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
Applicant’s response filed on 12/23/2025 is duly acknowledged.
Claims 6, 9, 11-17, and 20-24 were previously canceled by applicants.
Claims 1-5, 7, 8, 10, 18, 19, 25 and 26, as currently amended/presented, are currently pending in this application.
Claims 18 and 19 (non-elected Group II, taken as without traverse) remain withdrawn.
Claims 1-5, 7, 8, 10, 25 and 26 (elected Group I; directed to “A method of selectively engineering at least one bacterial strain…”) as currently amended/presented have been examined on their merits in this action hereinafter.
Priority
This application is a 371 of PCT/US2021/032182 (filed on 05/13/2021), which claims domestic benefit from a US PRO 63/024,932 filed on 05/14/2020.
Objection to Specification - Withdrawn
In view of current amendment to specification (for embedded hyperlinks) filed by applicants on 12/23/2025, the objection to specification as previously made by the examiner has been withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
In view of current amendments to claim 10, the 112b rejection, as previously made by the examiner, has been withdrawn.
The following contains new grounds of objections/rejections necessitated by applicant’s current amendment to pending claims.
NOTE: 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.
Claim Rejections - 35 USC § 102 – Made/Maintained
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.
1. Claims 1-5, 7, 8, 10 and 25 (as presented) are/remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Clube et al (US 2017/0246221 A1; cited in applicant’s IDS dated 07/27/2023).
Claim 1 as currently amended is as follows:
PNG
media_image1.png
317
690
media_image1.png
Greyscale
See also dependent claims 2-5, 7, 8, 10 and 25 as currently presented.
Clube et al (2017), while teaching altering microbial populations and modifying microbiota (see (Title and Abstract), disclose a method (regarding instant claims 1 and 5, as currently amended) of selectively engineering at least one bacterial strain among a mixed population of bacterial strains in the gut of a subject (see Abstract; paragraphs [0003]-[0004], [0007]-[0008], [0237], [1250]-[1262], and Claims) using a host-modifying (HM) CRISPR/Cas system, wherein for each host cell the system comprises ... (i) at least one nucleic acid sequence encoding a Cas nuclease; (ii) an engineered HM-CRISPR array comprising a spacer sequence and repeats encoding a HM-crRNA ... (iii) an optional tracrRNA sequence ... (iv) wherein said components of the system are split between the host cell and at least one nucleic acid vector that transforms the host cell ... the method comprising introducing the vectors of (iv) into host cells (see Paragraph [1260]); and wherein each vector is a... phage (see Paragraph [1262], for instance); wherein said phage selectively infects the at least one bacterial strain under conditions that allow expression of said at least one nucleic acid (see para [1260], for instance); wherein the mixed population comprising a first and a second bacterial sub-population of a first and a second microbiota species respectively, wherein the species are different, the second bacterial sub-population comprising a host cell population . . . whereby HM-crRNAs guide Cas modification of host target sequences in host cells (including antibiotic resistance genes in the host cells; see [0038], [0062], [0209], [0227], for instance); wherein the first species is a human gut commensal species and/or a human gut probiotic species (see paragraphs [0241], [1255], for instance) comprising administering at least one bacteriophage comprising at least one nucleic acid (Paragraph [1250], for instance) combining the mixed population of microbiota bacteria with multiple copies of engineered nucleic acid sequences encoding host modifying crRNAs; and wherein the engineered sequence is comprised by a bacteriophage that is capable of infecting the host cells, wherein the transformation comprises transduction of the host cells by the bacteriophage (see paragraph [0237], for instance).
In addition, Clube et al disclose the method wherein “In an example the engineered nucleotide sequence, crRNA, gRNA or array is in combination with an antibiotic agent…” (see paragraph [0246], and [0038], [0062], [0210], [1154], for instance), wherein the targeted sequence is a sequence of an antibiotic resistance gene; wherein “In an example, the antibiotic is administered simultaneously with the system, array, crRNA, gRNA, engineered nucleotide sequence, vector or cell” (see paragraph [0247]), wherein “each vector is a virus or phage” (see claims 101 and 103, and paragraph [0368], for instance); and wherein “The method is, for example, used to alter the ratios in a gut microbiota population (eg, ex vivo or in vivo),…” (see paragraphs [0047], [0193], [0272], [0331], [0985], [1205], and [1404]-[1405], for instances). It is to be noted that the instantly amended claim 1 only requires the method step of “(a) administering at least one bacteriophage to the subject…”, in combination with “at least one antibiotic” to the subject (without reciting specific type of bacteriophage, or nucleic acid sequence, specific antibiotic, or any specific composition thereof), which has been fully disclosed by the cited prior art reference of Clube et al, as discussed above.
Regarding claims 2-4, Clube et al disclose the method of claim 1, wherein the at least one host bacterial strain is a member of a genus-species including Escherichia coli from Enterobacteriaceae (see paragraphs [0240]-[0241], [0259], [1250], [1270], for instance).
Regarding claim 7, Clube et al disclose the method, wherein the subject is a human (i.e. wherein the first bacteria are probiotic, commensal or symbiotic with humans (e.g. in human gut); see paragraph [1268], for instance).
Regarding claim 8, Clube et al disclose the method, wherein the bacteriophage vector that includes lambda or T4 phage that is capable of infecting host bacterial cells (in an example, the host cell is E. coli, and the phage is a lambda or T4 phage; see paragraph [0947], for instance).
Regarding claims 10 and 25, Clube et al disclose the method, wherein each vector is a plasmid, cosmid, virus, a virion, phage, phagemid or prophage (see paragraph [0217]); or wherein the vectors comprise low copy number vectors, e.g. plasmids, or phagemids (see paragraph [1398], for instance); and wherein said nucleic acid encodes one or more sequences or genes involved in RNA-guided genome modification (i.e. modifying the genome of one or more strain or species or genus of bacteria in an established community in the gut microbiota of a subject, such as using HM-crRNAs guide Cas modification of host target sequences in host cells; see paragraph [1250], for instance; and section “Phage Sequence Targets” on page 18, for instance, [0263]).
Thus, the disclosure from Clube et al meets all the limitations of instant claims 1-5, 7, 8, 10 and 25 as currently amended/presented.
Claim Rejections - 35 USC § 103 – Made/Maintained
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.
1. Claims 1-5, 7, 8, 10, 25 and 26 (as amended/presented) are/remain rejected under 35 U.S.C. 103 as being unpatentable over Clube et al (US 2017/0246221 A1; cited in applicant’s IDS dated 07/27/2023) taken with Lichtenstein et al (WO 2017/029485 A1; FOR previously made of record by examiner).
Claim 1 as currently amended has been discussed above.
Claim 25 (as currently amended) is directed to “The method of claim 1, wherein the at least one bacteriophage is selected from the group consisting of M13, T7, T4, lambda, T3, T1, P1 and Mu, and derivatives thereof, and wherein said at least one nucleic acid encodes one or more sequences or genes involved in RNA-guided genome modification.”
Claim 26 (as currently amended) is directed to “The method of claim 25, wherein the at least one bacteriophage is M13 and wherein said M13 comprises a nucleotide sequence encoding Cas9.”
The detailed teachings and/or suggestions from Clube et al as they pertain to claims 1-5, 7, 8, 10, and 25 as discussed above, have been further relied upon in the same manner hereinafter.
However, the method wherein the “bacteriophage is M13 and wherein said M13 comprises a nucleotide sequence encoding Cas9” has not been disclosed by Clube et al, as discussed above.
Lichtenstein et al (2017), while teaching pharmaceutical composition comprising nucleic acid bacteriophage-based delivery vehicle for delivering nucleic acid (NA) into a bacterial cell (also termed “Transmid”; see Title, Abstract, Summary of the invention on pages 2-3; page 17, lines 11-17; page 18, lines 25-32; page 35, 2nd paragraph, for instance), disclose bacteriophage vectors that comprising deliverable NA packaged into one or more bacteriophage that are capable of infecting the bacterial cell and delivering said NA into the cell; wherein the bacteriophage is M13 and wherein said M13 comprises a nucleotide sequence encoding Cas9 system (see various M13-based CRISPR-Cas9 constructs disclosed on page 50 in the entire Example 2, for instance) that was demonstrated to deliver NA Cargo resulting in inactivation of antibiotic resistance genes (such as beta-lactamase gene, bla) in Escherichia coli and Klebsiella pneumoniae, for instance (see also Example 2.1.3 on page 65; and page 70, section “NSA Assay by bacteriophage M13 infection”, Table 9, for instance). Lichtenstein et al also disclose that “A Transmid may be used, for example, for the inactivation of antibiotic resistance and virulence genes in bacterial pathogens or for altering the population structure of the microbiome - in other words, microbiome engineering. Microbiome engineering may also be effected by Transmid delivery of desirable or beneficial genes to an existing microbiome in situ, for example, vaccines, therapeutics and nutraceuticals, in for example, the gastrointestinal tract. The Transmids of the present invention may be used in, for example, food and fermentation technology and in biochemical engineering and biofuel production” (see page 17, 2nd paragraph, for instance).
Thus, given the demonstration and use of M13 bacteriophage as a delivery vehicle that encodes Cas9 as part of the CRISPR-Cas9 system for modifying or engineering suitable bacterial host cells (in a subject in need such as in gastrointestinal tract; see detailed teachings/suggestions from Lichtenstein et al, discussed above), it would have been obvious to an artisan of ordinary skill in the art to modify the method disclosed by Clube et al such that it can employ an alternative phage delivery vehicle such as M13 for microbiome engineering, as already successfully demonstrated by Lichtenstein et al. Since, Lichtenstein et al disclose the bacteriophage M13 that comprises and encodes Cas9 as part of CRISPR-Cas9 constructs/system, an artisan in the art would have had a reasonable expectation of success in such modification in the method disclosed by Clube et al, unless evidence/data presented on record to the contrary (which is currently lacking on record).
Thus, the claim as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention as generically claimed.
As per MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. In re American Academy of Science Tech Center, F.3d, 2004 WL 1067528 (Fed. Cir. May 13, 2004)(The USPTO uses a different standard for construing claims than that used by district courts; during examination the USPTO must give claims their broadest reasonable interpretation.). This means that the words of the claim must be given their plain meaning unless applicant has provided a clear definition in the specification. In re Zletz, 893 F.2d 319, 321, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989).
Examiner’s Response to Arguments
Applicant’s arguments with respect to pending claims of record (see REM dated 12/23/2025, p. 6-8 regarding the prior art rejections of record) have been considered but are moot in view of the new grounds of objection/rejections made in this office action as discussed above. However, for the record, applicant’s main arguments have been responded to hereinafter.
Regarding the 102(a)(1) rejection of record over the cited prior art of Clube et al, applicants argue the following:
“Clube does not disclose the step of administering the at least one bacteriophage to the subject nor does it teach the step of administering the at least one antibiotic to the subject, as instantly claimed. Instead, Clube teaches a method of transducing a bacterium in vitro and then introducing the transduced bacterium to a subject. This is distinct from the presently claimed method of introducing the bacteriophage to the subject resulting in transduction of a bacterium in vivo. There is nothing in Clube that would teach or suggest the transduction of a bacterium in vivo. Accordingly, Clube does not anticipate the instant claims at least because it fails to disclose each and every feature of the claims as amended. Reconsideration and withdrawal of the rejection under 35 U.S.C. § 102(a)(1) is respectfully requested.”
In response, first, it is to be noted that instant claim 1 as currently amended only requires the method step of “(a) administering at least one bacteriophage to the subject…”, in combination with “at least one antibiotic” (step (b)) to the subject, which has been fully disclosed by the cited prior art reference of Clube et al, as discussed above in the rejection of record. Therefore the argument that Clube “fails to disclose each and every feature of the claims as amended” is duly noted and considered, but is not found to be persuasive. Secondly, claim 1 as amended is not limited to any particular type of bacteriophage per se (such as lysogenic or lytic phage, for instance), any specific antibiotic and/or antibiotic-resistance gene per se, and only requires administration of “at least one bacteriophage” and “at least one antibiotic” to the subject in any form, dosage and/or composition(s) thereof, without requiring any specific feature(s) of the bacteriophage composition. Since, Clube et al teach the fact that the vector in the form of bacteriophage can be made in various composition/dosage forms for ex vivo as well as in vivo applications (for targeting genes for resistance to antibiotics; see specific teachings detailed above), and wherein the composition is administered in combination with an antibiotic agent, the specific argument for the lack of “transduction of bacterium in vivo” as currently made by the applicants is duly noted, but is not found to be pertinent and/or persuasive.
For the same reasons, applicant’s arguments presented for the 103(a) rejection of record using Clube et al reference (see REM, p. 7-8), is duly noted and considered, but is not persuasive.
Therefore, the rejections of record are deemed proper and have been properly made/maintained.
Conclusion
NO claims are currently allowed.
Pertinent Art:
1. SORDI ET AL (2019; NPL cited as ref. [U] on PTO 892 form)- “The battle within: Interactions of Bacteriophages and bacteria in the gastrointestinal tract”, Cell Host & Microbe, A review, February 13, 2019, 25, pages 210-218 (discloses the recent work on how bacteriophages drive and maintain bacterial diversity in the gut, and various complexities of phage-bacteria interactions in the intestinal microbiota; see Abstract, Fig. 2, page 213, for instance).
2. LAM ET AL (2021; Post-filing NPL cited as ref. [V] on PTO 892 form)- “Phage-delivered CRISPR-Cas9 for strain-specific depletion and genomic deletions in the gut microbiome”, Cell Report, Nov. 15, 2021, 37(5):109930 (doi:10.1016/j.celrep.2021.109930), Author Manuscript, total pages 1-37.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SATYENDRA K. SINGH whose telephone number is (571)272-8790. The examiner can normally be reached M-F 8:00- 5:00.
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, LOUISE W HUMPHREY can be reached at 571-272-5543. 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.
SATYENDRA K. SINGH
Primary Examiner
Art Unit 1657
/SATYENDRA K SINGH/Primary Examiner, Art Unit 1657