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
Acknowledgement is hereby made of receipt and entry of the communication filed on Nov. 11, 2022. Claims 1-32 are pending and are currently examined.
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.
Claims 1, 10, 13-14, 16, 18-21, 23-25, 27-28 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Wrapp et al. (Science. 2020 Mar 13;367(6483):1260-1263; Supplementary Materials, published on Feb. 19, 2020) in view of Cusabio-mutation (https://www.cusabio.com/mutations-in-spike-protein-of-SARS-CoV-2?srsltid=AfmBOoo5RJSsg9hHoxyCS3tNTuhnxQjpypPg0ngVeusRql_L-wnZQTnK, April 16, 2020) as evidenced by Daniloski et al. (Elife. 2021 Feb 11;10:e65365) and Banerjee et al. (Biology and Life Science, Preprint, April 16, 2020 https://www.preprints.org/manuscript/202004.0281/v1) and further in view of Csiszovszki et al. (US 10,973,909 B1, patented on Apr. 13, 2021, Filed on Apr. 7, 2020).
The base claim 1 is directed to Recombinant pre-fusion SARS-CoV-2 S protein, or a fragment thereof, comprising an S1 and an S2 domain, and comprising at least one mutation selected from the group consisting of a mutation of at least one amino acid in the loop region corresponding to amino acid residues 941 - 945 into P, a mutation of the amino acid at position 892, a mutation of the amino acid at position 614, a mutation at position 572, a mutation at position 532, a disulfide bridge between residues 880 and 888, and a disulfide bridge between residues 884 and 893, wherein the numbering of the amino acid positions is according to the numbering of the amino acid positions in SEQ ID NO: 1.
Wrapp et al. teaches expressing the prefusion S ectodomain, a gene encoding residues 1−1208 of 2019-nCoV S (GenBank: MN908947) with proline substitutions at residues 986 and 987, a “GSAS” substitution at the furin cleavage site (residues 682–685), a C-terminal T4 fibritin trimerization motif, an HRV3C protease cleavage site, a TwinStrepTag and an 8XHisTag was synthesized and cloned into the mammalian expression vector pαH (See Supplementary-Wrapp: page 2, paragraph 1), where the furin site mutation teaches claim 14. Wrapp et al. also teaches that the recombinant pre-fusion SARS-CoV-2 S protein contains S1 and S2 domain (See page 1, Fig. 1 and below).
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The mutation of the amino acids at position 986 and/or 987 into P of Wrapp teaches claim 16. Wrapp et al. also describes that domains that are excluded from the ectodomain expression construct or could not be visualized in the final map are colored white. SS, signal sequence (See Fig. 1 above and page 1), which indicates the prefusion protein does not contain signal peptide, therefore, it teaches claim 18. Wrapp discloses that they expressed ectodomain residues 1 to 1208 of 2019-nCoV S, adding two stabilizing proline mutations in the C-terminal S2 fusion machinery using a previous stabilization strategy that proved effective for other betacoronavirus S proteins (See page 1, right column; Fig. 1 above), which indicates that the transmembrane/cytoplasmic domain is removed for the soluble expression and teaches claims 19 and 20 that the S2 used in Wrapp is a truncated domain and the profusion S protein used in Wrapp is a ectodomain. Wrapp et al. also teaches claim 21 by stating that S2 subunit is a symmetric trimer link domain (See page 3, left column, paragraph 2; middle column, paragraph 1). In addition, Wrapp et al. discloses expressing the prefusion S ectodomain, a gene encoding residues 1−1208 of 2019-nCoV S (GenBank: MN908947) to teach claims 23-24. Wrapp et al. also teaches claims 25 and 31 by disclosing a mammalian expression vector pαH that is expressed in FreeStyle293F cells (See Supplementary-Wrapp, page 2). Furthermore, Wrapp et al. teaches that The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics (See Abstract) and the prefusion S protein would provide atomic-level information to guide vaccine design and development (See page 1, right column, paragraph 1) and the structure of the prefusion protein provides assurance that the protein produced by this construct is homogeneous and in the prefusion conformation, which should maintain the most neutralization sensitive epitopes when used as candidate vaccine antigens or B cell probes for isolating neutralizing human mAbs (See page 4, middle column). Here the descriptions teach that the prefusion protein can be a vaccine candidate against COVID-19 as claimed in claim 28. It would be obvious that a vaccine includes the compositions comprising pre-fusion SARS-CoV-2 S protein as claimed in claim 27.
Accordingly, Wrapp et al. teaches the base claim 1 for the prefusion SRAS-COV-2 S protein with the S1 and S2 ectodomains, the stabilized proline mutations at residences 986 and 987 and the ‘RRAR” furin substitution of GSAS (See page 3, right column, paragraph 2 for “furin” site). However, it is silent on the specific mutation as claimed and their sites being based on the SEQ ID NO: 1.
Cusabio. describe the mutations in Spike Protein of SARS-CoV-2 and teaches that three majors hot spots of mutations (G476S, V483A, D614G) in the S1 subunit of SARS-CoV-2 isolated from the North America (See Cusabio, page 3, paragraph 2) with an evidence reference of Banerjee’s study. Banerjee et al. discloses the D614 G mutation (See Table 1). Here the 614 mutation teaches the instant base claim 1 limitation on the specific mutation as claimed. Also, the D614G mutation teaches claims 10 and 13.
As for the amino acid site based on the Seq ID NO: 1, the SEQ ID NO: 1 claimed in the instant application is identical to the SEQ ID NO: 122, a spike protein of SARS-COV-2, in Csiszovszki’s study (See Table 1 below). Therefore, the D614 position is present in Csiszovszki’s invention.
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the hot mutation of D614G into Wrapp’s design to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because the detailed pathogenesis features and the strain variants of SARS-COV-2 is still unknow at that time. It is obvious that the hot spot mutation will provide critical information for understanding the pandemic SARS-COV-2 virus and for vaccine and drug developments for targeting the Covid-19. As evidence, D614G is prove later that the Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types from Daniloski’s study. Daniloski et al. teaches that the G614 variant is more resistant to proteolytic cleavage, suggesting a possible mechanism for the increased transduction (See Abstract). There would be a reasonable expectation of success to develop a D614G mutation in the prefusion SARS-CoV-2 S protein as claimed.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 2-9, 11-12 and 15, based on the description above, Wrapp teaches the mutation at 986 and 987 and the furin site, and Cusabio and Banerjee teaches a serial hot mutation spot in Spike protein of COVID-19, but they are not specifically point out the specific mutation as claimed in the instant claims above. However, the SEQ ID NO: 1 is taught by Csiszovszki’s invention at their SEQ ID NO: 122, so it would be obvious for the claimed amino acids mutation/substitution in a known amino acid sequence because the gene mutation technology is a routine experiment in the art.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Wrapp et al. (Science. 2020 Mar 13;367(6483):1260-1263; Supplementary Materials, published on Fe. 19, 2020) in view of Cusabio-mutation (https://www.cusabio.com/mutations-in-spike-protein-of-SARS-CoV-2?srsltid=AfmBOoo5RJSsg9hHoxyCS3tNTuhnxQjpypPg0ngVeusRql_L-wnZQTnK, April 16, 2020) as evidenced by Daniloski et al. (Elife. 2021 Feb 11;10:e65365) and Banerjee et al. (Biology and Life Science, Preprint, April 16, 2020 https://www.preprints.org/manuscript/202004.0281/v1) and in view of Csiszovszki et al. (US 10,973,909 B1, patented on Apr. 13, 2021, Filed on Apr. 7, 2020) as applied to claims 1, 10, 13-14, 16, 18-21, 23-25, 27-28 and 31 above, and further in view of Jerala et al. (WO 2011/046520 A1, published on April 21, 2011).
Claim 22 requires that the protein, or fragment thereof, according to claim 21, wherein the heterologous trimerization domain is a foldon domain comprising the amino acid sequence of SEQ ID NO:4.
Based on the description above, Wrapp et al. teaches a C-terminal T4 fibritin trimerization motif (See Supplementary, page 1), however, it is silent on a specific sequence of a foldon domain.
Jerala et al. teaches that the polypeptide material according to any claim from 1 to 8, where protein domain prone to oligomerization is preferentially selected among the SEQ ID no. 8, SEQ ID no. 10, SEQ ID no. 12, SEQ ID no. 14, SEQ ID no. 84 and sequences with homology above 50 % to the sequences, which retain the ability to form oligomers of the same type (See claim 9, page 68), where the SEQ ID NO: 8 is identical to the claimed SEQ ID NO: 4 (See Table 2). Jerala et al. teaches the SEQ ID NO: 8 is with adjustable pore properties where protein domain prone to oligomerization is preferentially (See page 4).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the SEQ IS NO: 8 of Jerala into Wrapp’s study to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to use the known sequence SEQ ID NO: 8 that has an adjustable pore property, and there would be a reasonable expectation of success to design a pre-fusion SARS-CoV-2 S protein with a foldon domain comprising the amino acid sequence of SEQ ID NO:4 as claimed in the instant applciation.
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Claims 26, 29-30 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Wrapp et al. (Science. 2020 Mar 13;367(6483):1260-1263; Supplementary Materials, published on Fe. 19, 2020) in view of Cusabio-mutation (https://www.cusabio.com/mutations-in-spike-protein-of-SARS-CoV-2?srsltid=AfmBOoo5RJSsg9hHoxyCS3tNTuhnxQjpypPg0ngVeusRql_L-wnZQTnK, April 16, 2020) as evidenced by Daniloski et al. (Elife. 2021 Feb 11;10:e65365) and Banerjee et al. (Biology and Life Science, Preprint, April 16, 2020 https://www.preprints.org/manuscript/202004.0281/v1) and in view of Csiszovszki et al. (US 10,973,909 B1, patented on Apr. 13, 2021, Filed on Apr. 7, 2020) as applied to claims 1, 10, 13-14, 16, 18-21, 23-25, 27-28 and 31 above, and further in view of CTV-Trial-2019 ( https://ctv.veeva.com/study/a-shedding-study-of-adenovirus-serotype-26-based-respiratory-syncytial-virus-pre-fusion-f-protein-a) as evidenced by Geisbert et al.( J Virol. 2011 May;85(9):4222-33).
Claims 26 and 32 require a recombinant human adenovirus of serotype 26.
Claims 29 and 30 are directed to a method for SARS-COV-2 vaccination and reduction of infection and/or replication of SARS-CoV-2 in a subject.
Based on the description above, Wrapp et al. teaches using FreeStyle293F cells to express the prefusion S protein and the prefusion protein can be used for vaccine as a composition to reduce the infection of SARS-COV-2 (See e.g., page 4, middle column). However, it is silent on a human vector that is the adenovirus of serotype 26 and it also does not explicitly teach the details of the method.
CTV teaches a Shedding Study of Adenovirus Serotype 26 Based Respiratory Syncytial Virus Pre-fusion F Protein (Ad26.RSV.preF) Vaccine in Adults. Although it does not use the prefusion protein of SARS-COV-2, CTV teaches the detailed protocol for an antiviral vaccine study using the Adenovirus Serotype 26 to deliver the Respiratory Syncytial Virus Pre-fusion F Protein. CTV teaches that the purpose of this study is to assess the shedding and kinetics of the Adenovirus Serotype 26. Based Respiratory Syncytial Virus Pre-fusion F Protein (Ad26.RSV.preF) vaccine after one intramuscular injection of Ad26.RSV.preF in adults (See page 2). Here CTV teaches that Ad26 can be used for delivering prefusion protein for vaccine development. At the same time, it is a common knowledge in the art that AD26 is a commonly used vector in vaccine development due to its low seroprevalence in human populations, robust and durable immune response, and high stability, which can be evidenced by Custers’ study. Custers et al. teaches that Ad26-based vaccines have been extensively tested in completed and ongoing clinical studies from multiple clinical programs and the safety, tolerability and immunogenicity of Ad26-based vaccines in humans has been demonstrated (See page 3083, left column).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the Ad26-based vaccines of CTV into Wrapp’s study and arrive at an invention as claimed. One of skill in the art would have been motivated to do so based on the advantage using AD26-base vaccine study, and there would be a reasonable expectation of success to develop a method for vaccine development for reduce SARS-COV-2 infection using a Ad26-based vaccine with SARS-COV-2 prefusion S protein.
Allowable Subject Matter
The nucleic acid sequence SEQ ID NO: 5-194 and SEQ ID NO: 197-418, SEQ ID NO: 420 and SEQ ID NO: 421 are free of prior art. Accordingly, claim 17 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
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/RUIXUE WANG/Examiner, Art Unit 1671
/JANET L ANDRES/ Supervisory Patent Examiner, Art Unit 1671