proliferative and anti-metastatic effects of PKD118-310 in osteosarcoma cell lines by inhibiting downstream β-catenin/TCF transcriptional activities. A person of ordinary skill in the art would have been motivated to combine these agents to achieve a synergistic therapeutic effect with reduced toxicity, and would have had a reasonable expectation of success. The combination yields no change in function and represents a predictable result of combining two known anti-tumor agents.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Regarding claims 93-96, it is obvious to vary and/or optimize the amount of ascorbyl palmitate, as well as PKF118-310, according to the guidance established by both Lu and Leow to provide a therapeutically effective amount of a compound, combination or composition having the desired properties such as the desired ratios and concentrations. It is noted that "[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).
Taken together, all this would result in the method of instant claims 65 and 93-96 with a reasonable expectation of success.
Applicant argues:
Applicant contends that combination effects cannot reasonably be predicted due to complex interactions between anticancer agents. The combined effect may be influenced by mechanism of action, cross resistance, toxicity and pharmacokinetic interactions. Toxicity concerns could exist as seen in the combination of ipilimumab combined with leflunomide or vemurafenib.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As discussed in the above rejection, Lu clearly demonstates that doxorubicin/vitamin C palmitoyl ester (herein referred to as ascorbyl palmitate) as a combination yielded greater antitumor effects than either agent alone. Lu further reports the weight changes of tumor-bearing mice in each treatment group were not very obvious, indicating that the compound ascorbyl palmitate nanoparticles have reduced toxicity in light of their significantly smaller tumor mass (page 25, Experiment 3); which is clear evidence that combining ascorbic acid derivatives with anti-tumor agents was known in the art to have no apparent increase in systemic toxicity.
Applicant argues:
Applicant contends an unexpected synergistic effect has been discovered between ascorbic acid, or its pharmaceutically acceptable salts, in combination with PKF118-310 or its derivatives, inhibiting tumor growth and migration without increased toxicity as demonstrated in Examples 1-3, 7-9, 10 and 12-13.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Examples 7-8, 10 and 12-13 disclose experimental data for compounds and/or conditions that are not currently under examination based upon the Applicant’s election of osteosarcoma and PKF118-310 in the reply filed on July 17th, 2025.
While Examples 1-3 do disclose improved therapeutic inhibitory effect on osteosarcoma cell growth, inhibition of migration of osteosarcoma cells, and no increased therapeutic risk from PKF118-310 in combination with sodium ascorbate; this is not unexpected in view of the prior art.
As discussed in the above rejection, Leow clearly demonstrates that PKF118-310 has significant antitumor activity, including inhibiting cell migration in a dose- and time-dependent manner, against osteosarcoma cell lines. Lu clearly demonstrates that another antitumor agent, namely doxorubicin, in combination with vitamin C palmitoyl ester (herein referred to as ascorbyl palmitate) as a combination produced greater tumor inhibition effects than either agent alone, which is clear evidence that enhanced therapeutic efficacy from combining ascorbic acid derivatives with anti-tumor agents was known in the art.
Furthermore, Lu reports the weight changes of tumor-bearing mice in each treatment group were not very obvious, indicating that the compound ascorbyl palmitate nanoparticles “have reduced toxicity in light of their significantly smaller tumor mass” (page 25, Experiment 3).
Conclusion
Claims 65 and 93-96 are rejected.
No claim is allowed.
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 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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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691