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 .
This action is in response to the papers filed September 10, 2025.
Claim 30 is amended and independent.
Thus, claims 30, 32 and 33 are pending in the application and examined on the merits.
Priority
The present application is a DIV of Application 16/958,432 filed June 26, 2020.
16/958,432 is a 35 U.S.C. 371 national stage filing of International Application No. PCT/KR2018/016869, filed December 28, 2018.
PCT/KR2018/016869’s claim for the foreign benefit of Korean Patent Application 10-2017-0183653 filed December 29, 2017 is acknowledged.
Thus, the earliest possible priority for the instant application is December 29, 2017.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112- First paragraph- New Matter
Claim 30, 32 and 33 remain 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.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
Newly recited claim 30 contains new matter not previously described in the specification in a way to reasonably convey to one skilled in the relevant art that the inventor at the time the application was filed had possession of the claimed invention.
Specifically, claim 30 recites transplanting a double-layered cell sheet comprising a first layer comprising somatic cells, e.g., fibroblasts or chondrocytes and a second layer comprising mesenchymal stem cells comprising an oncolytic adenovirus which carries a cancer therapeutic gene. Moreover, claim 30 has been amended to recite “ wherein the oncolytic adenovirus proliferates in cancer cells of the subject, and replication of the oncolytic adenovirus in normal cells of the subject is inhibited”. There is not support for a double-layered cell sheet comprising a layer with mesenchymal stem cells, and ii) an oncolytic adenovirus which carries a cancer therapeutic gene wherein the oncolytic adenovirus proliferates in cancer cells of the subject, and replication of the oncolytic adenovirus in normal cells of the subject is inhibited.
Applicants only have support for “a double-layered cell sheet composed of a human brain glioblastoma cell line (U343) and a mouse fibroblast cell line (NIH3T3)” para. 0181 in the originally filed claim set and specification. Furthermore, while paragraph [0077] cited by applicants provides support for “a cell layer to which a gene delivery system is introduced may include cancer cells”, that is, a cell sheet comprising the oncolytic adenovirus and cancer cells, there is not specific support for a gene delivery system, e.g., an oncolytic adenovirus and mesenchymal stem cells. In contrast to Applicants’ remarks, there is not support for a MSC layer delivering the therapeutic gene via the oncolytic virus (Remarks 09/10/2025, page 9, last paragraphs)
There is no support within the specification for the utilization of mesenchymal stem cells comprising the oncolytic adenovirus in a layer with another layer of fibroblasts or chondrocytes. There is only a generic disclosure of MSCs (para. 0080).
Furthermore, the U343 cell line is the only cell line evidenced that infection with the oncolytic virus does not destroy structure and maintains structural integrity of the cell sheet (para. 0198). Moreover, the cancer cells are irradiated allowing the oncolytic adenovirus to be functional (para. 0168).
Thus, the application only has adequate support at the time of the filing date for a double-layered cell sheet composed of a human brain glioblastoma cell line (U343) and a mouse fibroblast cell line (NIH3T3) wherein the U343 cells are irradiated and comprise an oncolytic adenovirus which encodes Decorin (DCN).
Therefore, claim 30 and its dependent claims are directed towards new matter.
Claims 30, 32 and 33 will remain rejected until Applicant cancels all new matter.
In response to Applicant’s arguments and amendments filed 09/10/2025 regarding new matter,
Applicant’s arguments and amendments filed 09/10/2025 have been considered. However they are not persuasive. Applicant points to para. 0031, 0034, 0035-37, 0077, 0135 and 00179, however these are all merely generic disclosures which are insufficient to convey possession of the claimed invention in regards to stem cells in combination with the adenovirus and somatic support layers.
Furthermore, Applicant’s pointing to para. 00135 and 00179 as support only further supports the possession of only infected U343 cells with fibroblasts. As stated previously, the U343 cell line is the only cell line evidenced that infection with the oncolytic virus does not destroy structure and maintains structural integrity of the cell sheet (para. 0198). Moreover, the cancer cells are irradiated allowing the oncolytic adenovirus to be functional (para. 0168). This is evident throughout all experimental data with no other cell sheets tested.
Thus, the application only has adequate support at the time of the filing date for a double-layered cell sheet composed of a human brain glioblastoma cell line (U343) and a mouse fibroblast cell line (NIH3T3) wherein the U343 cells are irradiated and comprise an oncolytic adenovirus which encodes Decorin (DCN).
Claim Rejections - 35 USC § 103
Claim 30 and 33 remain rejected under 35 U.S.C. 103 as being unpatentable over Alshareeda (PLoS One, 2017 Aug 29;12(8):e0184004) in view of Martinez-Quintanilla (Mol Ther. 2014 Nov 18;23(1):108–118) and Zhou (Stem Cell Rev and Rep (2016) 12:560–572). This rejection has been modified as necessitated by Applicant’s amendments and arguments filed 09/10/2025.
Regarding claims 30 and 33, Alshareeda teaches a cell sheet comprised of HepG2 cells and UC-MSCs as well as BM-MSCs and HepG2 cells for the purpose of treating hepatocellular carcinoma (i.e. liver cancer) in mice via the transplantation of cell sheets (p. 5, 1st section; p. 5-6, bridging section). As the cell sheets are applied to the liver in treating hepatocellular carcinoma, it is interpreted that the sheets are formulated for local delivery.
However, Alshareeda does not teach an oncolytic adenovirus within the MSCs.
Martinez-Quintanilla teaches MSCs loaded with ICOVIR17, an oncolytic adenovirus armed with a PH20 hyaluronidase gene (i.e. cancer therapeutic gene) in order to deliver the oncolytic adenovirus to a subject with glioblastoma (i.e. brain cancer) (Abstract; p. 116, 1st column; p. 116, last paragraph). The MSCs loaded with ICOVIR17 demonstrated antitumor effects such as a significant reduction in tumor volume and an increase of survival in mouse models (p. 109, 2nd column). Moreover, Martinez-Quintanilla teaches that the MSCs are infected at multiplicity of infections of 7 and 70 to treat glioblastoma (p. 109, last paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to load the MSCs within the cell sheet of Alshareeda with an oncolytic adenovirus expressing a cancer therapeutic gene such as ICOVIR17 comprising a therapeutic gene as taught by Martinez-Quintanilla with a reasonable expectation of success. An artisan would have been motivated to combine both the cell sheet technology for treating cancer of Alshareeda with the teachings of Martinez-Quintanilla which demonstrate MSCs carrying an oncolytic adenovirus expressing a cancer therapeutic gene such as ICOVIR17 for the purpose of treating tumors associated with cancer as both are known techniques in the art for the treatment of cancer. Moreover, as discussed above, the MSCs loaded with ICOVIR17 demonstrated antitumor effects such as a significant reduction in tumor volume and an increase of survival in mouse models (Martinez-Quintanilla; p. 109, 2nd column).
However, Alshareeda and Martinez-Quintanilla do not teach a support layer of somatic cells such as fibroblasts with the loaded MSCs in the UC-MSCs cell sheet as a base layer of fibroblast
Zhou teaches a human dermal fibroblast derived ECM (hECM) to support the growth and pluripotency of MSCs (Abstract). Human dermal fibroblasts are extensively used as feeder
cells in the hESC culture system to support hESC (p. 569, 1st column). Human MSCs treated with hECM increasingly proliferate compared to those without hECM exposure while no differences in regulation of cellular senescence between hMSCs cultured with and without
hECM were found (p. 569, 2nd column). The ECM provides not only a structural support but also physical, mechanical and chemical cues to regulate MSC activities (p. 561, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to provide a fibroblast support to the MSC cell sheet with a reasonable expectation of success thus obtaining a double-layered cell sheet as required in claim 30. An artisan would be motivated to include a fibroblast support in a MSC cell sheet as fibroblast ECM supports show increased proliferation of MSCs (Zhou, p. 569, 2nd column).
Regarding the limitations “wherein the oncolytic adenovirus proliferates in cancer cells of the subject, and replication of the oncolytic adenovirus in normal cells of the subject is inhibited,” Martinez-Quintanilla teaches oncolytic virotherapy for cancer is a novel approach in which viruses are modified to preferentially replicate in tumor cells and selectively destroy them (p. 108, 2nd column). This demonstrates that the goal is to select cancer cells where the adenovirus proliferates, and to not replicate in normal cells. Therefore, it would be a functional characteristic of the oncolyic adenovirus within the cell sheet made obvious by the combination of Alshareeda, Martinez-Quintanilla and Zhou. Thus, the claim is directed to an inherent result based on the methodology of transplanting a double-layered cell sheet onto a region of the subject. Therefore, the invention would have been prima facie obvious to one of ordinary
skill in the art at the time of the effective filing date.
Claims 32 remains rejected under 35 U.S.C. 103 as being unpatentable over Alshareeda (supra) in view of Martinez-Quintanilla (supra) and Zhou (supra) as applied to claim 30 above, and further in view of Yun (2008, Nature Precedings; Applicant’s own work). This rejection has been modified as necessitated by Applicant’s amendments and arguments filed 09/10/2025.
As discussed above, Alshareeda in view of Martinez-Quintanilla and Zhou teaches a cell sheet comprising MSCs infected with an oncolytic adenovirus expressing a cancer therapeutic gene with a fibroblast layer in order to treat cancer, as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety. Moreover, Martinez-Quintanilla teaches that the MSCs are infected at multiplicity of infections of 7 and 70 to treat glioblastoma (p. 109, last paragraph).
These references do not teach infection of the MSCs at a MOI of 0.1 to 5.
Yun teaches infecting cells with an oncolytic adenovirus expressing Decorin (DCN; i.e. cancer therapeutic gene) at MOIs of 0.1 to 20 for glioma cell lines in order to analyze the tumor cell killing effects (p. 8, last paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to have the oncolytic adenovirus applied at a MOI of 0.1 to 5 as taught by Yun with a reasonable expectation of success. An artisan would have been motivated to do so as Yun demonstrates that MOIs of 0.1 to 20 for oncolytic adenoviruses carrying cancer therapeutic genes are utilized within antitumor treatments (p. 8, last paragraph).
Therefore, the invention would have been prima facie obvious to one of ordinary
skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments filed 09/10/2025 regarding the 103 rejections,
Applicant’s arguments and amendments filed 09/10/2025 have been considered. However, they are not persuasive.
Regarding the amendments in the claim set filed 09/10/2025, the rejection has been revised to address the newly recited limitations.
First, Applicant argues reliance on 3 references is evidence of a lack of obviousness.
In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Second, Applicant argues that Alshareeda shows a monolayer cellular sheet with no distinct layer by layer arrangement and not the double cell sheet of the present invention and Martinez-Quintanilla does not describe a cell sheet. Additionally, Applicant argues no motivation to combine and that the references are based on hindsight reasoning.
The examiner disagrees. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Alshareeda does show a monolayer sheet, however, it is relied on for the teaching of cell sheets (even monolayers) comprised of HepG2 cells and UC-MSCs as well as BM-MSCs and HepG2 cells are utilized for the purpose of treating hepatocellular carcinoma (i.e. liver cancer) in mice via the transplantation of cell sheets. This addresses one of the layers in the double layer construct with MSCs.
Martinez-Quintanilla teaches MSCs loaded with ICOVIR17, an oncolytic adenovirus armed with a PH20 hyaluronidase gene (i.e. cancer therapeutic gene) in order to deliver the oncolytic adenovirus to a subject with glioblastoma (i.e. brain cancer) (Abstract; p. 116, 1st column; p. 116, last paragraph). This provides teaching and suggestion to modify the MSCs in the single layer with an oncolytic adenovirus comprising a cancer therapeutic gene.
Zhou teaches a human dermal fibroblast derived ECM (hECM) to support the growth and pluripotency of MSCs (Abstract). This provides teaching and suggestion to have a second layer of somatic cells, making it a double layer cell sheet. Furthermore, and in contrast to applicants’ remarks (page 10, first para) , even if Alshareeda' s MSCs layer comprises “a structure where different cell types are intermingled within the same collagen matrix ”, the claims are "open" and thus lend themselves to additional cell types within the first and second layers. There is no requirement that a second cell layer only comprises i) mesenchymal stem cells, and ii) an oncolytic adenovirus which carries a cancer therapeutic gene in claim 30 is so limited as argued by Applicants. There is not requirement that the instant cells of the layers required functional and spatial separation. Therefore, the teachings of Alshareeda are relevant.
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, an artisan would have been motivated to combine both the cell sheet technology for treating cancer of Alshareeda with the teachings of Martinez-Quintanilla which demonstrate MSCs carrying an oncolytic adenovirus expressing a cancer therapeutic gene such as ICOVIR17 for the purpose of treating tumors associated with cancer as both are known techniques in the art for the treatment of cancer. Moreover, as discussed above, the MSCs loaded with ICOVIR17 demonstrated antitumor effects such as a significant reduction in tumor volume and an increase of survival in mouse models (Martinez-Quintanilla; p. 109, 2nd column).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight 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).
Conclusion
No claims are allowed.
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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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634