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 .
Remark
Preliminary amendment filed on May 12, 2023 is acknowledged.
claims 10-11, 13, 15-18, 20, 23-24, 36-43, 46-50, 52, 54, 56-58 were canceled.
Claims 3-5, 7-8, 12, 14, 19, 44-45,51, 53 and 55 were amended.
Claims 1-9, 12, 14, 19, 21-22, 35, 44-45, 51, 53, 55 are pending.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-7, 12, 14 and 22 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Cao et al. (PLOS. Pathogens, May 22, 2019, pages 1-26; https://doi.org/10.1371/journal.ppat.1007759).
Cao et al. teach a method for making at least two oligomers of HCV E1/E2 genetically engineered recombinant HCV E1/E2 heterodimer that comprises ectodomains of HCV E1E2 heterodimer with either an Fc-tag or DHD15 Tag a de novo designed heterodimeric, wherein each of the “Tag “ is covalently linked to the truncated C terminus of the E1 or E2 respectively. The method for making such E1/E2 modified construct is presented by the cited reference at the section of Materials and methods, the first section named as Protein expression and purification set forth below:
“The cDNA sequences encoding E1 and E2 of HCV genotype 1b, Con1 (Accession number AJ238799) and genotype 1a, H77 (Accession number AF009606) were synthesized. In order to co-express E1 (residues 192–354, for both Con1 and H77) and E2 (residues 384–717, for both Con1 and H77) glycoproteins in insect cells, the cDNA fragments of E1 and E2 excluding the transmembrane domains were sub-cloned into a p FastBac Dual vector (Invitrogen) (E1E2), then mouse IgG Fc homodimeric fragment with a Flag and a 6xHis tag at its C-termini was fused to the C-termini of E1 and E2, respectively (E1E2-Fc). Similarly, a de novo designed heterodimeric tag (DHD15), which contains a 6xHis tag and a Flag tag at its C-termini, was fused to the C-termini of E1 and E2, respectively (E1E2-DHD15). In parallel, both E1 and E2 fused with mouse IgG Fc with a 6xHis tag at the C-termini were also individually cloned to the pFastBac vector (E1-Fc and E2-Fc). Similar cDNA fragments, including E1E2, E1E2-Fc, E1E2-DHD15 as well as E1-Fc and E2-Fc were sub-cloned into pMlink co-expression vector [for transient expression in HEK293F cells.
It is worth to note that the Fc-Tag and DHD15 Tag are considered as a scaffold element as evidenced by Knopp et al. Current Pharmaceutical Biotechology, 2016, Vol. 17, pp. 1315-1323). The helical hairpin DHD15 (PDB entry 6DMA) is also a computationally designed, de novo protein scaffold used as a modular, orthogonal, and stable platform for creating protein-protein interactions (PPIs). It has been specifically applied to structural biology, vaccine design, and synthetic biology to control the assembly of other proteins as evidenced by Chen et al. (Nature. 2018 Dec 19;565(7737):106–111).
Because the citation of “capable of” is only considered as a function potential rather than a structure limitation already possessed by the claimed molecule, and also because both Fc-Tag and DHD15 Tag are considered as a scaffold element as described above, the limitation of claim 1-7 are met by the cited reference explitely.
Furthermore, it is well-known in the art as evidenced by Merljak et al. (Nat. Commun. 2023, Vol. 14, 1995, pages 1-12, see Figs. 4-6), the DHD15 is a de novo designed protein that belongs to a class of four-helices bundle (4HB) heterodimers, which are structured as a bundle of alpha-helices, which is defined as a coiled-coil structure. Regarding the Fc Tag structure , the cited reference also teach that E2 adopts a central immunoglobin-like fold formed by β-sheets surrounded by short α-helices dispersed in loops. Because the Coiled-coils as a best-understood protein folds, which can be a parallel β sheets coiled-coil together and even more typically with α-helices across called α/β coiled-coil as evidenced by Hartmann et al. (eLIFE 2016, page 1-23). The cited reference teaches that the E2 of the E1E2 heterodimer adopts a central immunoglobin-like fold formed by β-sheets surrounded by short α-helices dispersed in loops . As it is shown at the last two paragraphs in section of Introduction and also Figs. 1&5, both Fig. 1 and 5 show that the secondary structures of E1 and E2 are shown as bars with α-helix in magenta and β-sheet in cyan. To this context, either the oligomers for the E1E2 heterodimers either made by DHD15, or Fc-Tag meets the limitation of claims 14.
Regarding claim 12, the citation of “capable of” is interpreted as an imbedded or inherited potential rather than a structural element. Hence, the cited reference also meet the limitations of claim 12.
It is well known in the art that the HCV envelope is made from two proteins, i.e. E1 and E2, wherein the E1 envelope protein ranges from amino acid residue 194 to 384 with transmembrane domain (TME1) located around 30 amino acid residues towards the C terminus wherein the E2 stars with amino acid residues 385 to 747 , wherein the transmembrane domainTME2) is located from amino acid residues from 717 to 746 as evidenced by Beeck et AL. (The Journal of Biological Chemistry , Vol. 275, No. 40, published on Oct. 2000, pp. 31428-31437, See Fig. 1). The antigen domain D of the E2 comprises a confirmation epitope located at the amino acid residues from 434-446. Cao et al. teaches that it is only transmembrane domain of E2 (717-746) is removed and substituted with the either FcTag or DHD15Tag. The E1E2 heterodimer taught by Cao et al. still comprises the CD81 binding site, which is the domain A of HCV E2 ranging from amino acid residues at 480-493 and 544-551, which indicated that the domain A is still present and domain D is also present, wherein the substitution is only located from Trans. Domain with the short Fc/Tag or DHD15 Tag insertion. Therefore, the cited reference also meet the limitaiton of claim 22.
To this context, the cited reference anticipates claims 1-7, 12, 14 and 22.
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.
Claim(s) 1-9, 12, 14, 19, 22, 35, 44-45, 51, 53 and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al. (PLOS. Pathogens, May 22, 2019, pages 1-26) and further in view of Houghton et al. (US Patent No. 11,186,615 ).
As it is described in the 102(a) (1) rejection, the Cao et al. teach the limitations of claims 1-7, 12, 14, 22 , however, The reference does not teach the E1E2 recombinant comprising a leader (signal ) sequence, more preferably tPA, a cleavage linker site, the particular sequence of E1 comprising the SEQ ID NO: 1, the sequence of E2 comprising the SEQ ID NO: 2 as well as using the modified E1E2 glycoprotein to induce an immune response.
Dr. Houghton et al. in US Patent 11,186615 also teach a genetically modified HCV E1E2 heterodimer, named E1-Fc Fusion/E2 Heterodimer )and a method for making and using the same, wherein the method comprises using said genetically modified E1E2 as an immunogenic antigen to make an immunogenic composition for inducing an immune response in patient. More importantly, Dr. Houghton et al. also teach using the same IgG Fc fragment to be inserted into the truncated transmembrane domain of E1 to make the E1E2 heterodimer, wherein the transmembrane domain of the E1 is removed from amino acid 330 to amino acid 384, or from amino acid 360 to amino acid 384 with a leader sequence, particularly the tPA as well as a cleavage site placed downstream of the Fc domain (The 1st paragraph of SUMMARY, and also columns 22-23) as well as E1 recombinant protein comprising a sequence comprising the SEQ ID NO: 1 and E2 comprising the SEQ ID NO: 2.
The cited reference also teaches a method for using the compositions to induce an immune response to HCV (The Abstract, the 1st paragraph of Summary and last paragraph of Summary).
Therefore, it would have been obviously for any person with an ordinary skill in the art to arrive the claimed immunogenic E1E2 heterodimers and use the same to induce an immune response because the combination of the disclosures by Cao et al. and Houghton et al. teach each of limitations with all successful approaches and results.
As there are no unexpected results have been provided, hence the claimed invention cited in claims 1-9, 12, 14, 19, 21 and 22, 4-45, 51, 53 and 54 as a whole is prima facie obvious absence unexpected results.
Conclusion
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BAO Q. LI
Examiner
Art Unit 1671
/BAO Q LI/ Primary Examiner, Art Unit 1671