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
Priority
The certified English language translation copy of the Chinese application 202111177854.3 filed on 24 April 2026 is acknowledged, as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 April 2026 has been considered by the examiner.
Status of applications, Amendments, and/or Claims
The Response filed 24 April 2026 has been entered in full. Claims 1-3 have been canceled without prejudice or disclaimer, and claims 4-13, 19 have been amended currently. Claims 14-23, previously withdrawn from consideration, stand by withdrawn as rejection is final and proper. Therefore, claims 4-13 are the subjected of this Office Action.
Withdrawn Objections and/or Rejections
The rejection of claims 4-7 and 10 on the ground of nonstatutory double patenting as set forth at pp. 7-10 of the previous Office action (mailed 28 January 2026) is withdrawn in view of Applicant’s terminal disclaimer (filed 24 April 2026), US Pat. 10314809-B2.
Maintained and/or New Objections and/or 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 4-7, 10 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT03435952 (ClinicalTrials.gov number, NCT03435952, public record history available: February 9, 2018; hereafter PTO-892) in view of Wei et al. (US 9,962,412 B2, hereafter Wei; PTO892), and further view of Andre (Published December 3, 2020; hereafter Andre; PTO-892). Andre et al. (Andre; hereafter PTO-892) has been added to the rejection under 35 U.S.C. 103 to improve the clarity thereof, reciting a drug combination for treating cancer, regarding pembrolizumab. The basis for this rejection is set forth at pp. 3-4 of the previous Office action. The instant claims are drawn to a drug combination for treating, cancer comprising pembrolizumab and active ingredients of Clostridium ghonii spore, and recite methods of treating colon cancer utilizing the same. While the non-patent literature, ClinicalTrials.gov ID: NCT03435952 (submitted and recorded in September 9th 2018; see document) does not teach spores of the same species of Clostridium (Clostridium ghonii) NCT03435952 teaches the combination of spores of Clostridium novyi-NT and, the anti-cancer monoclonal antibody, pembrolizumab for treating colon cancer, which is pertinent to claim 4.
Wei teaches Clostridium novyi-NT and Clostridium ghonii can be used to treat cancers as claims 4. See for example, see for example column 27; claims 1-3, column 28; claims 18-21, column 4; lines 5-29. However, Wei teaches the advantages of using Clostridium ghonii compared to Clostridium novyi-NT, which is pertinent to claim 4. See for example, column 2; lines 30-65. For example, Wei teaches that “C. ghonii induced obvious oncolysis without any signs of toxicity typically associated with other clostridial strains (C. novyi-NT, C. sporogenes and C. sordellii) at a dose of 108 CFU/mouse.”, which is pertinent to claim 4. See column 2; lines 30-65; column 8; lines 5-19; column 26; lines 9-11. Wei also teaches derivatives avirulent, non-pathogenic strain of Clostridium ghonii, such as MW-DCG-LCv-26, DCG-HNCv-18 and DCG-CCv-17, and 17 isolates colon cancer C. ghonii strains which is pertinent to claims 5-7. See for example, columns 3-4, column 13-14; column 21; lines 46-55; column 24; lines 40-57.
Wei teaches the strain of Clostridium ghonii MW-DCG_CCv17 have specificity for and is therapeutically effective against solid tumors of colon cancer, which is pertinent to claim 7. See for example, column 10; lines 58-63; Fig. 5.
NCT03435952 also teaches “Keytruda (pembrolizumab) is a programmed death receptor (PD-1) blocking antibody”, and that pembrolizumab is to be injected, which is pertinent to claim 10; see NCT03435952 page 7, first paragraph under Study Drug Administration.
Wei teaches “Spores of the present invention and other anti-cancer agents such as antibodies may be administered to subjects as compositions/components in a combination therapy. In a therapeutic application, compositions are administered to a subject already possessing a solid tumor cancer, in an amount sufficient to destroy or at least arrest growth of the tumor. The composition should provide a quantity of spores and other anti-cancer agents such as antibodies sufficient to effectively treat the subject, which is pertinent to claims 4-7. See for example, column 5; lines 39-43; columns 17; lines 4-9, column 16; lines 54-62, 58-67; column 18-19; column 20; lines 1-47.
Wei also teaches “one or more antibodies is an anti-cancer monoclonal antibody”, which is pertinent to claim 4. See for example, column 16; lines 63-67; column 17; lines 9-10; column 18.
While Wei does not specifically teach pembrolizumab, NCT03435952 teaches the administration for treating colon cancer.
Regarding the specific use of Pembrolizumab in combination with the Clostridium spores taught by Wei, Andre teaches that “Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H–dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002)”.
It would have been obvious to one of ordinary skill in the art to modify the teachings of NCT03435952 by combining the anti-cancer monoclonal antibody, Pembrolizumab of NCT03435952 and Andre, and the particular Clostridium strains of Wei used for treating cancer, including colon cancer, thereby arriving at the invention of claim 4-7, 10. Since the anti-cancer monoclonal antibody, Pembrolizumab (Keytruda) of NCT03435952 and Andre is a first-line therapy for colorectal cancer, and the Clostridium Ghonii spores of Wei were both shown in the prior art to be effective in treating colon cancer, it would have been obvious to substitute these known equivalents; see MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Furthermore, In re Kerkhoven (205 USPQ 1069, CCPA 1980) summarizes:
"It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for the same purpose in order to form a combination that is to be used for the very same purpose: the idea of combining them flows logically from their having been individually taught in the prior art."
Reasonable expectation of success would be expected because Wei et al. (US 9,962,412 B2, hereafter Wei; PTO-892) specifically suggests using anticancer drug combining spores of Clostridium ghonii for treating cancer, including colon cancer and does not specify any medicine that should not be used.
Therefore, claims 4-7 would have been prima facie obvious, absent evidence to the contrary.
This is a rejection reintroduced in response to the most recent amendment to the claims. Therefore, there are no outstanding arguments directed to this current ground of rejection. Applicant’s arguments directed to the previous 103 for claims 4-7, 10 will be addressed below. See response to arguments.
Claims 8-9 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT03435952 (ClinicalTrials.gov number, NCT03435952, public record history available: February 9, 2018; hereafter PTO-892) in view of Wei et al. (US 9,962,412 B2, hereafter Wei; PTO-892), as applied to claims 4-7, 10 above, and further in view of OPS Diagnostics. The basis for this rejection is set forth at pp. 4-5. The claims are drawn to freeze-dried powder with 1% sucrose as in claim 8 and the particular protocol in claim 9. While both NCT03435952 and Wei do not teach the methods of freeze-dried powder with 1% sucrose and/or protocol to Freeze-Drying spores of Clostridium ghonii, OPS diagnostics teaches bacterial freeze-drying protocols, see web address page) and sucrose, which is pertinent with claims 8-9. OPS Diagnostics, Bacterial Freeze-Drying protocol also suggests that minor adjustments can be made to improve the efficiency in the procedure which is pertinent with claim 9. While the reference does not specifically teach the Bacterial Freeze-Drying protocol for Clostridium spores, the use of the Bacterial Freeze-Drying protocol does teach several alternatives and modifications in the procedure that can be adapted to any bacteria, and would have been within the skill and knowledge of the artesian at the time the invention was made, absent evidence to the contrary. Therefore, the invention as a whole would have been prima facie obvious, absent to the contrary. It would have been obvious to substitute these known equivalents; see MPEP 2144.06.
This is a rejection reintroduced in response to the most recent amendment to the claims. Therefore, there are no outstanding arguments directed to this current ground of rejection. Applicant’s arguments directed to the previous 103 for claims 8-9 will be addressed below. See response to arguments.
Claims 11-13 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT03435952 (ClinicalTrials.gov number, NCT03435952, public record history available: February 9, 2018; hereafter PTO-892) in view of Wei et al. (US 9,962,412 B2, hereafter PTO-892) as applied to claims 4-7, 10 above, and further in view of Reference ID: 4277239 (labeling information, https://www.accessdata.fda.gov, January 12, 2020 hereafter PTO-892). The basis for this rejection is set forth at pp. 5-7. The claims are drawn to Clostridium ghonii combined with pembrolizumab as in claim 11 or the particular solvent as in claims 12-13. While, neither reference teaches Clostridium ghonii combined with pembrolizumab or the particular solvent, and pembrolizumab is a PD-1 antibody injection, Wei teaches the therapeutically effective amount of a spores from derivative strain of Clostridium ghonii to treat solid tumors in humans is about 106 CFU to about 1014 CFU per dose (see page 21, column 17, lines 22-25) and NCT03435952 teaches the use of pembrolizumab in combination with a starting dose of 104 spores of clostridial bacteria (see page 13), which is pertinent to claim 11. Regarding the class of antibody, dosage and administration of pembrolizumab, the FDA access data, Reference ID: 4277239 teaches dosage and administration of pembrolizumab is dependent on type/form of cancer and patient conditions such as age and prior health conditions. The FDA access data, Reference ID: 4277239 also teaches the reconstitution of pembrolizumab, lyophilized powder using sterile water and preparation for intravenous infusion as the reconstituted required vial (s) of pembrolizumab transferred into an intravenous bag containing 0.9% Sodium Chloride Injection or 5% Dextrose injection at the final concentration of 1mg/mL to 10 mg/mL (diluted concentration), which is pertinent to claims 11-13. See page 7, paragraph 2.12. See also Wei, columns 17; pages 10-16, regarding therapeutically effective doses.
While the references do not explicitly teach every 1x107CFU of the Clostridium ghonii spore is combined with 0.2 mg of a pembrolizumab solution at a concentration of 1 mg/mL, Wei teaches a dose range for treating humans of about 106 CFU to about 1014 CFU per dose, and The FDA access data, Reference ID: 4277239 teaches that dosage and administration of pembrolizumab is dependent on type/form of cancer and patient conditions such as age and prior health conditions. Thus, it would have been within the skill and knowledge of the artesian at the time the invention was made, absent evidence to the contrary to make modifications in the procedure by tailoring the doses in the drug combination, pembrolizumab and Clostridium ghonii spore for treating cancer, and would have been within the skill and knowledge of the artesian at the time the invention was made, absent evidence to the contrary.
Therefore, the invention as a whole would have been prima facie obvious, absent to the contrary. It would have been obvious to substitute these known equivalents; see MPEP 2144.06.
This is a rejection reintroduced in response to the most recent amendment to the claims. Therefore, there are no outstanding arguments directed to this current ground of rejection. Applicant’s arguments directed to the previous 103 for claims 11-13 will be addressed below. See response to arguments.
Response to Amendments
Applicant’s arguments as they pertain to the rejections have been fully considered but are not persuasive for the following reasons.
Applicant argues at pg. 7-9 of the Response (filed 24 April 2026) that 1) no data for the results of the study is provided in the reference, the “Study Details” section of the NCT03435952 clinical trial, in Version 1, and that the teachings of NCT03435952 can most fairly be described as teaching the study of treating solid tumors with a combination of spores of Clostridium novyi-NT and pembrolizumab; 2) the full document reporting the results of the NCT03435952 entered concurrently with this amendment show that the combination of pembrolizumab with Clostridium novyi-NT is not an effective regimen for treating colon cancer; 3) NCT03435952 does not teach or make any suggestion of the drug combination with Clostridium ghonii spore for treating colon cancer; 4) NCT03435952 actually teaches that the combination of Clostridium novyi-NT is not effective for treating colon cancer and 5) that a person of ordinary skill in the art, with knowledge of NCT03435952 teaching the ineffectiveness of the combination of Clostridium novyi-NT and pembrolizumab in treating colon cancer, would be led away from another strain (such as Clostridium ghnoii) combined with pembrolizumab to treat colon cancer, as the expected result based on teachings of NCT03435952 would be for other Clostridium strains combined with pembrolizumab to also be ineffective in treating colon cancer.
In response to applicant’s argument that there is no teachings, suggestion or motivation to the reference, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where 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.
Applicant should note that the document NCT03435952 entered by the examiner had the purpose of showing that the prior art, NCT03435952 comprises the combination of pembrolizumab and Clostridium spores for treating cancers, including colon cancer, where is teaching, suggestion or motivation to do so found either in the reference themselves or in the knowledge generally available to one of ordinary skill in the art. Furthermore, in response to the applicants conclusion of “with knowledge of NCT03435952 teaching the ineffectiveness of the combination of Clostridium novyi-NT and pembrolizumab in treating colon cancer, would be led away from another strain (such as Clostridium ghnoii) combined with pembrolizumab to treat colon cancer, as the expected result based on teachings of NCT03435952 would be for other Clostridium strains combined with pembrolizumab to also be ineffective in treating colon cancer”.
However, Applicants’ arguments at pg. 9-10, and paragraph [0019] of the present application have indicated knowledge of the teachings of Wei on Clostridium genus and species, including Clostridium novyi-NT (The subject of NCT03435952) and Clostridium ghonii (the subject of Wei et al. and applicant’s invention), and also that some Clostridium bacteria are toxic to humans, while some can be used for treating cancers, which would be the rationale, suggestion and motivation of one of skill in the art to modify the teachings of NCT03435952 (clinical trials, human colon cancer patients) by combining the successful and beneficial Clostridium spores of Wei, endorsed by the applicants invention and their “superior efficacy results” in CT26.WT colon cancer tumor-bearing mouse model treated with a Clostridium ghonii spore and a MC38 colon cancer tumor-bearing mouse model treated with a Clostridium ghonii spore combined with pembrolizumab in Example 2; See applicants’ specifications, paragraphs [0020-0021]; Fig. 1a and 1B. The examiner reminds the applicants that NCT03435952 clinical trial was performed in human patients with colon cancer.
It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
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). Furthermore, in response to applicant's argument that the examiner's conclusion of obviousness is based upon “most fairly be described as teachings” reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon straightforward evidences. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was filed to substitute the Clostridium Novyi-NT spores of NCT03435952 by the Clostridium ghnoii spores taught by Wei in a composition comprising the anticancer monoclonal antibody, pembrolizumab for treating colon cancer of NCT03435952 and further view of Andre, as both of the compounds have been shown to be useful in treating colon cancer.
Applicant argues at pg. 10 of the Response (filed 24 April 2026) that neither OPS diagnostics or FDA’s Reference ID: 4277239 teach or suggest the combination of pembrolizumab with Clostridium ghonii spore for treating colon cancer.
In response to applicant’s argument that there is no teachings, suggestion or motivation to the references recited above, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where 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. OPS diagnostics teaches bacterial freeze-drying protocols, and suggests that minor adjustments can be made to improve efficiency in the procedure, which fits its use for Clostridium, since it is a bacteria and the use of the sucrose claimed in this invention. FDA access data, Reference ID: 4277239 teaches dosage and administration of pembrolizumab is dependent on type/form of cancer and patient conditions such as age and prior health conditions. FDA access data, Reference ID: 4277239 also teaches 0.9% Sodium Chloride Injection or 5% Dextrose injection at the final concentration of 1mg/mL to 10 mg/mL (diluted concentration).
Motivation for combining the references is clear from the teachings as each reference teaches methods of use and/or preparation of each drug. While there is not a single reference that includes all the limitations of the claims, the various aspects of the claims are contained in multiple references and it would have been prima facie obvious to combine the teachings as stated above to arrive at the claimed invention with an expectation of success for the reasons provided, it would have been obvious to substitute these known equivalents; see MPEP 2144.06.
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results".
Conclusion
No claims are allowable. Claims 4-13 remain rejected.
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.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571)272-2784. The examiner can normally be reached M-F 6:15AM-3:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PRICILA NMN HAUK TEODORO/ Examiner, Art Unit 1645
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684
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