DETAILED OFFICE ACTION
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s preliminary amendment to the claims, filed on March 7, 2024, is
acknowledged. This listing of the claims replaces all prior versions and listings of the
claims.
Claims 1-18 and 20-21 are pending and are being examined on the merits.
Claim 19 is cancelled.
Applicant’s amendments to the specification are acknowledged. The amended specifications were filed: June 20, 2023; November 20, 2023; and March 7, 2024.
Priority
This application is filed under 35 U.S.C. 371 as a national stage of international
application PCT/KR2021/006758, filed on May 31, 2021, which claims foreign priority under 35 U.S.C. 119(a)-(d) to Korean applications KR10-2021-0061143 and KR10-2020-0066119 filed on May 12, 2021 and June 1, 2020, respectively. A certified copy of each of the foreign priority applications has been filed in this application on November 30, 2022.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on November 30, 2022, June 21, 2023, March 26, 2024, and July 8, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs have been considered by the examiner and those references therein have been indicated as such.
Claim Objections
Claims 1 and 2 are objected to for reciting “recombination vector.” In the interest of improving claim form, the Office suggests amended “recombination” to “recombinant.”
Claim 6 is objected to because of the recitation of “TEV” without first writing out the full phrase for which the abbreviation “TEV” is used.
Claim 10 is objected to because of the recitation of “E. coli” without first writing out the full phrase for which the abbreviation “E. coli” is used.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. — The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 3, 6, and 15 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 3 and 15 are rejected as indefinite because reciting “increasing.” The term “increasing” is a relative term and the claims do not recite a reference for determining a “increasing” an expression level or water solubility of the vaccine. The Office suggests that applicant clarify the meaning of the term “increasing” or remove it. For the purpose of compact prosecution, the limitation of “wherein the RID protein is a fusion partner for increasing an expression level or water solubility of the vaccine” is interpreted as the RNA interacting domain (RID) protein directly or indirectly increases the level of any RNA transcript or protein encoded therefrom as compared to when the encapsuling is not present as well as that the RID protein directly or indirectly increases the water solubility of the vaccine and/or one or more of its components as compared to when the encapsuling is not present.
Claim 6 is rejected because the recitation of “the polynucleotide further encodes a TEV protein for cleavage of the RID protein” is unclear. Since claim 1 is drawn to a plurality of polynucleotides, it is unclear which polynucleotide is intended to encode a TEV protein. The Office suggests that applicant amend the claim to clarify which polynucleotide is to encode a TEV protein or amend the claim to recite “wherein the vector further comprises a polynucleotide encoding a TEV protein for cleavage of the RID protein.” For the purpose of compact prosecution, the claim is construed as “The recombinant expression vector of claim 1, wherein the vector further comprises a polynucleotide encoding a TEV protein for cleavage of the RID protein.”
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 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.
Claims 1-4, 6-9, 11, 14-16, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Graham et al. (US 2018/0021258 A1; cited on the attached Form PTO-892; hereafter “Graham”) in view of Seong et al. (WO 2017/160124 A2; cited on the attached Form PTO-892). Reference is made to a machine translation of WO 2017/160124 A2 obtained from Google Patents; cited on the attached Form PTO-892; hereafter “Seong”).
Regarding claims 1-4, 6-7, and 11, Graham teaches a nanoparticle-based vaccine comprising a fusion protein comprising a monomeric subunit of a self-assembly protein and an immunogenic portion of a protein from an infectious agent as well as a nucleic acid encoding thereof (Abstract; para [0006, 0028]; Claim 16). An ordinary artisan would have immediately recognized the immunogenic portion of a protein from an infectious agent used in the vaccine as an antigen. The monomeric subunit of a self-assembly protein can comprise a monomeric encapsulin protein, or at least 25 contiguous amino acids thereof, with the sequence of SEQ ID NO: 79 which is identical to amino acids 1-264 of instant SEQ ID NO: 1 (para [0005, 0016, 0057, 0065, 0103]; Table 1; Claims 16-17; SEQ ID NO: 79, see sequence alignment below).
PNG
media_image1.png
351
577
media_image1.png
Greyscale
Graham teaches wherein the fusion protein comprises a linker sequence between the amino acid sequences not normally found joined together via peptide bond in their natural environment (para [0058]).
Regarding claims 9, 14-16, and 18, Graham teaches a method of producing the nanoparticle-based vaccine comprising a fusion protein comprising a monomeric subunit of a self-assembly protein and an immunogenic portion of a protein from an infectious agent by introducing one or more nucleic acids encoding thereof into a cell, incubating the cell under conditions suitable for expression, and purifying and/or isolating the vaccine nanoparticles (para [0006, 0029, 0124-0125]; Claim 26). An ordinary artisan would immediately recognize incubating is synonymous with culturing in the context of a host cell.
Regarding claims 8 and 20, Graham teaches the viral infection agent can be from dengue virus or a coronavirus (para [0005, 0062, 0066, 0069]).
Graham does not explicitly teach wherein the nucleic acid comprising a vaccine or a protein encoding thereof comprises an RNA interacting domain (RID).
Seong teaches an expression vector for producing viral vaccine fusion protein wherein the fusion protein comprises an N-terminal human RNA binding domain (hRBD) fused via TEV sequence to a viral antigen target protein (i.e., VP1) that self-assembles into virus like particle (Abstract; p. 1, paragraph beginning with “A gene encoding”; p. 2, paragraph beginning with “The present invention”; Figure 1, see vector map of Figure 1 below). An ordinary artisan would immediately recognize an RNA binding domain constitutes an RNA interacting domain
PNG
media_image2.png
580
739
media_image2.png
Greyscale
The hRBD increases the solubility of the target (p. 1, paragraph beginning with “A gene encoding”; p. 2, paragraph beginning with “Therefore, the present” – p. 2, paragraph beginning with “An object of the present”; p. 3, paragraph 4). The hRBD can comprise an amino acid sequence that comprises instant SEQ ID NO: 13 (p. 3, paragraph beginning “In one embodiment of the present invention, the hRBD”; SEQ ID NO: 1, see sequence alignment below).
PNG
media_image3.png
235
624
media_image3.png
Greyscale
In view of the combined teachings of Graham and Seong, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the nucleic acid encoding a vaccine, the protein based vaccine encoded by the nucleotide, and a method of producing the vaccine taught by Graham that comprises a fusion of a viral antigen (i.e., dengue virus or coronavirus antigen) and encapsulin via a linker sequence such that the N-terminus comprises the hRBD fused to the fusion protein with a linker comprising linker with a TEV cleavage site sequence taught by Seong, thereby arriving at the invention of claims 1-4, 7-9, 11, 14-16, 18, and 20.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success of fusing the hRBD fusion taught by Seong via linker comprising a TEV cleavage site to the fusion of a viral antigen (i.e., dengue virus or coronavirus antigen) and encapsulin taught by Graham. This is because Seong taught fusing the hRBD to a viral protein increases the solubility of the target protein.
Consequently, the invention of claim 1-4, 6-9, 11, 14-16, 18, and 20 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 5, 13, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Graham in view of Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 above, and further in view of Chichili et al. (Protein Science, published 2013, Vol. 22, No. 2, p. 153-167; cited on the attached Form PTO-892; hereafter “Chichili”) and Odani et al. (US 2009/0155277 A1; cited on the attached Form PTO-892; hereafter “Odani”).
The relevant teachings of Graham and Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 are discussed above and incorporated herein.
Regarding claims 5, 13, and 21, the combined teachings of Graham and Seong do not explicitly teach a linker encoded by the gene sequence of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.
Chichili teaches glycine-rich linkers are flexible, connecting various domains in a single protein without interfering with the function of each domain and can be used in recombinant fusion proteins (Abstract; p. 164, col 1, para 4 – p. 164, col 2, para 1). Chichili teaches a glycine-rich amino acid sequence comprising the amino acid sequence of GSGSGS (Table 1; Figure 1).
Odani teaches all codons for each amino acid (para [0112]).
In view of the combined teachings of Graham, Seong, Chichili, and Odani, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the nucleic acid sequences or amino acid sequence of linkers in the fusion protein taught by Graham and Seong, and for the GSGSGS linker taught by Chichili and/or to convert the GSGSGS linker to a nucleic acid sequence of ggt tct ggt tct ggt tct in order to incorporate a nucleic acid encoding the GSGSGS linker into an expression construct encoding the fusion protein, thereby arriving at the invention of claims 5, 13, and 21.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to substitute linkers in the fusion protein taught by Graham and Seong because it is obvious to substitute one fusion protein linker for another, such as the GSGSGS linker taught by Kwong, to achieve a predictable result because they are equivalent linkers with the same function. An ordinary artisan would have been motivated to convert the amino acid sequence of the GSGSGS linker taught by Kwong to a nucleotide sequence in order to use of the linker and/or fusion protein in an expression construct in an expression construct because Odani taught the use of any known codon for the desired amino acid in a peptide chain is merely use of a known codon to arrive at predictable result.
Consequently, the invention of claim 5, 13, and 21 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 6, 10, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Graham in view of Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 above, and further in view of Lagoutte et al. (Vaccine, published online May 11, 2018, Vol. 36, No. 25, p. 3622-3628; cited on the IDS filed November 30, 2022; hereafter “Lagoutte”).
The relevant teachings of Graham and Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 are discussed above and incorporated herein.
Regarding claims 10 and 17, the combined teachings of Graham and Seong do not explicitly teach wherein the transformed host cell is E. coli.
Lagoutte teaches producing encapsulin-based nanoparticle in Escherichia coli (E. coli) that can be used for vaccines (Abstract; p. 3624, col 1, para 2; p. 3626, col 2, para 4).
In view of the combined teachings of Graham, Seong, and Lagoutte, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention that the host cell transformed with the expression vector to produce the vaccine taught by Graham and Seong be E. coli cells as taught by Lagoutte, thereby arriving at the invention of claims 10 and 17.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to substitute the host cell for producing a recombinant protein and/or vaccine for another host, such as E. coli taught by Lagoutte, to achieve a predictable result because they are equivalent host cells with the same function. Furthermore, an ordinary artisan would have been motivated to and would have had a reasonable expectation of success modify the host cell transformed with the expression vector to produce the vaccine taught by Graham and Seong to be E. coli cells because Lagoutte taught producing encapsulin-based nanoparticles in E. coli that can be used for vaccines.
Regarding claim 6, Seong further teaches a TEV protein cleavage enzyme to cleave a TEV cleavage site and remove hRBD from the fusion protein (p. 3 – “In the present invention, the protein cleavage enzyme may be TEV, and specifically, the sequence encoding the TEV recognition site may be represented by SEQ ID NO: 8.”; p. 4, paragraph beginning “The protein expressed and purified above was” – p. 4, paragraph beginning “Next, the RBD-remove”; p. 5, paragraph beginning “According to the results of the previous study”). Seong teaches purifying the vaccine viral-like particles formed after cleaving with TEV protein cleavage enzyme (p. 4, - paragraph beginning “Figure 6 is a chromatogram”). Seong teaches the vaccine does not form viral-like particles, and instead forms aggregates, when the fusion protein does not have the hRBD domain removed by a TEV protein cleavage enzyme (p. 5, paragraph beginning “As a result, as shown in FIG. 7,”).
The combined teachings of Graham and Seong do not explicitly teach wherein the nucleic acid comprising the vaccine also comprises a TEV cleavage protein.
However, Lagoutte teaches expression construct to produce encapsulin-based nanoparticles that is bicistronic and produces more than one protein(Abstract; p. 3623, col 2, para 3; Figure 1).
In view of the combined teachings of Graham, Seong, and Lagoutte, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the expression vector to produce the vaccine taught by Graham and Seong such that it is bicistronic as taught by Lagoutte and to include in the expression vector the TEV protein cleavage enzyme by Seong, thereby arriving at the invention of claim 6.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to modify the expression vector to produce the vaccine taught by Graham and Seong such that it is bicistronic as taught by Lagoutte and to include in the expression vector the TEV protein cleavage enzyme by Seong. This is because Lagoutte taught bicistronic expression vectors for the use of producing encapsulin-based nanoparticles for vaccines, and Seong taught removal of the hRBD from a viral vaccine fusion protein is needed to prevent protein aggregation and permit viral-like particle formation and the hRBD is removed before purification. Therefore, the inclusion of the TEV protein cleavage enzyme in the expression construct would allow for the removal of the hRBD without exogenous TEV protein cleavage enzyme as well as permit nanoparticle formation and purification.
Consequently, the invention of claim 6, 10, and 17 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Graham in view of Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 above, and further in view of Choi et al. (ACS Nano, published July 8, 2016, Vol. 10, No. 8, p. 7339-7350; cited on the attached Form PTO-892; hereafter “Chen”).
The relevant teachings of Graham and Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 are discussed above and incorporated herein.
Regarding claim 12, the combined teachings of Graham and Seong do not explicitly teach wherein the vaccine fusion protein comprises the viral antigen fused to the C-terminus of the encapsulin protein.
Choi teaches antigen-encapsulin nanoparticle vaccines including comprising an antigen inserted at the N-terminal or C-terminal ends of encapsulin (i.e., OT-1-Encap-N and OT-1-Encap-C, respectively) or the loop region of encapsulin (i.e., OT-1-Encap-L) (Abstract; p. 7341, col 1, para 1). OT-1-Encap-C demonstrated the ability to induce T cell proliferation at low concentrations while OT-1-Encap-N and OT-1-Encap-L required high or moderate concentrations to induce proliferative responses (p. 7342, col 1, para 1 – p. 7342, col 2, para 1). Choi teaches the difference in the capacity to induce T cell proliferation may could be due to less effective processing of antigen peptides inserted in loop region and at the N-terminal of encapsulin, compared to those inserted at the C-terminal end, consistent with their previous study (p. 7342, col 1, para 1 – p. 7342, col 2, para 1).
In view of the combined teachings of Graham, Seong, and Choi, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the fusion protein taught by Graham and Seong such that the viral antigen is linked to the C-terminus of the encapsulin protein as taught by Choi, thereby arriving at the invention of claim 12.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to modify the fusion protein taught by Graham and Seong such that the viral antigen is linked to the C-terminus of the encapsulin protein. This because Choi teaches antigen-encapsulin nanoparticle vaccines including comprising an antigen inserted at the N-terminal or C-terminal ends of encapsulin or the loop region of encapsulin, and the most effective formulation was the OT-1-Encap-C.
Consequently, the invention of claim 12 would have been obvious to one of ordinary skill in the art before the effective filing date.
Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6-9, 11, 14-16, 18, and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, and 8 of U.S. Patent No. 11,591,630 B2 (hereafter “patent’630”) in view of Lopez-Sagaseta et al. (Computational and Structural Biotechnology Journal, published 2016, Vol. 14, p. 58-68; cited on the attached Form PTO-892; hereafter “Lopez-Sagaseta”), Graham and Seong.
Regarding claims 1-4, 6-9, 11, 14-16, 18, and 20, claim 1 of patent’630 recites a fusion comprising:
a peptide for enhancing expression efficiency of a target protein, and
a target protein,
wherein the peptide is linked to the N-terminus of the target protein and wherein the peptide consists of the amino acid sequence represented by SEQ ID NO: 1. The amino acid sequence of SEQ ID NO: 1 of the fusion protein from patent’630 is identical to instant SEQ ID NO: 12 (See sequence alignment below).
PNG
media_image4.png
137
638
media_image4.png
Greyscale
Claim 4 of patent’630 recites the fusion protein according to claim 1, wherein the target protein is at least one selected from the group consisting of an antigen, an antibody, a cell receptor, an enzyme, a structural protein, a serum protein, and a cellular protein.
Claim 5 of patent’630 recites the fusion protein according to claim 1, further comprising: an RNA interacting domain (RID) as a fusion partner of the fusion protein, wherein the RID contains the amino acid sequence represented by SEQ ID NO: 7. The amino acid sequence of SEQ ID NO: 7 of the fusion protein from comprises instant SEQ ID NO: 13 (See sequence alignment below).
PNG
media_image5.png
204
637
media_image5.png
Greyscale
Claim 6 of patent’630 recites the fusion protein according to claim 5, wherein the fusion protein contains the amino acid sequence represented by SEQ ID NO: 9. Amino acid residues of 1-7 of SEQ ID NO: 9 of the fusion protein from patent’630 is identical to instant SEQ ID NO: 12 (See sequence alignment below).
PNG
media_image6.png
110
580
media_image6.png
Greyscale
Amino acid residues of 8-77 of SEQ ID NO: 9 of the fusion protein from patent’630 is identical to instant SEQ ID NO: 13 (See sequence alignment below).
PNG
media_image7.png
171
581
media_image7.png
Greyscale
Claim 8 of patent’630 recites a method for producing a soluble target protein, comprising the steps of:
constructing an expression vector that comprises
a polynucleotide encoding the target protein,
a polynucleotide linked to the 5′-end of the polynucleotide encoding the target protein and encodes a peptide that enhances expression efficiency of the target protein and RID that increases solubility of the target protein;
(B) introducing the expression vector into a host cell to prepare a transformant; and
(C) culturing the transformant so that expression of a recombinant target protein is induced, and obtaining the recombinant target protein. An ordinary artisan would immediately recognize the vector comprising a nucleotide encoding the RID domain fused to 5’-end of the target protein is
The claims of patent’630 do not recite an encapsulin.
Lopez-Sagaseta teaches vaccines that made of killed, inactivated, or live-attenuated pathogens as well as modern vaccines containing isolated, highly purified antigenic protein subunits tend to induce lower levels of protective immunity (Abstract). Lopez-Sagaseta teaches a strategy to overcome the low level of immunity of vaccines is to design antigen nanoparticles: assemblies of polypeptides that present multiple copies of subunit antigens in well-ordered arrays with defined orientations that can potentially mimic the repetitiveness, geometry, size, and shape of the natural host-pathogen surface interactions (Abstract). Lopez-Sagaseta nanoparticle vaccines offer a collective strength of multiple binding sites (avidity) and can provide improved antigen stability and immunogenicity (Abstract). Lopez-Sagaseta teaches an encapsulin-based nanoparticles (p. 64, col 1, para 2; Table 2). Lopez-Sagaseta teaches Hepatitis B virus core antigen (HBcAg) self-assembles into nanoparticles as well as using HBcAg fused to malaria antigens to produce a nanoparticle-based vaccine against malaria (p. 61, col 1, para 2-3; Table 1).
Graham teaches a nanoparticle-based vaccine comprising a fusion protein comprising a monomeric subunit of a self-assembly protein and an immunogenic portion of a protein from an infectious agent as well as a nucleic acid encoding thereof (Abstract; para [0006, 0028]; Claim 16). An ordinary artisan would have immediately recognized the immunogenic portion of a protein from an infectious agent used in the vaccine as an antigen. Regarding claims 8 and 20, Graham teaches the viral infection agent can be from dengue virus or a coronavirus (para [0005, 0062, 0066, 0069]). The monomeric subunit of a self-assembly protein can comprise a monomeric encapsulin protein, or at least 25 contiguous amino acids thereof, with the sequence of SEQ ID NO: 79 which is identical to amino acids 1-264 of instant SEQ ID NO: 1 (para [0005, 0016, 0057, 0065, 0103]; Table 1; Claims 16-17; SEQ ID NO: 79, see sequence alignment below).
PNG
media_image1.png
351
577
media_image1.png
Greyscale
Graham teaches wherein the fusion protein comprises a linker sequence between the amino acid sequences not normally found joined together via peptide bond in their natural environment (para [0058]).
Seong teaches an expression vector for producing viral vaccine fusion protein wherein the fusion protein comprises an N-terminal human RNA binding domain (hRBD) fused via TEV sequence to a viral antigen target protein (i.e., VP1) that self-assembles into virus like particle (Abstract; p. 1, paragraph beginning with “A gene encoding”; p. 2, paragraph beginning with “The present invention”; Figure 1, see vector map of Figure 1 below). An ordinary artisan would immediately recognize an RNA binding domain constitutes an RNA interacting domain.
PNG
media_image2.png
580
739
media_image2.png
Greyscale
The hRBD increases the solubility of the target (p. 1, paragraph beginning with “A gene encoding”; p. 2, paragraph beginning with “Therefore, the present” – p. 2, paragraph beginning with “An object of the present”; p. 3, paragraph 4). The hRBD can comprise an amino acid sequence that comprises instant SEQ ID NO: 13 (p. 3, paragraph beginning “In one embodiment of the present invention, the hRBD”; SEQ ID NO: 1, see sequence alignment below).
PNG
media_image3.png
235
624
media_image3.png
Greyscale
In view of the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong, it would have been obvious for a person of ordinary skill in the art to modify the vector encoding a fusion protein comprising an RID domain fused to N-terminus of the target protein such the target protein comprises a dengue virus or a coronavirus antigen and that the fusion comprises the self-assembling encapsulin protein taught by Graham in order to produce nanoparticle-based vaccines, thereby arriving at the invention of claims 1-4, 7-9, 11, 14-16, 18, and 20.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success of modifying the vector encoding a fusion protein comprising an RID domain fused to N-terminus of the target protein such the target protein comprises a dengue virus or a coronavirus antigen in order to produce a vaccine for dengue virus or a coronavirus. It is also obvious to substitute one antigen for another, such as the dengue virus or a coronavirus antigens taught by Graham, with predictable and expected results because they perform the same antigenic function for vaccines. An ordinary artisan would have been motivated to and would have had a reasonable expectation of success of modifying the vector encoding a fusion protein comprising an RID domain fused to N-terminus of the target protein such the fusion comprises the self-assembling encapsulin protein taught by Graham in order to produce nanoparticle-based vaccines. This is because Graham taught encapsulin is a self-assembling protein and Lopez-Sagaseta taught encapsulin is used as a platform for nanoparticle as well as taught fusing antigens to self-assembling proteins to produce nanoparticle-based vaccines strengths of multiple binding sites (avidity) and can provide improved antigen stability and immunogenicity.
Regarding claim 6, the combination of claims 1, 4-6, and 8 of patent’630 and the relevant teachings of Lopez-Sagaseta, Graham, and Seong as applied to claims 1-4, 7-9, 11, 14-16, 18, and 20 are discussed above and incorporated herein.
Seong further teaches a TEV protein cleavage enzyme to cleave a TEV cleavage site and remove hRBD from the fusion protein (p. 3 – “In the present invention, the protein cleavage enzyme may be TEV, and specifically, the sequence encoding the TEV recognition site may be represented by SEQ ID NO: 8.”; p. 4, paragraph beginning “The protein expressed and purified above was” – p. 4, paragraph beginning “Next, the RBD-remove”; p. 5, paragraph beginning “According to the results of the previous study”). Seong teaches purifying the vaccine viral-like particles formed after cleaving with TEV protein cleavage enzyme (p. 4, - paragraph beginning “Figure 6 is a chromatogram”). Seong teaches the vaccine does not form viral-like particles, and instead forms aggregates, when the fusion protein does not have the hRBD domain removed by a TEV protein cleavage enzyme (p. 5, paragraph beginning “As a result, as shown in FIG. 7,”).
In view of the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong, it would have been obvious for a person of ordinary skill in the art to modify nucleotide encoding fusion protein such that the RID domain linker region to comprise a TEV cleavage site and to modify for the vector encoding thereof to also encode a TEV cleavage protein, thereby arriving at the invention of claim 6.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success of modifying nucleotide encoding fusion protein such that the RID domain linker region to comprise a TEV cleavage site in order provide a cleavage site to remove the RID domain of the expressed proteins to form nanoparticles and prevent aggregate formation. This is because Seong taught purifying the vaccine viral-like particles formed after cleaving with TEV protein cleavage enzyme, the vaccine forms aggregates and not viral-like particles when the hRBD domain is still attached. An ordinary artisan would have been motivated to and would have had a reasonable expectation of success of modifying the vector to also comprise a TEV protein cleavage enzyme in order to direct the cleavage of the RID domain and support nanoparticle formation.
For the reasons stated herein, claims 1-4, 6-9, 11, 14-16, 18, and 20 of this application are unpatentable over claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong.
Claims 5, 13, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, and 8 of patent’630 in view of Lopez-Sagaseta, Graham, and Seong, as applied to 1-4, 6-9, 11, 14-16, 18, and 20 above, and further in view of Chichili and Odani.
Claims 1, 4-6, and 8 of patent’630 and the relevant teachings of Lopez-Sagaseta, Graham, and Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 are discussed above and incorporated herein.
Graham further teaches a nanoparticle-based vaccine fusion protein comprising a linker sequence between the amino acid sequences not normally found joined together via peptide bond in their natural environment (para [0058, 0150]). Graham teaches the linkers can be used to ensure domains are in a proper special orientation such as positioning the immunogenic portion to elicit an immune response (para [0112]).
The combination of claims 1, 4-6, and 8 of patent’630, Graham, and Seong does not explicitly recite wherein at least one linker protein is located between the target protein, the encapsulin protein and the RNA interacting domain (RID) protein, and a linker with an amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18.
Chichili teaches glycine-rich linkers are flexible, connecting various domains in a single protein without interfering with the function of each domain and can be used in recombinant fusion proteins (Abstract; p. 164, col 1, para 4 – p. 164, col 2, para 1). Chichili teaches a glycine-rich amino acid sequence comprising the amino acid sequence of GSGSGS (Table 1; Figure 1).
Odani teaches all codons for each amino acid (para [0112]).
In view of the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong, Chichili, and Odani, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the nucleic acid encoding a fusion of an RID domain, encapsulin, and an antigen as well to comprise the GSGSGS linker taught by Chichili and/or to convert the GSGSGS linker to a nucleic acid sequence of ggt tct ggt tct ggt tct in order to incorporate a nucleic acid encoding the GSGSGS linker into an expression construct encoding the fusion protein, thereby arriving at the invention of claims 5, 13, and 21.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to substitute linkers in the fusion protein taught by the combination of patent’630, Lopez-Sagaseta, Graham, and Seong because it is obvious to modify the nucleic acid encoding a fusion of an RID domain, encapsulin, and an antigen as well to comprise the nucleic acid comprising the GSGSGS linker taught by Chichili in order to join sequences not normally found joined together to ensure domains in the fusion protein are able to function properly in the nanoparticle. An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to convert the amino acid sequence of the GSGSGS linker taught by Kwong to a nucleotide sequence in order to use of the linker and/or fusion protein in an expression construct in an expression construct because Odani taught the use of any known codon for the desired amino acid in a peptide chain is merely use of a known codon to arrive at predictable result.
For the reasons stated herein, claims 5, 13, and 21 of this application are unpatentable over the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, Seong, Chichili, and Odani.
Claims 10 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, and 8 of patent’630 in view of Lopez-Sagaseta, Graham, and Seong, as applied to 1-4, 6-9, 11, 14-16, 18, and 20 above, and further in view of Lagoutte.
Claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong as applied to instant claims 1-4, 6-9, 11, 14-16, 18, and 20 are discussed above and incorporated herein.
Regarding claim 10 and 17 , The combination of claims 1, 4-6, and 8 of patent’630, Graham, and Seong does not explicitly recite wherein the transformed host cell is Escherichia coli.
Lagoutte teaches producing encapsulin-based nanoparticle in Escherichia coli (E. coli) that can be used for vaccines (Abstract; p. 3624, col 1, para 2; p. 3626, col 2, para 4).
In view of the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, Seong, and Lagoutte, it would have been obvious for a person of ordinary skill in the art that the host cell transformed with the expression vector to produce the vaccine taught by the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong, be E. coli cells as taught by Lagoutte, thereby arriving at the invention of claims 6, 10, and 17.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to substitute the host cell for producing a recombinant protein and/or vaccine for another host, such as E. coli taught by Lagoutte, to achieve a predictable result because they are equivalent host cells with the same function. Furthermore, an ordinary artisan would have been motivated to and would have had a reasonable expectation of success modify the host cell transformed with the expression vector to produce the vaccine taught by the combination of claims 1, 4-6, and 8 of patent’630, Graham, and Seong to be E. coli cells because Lagoutte taught producing encapsulin-based nanoparticles in E. coli that can be used for vaccines.
For the reasons stated herein, claims 10 and 17 of this application are unpatentable over the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, Seong, and Lagoutte.
Claim 12 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, and 8 of patent’630 in view of Lopez-Sagaseta, Graham, and Seong, as applied to 1-4, 6-9, 11, 14-16, 18, and 20 above, and further in view of Choi.
Claims 1, 4-6, and 8 of patent’630 and the relevant teachings of Lopez-Sagaseta, Graham, and Seong as applied to claims 1-4, 6-9, 11, 14-16, 18, and 20 are discussed above and incorporated herein.
Regarding claim 12, the combination of claims 1, 4-6, and 8 of patent’630, Graham, and Seong does not explicitly recite wherein the vaccine fusion protein comprises the viral antigen fused to the C-terminus of the encapsulin protein.
Choi teaches antigen-encapsulin nanoparticle vaccines including comprising an antigen inserted at the N-terminal or C-terminal ends of encapsulin (i.e., OT-1-Encap-N and OT-1-Encap-C, respectively) or the loop region of encapsulin (i.e., OT-1-Encap-L) (Abstract; p. 7341, col 1, para 1). OT-1-Encap-C demonstrated the ability to induce T cell proliferation at low concentrations while OT-1-Encap-N and OT-1-Encap-L required high or moderate concentrations to induce proliferative responses (p. 7342, col 1, para 1 – p. 7342, col 2, para 1). Choi teaches the difference in the capacity to induce T cell proliferation may could be due to less effective processing of antigen peptides inserted in loop region and at the N-terminal of encapsulin, compared to those inserted at the C-terminal end, consistent with their previous study (p. 7342, col 1, para 1 – p. 7342, col 2, para 1).
In view of the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, Seong, and Choi, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the fusion protein taught by the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong such that the viral antigen is linked to the C-terminus of the encapsulin protein as taught by Choi, thereby arriving at the invention of claim 12.
An ordinary artisan would have been motivated to and would have had a reasonable expectation of success to modify the fusion protein taught by the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, and Seong such that the viral antigen is linked to the C-terminus of the encapsulin protein. This because Choi teaches antigen-encapsulin nanoparticle vaccines including comprising an antigen inserted at the N-terminal or C-terminal ends of encapsulin or the loop region of encapsulin, and the most effective formulation was the OT-1-Encap-C.
For the reasons stated herein, claim 12 of this application are unpatentable over the combination of claims 1, 4-6, and 8 of patent’630, Lopez-Sagaseta, Graham, Seong, and Choi.
Relevant Art Not Relied Upon In Rejections
Kwong et al. (US 2014/0271699 A1; cited on the attached Form PTO-892; hereafter “Kwong”) teaches a viral protein antigen linked to an encapsulin as well as a viral antigen stabilized by an encapsulin nanoparticle (para [0169, 0321, 0324]; Claim 23 and 28). Kwong teaches an encapsulin with an amino acid sequence identical to the amino acid sequence of instant SEQ ID NO: 1 (para [0040, 0324]; SEQ ID NO: 354, see sequence alignment below).
PNG
media_image8.png
486
617
media_image8.png
Greyscale
Conclusion
No claims are currently allowed for the reasons as stated above. Applicants must
respond to the objections/rejections in this Office action to be fully responsive in
prosecution.
The instant Office Action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SCOTT E. MULDER whose telephone number is (571)272-2372. The examiner can normally be reached Monday - Friday 7:30 AM - 3:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SCOTT E. MULDER/Examiner, Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656