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
This application is a US national phase of PCT/CN2020/133810, filed December 4, 2020, with foreign priority application CN202010594000.4, filed June 24, 2020.
Applicants filed a claim amendment on November 28, 2025: claims 2-4 are canceled; and claims 11-16 are newly added. Claims 1, 6-7, and 9-10 are amended.
Currently claims 1 and 5-16 are pending and under examination.
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.
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.
Claims 1 and 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over Hatai et al. (CELL STRUCTURE AND FUNCTION, Vol. 17, 31 December 1992, pp. 293-300, cited in IDS filed 01/05/2023, hereinafter “Hatai”) in view Zeigler (US 2019032017 A1, cited in IDS filed 01/05/2023) and Takashi et al. (JP2002058485-A, cited in PTO-892 mailed 8/28/2025, hereinafter “Takashi”).
Hatai teaches recombinant fusion proteins comprising fibronectin (C277) and the insulin-and heparin-binding domain of the α1 chain of human type V collagen, wherein the fusion protein has a cell adhesive activity and insulin binding activity; and the C277 contains three type III fibronectin repeats and one C-terminal Arg-Gly-Asp-Ser sequence (abstract, pg. 293, col. 2, para 2, Fig. 1). Hatai teaches a new biological function could be added to the cell-binding peptide of fibronectin using gene technological methods, and that these bifunctional fusion proteins, that have both cell-adhesive and growth enhancing activities, would probably be effective in the concentration of growth factors in the vicinity of cell surfaces or in the stabilization of their activities, thus the recombinant techniques taught by Hatai seem to be useful to construct the cell-adhesive proteins that are more advantageous for the proliferation of the cells in culture, as well as apply for clinical uses such as wound healing (pg. 300, col. 1, para 2).
Hatai does not teach the fusion protein comprises SEQ ID NO’s: 1
However, Takashi teaches osteogenesis-promoting fusion proteins having collagen-binding property that comprise a collagen-binding domain derived from a fibronectin, as well as conjugating the fusion protein to a collagen (abstract). Takashi teaches the human fibronectin collagen-binding domain (Geneseq Accession # ABB07964) has 100% sequence identity to instant SEQ ID NO: 4 (See sequence comparison below). Takashi teaches the osteogenesis-promoting protein is linked to the fibronectin-derived polypeptide by a genetic engineering technique, and is preferably produced in bacteria or yeast, and an amino acid or a polypeptide may be inserted as a spacer at the connecting site between the osteogenesis-promoting protein and the polypeptide derived from the fibronectin, preferably either the spacer or the spacer and its adjacent sequence include a protease recognition sequence (pg. 7, sec. 5), which meets the limitation of a linker peptide in claim 6.
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Ziegler teaches compositions for manufacturing extracellular matrix proteins, and teach extracellular matrix may comprise a plurality of collagens, and the sequences of exemplary types I-VI collagen α chains are shown in table 1, wherein SEQ ID NO: 10 contains the sequence of instant SEQ ID NO: 1 (pg. 8, Table 1, [0022]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate fusion polypeptides comprising collagen and fibronectin type III binding domains utilizing the recombinant techniques of creating fusion proteins of collagen and fibronectin domains taught by Hatai, and substitute the collagen binding domain of the fusion protein with the human collagen alpha-6 (IV) chain according to SEQ ID NO: 10 taught by Zeigler as well as substitute the fibronectin domain with the human fibronectin collagen-binding domain taught by Takashi, with a reasonable expectation of success. It would have been readily conceivable for a person skilled in the art to use a functional domain of other human collagen α chains, such as the human collagen α chain in SEQ ID NO: 10 of Ziegler, and other known human collagen α chains to obtain human collagen fragments and sequences thereof having the function of extracellular matrix active ingredients via conventional means, similarly obvious to substitute other functional fibronectin domains. Furthermore, it would be obvious and within one of ordinary skill’s wheelhouse to join two known biologically active domains with a linker as taught by Takashi, such as the linker between the collagen VI and fibronectin III binding domains, that is in the instant SEQ ID NO: 7 recited in claim 7.
Hatai teaches the resulting plasmid comprising the nucleotide sequence that encodes the fusion protein of fibronectin and type V collagen was termed pTF7520-Col-V, which meets the limitation of nucleic acid encoding the fusion protein in claim 8 and the limitation of an expression vector comprising said nucleic acid in claim 9 (pg. 294, col. 1, para 2).
Hatai teaches the fusion protein was expressed in the E. coli strain JM109 comprising the expression vector (pg. 294, col. 1, para 3), which meets the limitation of a host cell in claim 10.
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Hatai, Ziegler, and Takashi as applied to claims 1 and 5-10 above, and further in view of De Laporte et al. (PLOS ONE, 2013, vol. 8, issue 4, e2076, pgs. 1-9, hereinafter “Laporte”).
As discussed above, Takashi teaches a linker peptide in fusion proteins comprising fibronectin and collagen. Neither Hatai, Zielgler, or Takashi teach the linker peptide is (GGGS)n, where n is an integer of 1-5, nor that the protein further includes a His tag.
However, Laporte teaches construction of recombinant tenascin C, comprising fibronectin type III-like (TNCIII) domains, with a short linker sequence, GGGS, followed by a 6xHis tag at the C-terminus (abstract, pg. 2, col. 2, para 1; Figure 1).
Therefore it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate fusion polypeptides comprising collagen and fibronectin type III binding domains as taught by Hatai, Ziegler, and Takashi, and incorporate a linker peptide (GGGS)n followed by a His tag as taught by Laporte with a reasonable expectation of success. One of ordinary skill in the art would have used common well-known laboratory techniques in constructing fusion polypeptides using convention linkers (GGGS) and His tag for efficient protein production and purification.
Claims 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Hatai, Ziegler, and Takashi as applied to claims 1 and 5-10 above, and further in view of Silva (PhD Dissertation, 2013, Wageningen University, pgs. 1-166).
As discussed above, Hatai teaches the fusion proteins were produced in E. coli host cells, but does not teach the host cells are Pichia pastoris GS115 strain, nor the expression vectors recited in claim 13.
However, Silva teaches Pichia pastoris as a cell factory for the secreted production of tunable collagen-inspired gel-forming proteins (title). Silva teaches the monomeric S9 gene designed to prevent formation of collagen triple helices was inserted into the expression vector pPIC9 and transformed into strain P. pastoris GS115 (pg. 37, para 3, pg. 38, para 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to express the fusion protein comprising collagen and fibronectin type III binding domains as taught by Hatai, Ziegler, and Takashi, in a pPIC9 vector to transform a P. pastoris GS115 strain as taught by Silva with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to utilize P. pastoris strains as an efficient cell production factory for recombinant proteins as disclosed by Silva.
Response to Arguments
Applicant's arguments filed November 28, 2025 have been fully considered but they are not persuasive.
Regarding Remarks directed to the 103 rejection, Applicant argues the claimed invention is nonobvious over the combination of Haiti, Zeigler, and Takashi for at least the reason that the presently claimed fusion protein promotes cell adhesion, cell extension, and wound repair to an extent that would not have been predicted by the cited references. Applicant argues the disclosure demonstrates that the claimed fusion protein not only promotes cell adhesion, but also significantly promotes cell extension, and the cell adhesion performance is significantly higher than that of recombinant protein rhCol and recombinant protein rhFN, as seen in Fig. 4, and promotion of wound repair as seen in Fig. 5. Applicant argues the skilled artisan would not have predicted such an increase in cell extension and adhesion from the cited references.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Hatai teaches fusion proteins comprising collagen and fibronectin that promote cell adhesion and proliferation, Ziegler teaches exemplary collagen domains (such as SEQ ID NO: 1), and Takashi teaches recombinant fusion proteins comprising fibronectin that have biological effects such as cell adhesion, tissue construction and repair of tissue damage (such as SEQ ID NO: 4). Therefore, it would have been obvious to try other collagen and fibronectin domains in the teachings of Hatai to construct an optimized fusion polypeptide as presently claimed. Furthermore, Applicant’s assertion that this polypeptide has superior properties than others in the art is not clear, since the specification fails to identify if the rhCol-rhFn consists of SEQ ID NO: 1 & 4, as the only identifying information for the domains is that they are encoded by SEQ ID NO’s: 10 & 11 (pg. 9, para 2), which SEQ ID NO: 10 has 95.6% identity to SEQ ID NO: 1. Therefore, the advantageous effect the Applicant argues can not be read into the claims to assert overcoming obviousness.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657