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 .
Claims 1, 5-18 are pending in the application. Claims 9-18 are withdrawn. Claims 1, 5-8 are currently under examination.
This office action is in response to the amendment filed on 4/30/2026.
All previous rejection not reiterated in this office action are withdrawn.
Nucleotide and/or Amino Acid Sequence Disclosures
The sequence listing filed on 4/30/2026 is defective (see attached report). Appropriate correction is required.
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.
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(s) 1, 5-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over He et al (CN1990042, IDS), in view of Zhang (CN111228475, IDS) and Tomchuck (IDS).
Claim 1 is drawn to a cell-mediated sars-cov-2 vaccine, comprising stem cells comprising vector containing the nucleic acid encoding S protein, M protein and N protein of SARS-COV-2.
He et al. teach according to research results of other coronaviruses, the spike (S) protein, the nucleocapsid (N) protein and membrane (M) all can induce immune effects, so the S, M and N proteins can be used in the research of anti-SARS coronavirus vaccines. He et al. teach anti-SARS coronavirus cellular vaccine can be prepared using the cDNA encoding the SARS coronavirus S, M and N protein (paragraph [0059]). He et al. teaches eukaryotic expression vector pDNA3.1 can be used to express the target gene (paragraph [0149]). He et al. further teaches said vector maybe transfected into 293 cells (paragraph [0134]), or B cells (paragraph [0153]).
The teaching from He differs from claim 1 that it does not teach S, M and N protein of SARS-COV-2, or specially a stem cell that comprises said vector encoding S, M and N protein.
Zhang teaches that COVID19 (SARS-CoV-2) is an enveloped positive strand RNA virus with a genome length of 29.9Kbp, which comprises S, N and M protein (paragraph [0015] and Figure 1). Zhang teaches expressing both S and N protein in HEK293 cells (paragraph [0029]).
Tomchuck et al. teach mesenchymal stem cells (MSCs) has the ability to stimulate antigen-specific antibody production in vivo (page 4, 1st col-2nd col., bridging paragraph, and Figure 3 and legend). Tomchuck et al. teach also teaches MSCs can promote adaptive immunity (page 5, Table 1). Tomchuck et al. teach MSC may be used as a vaccination platform generating protective immunity because it can deliver vaccine antigens that are highly immunogenic and a more immunostimulatory phenotype of the MSC (page 6, 1st col., 2nd paragraph, lines 1-10).
It would have been obvious to an ordinary skilled in the art that SARS-CoV-2 virus is closely related to SARS-CoV coronavirus based on the nucleotide sequence. The ordinary skilled in the art trying to develop a vaccine for SARS-CoV-2 would be motivated to follow the teaching from He to develop a cell based vaccine that comprises vectors expressing S, N and M protein using SARS-CoV-2 nucleotide sequence encoding S, N and M (taught by Zhang) because He demonstrated the strategy for expressing multiple antigenic peptide for safe and effective vaccine for SARS-CoV. It would have been obvious to an ordinary skilled in the art to use MSCs transfected with vectors expressing S, N and M protein of SARS-CoV-2 to prepare a vaccine composition based on the teaching from Tomchuck et al., because Tomchuck et al. teach MSC produces antigen that are highly immunogenic in vivo. Following combined teaching from He, Zhang and Tomchuck, an ordinary skilled in the art would have reasonable expectation of success to replace the sequence of SARS-CoV S, N and M protein taught by He, with the SARS-CoV-2 S, N and M protein taught by Zhang, and transfect the vector into a MSC following teaching from Tomchuck. Therefore, the claimed invention of claims 1 and 5 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 5, the claim also recites the stem cells is human embryonic kidney cells. It would have been obvious to an ordinary skilled in the art that SARS-CoV-2 virus is closely related to SARS-CoV coronavirus based on the nucleotide sequence. The ordinary skilled in the art trying to develop a vaccine for SARS-CoV-2 would be motivated to follow the teaching from He to develop a cell based vaccine that comprises vectors expressing S, N and M protein using SARS-CoV-2 nucleotide sequence encoding S, N and M because He demonstrated the strategy for expressing multiple antigenic peptide for safe and effective vaccine for SARS-CoV. The ordinary skilled in the art would recognize that HEK293 cells (human embryonic kidney cells) are well known in the art for expressing the viral protein such as S, N and M as demonstrated by both He and Zhang. Therefore, the claimed invention of claim 5 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claims 6 and 7, He teaches a eukaryotic expression vector pcDNA 3.1 for expressing the cDNA (paragraph [0149]).
Regarding claim 8, He teaches expressing cDNAs together in the eukaryotic expression vector (paragraph [0129]).
Response to Arguments
In response to the rejection, Applicant argues that Zhang does not teach introducing the M gene together with S and N into cells for vaccine preparation. Applicant argues even if Zhang is combined with He, the resulting vaccine would still only comprise S and N proteins. Applicant argues that the S, M and N proteins of SARS-CoV2 and of those of SARS-CoV have substantial sequence differences, particularly in RBD region of the two viruses, and their immunogenicity is not the same, so that a person skilled in the art would not have been able to predict whether applying a vaccine strategy directed to SARS-CoV to SARS-CoV-2 would be successful.
The above argument has been fully considered but deemed unpersuasive. 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). As discussed in the above rejection, the combined teaching from He and Zhang suggest follow the teaching from He to develop a cell based vaccine that comprises vectors expressing S, N and M protein would be beneficial because expressing multiple proteins using SARS-CoV-2 nucleotide sequence encoding S, N and M (taught by Zhang) because He demonstrated the strategy for expressing multiple antigenic peptide for safe and effective vaccine for SARS-CoV. Even though there is sequence variation between S, N and M of SARS-CoV and SARS-CoV-2, the prior art teaches sequences encoding S, N and M for both SARS-CoV and SARS-CoV-2, and replacing sequences encoding S, N and M of SARS-CoV with sequences encoding S, N and M of SARS-CoV-2 would have been routine experimentation with predictable result. In addition, both He and Zhang teaches the vectors expressing the antigen are introduced into 293 cells, which meets the limitation of human embryonic kidney cells (amended claim 1).
Applicant argues that the pSWTK-gp120 taught by Tomchuck is “generously provided by Dr. V. S. Kalyanaraman of ABL Inc Kensington, MD,” with no information of the genetic elements or vector map of pSWTK or how it is constructed, and a person skilled in the art would be unable to find any sequence information or plasmid map for pSWTK through publicly available databases. Applicant argues that Tomchuck does not teach other vector, what promoter strength, selection marker, and other design elements should be chosen to achieve effective delivery of antigen proteins in MSCs. Applicant alleges that a person skilled in the art would have no motivation to combine MSC vaccine platform in Tomchuck with the technique of He and Zhang. Applicant states that one of the core mechanisms of the MSC vaccine platform is the continuous secretion of antigen in vivo, which requires that MSCs remain alive in the body for at least several days. Applicant argues that D1 teaches away from Tomchuck on inactivation because D1 explicitly teaches that when using exogenous cells to prepare a vaccine, they must be inactivated to eliminate safety risks. Applicant argues teaching from D1 and Tomchuck adopt completely opposite cell viability strategies, an ordinary skilled in the art cannot simultaneously follow two contradictory teachings. Applicant argues that gp120 used by Tomchuck is a typical weak immunogenic antigen so that the electroporation conditions, plasmid content and MSC inoculation number of Tomchuck were all determined based on the weak immunogenicity of gp120. The S, M and N proteins of SARS-CoV-2 have significantly stronger immunogenicity so that the condition taught by Tomchuck may lead to unpredictable risks such as MSCs have immunomodulatory functions that can suppress T cell proliferation. Applicant asserts that combining the strongly immunogenic S, M, N proteins with MSCs might produce antagonistic effect whereby the immunosuppressive properties of MSCs instead weaken the robust responses that S, M, N proteins would otherwise elicit, and the ultimate effect cannot be reasonably predicted. Applicant argues that for strongly immunogenic antigens, the persistent exposure may increase the risk of immunopathology. Applicant asserts that after reading Tomchuck, a person skilled in the art would derive this platform is suitable for difficult antigens that are almost non-immunogenic when used alone, not for strongly immunogenic S, M and N proteins.
The above argument have been fully considered but deemed unpersuasive. The claimed invention of claim 1 is drawn to a product, a stem cell comprising vector containing the nucleic acids encoding S, M and N protein of SARS-CoV-2, and claim 5 further limits the stem cell to a mesenchymal stem cell. There is no limitation for the claimed vector other than it encodes S, M and N protein from SARS-CoV-2. As such, any mammalian expression vector that encodes S, M and N protein from SARS-CoV-2 meets the claim limitation. As such, even though Tomchuck did not provide a plasmid map, the argument for lack of information for the vector expressing S, M and N protein is not persuasive because an ordinary skilled in the art at the time of filing may use either commercially available mammalian expression vector or other prior art known vector such as pc3.1 vector taught by He for expressing S, M and N protein. The argument that D1 teaches away from Tomchuck is not persuasive because it is unclear which reference is D1. Assuming Applicant is referring to He, there is no teaching from He to indicate that MSC needs to be inactivated. Moreover, there is no teaching from Tomchuck that suggests using MSC as a platform for vaccine is only appropriate for weak antigen such as gp120. Although Tomchuck gave the example of using gp120 as antigen, Tomchuck further discussed stimulatory effects of mesenchymal stem cell on immune responses and explore the potential for MSC as a novel, universal vaccine platform (see abstract). The ordinary skilled in the art reading Tomchuck would recognize the potential advantage of using MSC as a vaccine platform, and be motivated at least to try to introducing an expression vector encoding S, M and N of SARS-CoV-2 and testing said vaccine platform in an animal model. Therefore, for reason discussed in previous office action and set forth above, this rejection is still considered proper and thus maintained.
Conclusion
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 CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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