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 .
DETAILED ACTION
Response to Amendment
Acknowledgement is made of Applicant's amendment filed 12/01/2025, wherein claim 1 is amended.
Status of Claims
Claims 1 and 10 are pending in the present application.
Claims 10 remains withdrawn.
Claims 1 is currently under examination.
Action Summary/Response to Arguments
Applicant's remarks filed 12/01/2025 have been fully considered, but NOT persuasive to overcome WD rejection and non-statutory double patenting rejection in the last office action mailed on 06/27/2025. The amendment filed 12/01/2025 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure (newly applied).
Applicant argues “ upon full consideration of the full specification including the experiments, it will be clear that "LB-1" and monochlorinated myricetin (formula II) are the same” .
RESPONSE: The examiner does not dispute the Material and Method section recite Formula II, along with other drugs. However, the experimental results in the summary in Table 13 and other tables (Tables 14, 25,33 and 65 etc.) list LB-1 as the compound tested in combination with other drugs. Although the footnote of tables also recite LB-1, as explained in the interview on 05/01/2025, “LB-1” is not analogues /synonymous to Formula II, there is NO explicit definition of "LB-1" is the instantly claimed monochlorinated myricetin formula II and there is no structure for LB-1 demonstrating LB-1 is compound of Formula II. The experimental data marked ”LB-1” in Table 13 or other tables might be generated and/or imported from other assay that’s not tested with Formula II, since instant Spec also disclosed other chlorinated myricetin/different compound species, e.g. Formula III (dichlorinated myricetin) that’s not Formula II, or other Formula II isomers with chlorine at the different positions of the myricetin core structure.
Since the specification at the time of original filing does not clearly associate the experiment results of ”LB-1” with the specific chlorinated compound of Formula II, the original disclosure does not clearly demonstrate instant claimed specific compound of Formula II in combination with 30uM cisplatin exhibit the claimed anticancer activity. Please note the amended spec filed on 12/01/2025 introduces new matter and cannot be relied on for the definition of “LB-1” that’s not in the original spec at the time of filing. Applicant is advised to provide evidence of nexus between “LB-1” and compound of Formula II in the form of Affidavit or Declaration.
Claim 1 is amended to recite a pharmaceutical composition comprising a combination of 50 to 100uM of chlorinated myricetin having chemical formula II and 30uM of cisplatin, that exhibits “at least 95%” or “great than 99% ”control of cancer cell in cell growth assay. Please note the transitional phrase ”comprising” is open-ended that do not limit instant claimed composition to the combination of 50 to 100 μM chlorinated myricetin and 30 μM cisplatin only. The instantly claimed full range/scope of combination of chlorinated myricetin formula II from 50 to 100uM and 30uM cisplatin lacks sufficient support for the recited activity by instant specification. Instant specification does NOT disclose 100 μM chlorinated myricetin in combination with 30uM cisplatin on the assay with LNCaP cell line or U87MG cell line, and there is no support for 50 μM chlorinated myricetin in combination with 30uM cisplatin on the assay with SK-Hep-1 cell line (Table 65). As such, instant claimed combination of 50-100 μM chlorinated myricetin and 30uM cisplatin lacks sufficient support for the recited activity.
Priority
This application 17/530,956 filed on 11/19/2021 claims no domestic benefit or foreign benefit.
Specification
The amendment filed 12/01/2025 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: LB-1 as monochlorinated myricetin (formula II) in [0003] , [0011], [0013] and [0029] and the tables, etc.
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As discussed in the interview and office action mailed on 06/27/2025, the experiment data marked “LB-1” is not clearly associated with compound of Formula II at the time of specification was originally filed. The experimental data marked ”LB-1” in Table 13 or other tables might be generated and/or imported from other assay that’s not tested with Formula II. Applicant’s mere argument that LB-1 is the compound of Formula II in absence of convincing evidence in the form of affidavit or declaration is NOT persuasive. Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention (maintained).
Claim 1 is amended to recite a pharmaceutical composition comprising a combination of 50 to 100uM of chlorinated myricetin having chemical formula II and 30uM of cisplatin, wherein the pharmaceutical composition of 50 uM chlorinated myricetin and 30 uM cisplatin exhibits i) at least 95 % control of glioblastoma line U87MG cells in a cell growth assay, and (ii) greater than 99 % control of prostate adenocarcinoma line LNCap cells in a cell growth assay, and wherein 100 uM chlorinated myricetin and 30 uM cisplatin exhibits 95 % control of liver cancer line SK-HEP-1 cells in a cell growth assay.
However, the cell growth assay on glioblastoma line U87MG, prostate adenocarcinoma line LNCap cells and liver SK-HEP-1 cells with the recited efficacy disclosed by instant specification are described as combination of “LB-1” and cisplatin (See [0035]-[0036], [0040], Table 13, 25, 33, 65, etc.). There is NO explicit definition of "LB-1" is the instantly claimed chlorinated myricetin formula II and there is no clear nexus between "LB-1" and monochlorinated myricetin formula II.
Instantly recited efficacy limitation "at least 95% " or "greater than 99% " control of cancer cell in cell growth assay by combination of 30uM of cisplatin with formula II ranging from 50uM to 100uM lack sufficient support by instant specification. The limitation "at least 95% " is interpreted as high as 100% or so which lacks sufficient support by instant disclosed assay. For example, Table 65 disclosed SK-Hep-1 cell assay wherein 'The highest inhibition rate is 95.36%, at concentration of 100 μM LB-1 and 30 μM cisplatin. The inhibition rate is 61.33% at 100 μM LB-1 only, and the inhibition rate is 70.68% at 30 μM cisplatin only". However, the standard deviation of the inhibition for combination of 100 μM LB-1 and 30 μM cisplatin is 0.95. The only one assay tested with 100 μM LB-1/ 30uM cisplatin on SK-Hep-1 cell might have measurement /statistical error and inhibition rate might be lower than 95% control. There is no assay to support 50 μM LB-1 in combination with 30 μM cisplatin on SK-Hep-1 cell. Table 33 discloses LNCaP cell line “wherein the highest inhibition rate is 99.48%at concentration of 50 uM LB-1 and 30 uM cisplatin. The inhibition rate is 97.41% at 50 uM LB-1, and the inhibition rate is 53.09% at 30 uM cisplatin”. However, the alleged “synergistic” inhibition at 99.48% compared with estimated additive inhibition (98.8% ) is not statistically significant to support the instant alleged inhibition activity of greater than 99 % control in LNCaP cell.
It's noted the transitional phrase ”comprising” is open-ended that do not limit instant claimed composition to the combination of 50- 100 μM chlorinated myricetin and 30 μM cisplatin only. The instantly claimed full range/scope of monochlorinated myricetin formula II from 50 to 100uM and 30uM cisplatin lacks sufficient support by instant specification. Instant specification only disclosed combination of 50μM LB-1 and 30 μM cisplatin or 100 μM LB-1 and 30 μM cisplatin in certain assays that might achieve instantly recited efficacy. Instant specification does not disclose any assay wherein LB-1 at concentration between 50-100uM(e.g. 75, 90uM) in combination of 30 μM cisplatin that can achieve instantly recited efficacy. Instant specification does NOT disclose 100 μM chlorinated myricetin in combination with 30uM cisplatin on the assay with LNCaP cell line or U87MG cell line, and there is no 50 μM chlorinated myricetin in combination with 30uM cisplatin on the assay with SK-Hep-1 cell line (Table 65). As such, instant claimed combination of 50-100 μM chlorinated myricetin and 30uM cisplatin lacks sufficient support for the alleged synergistic inhibition for different cell lines.
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6 of US 10,966,954 in view of Li et al.( Cells 2019, 8, 358; doi: 10.3390/cells8040358, “Myricetin Suppresses the Propagation of Hepatocellular Carcinoma via Down-Regulating Expression of YAP”)(maintained) .
Reference claims are directed to a pharmaceutical composition comprising a compound that is instant claimed monochlorinated formula II. Reference claim 6 recites method of treating cancerous disease with compound of formula II.
Reference claims are silent about monochlorinated myricetin in combination with cisplatin. However, combination therapy is common practice for cancer treatment. Li collectively teaches pharmaceutical composition comprising combination of myricetin and cisplatin at various concentration that are synergistically effective in treating cancer through potential new mechanism. Li teaches combination of myricetin and cisplatin at various concentration (e.g. 100 uM myricetin and 2uM cisplatin( See Figure 5), myricetin (30 mg/kg/day) and cisplatin (5 mg/kg/3 days)(see Figure 6, page 11 of 16). Li’s embodiments comprising 100 uM myricetin overlaps/reads on instantly 100uM of chlorinated myricetin. Where 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. MPEP 2144.05.
Li teaches “ combination of myricetin and cisplatin led to a significant decrease in cell proliferation (Figure 5 A, B) and an increase in cell apoptosis (Figure 5 C, D), compared to treatment with myricetin or cisplatin alone. Furthermore, the combination of myricetin and cisplatin can synergistically inhibit Huh7 cells growth (Figure 5 E).Concordantly, treatment with cisplatin clearly induced up-regulated expression of YAP, whereas the combination of myricetin and cisplatin resulted in much lower levels of YAP than in cells treated with cisplatin alone (Figure 5F). Notably, the combination of myricetin and cisplatin resulted in much higher levels of cleaved caspase 3, and much lower levels of surviving, than in cells treated with cisplatin or myricetin alone (Figure 5F). Similar effects were observed in Huh-7 cells treated with myricetin and cisplatin (Figure 5F). Together, these results imply that YAP-induced cisplatin resistance could be reversed by myricetin in HCC cells”(See page 10 of 16).
A skilled artisan would have known anticancer chlorinated myricetin of refence claims are derivative of myricetin. It would have been obvious for one of the ordinary skilled in the art to explore combination of chlorinated myricetin of reference claims with cisplatin based on the Li’s beneficial teachings of pharmaceutical composition comprising combination of myricetin and cisplatin in cancer treatment. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to explore more combination therapy comprising myricetin derivative/analogs with commonly known anticancer cisplatin in cancer treatment.
It’s noted the effect/efficacy of pharmaceutical composition comprising monochlorinated myricetin and cisplatin is intrinsic property of the pharmaceutical composition once the components( monochlorinated myricetin and cisplatin) are set forth, which do not necessarily contribute to the structural limitation of instantly claimed pharmaceutical composition.
The instant application shares at least one common inventor and applicant with the reference patent. Further, instant application is not related to reference patent on the record, thus no 35 USC 121 shield exists.
Response to Arguments
Applicant argues the '954 patent in view of Li fails to teach or in any way make obvious the claimed combination in respective amounts having synergistic properties as demonstrated in the specification as filed including the experiments. Absent the present disclosure, a person of ordinary skill in the art would not have known to combine chlorinated myricetin and cisplatin in specific amounts claimed would produce a beneficial chemotherapeutic treatment having the efficacy claimed”.
RESPONSE: Applicant’s argument is fully considered, but NOT persuasive. Li explicitly teaches combination of myricetin and cisplatin at various concentration (e.g. 100 uM myricetin and 2uM cisplatin( See Figure 5), myricetin (30 mg/kg/day) and cisplatin (5 mg/kg/3 days)(see Figure 6, page 11 of 16). A skilled artisan would have known to explore combination of chlorinated myricetin at 100 uM in combination with cisplatin at various amount as taught by LI and reasonably expect the resulting combination exhibit certain inhibitory activity on the recited cell lines. Please note the expectation of success need only be reasonable, not absolute. Exploration of different cancer cell lines and measurement of inhibition activity thereof are within general knowledge and skills of POSA. As such, the double patenting rejection is maintained.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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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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/L.M./Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628