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 the Claims
Claims 1, 4, 9, 17-19, 21-25, 27, 30, 35, 37, and 41-42 are currently pending.
Claim 1 is amended.
Claims 2-3, 5-8, 10-16, 20, 26, 28-29, 31-34, 36, and 38-40 are cancelled.
Claims 1, 4, 9, 17-19, 21-25, 27, 30, 35, 37, and 41-42 have been considered on the merits.
Withdrawn Rejections
The 135 U.S.C. 102 rejection made onto the claims is withdrawn in light of the amendments made onto the claims in the reply filed on 07/10/2026.
Maintained Rejections Necessitated by Amendment
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 (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.
Claims 1, 4, 9, 17-19, 21-25, 27, 30, 35, 37, and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (US20160208243A1), in view of Alberini et al (US20030166555A1).
Regarding claim 1, Zhang teaches a transcriptional relay system which contains a transcriptional factor nucleic acid (NA) with both a response element regulated promoter ([0659]) and a synthetic transcription factor ([0945]/[0946]/[1009]), and a reporter NA with both a synthetic transcription factor promoter and a reporter ([0945]). Zhang teaches numerous embodiments of this transcriptional relay system. Zhang teaches that the synthetic transcription factor is a chimeric or fusion protein that comprises a comprises a DNA binding domain from a first transcription factor and a transcription activating domain from a second transcription factor ([0039]/[0232]/[0945]/[1009]). More specifically, Zhang states that the “CRISPR enzyme may be fused to a gene sequence encoding a protein or a fragment of a protein that bind DNA molecules or bind other cellular molecules, including but not limited to maltose binding protein (MBP), S-tag, Lex A DNA binding domain (DBD) fusions, GAL4 DNA binding domain fusions” which meets the limitation of a synthetic transcription factor which is a chimeric protein that comprises a DNA binding domain polypeptide ([0945]/[1009]). Zhang teaches that there is a regulatory element (defined by Zhang as being a promoter) which is operably connected/specifically binds to the Cas protein DNA binding domain polypeptide of the synthetic transcription factor, and further is operatively connected to a promoter provided on a separate nucleic acid molecule in one embodiment ([0376]). Zhang also teaches that the guide RNA is able to target a regulatory sequence on a separate nucleic acid molecule as required by claim 1 ([0220]). Zhang also teaches that the guide RNA can target a CRISPR molecule fused to a reporter as required by claim 1 ([0945]). Zhang teaches that a reporter can comprise a unique molecular identifier (a.k.a. a molecular barcode) as required by claims 1 ([0945]/[1692]).
Regarding claim 4, Zhang teaches that the DNA binding domain can be one of the proteins Gal4 or LexA ([0945]).
Regarding claim 9, Zhang teaches that the transcription activating domain comprises VP64, p65, and RTA ([1009]).
Regarding claims 17 and 18, Zhang teaches that the synthetic transcription factor comprises a polypeptide sequence that destabilizes the synthetic transcription factor and that the sequence is PEST ([0596]-[0597]).
Regarding claim 19, Zhang teaches that the synthetic transcription factor comprises a sequence that is bound by Gal4 and/or LexA ([0945]).
Regarding claim 21, Zhang teaches that a reporter can comprise a fluorescent protein, a luciferase protein, beta-galactosidase, beta-glucuronidase, chloramphenicol acetyltransferase, placental alkaline phosphatase, or a unique molecular identifier (a.k.a. a molecular barcode) ([0945]/[1692]).
Regarding claim 22, Zhang teaches that the unique barcodes are sample specific to the target amplicons ([1692]).
Regarding claims 23-25, Zhang teaches that the NA contains a transcriptional repressor domain and a repressor which reduces the translation of the synthetic transcription factor ([0994]).
Regarding claim 27, Zhang teaches that the transcriptional relay system is contained in a cell ([0015]).
Regarding claim 30, Zhang teaches that the whole relay system is integrated into the cell in a single copy (i.e. a single vector) ([0460]).
Regarding claims 35 and 37, Zhang teaches the same transcriptional relay system of claim 1 and that the system is comprised in a cell as required by claim 27. Therefore, the cell containing the transcriptional relay system of Zhang would inherently result in high basal reporter activity and low biological coefficient of variance for reporter activity absence evidence to the contrary.
Regarding claim 41, Zhang teaches that the cell is mammalian ([0015]).
Regarding claim 42, Zhang teaches that the nucleic acid targeting system elements can be combined in a single vector in any suitable orientation, “such as one element located 5’ with respect to (“upstream” of) or 3’ with respect to (“downstream” of) a second element” ([0220]).
Zhang does teach that the “regulatory element” is meant to include promoters and that they may be both tissue specific promoters, more specifically that the promoter can be a cell type specific promoter ([0933]).
Zhang does not explicitly teach that the response element regulated promoter is one selected from cAMP, NFAT, FOS, or serum response element as required by claim 2.
However, Alberini teaches about response element regulated promoters of cAMP as required by claim 2 ([0051]/[0139]). Alberini also teaches that the promoters may also be tissue and cell specific ([0060]). Further, that the promoter could also be exchanged from an endogenous promoter to a heterologous promoter ([0133]).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the transcriptional relay system of Zhang with the promoter taught by Alberini to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because both Zhang and Alberini teach that one of ordinary skill in the art is capable of interchanging promoters which are specific to the desired outcome (i.e. choosing a tissue or cell specific promoter taught by both Zhang and Alberini above). One of ordinary skill in the art would have a reasonable expectation of success when combining Zhang with Alberini because both teach a genetic modulation/relay system containing promoters and that the promoter are interchangeable based on desired target.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 07/10/2026, regarding the rejection of the claims under 35 U.S.C. 103, have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 7-8) that Zhang does not disclose the synthetic transcription factor which is a chimeric protein that comprises a DNA binding domain polypeptide from a first transcription factor and a transcription activating domain polypeptide from a second transcription factor. Applicant argues that “the DNA binding portion of the synthetic transcription factor must be from a transcription factor. A CAS enzyme whether active or dead, is not a transcription factor even under the broadest reasonable interpretation”.
In response, the arguments are not found persuasive. Zhang teaches that the synthetic transcription factor is a chimeric or fusion protein that comprises a comprises a DNA binding domain from a first transcription factor and a transcription activating domain from a second transcription factor ([0039]/[0232]/[0945]/[1009]). More specifically, Zhang states that the nucleic acid-targeting effector protein is part of a fusion protein and then states that the “CRISPR enzyme may be fused to a gene sequence encoding a protein or a fragment of a protein that bind DNA molecules or bind other cellular molecules, including but not limited to maltose binding protein (MBP), S-tag, Lex A DNA binding domain (DBD) fusions, GAL4 DNA binding domain fusions” which meets the limitation of a synthetic transcription factor which is a chimeric protein that comprises a DNA binding domain polypeptide ([0945]/[1009]), and Zhang teaches that the DNA binding domain is a LexA or GAL4 binding domain which is required by dependent claim 19. Additionally, Zhang teaches the presence of a transcription activating domain which can be VP64, p65, or RTA ([1009]), which are specific transcription activating domains which are required by dependent claim 9. Finally, Zhang states that the “CRISPR effector protein of the present invention, i.e. Cpf1 effector protein is sometimes referred to herein as a CRISPR enzyme…the effector protein may, as required in some embodiments, have DNA or RNA binding, but not necessarily cutting or nicking, activity, including a dead-Cas effector protein function” ([0811]). The plain meaning of the term “transcription factor” is a specialized protein that controls the rate at which genetic information is copied from DNA into messenger RNA. Therefore, the CRISPR effector protein which retails the claimed transcription activating domain and DNA binding abilities but does not contain any ability to cut/nick DNA would act as a transcription factor. Thus, the fusion proteins described by Zhang act as CRISPR-based transcription factors which meets the limitation of a synthetic transcription factor. Therefore, Zhang teaches an embodiment which meets the limitations of the currently presented claims and the arguments are not found persuasive.
Applicant argues (Remarks, pg. 8, last para spanning pg. 9) that there would be no reasonable expectation of success to arrive at the claims based on the combination of the references Zhang and Alberini because the claimed system demonstrates a significant increase in luciferase signal and a decrease in coefficient of variation of luciferase signal compared to a system without a transcriptional relay. Further, Applicant argues that Zhang nor Alberini discloses a transcriptional relay system with a synthetic transcription factor and that the increased size of the embodiment taught by Zhang would reduce the efficiency of transcription and translation. Further that the Cpf1 enzyme of Zhang could also interfere with the transcriptional activation of the transcription activation domain at the promoter of the reporter concluding that “these factors would negatively impact whether a skilled artisan would have any reasonable expectation of success in modifying Zhang.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., an increase in luciferase signal and a decrease in coefficient of variation of luciferase signal compared to a system without an transcriptional relay) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Further, one of ordinary skill in the art would have a reasonable expectation of success when combining Zhang with Alberini because both teach a genetic modulation/relay system containing promoters and that the promoter are interchangeable based on desired target.
Therefore, the argument is not found persuasive.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/DAVID A MONTANARI/Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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