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 .
Claim status
In the reply filed 07 January 2026, Applicant has amended claims 1-3, 9, 11, and 17. Claims 4, 6-7, 12, 14-16 and 18 are cancelled. Therefore, 1-3, 5, 8-11, 13, and 17 are herein pending.
Election/Restrictions/ Rejoinder
Applicant previously elected with traverse of Group I, claims 1-3, 5, 8-11, and 13 drawn to mesenchymal stem cells (MSCs) for delivering an oncolytic virus, comprising a glucose regulated protein 78 (GRP78) gene and E1B55K gene in the reply filed on 15 September 2025.
The restriction requirement between Groups II-III, as set forth in the Office action mailed on 07/30/2025, has been reconsidered in view of the allowability of claims to the elected invention pursuant to MPEP § 821.04(a). The restriction requirement between Groups I-II is hereby withdrawn as to any claim that requires all the limitations of an allowable claim. Claim 17 is directed to previously non-elected Groups III are no longer withdrawn from consideration because the claim(s) requires all the limitations of an allowable claim. In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a continuation or divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Therefore, claims 1-3, 5, 8-11, 13, and 17 are under current examination.
Priority
This application was filed 11/18/2022 and is a 371 application of PCT/KR2021/015179 filed on 10/27/2021, which claims benefit to the foreign application 10-2020-0139918 filed on 10/27/2020. A certified English translation of non-English PCT publication of the Korean Application No. 10-2020-0139918 for provisional rights under 35 U.S.C. 154(d) filed 01/07/2026 is acknowledged.
Therefore, the earliest possible priority for the instant application is 10/27/2020.
Withdrawn Objections
Applicant has submitted amended drawing on 01/07/2026, and submits herewith replacement drawings that clearly display Figures 3, 4, 7, 8, 9a, 9b, 14, 17a-17d, 27a, 27b, 28, 29, 33a-33c, and 34 for readable and reproducible publication purposes. Therefore, the objection to drawing is withdrawn.
Withdrawn Claim Rejections
Applicant has amended claims 1-3 to recite that GRP78 and/or ElB55K genes are introduced into the mesenchymal stem cells. Applicant asserts that claims 1-3 clearly point out and distinctly claim the subject matter of the invention. Furthermore, Applicant has also cancelled claim 4. Therefore, the prior rejection of claims 1-4 and 11 under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention is hereby withdrawn.
Applicant has amended the claim 1 and exclusively included “into the mesenchymal stem cell, and wherein the mesenchymal stem cell expresses a GRP78 protein for improving tumor-targeting ability.” Applicant also amended the claim 3 and exclusively included “wherein the GRP78 gene and the EIB55K gene are introduced into the mesenchymal stem cell, and … after the mesenchymal stem cell is introduced into a body.” In the remark applicant argues that “Chada allegedly discloses increasing anticancer efficacy by incorporating a tumor suppressor gene and ADP (adenovirus death protein) into an oncolytic adenovirus and the viral vector structure may include nucleotide sequences encoding regulatory elements (e.g., enhancers), such as GP78, within the viral genome. This indicates that the Chada treats GRP78 as a regulatory element within the viral genome. Therefore, Chada treats GRP78 as an enhancer used to modulate transcription, and does not consider it as a gene encoding the GRP78 protein (see remark p. 8 3rd ¶). Therefore, the presently claimed invention contrary from the prior art by disclosing the GRP78 gene itself is introduced into mesenchymal stem cells to overexpress the GRP78 protein. Therefore, the prior rejection of claims 1,3, 4, 9-11, 13 under 35 U.S.C. 103 as being unpatentable over Yun et al., (EP3725875A1; Date of publication: 10/21/2020; cited in PTO892; hereinafter “Yun”), in view of Chada et al., (US20080292592A1; Date of publication: 11/27/2008; cited in PTO892; hereinafter “Chada”) and further in view of Jin et al. (KR1020190139763, cited in IDS filed 11/18/2022; attached STIC machine translation copy; hereinafter “Jin”) is withdrawn. The withdrawal is in light of Applicant’s arguments filed on 07 January 2026, which have been considered.
Modified 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim 2 is stand rejected in modified form under 35 U.S.C. 103 as being unpatentable over Yun et al., (EP3725875A1; Date of publication: 10/21/2020; cited in PTO892; hereinafter “Yun”), in view of Jin et al. (KR1020190139763, cited in IDS filed 11/18/2022; attached STIC machine translation copy; hereinafter “Jin”). This rejection is maintained for reasons of record and current applicant’s amendments.
Examiner’s claim interpretation:
For the sole purpose of expediting prosecution, examiner interprets that the amended claim 2 is required recombination an adenoviral vector expressing GRP78 gene (see SPEC [0144] ¶ of US20230210927A1) and the oncolytic virus is introduced into the mesenchymal stem cell (MSC).
Regarding claim 2, Yun discloses a mesenchymal stem cells (MSCs) containing a recombinant adenovirus (i.e., Oncolytic adenovirus, [0002]) loaded therein (Ad-MSC), the recombinant adenovirus having an excellent ability to be introduced into a mesenchymal stem cell even at a low concentration due to an excellent ability to deliver a gene into the mesenchymal stem cell ([0020], Fig. 18, 22 of Yun), and exhibiting an excellent ability to regulate the expression of the gene and improved tumor-targeting ability for treating cancer [0071].
Although, Yun discloses the MSCs containing a recombinant oncolytic adenovirus comprising a gene expression regulatory sequence that regulates the expression of a target gene, and the target gene [0010], Yun is silent to the E1B55K gene. However, such was known in the prior art.
Regarding claim 2, Jin discloses a novel mesenchymal stem cells (MSCs) to enable genetically modified adenoviral infection and replication, comprising E1B55KD gene to facilitate delivery of oncolytic virus in systemic blood to the patient ([0016], [0018], [0020] of Jin). Jim is introducing the GM-CSF, Flt3L-TRAIL, shTGF-β and shHSP co-expression gene carrier (YSC-02) into a modified stem cell line, such as expression inducer that increase in replication rate ([0098] of Jim). Furthermore, Jin teaches the MSCs that was genetically modified for effective anti-tumor activity by a large number of viruses produced during the migration to the target tumor site ([0101] of Jin), therefore POSITA would recognize the E1B55K gene is expressed after the mesenchymal stem cell is introduced into a body.
MPEP 2143 (A) states that combining prior art elements according to known methods to yield predictable results. The 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. Accordingly, it would have been obvious to practice MSCs with recombinant oncolytic adenovirus of Yun and combine the E1B55K gene as taught by Jin with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Jin because genetically modified virus with E1B55K gene induced the virus production in the genetically-introduced modified MSC ([0101], [0107], [0141-0146] ¶ of Jin). The POSITA would have a reasonable expectation of success in combining the teachings of Yun and Jin because each of these teachings both successfully modified MSCs with recombinant oncolytic adenovirus for immunotherapy. Therefore, the products and method as taught by Yun et al. in view of Jin et al. would have been prima facie obvious over the products and method of the instant application. In regard to the reasonable expectation of success in doing so, including the E1B55K gene of Jin had a reasonable expectation of success since the steps thereof required no more than recombinant DNA and cell culture technology.
Consequently, it would have been obvious for POSITA to combine genetically modified adenoviral infection to MSCs and E1B55K gene as disclosed by Jin, because it would have enabled genetically modified adenoviral infection to MSCs comprising E1B55KD gene for effective anti-tumor activity.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 07 January 2026 are acknowledged.
Applicant argues that Jin is related to mesenchymal stem cell lines capable of adenovirus infections and replication, in which E1B55K induces degradation of p53 by binding to another viral protein (E40RF6). However, Applicant demonstrates, for the first time, that when the E1B55K gene is cloned and separately induced to be expressed alone in mesenchymal stem cells, p53 transcription and translation increase thus leading to stem cell death. Applicant asserts that Jin does not identify any problems that occur when introducing the E1B55K gene into stem cells and does not mention timing of expression, but instead requires a CAR gene to be introduced as an essential component with the E1B55K gene. Applicant also asserts that none of the cited references disclose expressing E1B55K in a mesenchymal stem cell specifically after the mesenchymal stem cell is introduced into a body (see remark p. 10 3rd ¶).
In response to applicant's argument that the Jin et al. fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the E1B55K gene is cloned and separately induced to be expressed alone in mesenchymal stem cells) are not recited in the rejected claim 2. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that Jin does not mention the "problem that occurs when introducing 'E1B55K' into stem cells," and it is impossible for a person skilled in the art to recognize such a problem based on Jin alone. Therefore, since the motivation to achieve the technical configuration of the presently claimed invention ("E1B55K expression is induced by an expression inducer after introduction into the body"), there is no basis for deriving the presently claimed invention based on the teachings of Jin (see remark p. 11 2nd ¶).
Applicant arguments have been fully considered but they are not persuasive. In the modified rejection, Jin teaches the MSCs that was genetically modified for effective anti-tumor activity by a large number of viruses produced during the migration to the target tumor site ([0101] of Jin). Figure 11 confirms the production of oncolytic adenovirus two types of control and YSC-02 in mesenchymal stem cells MSC-CAR-E1B55KD expressing CAR and E1B55kD at the same time. Figure 12 shows the injection of MDAMB231, a human-derived breast cancer cell with luciferase in nude mice, into the abdominal wall to form a tumor, followed by injection of YSC-02 infected with modified MSC MSC-CAR-E1B55KD into the tail vein of nude mice. It is confirmed that it disappears over time. Figure 13 shows the results of the colonogenic assay (clonogenic assay) to verify the anti-tumor effect of YSC-02 produced from Modified MSC. 14 confirms the presence or absence of tumorigenic MSC upon infection with YSC-02 virus ([0101] of Jin, see the attached KR20190139763A PDF file). Therefore, POSITA would recognize the E1B55K gene is expressed after the mesenchymal stem cell is introduced into a body.
Subject matter free of art
The amended independent claim 1 discloses a MSC for delivering an oncolytic virus, having improved tumor-targeting ability, wherein a GRP78 gene is introduced into the MSC, and wherein the MSC expresses a GRP78 protein for improving tumor-targeting ability. Another independent claim 3 discloses a MSC for delivering an oncolytic virus, comprising GRP78 gene and an E1B55K gene, wherein the GRP78 gene and the E1B55K gene are introduced into MSC, and wherein the E1B55K gene is expressed by an expression inducer after the MSC is introduced into a body.
In the closet prior art Chada et al., (US20080292592A1; Date of publication: 11/27/2008; cited in PTO892; hereinafter “Chada”) allegedly discloses increasing anticancer efficacy by incorporating a tumor suppressor gene and ADP (adenovirus death protein) into an oncolytic adenovirus and the viral vector structure may include nucleotide sequences encoding regulatory elements (e.g., enhancers), such as GP78, within the viral genome. This indicates that the Chada treats GRP78 as a regulatory element within the viral genome. Therefore, Chada treats GRP78 as an enhancer used to modulate transcription, and does not consider it as a gene encoding the GRP78 protein. Therefore, the presently claimed inventions contrary from the closest prior art by disclosing the GRP78 gene itself is introduced into mesenchymal stem cells to overexpress the GRP78 protein. Chada does not teach or fairly suggest to prepare homologous recombination to construct an adenoviral vector expressing GRP78 gene.
Therefore, according to instant claims 1, 3 and dependent claims 5, 9-11, 13, and 17, represent a novel, non-obvious product and distinct from the prior art for a MSC for delivering an oncolytic virus with GRP78 and E1B55K.
Claim 8 is objected because art does not teach or reasonably suggest the expression inducer is doxycycline or tetracycline is induced for delivering an oncolytic virus, wherein an E1B55K gene is introduced into the mesenchymal stem cell. Since claim 8 depends from rejected base independent claim 2. Claim 2 would be free of the art, if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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 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 date of this final action.
Claims 1, 3, 5, 9-11, 13, and 17 are allowed.
Claim 8 is objected
Claim 2 is rejected.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is (571)272-0196. The examiner can normally be reached M-F 8-5 (EST).
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/MASUDUR RAHMAN/ Patent Examiner, Art Unit 1633
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684