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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Jan. 16, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Jan. 16, 2026. Claims 1, 3-5, 7-9 and 15 are pending and are currently examined.
Claim Rejections - 35 USC § 112 (Written Description)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(New) Claims 1, 3-5, 7-9 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. However, a showing of possession alone does not cure the lack of a written description. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 969-70, 63 USPQ2d 1609, 1617 (Fed. Cir. 2002). For example, it is now well accepted that a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, that does not mean that all originally-filed claims have adequate written support. The specification must still be examined to assess whether an originally-filed claim has adequate support in the written disclosure and/or the drawings. See MPEP 2163. I.
In Regents of the University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997), the Court decided that adequate written description of genetic material "requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention." Id. 43 USPQ2d at 1404 (quoting Fiefs, 984 F.2d at 1171, 25 USPQ2d at 1606). In AbbVie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (Court of Appeals, Federal Circuit 2014), the Court ruled that “[W]ith the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and . . .cover any compound later actually invented and determined to fall within the claim' s functional boundaries.”).”
The amended claims 1, 8 and 9 are drawn to a method or a composition or a kit for producing a functional bacteriophage in a cell-free host- independent expression system comprising. Here the “functional” is directed to a bacteriophage with a generic function.
For the functional bacteriophage, the instant specification only discloses a lytic ability of the claimed bacteriophage such as shown in Figures 2-3 for the cell lysis function at the present of the bacteriophage-host specific expression factor encoded by sigA in a plasmid. However, a claimed functional bacteriophage also could include the ability of gene delivery, treatment, prevention, therapeutic, etc.
Therefore, the instant specification does not provide evidence to support or demonstrate that the claimed bacteriophage possessing a generic function except the lytic ability.
Based on the description above, the skilled artisan cannot envision the detailed method/composition/kit for producing a bacteriophage with any other functions except the lytic ability. Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph.
Accordingly, the specification does not provide sufficient written description support for the invention as claimed.
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 of this title, 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.
(Previous rejection-withdrawn) Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Garamella et al. (ACS Synth Biol. 2016 Apr 15;5(4):344-55, submitted in IDS on Jan. 20, 2022 ) as evidenced by Bervoets et al. (Nucleic Acids Res. 2018 Feb 28;46(4):2133-2144, submitted in IDS on Jan. 20, 2022 ) and Watabe et al. (Proc Natl Acad Sci U S A. 1982 Sep;79(17):5245-8) as applied to 1, 3-5, 7-10 and 15 above and in view of Haq et al. (Virol J. 2012 Jan 10;9:9, submitted in IDS on Jan. 20, 2022).
This rejection is withdrawn in view of the amendment filed on Jan. 16, 2026.
(Previous rejection-withdrawn) Claims 1, 3-5, 7-10 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Garamella et al. (ACS Synth Biol. 2016 Apr 15;5(4):344-55, submitted in IDS on Jan. 20, 2022 ) as evidenced by Bervoets et al. (Nucleic Acids Res. 2018 Feb 28;46(4):2133-2144, submitted in IDS on Jan. 20, 2022 ) and Watabe et al. (Proc Natl Acad Sci U S A. 1982 Sep;79(17):5245-8), and in view of Kilcher et al. (Trends Microbiol. 2019 Apr;27(4):355-367, Epub 2018 Oct 12.).
This rejection is withdrawn in view of the amendment filed on Jan. 16, 2026.
(New Rejection-necessitated by amendment) Claims 1, 3-5, 7-9 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Rustad et al. (J Vis Exp. 2017 Aug 17;(126):56144, hereinafter “Rustad”) in view of Bervoets et al. (Nucleic Acids Res. 2018 Feb 28;46(4):2133-2144, submitted in IDS on Jan. 20, 2022), Meijer et al. (Nucleic Acids Res. 2004 Feb 18;32(3):1166-76) and Nies et al. (Nat Commun 9, 1583 (2018)).
The amended base claims 1 and 8 are directed to a method or a composition for producing a functional bacteriophage in a cell-free host-independent expression system comprising: 1). providing a cell lysate derived from a microorganism which is different from the host of the bacteriophage, 2). adding at least one nucleotide sequence encoding at least one bacteriophage-host specific expression factor, and 3). adding a genome of a bacteriophage, wherein the cell lysate is an E. coli lysate, and wherein the bacteriophage-host specific expression factor is a sigma factor.
Rustad teaches a method for the synthesis of infectious bacteriophages (functional bacteriophage) in an E. coli-based Cell-free Expression System and discloses that the cell-free transcription/translation platform allows for an impressive level of control and flexibility of reaction conditions compared to in vivo methods of study. They can finely tune many biochemical and genetic components/composition of a phage reaction and directly observe the effects in less than 24 h (See Abstract; page 9, paragraph 1-3). Rustad teaches that the E. coli-based Cell-free Expression System uses E. coli extract (See page 2, paragraph 1) and add the genome DNA of the MS2 (RNA, 3.4 kb), ΦΧ174 (ssDNA, 5.4 kb), and T7 (dsDNA, 40 kb) phages (See page 1, Introduction) and the sigma factor of sigma 70 (See page 9, paragraph 1).
Accordingly, Rustad teaches the claims for producing the functional bacteriophage, E. coli-based cell-free host- independent expression system using the E. coli. cell lysate, and sigma factor 70 that is a primary (housekeeping) sigma factor in Gram-negative bacteria like E. coli. Although the cell lysate is derived from the E. coli and the produced phages are all E. coli. -hosted phages like MS2, ΦΧ174 and T7, Rustad teaches that the cell-free reaction system can recapitulate the entire sigma factor transcription scheme by exogenously supplying six other E. coli sigma factor genes under the promoter consensus sequence of sigma 70. This allows the capability to synthesize all bacteriophages whose genomes are compatible with E. coli's transcription/translation machinery (See page 9, paragraph 1), which indicates a host-independent possibility for producing the bacteriophage with an exogenous sigma factor. Rustad also discloses that the cell-free approach allows the researcher to probe complicated biological processes like the biophysics of self-assembly with model systems, like bacteriophages, without the intrinsic limitations of in vivo work (See page 9). Thus, one of skilled in the art can be motivated to use Rustad’s convenient E. coli-based Cell-free Expression System to produce bacteriophages of other hosts than E. coli. for overcoming the host limitations, and there would be a reasonable expectation of success based on the following teachings:
Bervoets teaches a set of orthogonal expression systems for use in Escherichia coli based on heterologous sigma factors from Bacillus subtilis. As this set covers a wide range of transcription initiation frequencies, it enables tuning of multiple outputs of the circuit in response to different sensory signals in an orthogonal manner. This sigma factor toolbox constitutes an interesting expansion of the synthetic biology toolbox and may contribute to the assembly of more complex synthetic genetic systems in the future (See Abstract). Bervoets discloses that for this work with E. coli as host, 6 out of the 19 known/predicted sigma factors from the distantly related Gram-positive model organism B. subtilis were selected (Figure 1B, page 2135 and below). Based on the teachings of Bervoets, the heterologous sigma factor from Bacillus subtilis can recognize specific promoter sequences of E. coli. for initiating the transcription cascade.
PNG
media_image1.png
527
686
media_image1.png
Greyscale
Meijer teaches analyzing the strong early sigA-RNA polymerase-dependent promoters C2, A2c and A2b of the lytic B.subtilis phage Phi29, and demonstrating that the phage promoters contain functional UP elements (See Abstract). Meijer discloses that native DNA sequences located upstream of the -35 boxes of the phi 29 promoters C2, A2b and A2c enhance promoter activity in vivo as well as in vitro. In addition, interaction of the αCTD of the B.subtilis RNAP with these upstream promoter sequences is required for stimulating promoter activity. Based on the results obtained, they conclude that the phi29 promoters A2b, A2c and C2 contain functional UP elements (See page 2, right column), where the presence of a UP element has been provided only for the sigA-dependent B.subtilis promoters (See page 2, left column, paragraph 1). Accordingly, Meijer teaches the important role of sigA for the expression of the lytic B.subtilis phage Phi29.
Nies discloses that they implementing the DNA replication machinery of the Φ29 (phi 29) virus in a cell-free gene expression system, which is so-called PURE (Protein synthesis Using Recombinant Elements) system, a well-defined E. coli-based reconstituted protein synthesis platform (See Abstract; page 2, left column, paragraph 3). Nies teaches that the minimal set of Φ29/Phi 29 replication proteins can be synthesized from their genes in the PURE E. coli system and can collectively amplify their own DNA template without loss of information (See page 2, right column, paragraph 3). Thus, one of ordinary skill in the art can use the E. coli system of Rustad to make a functional phi 29.
Accordingly, Bervoets teaches a heterologous sigma factors expression system in E. coli and the heterologous sigma factors including sigA are from Bacillus subtilis. The heterologous system will contribute to the assembly of more complex synthetic genetic systems in the future. Meijer teaches that the promoter of the phi29 contains the UP element that is sigA depended and the promoter activity of phi29 can be enhanced by sigA factor in vivo and in vitro (See page 1167, right column). Nies teaches the phi 29 virus can be replicated in a E. coli-based cell-free gene expression system.
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 combine the teachings of Rustad, Bervoets, Meijer and Nies to arrive at an invention as claimed. Rustad teaches that the E. coli. -based cell-free reaction system can recapitulate the entire sigma factor transcription scheme by exogenously supplied sigma factors. Bervoets teaches the benefit and possibility to generate a heterologous expression system by transforming and express Bacillus subtilis-specific sigma factors in E. coli cells and enhance the gene expression. Meijer teaches that the promoter regions of Bacillus subtilis Phi 29 phage contain the UP element that is a strong sigA-RNA polymerase-dependent promoters. In Nies’ study, the synthesizing phi 29 proteins are demonstrated in the well-defined E. coli-based reconstituted protein synthesis platform, PURE system. Therefore, one would have been motivated to replace the sigma factors of Rustad by the sigma factors such as sigA of Bacillus to express a heterologous bacteriophage like Phi29 other than E. coli phage. Nies already teaches that the phi 29 phage can be replicated and expressed in the E. coli-based cell free system, therefore, there would have been a reasonable expectation of success to use Rustad system with the sigma factors of Bervoets and Meijer to produce a functional bacteriophage as claimed.
Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Regarding claims 3-5 and 15, Nies teaches that phi 29 replication proteins can be synthesized from their genes in the PURE system and can collectively amplify their own DNA template without loss- of information (See page 2, right column, paragraph 3), where the PURE system is E. coli based but the host of phi 29 is the gram-positive bacteria, Bacillus, not E. coli.
Regarding claim 7, it requires that at least one bacteriophage-host specific expression factor is sigA. Because Rustad teaches that the cell-free reaction system can recapitulate the entire sigma factor transcription scheme by exogenously supplying (See page 9), Based on the teachings of Bervoets, Meijer and Nies, it would be obvious for one of skilled in the art to add the sigma factors of Bacillus to test the express of a bacteriophage of Bacillus in the E.coli-based cell free system because the TXTL systems has been simplified, facilitating the accessibility of this technology
to a larger community. Based the teachings, sigma 70 in E.coli and sigA in Bacillus are both housekeeping factor and are critical for transcribing gene essential for growth (See Bervotes, page 2134, left column, paragraph 3). Also, Meijer teaches that the promoters C2, A2c and A2b of the lytic B.subtilis phage phi29 is sigA-dependent. Therefore, it would be obvious for one of skilled in the art to select the sigA for the sigma factors if need, and the result would be predictable.
Regarding claim 9, it is directed to a kit for producing a functional bacteriophage as claimed. Rustad teaches that Noireaux laboratory receives research funds from MYcroarray, a distributor of the MYtxtl cell-free protein expression kit (See page 9, disclosures).
Responses to Applicant’s Remarks
Applicant’s arguments filed on Jan. 16, 2026 has been received and fully considered.
Applicant’s arguments on rejection under 35 U.S.C. § 103 is considered. The rejections are withdrawn. The references Garamella, Watabe and Kilcher are withdrawn. All arguments regarding these references are moot.
New references are cited based on the amendment filed on Jan. 16, 2026. The reference Bervoets are maintained in the current rejection for the combining teaching with the new cited primary prior art.
Applicant argued that Bervoets does not suggest any applicability in cell-free transcription or in the assembly of functional bacteriophages in a non-host, E. coli-based cell-free expression system and its plasmid-based expression of these sigma factors proved problematic and discourage a skilled artisan from using the simple coexpression approach employed in the present invention (See Remarks, page 3).
These arguments are not found persuasive because Bervoets is used here for teaching that the sigma factors of Bacillus subtilis can be recognized by E. coli. It is applicable to be used as a combined teachings to support the primary reference’s E. coli-based cell-free expression system. In addition, the instant specification also use a pET20b( +) plasmid to express sigma factors (See specification, e.g., [0025]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am to 4:30 pm, EST.
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, Thomas J. Visone can be reached on (571) 270-0684. 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.
/RUIXUE WANG/ Examiner, Art Unit 1672 /NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672