The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicants’ amendments/remarks received March 5, 2026.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 2-3, 6-8 are canceled. Claims 19-22 have been withdrawn. Claims 1, 4-5, 9-18, 23-26 are under consideration.
Priority: This application is a CIP of PCT/US2020/066731, filed December 22, 2020, which claims benefit of provisional application 62/953074, filed December 23, 2019.
Objections and Rejections
Where the description of a patent application discusses a sequence of 4 or more amino acids or a sequence of 10 or more nucleic acids, reference must be made to the sequence by use of the sequence identifier preceded by “SEQ ID NO:” in the text of the description even if the sequence is also embedded in the text of the description of the patent application (see 37 CFR 1.821, especially paragraphs (a)-(d)). The sequence identifier may be used in either the drawing or the Brief Description of Drawings (see MPEP 2422).
Objection to the Specification:
The specification is objected to for failure to comply with the sequence rules for the
reasons as given above. The specification refers to sequences without identifiers at: see at least
paragraphs 0016, 0098 (of the application publication).
The sequences must be in computer readable form (CRF) for search. See also MPEP
2422 for sequence compliance requirements. Appropriate correction is required.
Objection to the Drawings:
The drawings are objected to because at least Fig. 9 recites a sequence without a corresponding SEQ ID NO. The sequences must be in computer readable form (CRF) for search. See MPEP 2422 for sequence compliance requirements. Appropriate correction is required.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Reply: In the amendments/remarks filed March 5, 2026, Applicants have amended the specification to disclose sequences and their corresponding identifiers. However, the sequence listing submitted is not in the correct format. As noted in the sequence listing report, sequence listings submitted in either non-provisional applications filed under 35 U.S.C. 111(a) or provisional applications filed under 111(b) that have a filing date BEFORE July 1, 2022 must be in ASCII text format and comply with WIPO Standard ST.25 and 37 CFR 1.821 through 1.825. Sequence listings submitted in either PCT applications or U.S. national phase applications submitted under 35 U.S.C. 371(c) that have an international filing date BEFORE July 1, 2022 must be in ASCII text format and comply with WIPO Standard ST.25 and/or 37 CFR 1.821 through 1.825.
The instant non-provisional application has a filing date of June 24, 2022 and therefore ST.25 format is required. Applicants submitted a sequence listing having the ST.26 format when the ST.25 format is required.
Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-5, 9-18, 23-26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the genetically modified bacterial cell" in the claim. There is insufficient antecedent basis for this limitation in the claim.
Claims 4-5, 9-18, 23-26 are included in this rejection because they are dependent on the above claim.
Reply: In view of Applicants’ amendments/remarks, the previous 112(b) rejections have been withdrawn. However, the claims remain rejected under a new 112(b) rejection for the reasons noted above.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 5, 9-14, 17-18, 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Sorek et al. (US 20220175807; previously cited) in view of Duschene et al. (2012 BioMol Concepts 3(3): 255-266). Sorek et al. disclose viperins, including prokaryotic viperins (pVips), that synthesize antiviral compounds, and engineered host cells comprising nucleic acid molecules encoding the viperins (at least abstract, p. 1-5). Sorek et al. disclose a genetically modified cell comprising nucleic acid molecules encoding a pVip protein, the nucleic acid molecules operably linked to a promoter (at least paragraphs 0033-0041; instant claim 1). Sorek et al. disclose the cell is a bacteria cell selected from Bacteroides (at least paragraphs 0050, 0188). Sorek et al. disclose a genetically modified cell expressing human viperin and producing ddhCTP (at least paragraph 0039), where Sorek et al. disclose the human viperin gene (SEQ ID NO: 1) and human viperin protein (SEQ ID NO: 2), where SEQ ID NO: 2 of Sorek et al. has 100% sequence identity with instant SEQ ID NO: 1 and comprises the motif CXXXCXXC (Table 4). Sorek et al. disclose the pVip introduced into the bacterial cell can be a functional pVip fragment (at least paragraph 0279) and having at least 60% sequence identity to SEQ ID NO: 2 (at least paragraph 0068). Sorek et al. disclose that viperin found in eukaryotic cells is anchored through its N-terminal domain (at least paragraph 0043). Sorek et al. do not explicitly teach that the functional pVip lacks an N-terminal signal.
Duschene et al. disclose the structure of viperin (at least p. 258-260). Duschene et al. disclose that a viperin having loss of the N-terminal amino acids 1-44 has increased solubility and reconstitution of the truncated viperin improved the stability of the protein (at least p. 260).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the prior art references and arrive at the claimed genetically modified host cell comprising nucleic acid molecules linked to a promoter, the nucleic acid molecules encoding Vips that synthesize antiviral compounds, where the genetically modified host cell is a Bacteroides cell, where the Vip comprises human viperin protein thereby comprising instant SEQ ID NO: 1 and the motif CXXXCXXC and does not include an N-terminal human localization signal, and where the synthesized antiviral compounds include ddhCTP (instant claims 1, 23-24). The motivation to do so is given by the prior art. Sorek et al. disclose introducing nucleic acid molecules encoding Vip into a genetically modified bacterial cell, including a Bacteroides cell, and producing ddhCTP, where Sorek et al. disclose the Vip is a functional fragment of a Vip, where the Vip is human viperin protein. Sorek et al. disclose that viperin found in eukaryotic cells is anchored through its N-terminal domain. Duschene et al. disclose that viperin not having the N-terminal domain has increased solubility and improved stability. Therefore, one ordinary skill would have reasonable expectation to remove a N-terminal localization domain from the viperin of Sorek et al. as suggested in Duschene et al. in the genetically modified Bacteroides cell producing ddhCTP of Sorek et al. because doing so increases solubility and stability of the Vip and also maintains its functionality. One of ordinary skill would have a reasonable expectation of success because the structure of Vip proteins are known and the prior art disclose expressing Vi proteins in bacterial cells to produce antiviral compounds.
Regarding instant claims 5, 9, 23-24, Sorek et al. disclose a genetically modified cell expressing human viperin and producing ddhCTP (at least paragraph 0039), the cell is a bacteria cell selected from Bacteroides (at least paragraphs 0050, 0188), where Sorek et al. disclose the human viperin gene (SEQ ID NO: 1) and human viperin protein (SEQ ID NO: 2), where SEQ ID NO: 2 of Sorek et al. has 100% sequence identity with instant SEQ ID NO: 1 and comprises the motif CXXXCXXC (Table 4).
Regarding instant claims 10, 23-24, Sorek et al. disclose the Vip proteins are also selected from Table 3 or SEQ IDS: 409-789 (at least paragraphs 0079, 0111), where SEQ ID NO: 409 (Selenomonas ruminatium S137) has 100% sequence identity to instant SEQ ID NO: 2 (also Selenomonas ruminatium S137).
Regarding instant claims 11, 23-24, Sorek et al. disclose the Vip protein is SEQ ID NO: 411 (Psychrobacter lutiphocae DSM 21542) (Table 3), which has 100% sequence identity to instant SEQ ID NO: 3 (also Psychrobacter lutiphocae DSM 21542).
Regarding instant claims 12, 23-24, Sorek et al. disclose the Vip protein is SEQ ID NO: 428 (Fibrobacter sp. UWH6) (Table 3), which has 100% sequence identity to instant SEQ ID NO: 4 (also Fibrobacter sp. UWH6).
Regarding instant claims 13, 23-24, Sorek et al. disclose the Vip protein is SEQ ID NO: 430 (Pseudoalteromonas ulvae TC14) (Table 3), which has 100% sequence identity to instant SEQ ID NO: 5.
Regarding instant claims 14, 25-26, Sorek et al. disclose that the kinase cytidylate monophosphate kinase 2 (CMPK2) is adjacent to the viperin gene; this kinase phosphorylates CMP to become CTP thus generating the substrate of viperin enzyme (at least paragraphs 0005, 0044). Sorek et al. disclose that in some embodiments, a gene encoding Vip is located in the vicinity of a gene encoding a nucleotide kinase, the nucleotide kinase is selected from CMPK2 (at least paragraph 0065). It would have been obvious to one of ordinary skill in the art to further modify the genetically modified Bacteroides of Sorek et al. in view of Duschene et al. noted above to express CMPK2 because Sorek et al. disclose that CMPK2 generates the substrate for viperin enzyme. Additionally, regarding instant claim 26, Sorek et al. reasonably disclose a human CMPK2 (at least paragraph 0336).
Regarding instant claim 17, Sorek et al. disclose the genetically modified cell comprising the nucleic acid molecules encoding viperins (at least paragraphs 0013-0014), where the cell is a bacteria cell selected from Bacteroides (at least paragraphs 0050, 0188), where the Vip synthesized compounds are for treating viral infections, including a gastrointestinal viral infection (at least paragraphs 0150-0151).
Regarding instant claim 18, Sorek et al. disclose a composition comprising the genetically modified cells and the produced antiviral compounds (at least paragraphs 0039-0041).
Reply: In view of Applicants’ amendments/remarks, the claims remain unpatentable under 35 U.S.C. 103 for the reasons noted above.
Applicants assert that Sorek et al. do not teach a viperin polypeptide that lacks an N-terminal human localization signal.
Applicants’ remarks are not persuasive. Sorek et al. disclose a genetically modified cell expressing human viperin and producing ddhCTP (at least paragraph 0039), the cell is a bacteria cell selected from Bacteroides (at least paragraphs 0050, 0188), where Sorek et al. disclose the human viperin gene (SEQ ID NO: 1) and human viperin protein (SEQ ID NO: 2) (Table 4). Sorek et al. disclose that viperin found in eukaryotic cells is anchored through its N-terminal domain (at least paragraph 0043). Therefore, Sorek et al. reasonably disclose that the viperin polypeptide has a N-terminal localization domain.
Sorek et al. further disclose that the pVip introduced into the bacterial cell can be a functional pVip fragment (at least paragraph 0279) and having at least 60% sequence identity to SEQ ID NO: 2 (at least paragraph 0068).
While Sorek et al. do not explicitly teach that the functional pVip lacks an N-terminal signal, it would have been obvious to do so because Duschene et al. disclose that a viperin having loss of the N-terminal amino acids 1-44 has increased solubility and reconstitution of the truncated viperin improved the stability of the protein (at least p. 260).
Therefore, it would have been obvious to one of ordinary skill to remove a N-terminal localization domain from the viperin of Sorek et al. as suggested in Duschene et al. in the genetically modified Bacteroides cell producing ddhCTP of Sorek et al. because doing so increases solubility and stability of the Vip and also maintains its functionality. One of ordinary skill would have a reasonable expectation of success because the structure of Vip proteins are known and the prior art disclose expressing Vi proteins in bacterial cells to produce antiviral compounds.
Claims 1, 4 are rejected under 35 U.S.C. 103 as being unpatentable over Sorek et al. (US 20220175807; previously cited) in view of Duschene et al. (2012 BioMol Concepts 3(3): 255-266) and Whitaker et al. (2017 Cell 169: 538-546; previously cited). The teachings of Sorek et al. and Duschene et al. over at least instant claim 1 are noted above.
Regarding instant claim 4, Sorek et al. disclose the cell comprising pVips is a bacteria cell selected from Bacteroides (at least paragraphs 0050, 0188) and where the Vip synthesized compounds are for treating viral infections, including a gastrointestinal viral infection (at least paragraphs 0150-0151). Whitaker et al. disclose Bacteroides is the most abundant genus in the Western microbiota (p. 538) and the genetic tools available for engineering Bacteroides to assemble and integrate constructs so that protein expression can be tuned systemically and predictably (p. 538). Whitaker et al. disclose species of Bacteroides include B. thetaiotaomicron and B. ovatus (p. 539). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute or incorporate a B. thetaiotaomicron cell of Whitaker et al. for the Bacteroides host cell disclosed in Sorek et al. that is genetically modified to comprise nucleic acid molecules encoding pVip proteins and where the pVip lacks a N-terminal localization domain as suggested in Duschene et al. as noted above. One of ordinary skill would have a reasonable expectation of success because the prior art discloses Bacteroides is a bacteria cell that can be modified to comprise nucleic acid molecules encoding proteins.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining Sorek et al. and Duschene et al. are the same as noted above.
Claims 1, 14, 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Sorek et al. (US 20220175807; previously cited) in view of Duschene et al. (2012 BioMol Concepts 3(3): 255-266), Strickler et al. (2008 Fusion Tags for Protein Expression and Purification in BioPharm International, Vol. 2008 Supplement, Issue 5: 9 pages; previously cited), and Chen et al. (2013 Adv Drug Deliv Rev 65(10): 1357-1369, NIH Public Access copy (32 pages); previously cited). The teachings of Sorek et al. and Duschene et al. over at least instant claims 1, 14 are noted above.
Regarding instant claims 14, 15-16, Sorek et al. in view of Duschene et al. disclose a genetically modified Bacteroides cell expressing viperin that lacks a N-terminal localization domain and producing antiviral compounds including ddhCTP, and further modified to express CMPK2 (see the 103 rejection of Sorek et al. in view of Duschene et al. above). Duschene et al. disclose that a viperin having loss of the N-terminal amino acids 1-44 has increased solubility and reconstitution of the truncated viperin improved the stability of the protein (at least p. 260). Strickler et al. disclose fusion tags can improve the expression and solubility of recombinant proteins (at least p. 1-2). Strickler et al. disclose that while no single fusion tag can increase the expression and solubility of all target proteins, fusion tags having more success than others in increasing the solubility of many proteins include MBP and SUMO (at least p. 4, 7). Chen et al. disclose that an indispensable component of recombinant fusion proteins, linkers have shown increasing importance in construction of stable, bioactive fusion proteins, including improving biological activity, increasing expression yield (at least p. 1). Chen et al. disclose flexible linkers are usually applied when the joined domains require a certain degree of movement or interaction; the most commonly used flexible linkers have sequences consisting of Gly and Ser residues (“GS” linker), including the widely used Gly-Gly-Gly-Gly-Ser linker (at least p. 4). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to remove a N-terminal signal from the viperin of Sorek et al. as disclosed in Duschene et al. and incorporate a MBP fusion tag of Strickler et al. and a flexible GS linker (i.e. Gly-Gly-Gly-Gly-Ser) of Chen et al. at the truncated N-terminal of the viperin. One of ordinary skill would have a reasonable expectation of success because the prior art discloses fusion tags like MBP can be incorporated at the N-terminus of recombinant proteins to enhance expression and solubility.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining Sorek et al. and Duschene et al. are the same as noted above.
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Marsha Tsay whose telephone number is (571)272-2938. The examiner can normally be reached M-F.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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