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 .
Priority
This application claims priority to PCT/US2019/065226 with a filing date of 12/10/2018.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 11/22/2024 was acknowledged. Further, Applicant’s election without traverse of species from groups 1, 3 and 4 in the reply filed on 11/22/2024 was acknowledged. Applicant's election with traverse of the following species from groups 2 and 5 in the reply filed on 11/22/2024 was also acknowledged. Further, the traversal was not found persuasive.
The requirement is still deemed proper and is therefore made FINAL.
Amendments and Arguments
This action is in response to papers filed 28th Aug 2026, in which claims 1, 34, and 106 were amended, no claims were canceled, and no new claims were added.
Applicant’s arguments, also filed 28th Aug 2026, with respect to:
rejections of claims under 35 USC § 102 have been fully considered. The amendments have overcome the 35 USC § 102 rejection; the 35 USC § 102 rejection is withdrawn.
rejections of claims under 35 USC § 103 have been fully considered and are partly persuasive for the reasons discussed in this office action. However, a new § 103 rejection in view of amendments is made in this OA.
Rejections not reiterated here are withdrawn.
Status of Claims
Claims 1-2,5-6,9-12,14,17,20,24,28,31-34,42 and 105-109 are currently under examination due to applicants election of Group I in the response to the Requirement for Restriction/Election. Claims 44, 55, 59, 68, 81, 88, 100 and 103 are withdrawn.
Withdrawn Claim Rejections - 35 USC § 102
Response to Arguments
Applicant's arguments filed 28th Aug, 2026 to anticipation of original claims under 35 USC § 102 have been fully considered and are persuasive as discussed below. The 35 USC § 102 rejection of claim 1 and dependent claims in view of Galinski is withdrawn.
New Claim Rejections - 35 USC § 103 necessitated by Amendment
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.
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.
Claim(s) 1-2, 5-6, 9-12, 14, 17, 20, 31-34, 105-109 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kipniss (Nature Communications volume 8, Article number: 2212 (2017), IDS 09/23/2022) in view of Kosuri et al (US 2020/0255844 A1, claiming priority to Provisional application No. 62 / 528,833, filed on Jul .5 , 2017, cited on previous NFOA as relevant prior art, and on 892); where Claim 34 is evidenced by Inglese (Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8.). This is a new rejection necessitated by amendment.
Regarding claim 1, Kipniss discloses a method (ChaCha) for determining if a test compound modulates an activity of a first protein in vivo (toolkit of CRISPR-coupled GPCRs (a first protein) using a modular platform for rewiring diverse ligands (test compound) sensing to targeted genome regulation for engineering cellular functions (modulates an activity of GPCR in a living cell in culture) (abstract; Fig. 1a; to detect GPCR ligands in the tumor microenvironment, page 7 right col.; ChaCha systems can modulate gene expression in response to diverse ligands, second paragraph page 7 left col.), comprising:
(a) contacting said compound with a cell (HEK293T cells transfected with plasmid e.g., GPCR-V2-TEVp, the ARRB2-TCS-dCas9-VPR, sgRNA, ligand treatment; Methods on page 8, right side first and second paragraph) comprising
(i) a first nucleic acid molecule which encodes a first fusion protein; i.e., dCas9-VPR (VPR = a protein which activates transcription of a reporter gene in said cell) fused to the C-terminus of GPCR (first protein) and a TEV cleavage sequence (TCS) (legend to Fig. 1),
(ii) a second nucleic acid molecule which encodes a second fusion protein; i.e., An
adaptor protein, Beta-Arrestin 2 (ARRB2), is fused to the Tobacco Etch Virus protease (TEVp) (legend to Fig. 1),
and (iii) a third nucleic acid molecule which comprises a sgRNA that turns on a reporter gene; e.g., GFP (Figure 1),
and (b) determining the level of transcription of reporter (Fig 1c, Fig. 2a).
Kipniss do not teach that the reporter gene is a barcode sequence operably linked to an element responsive to the protein which activates its transcription.
Regarding claims 2 and 105, Kipniss teaches wherein the first nucleic acid molecule, the second nucleic acid molecule and the third nucleic acid molecule are clonally expressed and stable (Methods on pages 7-8: Generation of genetic constructs and Cell culture and generation of stable cell lines).
Regarding claim 6, Kipniss teaches reporter (GFP) activation on addition of test compound (CNO) and no activation in the absence of CNO. See recitation from page 4, first para:
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Regarding claims 9-10, Kipniss teaches GPCR, which is a transmembrane protein (title, Abstract).
Regarding claims 11-12, Kipniss contemplate the assay as useful in orphan GPCR and non-olfactory GPCR studies. See recitation from pg. 7, second para:
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Regarding claim 14, Kipniss teaches the protein which activates transcription of the reporter gene in said cell is a Cas9 fusion protein (title, Abstract; dCas9-VPR, fig. 1).
Regarding claim 17, Kipniss teaches B-arrestin as the adaptor protein that interacts with the first protein upon activation of the first protein (Beta-Arrestin 2 (ARRB2), is fused to the Tobacco Etch Virus protease (TEVp), fig. 1).
Regarding claim 33, Kipniss transfect cells with individual plasmids (nucleic acid molecules) for the first and second fusion proteins i.e., GPCR and adaptor which is arrestin respectively, and a third nucleic acid molecule for sgRNA that will activate the reporter (HEK293T cells transfected with GPCR-V2-TEVp, the ARRB2-TCS-dCas9-VPR, sgRNA, Methods).
Kipniss do not teach that the reporter gene is a barcode sequence operably linked to an element responsive to the protein which activates its transcription; rather the reporter gene is a fluorescent protein or an endogenous gene which is operably linked to a programmable sgRNA; nor does Kipniss teach wherein each barcode is specific for an individual GPCR.
However, before the effective filing date of instant invention, Kosuri had taught a method of interrogating GPCR activation wherein an operably linked inducible reporter is induced upon activation of a GPCR wherein the inducible reporter comprises a barcode comprising an index region that is unique to the GPCR in high-through put format (abstract, heterologous receptor gene, e.g., Fig.9, claim 115, [0235]). Kosuri discloses wherein the barcode sequence comprises wherein the barcode and/or index region comprises at least 10 nucleotides (claim 132). Kosuri’s Working examples, [0224], include GPCRs that turn on cAMP signaling in HEK293T cells. DNA barcodes are included in the 3 ' UTR of the reporter gene that uniquely associate with one receptor in the library expressed on the same plasmid. The relative abundance of each barcode is plotted into a heat map displaying affinity of the odors for each receptor. Kosuri teach the cells utilized can be adherent or non-adherent ([0187-0189]).
Thus, Kosuri’s Scalable, Multiplexed Assay for Decoding Receptor-Ligand Interaction Screens (title) provides the missing teachings of claims 1, 5, 20, 31-33, and 106-109.
Regarding claim 34, Inglese evidences that administering a combination of an agonist and an antagonist in an assay is a well-known pharmacological strategy used to probe receptor function, ligand interactions, and signaling mechanisms. See abstract and introductory paragraph. Inglese teaches the same in a high-throughput format. See Inglese, fig. 1 where concentration response curves with inhibitory (blue) or stimulatory (red) activity are graphed.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to integrate the format of Kosuri’s GPCR interrogation system into Kipniss’s method for determining if a test compound modulates an activity of a first protein comprising an active TEV protease for the advantage of: simultaneously interrogating multiple GPCRs. One of ordinary skill in the art would have been motivated to do so since high receptor density can confound conclusions made from individual GPCR interrogations. One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since both the prior art references were thoroughly detailed and thereof readily within reach of the skilled artisan. MPEP 2144 II.
Claim(s) 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kipniss (Nature Communications volume 8, Article number: 2212 (2017), IDS 09/23/2022) in view of Kosuri (Kosuri et al., US 2020/0255844 A1, claiming priority to Provisional application No. 62 / 528,833, filed on Jul .5 , 2017, cited on previous 892 as relevant prior art) as applied to claims 1-2, 5-6, 9-12, 14, 17, 20, 31-34, 105-109 above, and Claim 34 is evidenced by Inglese (Inglese J, et al., Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8.) further in view of Donald et al., (WO2002016940A2). This is a new rejection necessitated by amendment.
Regarding claim 24, neither Kipniss nor Kosuri teach a test compound contained within a microbiota of a subject.
However, before the effective filing date of instant invention, Doanld had taught a microbial metabolite compound (a metabolite from a bacterium (a microbial metabolite compound); page 4, line 11; page 68, lines 22-25); a method of preventing or treating a disease or disorder in a subject (a method of preventing or treating a disease or disorder in a subject; page 3, lines 15-26; page 4, lines 11-16), the method comprising administering one or more antibiotics effective to target a bacterial strain (the method comprising administering one or more antibiotics effective to target a bacterial strain; page 3, lines 15-26; page 4, lines 11-16) comprising a nucleic acid sequence encoding a metabolite producing gene (comprising molecular targets including proteins or mRNA coding for proteins associated with metabolites comprising a nucleic acid sequence encoding a metabolite production gene); page 3, lines 15-26, page 68, lines 22-25); a method for evaluating potential effectiveness of an agent or treatment (a method for evaluating potential effectiveness of an agent or treatment; page 54, lines 5-15). In microarray preparation §3.2.1, Donald teach, it is also possible to use cDNA from a single cell, and compare, for example, the absolute amount of a particular mRNA in, e.g., a drug-treated or pathway-perturbed cell and an untreated cell.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to have modified the disclosure of Kipniss and Kosuri to have included steps for evaluating an agent which is a microbial metabolite, as disclosed by Donald et al., the steps comprising introducing a nucleic acid probe or other reagent capable of binding specifically to a nucleotide expressed by a bacterial strain in order to enable the determination of the expression of metabolite producing genes as a means of determining the effects of the therapeutic agent or compound on the genes responsible for metabolite production, as well as direct measurement of metabolite production, to better and more accurately determine the efficacy of the compound. One would be motivated to do so for the advantage of evaluating potential effectiveness of an agent or treatment, amongst many others discussed by Donald. One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since the methodologies provided by both references were thoroughly detailed and thereof was readily within reach of the skilled artisan.
Thus, Kipniss and Kosuri in view of Donald make obvious instant claim 24.
Claim(s) 28 and 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kipniss (Nature Communications volume 8, Article number: 2212 (2017), IDS 09/23/2022) in view of Kosuri et al (US 2020/0255844 A1, claiming priority to Provisional application No. 62 / 528,833, filed on Jul .5 , 2017, cited on previous 892 as relevant prior art) as applied to claims 1-2, 5-6, 9-12, 14, 17, 20, 31-34, 105-109 above, and Claim 34 is evidenced by Inglese (Inglese J, et al., Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8.) further in view of Antti (WO 2011/064000 A1). This is a new rejection necessitated by amendment.
Regarding claims 28 and 42, neither Kipniss nor Kosuri teach identifying a bacterial strain or taxon which produces said test compound within said microbiota.
However, before the effective filing date of instant invention, Antti had taught methods for monitoring, identifying or diagnosing an infection in an individual, by assessing the metabolites produced and thus also identifying the bacterial strain (abstract, Table 1 on page 21 where the columns are microbe ID and the rows are different metabolites). The detection of metabolites is followed by analyzing the metabolite composition of said sample to determine a test metabolite profile of said sample, and comparing said test metabolite profile with a control metabolite profile. identity of metabolites was detected by corelating with NIST database (abstract, pg. 29). Antti’s method is advantageous as a method for assessing the efficacy of a treatment of an infection (abstract)..
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to have modified the disclosure of Kipniss and Kosuri to have included a method of determining the identity of the bacterial strain that produced the metabolite, as disclosed by Antti. The knowledge of the identity of the involved bacteria would be advantageous to guide further treatment. One would have had reasonable expectation of success in making the combination because in combination, each element would merely be performing the same function as it does separately. Identifying the bacteria following the combination of methods would have lead to predictable success because Antti provide the details of the method and apparatus and a computer-usable medium configured to perform said methods. See MPEP 2144 II and 2143 B.
Regarding claim 42, the inclusion of limitations taught by Kipniss, Kosuri and Antti into a single method as discussed above, would result in the method recited in claim 42.
Thus, Kipniss and Kosuri in view of Antti make obvious instant claims 28 and 42.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 28th Aug, 2026 to obviousness rejection of original claims under 35 USC § 103 have been fully considered and are partly persuasive.
Applicants argue:
Galinski does not teach an active protease. Further, a commonly authored paper states “In contrast to split-TEV assays, the full-TEV approach was in our hands less sensitive to monitoring GPCR activation in both transiently transfected heterologous and primary cultured cells.”. Therefore, Applicants argue, a skilled person would not have been motivated to substitute Galinski's split TEV with the full-TEV protease of Aper; and there is likewise no reasonable expectation of success in the Examiner's proposed combination of references.
This argument is persuasive. The 35 USC § 103 rejection of claims 20, 24, 28, 31-34, 42, 107-109 relied on Galinski in view of Aper and further in view of Donald is withdrawn.
unexpected and superior advantages over the method of Galinski.
The 35 USC § 103 rejection of claims 20, 24, 28, 31-34, 42, 107-109 relied on Galinski in view of Aper and further in view of Donald. Therefore, any unexpected and superior advantages of instant invention must be compared with the combined references of Galinski, Aper, and Donald. Applicants have not demonstrated this. Therefore, Applicants arguments regarding unexpected results are not persuasive.
However, in view of amendments, a new §103 rejection is made in this OA.
CONCLUSION
No claims are allowed.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm 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, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/ Primary Examiner, Art Unit 1635
