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 .
Status of Application/Amendments/Claims/RCE 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1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/20/2025 has been entered.
It is noted that the terminal disclaimer submitted on 11/20/2025 was disapproved since the applicant’s name listed on the TD should be exactly as it is on the ADS.
Claims 13 and 14 have been newly added. Claim 10 had been amended. Claims 1-10 and 12-14 are pending. Claims 1-9 are currently withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 10 and 12-14 are the subject of the present Official action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 62/971,130 filed on 2/6/2020 under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 2/6/2020.
Withdrawn Rejections
The 103 rejection of claims 10 and 12 has been withdrawn in light of applicants claim amendments and arguments. Specifically, applicant has amended claim 10 to include an additional identification step and new claims 13 and 14.
Claim Interpretation
Claim 10 describes determining the locations on a genome of a bacteriophage wherein insertion of an n-mer barcode into the genome that is not essential for the bacteriophage for infecting a host bacterium. Applicant provides a functional definition describing what is considered essential in not preventing the bacteriophage’s plaque forming capabilities with the host bacterium.
Claim Rejections - 35 USC § 103
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 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 10 and 12-14 stand rejected under 35 U.S.C. 103 as being unpatentable over Mutalik et al. "Dual-barcoded shotgun expression library sequencing for high-throughput characterization of functional traits in bacteria." Nature communications 10.1 (2019): 308 (hereinafter Mutalik, reference of record) in view of Bohm et al. "Genes affecting progression of bacteriophage P22 infection in Salmonella identified by transposon and single gene deletion screens." Molecular microbiology 108.3 (2018): 288-305 (hereinafter Bohm) and Xu et al. "Bacteriophage therapy against Enterobacteriaceae." Virologica Sinica 30 (2015): 11-18 (hereinafter Xu, reference of record). This rejection is newly applied to address applicants claim amendments on 11/20/2025.
Claim 10: Bohm describes high-throughput method for screening gene function in bacteriophages by transposon and single gene deletion screenings (Bohm, abstract). Bohm describes generating a random insertion transposon library of 240,000 mutants in Salmonella which was used to monitor effects of individual bacterial gene disruptions on bacteriophage P22 lytic infection (Bohm, abstract, pg 296 col 1). Bohm screened over 2000 Salmonella single gene deletion mutants to identify genes that impacted either plaque formation or culture growth rates (Bohm, pg 291 col 1, table 2 and Fig 6). Bohm describes the quantitative pattern of Tn5 insertions via measurement by PCR of a region that contains the barcode unique to each Tn insertion, followed by Illumina sequencing of the amplified DNA (Bohm, pg 290 and Fig 1). Bohn does not teach administering these barcoded bacteriophages to a subject caused or infected with the host bacterium to identify the unique barcode in a sample obtained from any subject to determine the source of the barcoded bacteriophage.
Claim 10: Mutalik describes a dual-barcoded shotgun expression library sequencing (Dub-seq) technique for performing high-throughput and quantitative gain-of-function (GOF) and loss-of-function (LOF) screens (Mutalik, abstract, intro col 2 and Fig 1). Dub-seq couples shotgun cloning of random DNA fragments with competitive fitness assays to assess the phenotypic importance of genes contained on those fragments in a single tube assay (Mutalik, Discussion para 1). Mutalik demonstrated this technique by generating an E. coli Dub-seq library and assayed the phenotypic consequences of overexpressing nearly all genes on E. coli fitness under dozens of experimental conditions (Mutalik, Fig 1). In Fig 2, Mutalik shows the E. coli Dub-seq library characterization. Notably, in 2A black and red line tracks represent genes essential for viability when deleted that are encoded on the negative and positive strands. Thus, Mutalik shows insertions of these barcodes into non-essential regions. Mutalik describes applying these approaches to LOF screens to study phage infection (Mutalik, pg 6 col 2). Mutalik compares large-scale genetic gain and loss of function screens, finding a moderate overlap between genes that are beneficial when overexpressed (Mutalik, pg 7 col 2 and pg 8 col 1). Although Mutalik demonstrates the efficacy of Dub-seq in E. coli (bacteria) and fails to apply these techniques to bacteriophages, Mutalik states that Dub-seq may readily be extended to DNA from other sources for genome-wide fitness assays (Mutalik, pg 8 col 2). Mutalik does not describe applying the Dub-seq techniques for performing LOF screens in bacteriophages, testing each bacteriophage’s plaque forming capabilities to determine the essentiality of the n-mer barcode location and administering these barcoded bacteriophages to a subject caused or infected with the host bacterium as described in newly amended claims 10 and 12.
Claim 14: Mutalik lists CRISPRi as an effective technique for interrogating essential genes under multiple conditions and building libraries (Mutalik, intro).
It would have been prima facie obvious to one of ordinary skill in the art to apply the plaque formation assay as described by Bohm in bacteriophages to evaluate the essentiality of the n-mer barcode location using the Dub-seq methods described by Mutalik. It would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to evaluate the effects of each n-mer barcode insertion on the plaque forming abilities of the bacteriophage. One would have been motivated to do so in order to ensure that the barcoded bacteriophage retains their respective replicative function and utility as a phage therapy. One would have a reasonable expectation of success given Mutalik’s statement that Dub-seq may be readily be extended to DNA from other organisms (like bacteriophages) for genome-wide fitness assays.
Neither Mutalik nor Bohm describe the use of RB-TnSeq to generate libraries and using this to identify the unique barcode form any subject.
Claim 10: Price teaches coupling TnSeq with random DNA barcoding of each mutant (RB-TnSeq) which makes it easier to measure phenotypes across many conditions. Price uses RB-TnSeq to address the sequence-to-function gap by systematically exploring the mutant phenotypes of thousands of genes from each of 32 bacteria under multiple experimental conditions (Price, pg 2).
Claim 13: Price describes the use of coupling TnSeq with random DNA barcoding of each mutant (RB-TnSeq) which makes it easier to measure phenotypes across many conditions (Price, intro).
It would have been prima facie obvious to one of ordinary skill in the art to apply the RB-TnSeq techniques described by Price to the plaque formation assay as described by Bohm in bacteriophages to evaluate the essentiality of the n-mer barcode location. It would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to evaluate the effects of each n-mer barcode insertion on the plaque forming abilities of the bacteriophage. One would have been motivated to do so in order to improve scalability, since RB-TnSeq requires the characterization of the mutant library only once when compared to Dub-seq. Furthermore, RB-TnSeq is highly effective at identifying genes that are essential for survival under specific conditions since it relies on disrupting genes (knockout) as compared to overexpression. One would have a reasonable expectation of success the reduced complexity of library generation using RB-TnSeq as compared to dubseq.
Neither Bohm, Mutalik nor Price describe administering these barcoded bacteriophages to a subject caused or infected with the host bacterium to identify the origin of the barcoded bacteriophage.
Claims 10 and 12: Xu describes the recent advances in bacteriophage therapy as an alternative approach towards using antibiotics for the treatment of Enterobacteriaceae and related bacterial infections (Xu, abstract). Xu describes the bacterial lytic mechanisms and lysins targeted on the peptidoglycan of the bacterial wall (Xu, Fig 2 and Section “The bacteriolytic mechanism”). Xu describes administering bacteriophages to patients suffering from an infection with the host bacterium (Xu, pg 15 col 2).
It would have been prima facie obvious to one of ordinary skill in the art to apply the RB-TnSeq techniques for performing LOF screens as described by Mutalik in view of Price on bacteriophages like those described by Xu rather than E. coli. It would have been a matter of simply substituting one known organism (E. coli.) for another (bacteriophage) to obtain predictable results. One would have been motivated to do so in order to characterize functional traits in bacteriophages for use in therapies against bacterial infections and identify the origin of the barcoded bacteriophage from a subject. One would have a reasonable expectation of success given that the Dub-seq techniques are broadly applicable to other organisms for performing high-throughput and quantitative gain-of-function (GOF) and loss-of-function (LOF) screens. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Nonstatutory Double Patenting
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 Langi, 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 706.02(1)(1) - 706.02(1)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 10 and 12-13 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of co-pending Application No: 17/473,968 (US Patent Application Publication Number US 2021/0403995). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims would anticipate the instant claims if they were available as prior art. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This rejection is maintained for the same reasons outlined in the Office Action mailed on 11/3/2025 and newly applied to claim 13. A reply to applicants’ traversal is found below.
Claim 10: The co-pending claims are drawn to a method for screening for gene function for a bacteriophage (Claims 1-11). The copending claims describe screening for LOF mutant phenotypes and providing DNA barcoded overexpression strain libraries such as Dub-seq using DNA of the host organism, which is equivalent to the method steps of the instant application. The co-pending claims describe infecting a host organism host species such as those described in Table 1, which broadly reads on administering the bacteriophage to a “subject” (Claims 8-10).
Claim 12: The co-pending claims describe various host “subjects” in Table 1 (Claims 8-10).
Claim 13: The co-pending claims describe constructing a library using RB-TnSeq (Claim 2).
Response to Traversal
Applicant traverses the instant rejection by pointing to the terminal disclaimer submitted on 11/20/2025.
This argument has been fully considered, but is not found persuasive since the terminal disclaimer submitted on 11/20/2025 was disapproved since the applicant’s name listed on the TD should be exactly as it is on the ADS.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1634