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, 3-18 are pending in the application. Claims 14-17 are withdrawn. Claims 1, 3-13 and 18 are currently under examination.
This office action is in response to the amendment filed on 4/2/2026.
All previous rejection not reiterated in this office action are withdrawn.
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, 3-6 and 10-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Galen (US 11,744,884), in view of OU et al (IDS). This rejection is rewritten to address the amendment.
Claim 1 is drawn to a DNA vaccine comprising a Salmonella typhi Ty21a strain comprising a DNA mole comprising a eukaryotic expression cassette encoding at least a COVID-19 coronavirus (SARS-CoV-2) spike protein (S) or a portion thereof, wherein the SARS-CoV-2 S protein comprises a SARS-CoV-2 full length protein and wherein the portion thereof comprises a SARS-CoV-2 S protein ectodomain, a SARS-CoV-2 S protein subunit S1, or a SARS-CoV-2 S protein receptor binding domain (RBD).
Galen teaches Salmonella has been one of the organisms most studied for use as a mucosal live carrier vaccine delivering foreign antigens to the immune system, and a number of attenuated strains expressing heterologous antigens have been produced and successfully tested in animal models and in humans, including Ty21a, licensed vaccine (col.4, lines 11-16 and col.11, lines 41-48). Galen teaches said strain may be used to deliver a variety of antigen including from pathogen SARS and associated coronavirus (col.13, line 32).
However, Galen does not teach the antigen is full length SARS-CoV-2 S protein.
OU et al. teaches expression of SARS-CoV-2 S protein in HEK293T cells from codon optimized cDNA construct (page 10, Methods section, constructs and plasmids). OU et al. teaches CoV uses its S protein to bind its receptor, which is a main target for neutralization antibody (page 2, 1st col., 2nd paragraph, lines 1-3). The teaching from OU et al. characterizes the S protein of SARS-CoV-2 on virus entry and provides potential targets for development of drugs and vaccines against this virus (page 9, 1st col., 5th paragraph).
It would have been obvious to an ordinary skilled in the art that to make a DNA vaccine encoding SARS-CoV-2 S protein may be delivered using Salmonella typhi Ty21a strain as a carrier based on combined teaching from Galen and OU et al. The ordinary skilled in the art would be motivated to use Ty21a strain as a carrier because Galen teaches Salmonella has been one of the organisms most studied for use as a mucosal live carrier vaccine delivering foreign antigens to the immune system, and Ty21a is a licensed vaccine strain. The ordinary skilled in the art would recognize SARS-CoV-2 is a respiratory virus which would benefit from mucosal delivery from Ty21a. Since OU et al. provides detailed characterization of SARS-CoV-2 structure and makes it a potential target for neutralization antibody, the ordinary skilled in the art would substitute this S protein with S protein from SARS coronavirus taught by Galen. Substitution one known antigen from another would have been within the capability of an ordinary skilled in the art. Therefore, the claimed invention of claim 1 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claims 3, OU teaches expressing full length S protein (page 10, 1st col., constructs and plasmids section).
Regarding claim 4-6, OU teaches SARS-CoV-2 S1 subunit and S2 (ectodomain) mediating attachment and membrane fusion, respectively, and S1 fold as two independent domains, which is RBD (page 2, 1st col., 2nd paragraph, lines 4-9).
Regarding claim 10, Galen teaches pharmaceutical composition that comprises pharmaceutically acceptable carrier or excipients (col.18, lines 16-19).
Regarding claim 11, Galen teaches the vaccine may be administered in oral form (col.18, line 52).
Regarding claim 12, Galen teaches the live vector may be prepared in the form a suspension or powder (col.19, lines 15-16).
Regarding claim 13, Galen teaches the pharmaceutical composition that comprises live S. Typhi vector may include various adjuvants known in the art (col.17, line 40).
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Galen and OU, as applied to claims 1 and 2 above, and further in view of Wrapp et al (Science, 13-3-2020, Vol.367, pages 1-4).
The teaching from Galen and OU has been discussed above.
However, neither reference teaches the SARS-CoV-2 S protein or a portion thereof is a prefusion-stabilized form full length S protein or SARS-CoV-2 protein ectodomain comprising two stabilizing mutation to proline.
Wrapp teaches Cryo-EM structure of the 2019-nCoV spike (SARS-CoV-2) in the prefusion conformation with two stabilizing proline mutations in the C-terminal S2 fusion machinery (page 1, 3rd col., 2nd paragraph, lines 1-7). Wrapp teaches characterization of the prefusion S structure would provide atomic level information to guide vaccine design and development.
It would have been obvious to an ordinary skilled in the art to use a prefusion stabilized form of the SARS-CoV-2 S protein because a stabilized form of antigen make the study of its function more effective than an unstable form. The ordinary skilled in the art would be motivated to use the two mutation of proline at C terminal S2 fusion because Wrapp demonstrates this mutation stabilizes the SARS-Co-V2 S protein ectodomain expression. Using a prior art known form of SARS-CoV-2 S protein mutant to replace the wild type S protein would have been within the capability of an ordinary skilled in the art. Therefore, the claimed invention of claim 7 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 8 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Galen and OU, as applied to claim 1 above, and further in view of Dutta et al (Immunology Letters, 2008, Vol.118, pages 65-71).
The teaching from Galen and OU has been discussed above. However, neither reference teaches additional SARS-CoV-2 protein or a portion thereof is a SARS-Co-V-2 N protein.
Dutta et al. teach that nucleocapsid protein N of SARS-CoV is one of the most promising antigen candidate for vaccine design (page 66, 1st col., 3rd paragraph). Dutta illustrated SARS N DNA vaccine expressing plasmid induces specific immune responses in mouse (Figure 3 and legend). Dutta et al. teach N protein does not appear to undergo rapid mutation like S protein and could be a better target for development of serological assays.
It would have been obvious to an ordinary skilled in the art to further include SARS-CoV-2 protein, N protein, in addition to the S protein when design a DNA vaccine based on combined teaching from Galen, OU and Dutta. The ordinary skilled in the art would be motivated to do so because Dutta teaches SARS N DNA vaccine expressing plasmid induces specific immune responses in mouse, and does not appear to undergo rapid mutation like S protein. Since SARS-CoV-2 virus share about 96% nucleotide sequence identity with SARS CoV (page 2, 1st col., 1st paragraph, bottom 4 lines), the ordinary skilled in the art would be motivated to include N protein from SARS-CoV-2 N protein into DNA vaccine. Therefore, the claimed invention of claim 8 and 9 would have been obvious to an ordinary skilled in the art at the time the application was filed.
Response to Arguments
Applicant argues that Galen relates to live attenuated Salmonella vectors expressing heterologous antigens, primarily bacterial outer membrane proteins from pathogen such as Acinetobacter and Klebsiella, and explicitly stated in Example 1 that “synthetic gene cassettes encoding these foreign antigens will be stably integrated into chromosomes of a live attenuated S. Typhi vaccine candidate, enabling high expression of OmpA and OmpW on the outer surface of the carrier vaccine.” Applicant asserts the purpose of the system described in Galen is to produce bacterial antigens, within the Salmonella vector and deliver the expressed antigens though bacterial outer membrane vesicles to induce immunity against bacterial infections. Applicant alleges that Galen is strictly limited to prokaryotic expression the pathogenic antigen by the live attenuated Salmonella vector, and heterologous antigen from the pathogen is delivered by the Salmonella vector to mucosal tissue, as disclosed in col.5, lines 56-66, col.19, lines 49-58, lines 59 to col.20, lines 2, line 66 to col.20, line 2). Applicant asserts that Galen does not disclose SARS-CoV-2. Applicant states that the present invention relates to a DNA vaccine comprising a Salmonella typhi Ty21a strain comprising DNA molecule with a eukaryotic expression cassette encoding the heterologous antigen from SARS-CoV-2 S protein, the vector delivers the DNA plasmid to the vaccinated subject and the heterologous antigen is expressed from the eukaryotic expression cassette within the cells of the immunized subject, and this DNA vaccine is conceptually different from the antigen vaccination disclosed in Galen. Applicant alleges Galen repeatedly states that the Salmonella vector is engineered to express the heterologous antigen after the protein is exported from the surface through bacterial outer membrane vesicles for presentation to the immune system, wherein the antigen synthesis occurs within the bacterial cell using prokaryotic transcription and translation machinery so that the antigen exists as a protein produced by the bacterium prior to the administration to the host. Applicant argues that OU does not make up for the deficiency of Galen because OU only concerns basic research on the biology of SARS-CoV-2. Applicant argues that OU only teaches CoV S protein is one of the key components determining virus virulence, tissue tropism and host range, and it is also a main target for neutralizing antibody and vaccine design, but does not give any information on a potential spike based vaccination. Applicant argues that the immunogenic sites of the S protein were not conserved between SARS-CoV and SARS-CoV-2 since cross neutralizing activity between sera from patients recovered from a SARS-CoV and SARS-CoV-2 is limited, and reading OU emphasis little is known about SARS-CoV-2 at the priority date of March 31, 2020 further lowering the expectation of the skilled person that a Salmonella based DNA vaccine encoding the S protein of SARS-CoV-2 would generate an antigen specific immune response. Applicant argues that use of the present application as a source of motivation is impermissible.
The above argument has been fully considered but deemed unpersuasive. Applicant’s characterization of Galen’s teaching is limited to some embodiments and examples is erroneous because Salmonella has been known to deliver foreign antigens through mucosal tissue to the immune system and has been extensively studied prior to the application of the present application (Galen, Col.4., lines 11-13). Galen teaches S. Typhi has been tested in murine intranasal model of immunogenicity for the pre-clinical assessment of S. Typhi-based vaccines, and has been used to advance at least 3 live carrier vaccines into clinical trials (col.5, lines 27-43), one of which encodes a heterologous viral antigen (Galen, reference 52). It would have been obvious from the teaching of Galen that the expression of heterologous antigen is not limited to bacterial outer membrane protein, and the list of heterologous antigen in col.13, including viral SARS antigen is encompassed by the teaching of Galen. Applicant is reminded that claim 1 of the present application is directed to a DNA vaccine comprising a Salmonella typhi Ty21a strain comprising a DNA molecule comprising a eukaryotic expression cassette encoding a SARS-CoV-2 S full length protein or portion of said protein, but does not recite any structural limitation for “DNA vaccine” or “eukaryotic expression cassette,” so that the claim can be interpreted as Ty21a strain that comprises an expression cassette encoding SARS-CoV-2 capable of expression within a eukaryotic host. As such, the mucosal delivery of a heterologous antigen expressed by Ty21a in a mouse model meets the claimed limitation. The argument directed to little is known of SARS-CoV-2 at the time of filing is not relevant because OU teaches full length S SARS-CoV-2 and portions thereof as claimed. The claimed invention is a product that comprises Ty21a and SARS-CoV-2 full length protein or portions thereof, naming it as a DNA vaccine does not set forth any structural limitation for this claimed product. As such, the combined teaching from Galen and OU renders the claimed product of claim 1 obvious for reason discussed in the rejection and set forth above. 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). The above analysis is based on the knowledge available from prior art as evidenced by the teaching from Galen and OU, which are prior to the filing of present application. Therefore, the above 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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