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 .
Claim Status
Claims 1 and 3-4 are pending.
Claims 1 and 3-4 currently amended.
Claims 2 and 5-21 are newly cancelled.
Claims 1 and 3-4 remain rejected.
Response to Applicant Arguments - Claim Objections
In response to applicant’s arguments and amendments to the claims dated 07/28/2025 the objections to the claims of record are withdrawn. However, applicant’s amendments to the claims requires a new claim objection.
Claim Objections
Claim 1 is newly objected to because of the following informalities: “comprising” is duplicated and one copy should be deleted. Appropriate correction is required.
Response to Applicant Arguments - 35 USC § 112 (Indefiniteness)
In response to applicant’s arguments and amendments to the claims dated 07/28/2025 the indefiniteness rejections of record are withdrawn.
Response to Arguments - 35 USC § 103
In response to applicant’s amendments filed 07/28/2025, the rejections of record are withdrawn. Applicant’s amendments to the claims require new obviousness rejections and applicant’s arguments that remain relevant to the new rejections are addressed below.
Applicant’s arguments are summarized as follows:
Applicant has amended the independent claim and cancelled specific independent claims such that the scope is drawn to the synthetic transcription factors having the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 22. These synthetic transcription factors represent an unexpected result because they have nearly double the activating activity compared wild-type transcription factors.
With respect to 1 above, this argument is not found to be persuasive. First, given that the two synthetic transcription factors are made up several distinct known elements, for SEQ ID NO: 7, MATAL1-SV40-VP16 and for SEQ ID NO: 22, TF1α-SV40-VP16, it is not clear which wild type transcription factor the synthetic transcription factor should be compared to (Specification, Page 9, Lines 2-3; Specification, Page 14, Lines 6-7). This is complicated because the specification indicates that synthetic transcription factors should be assembled from the following components in this order: DNA binding domain, nuclear localization signal (NLS) and then activator domain (Specification, Page 6, Paragraph 0034). Paragraph 0013 on page 3 of the specification demonstrates that MATAL1 including the sequence of SEQ ID NO: 37 can be used as a DNA binding domain, paragraph 0028 on page 5 of the specification makes clear that the SV40 nuclear localization signal of SEQ ID NO: 88 can be used in the synthetic transcription factors and paragraph 0018 on page 3 of the specification notes that the herpes VP16 activator domain of SEQ ID NO: 44 can be used in the invention. Alignments against SEQ ID NO: 7 demonstrate that it is these sequences in that order that make up the synthetic transcription factor. Given this it is the VP16 activator domain that is increasing the expression of a target and it is a portion of the MATAL1 DNA binding domain that is directing the activator to a target but given that this is simply a fragment of the MATAL1 transcription factor the exact targets are unclear and therefore what exactly the expression induced by the synthetic transcription factor is compared to is unclear.
However, it is known that the VP16 activation domain is a potent activator that is capable of transcribing a target gene with more than 100-fold higher efficiency than another activator domain (TAT) and 20 fold higher expression than a fusion protein comprising the GAL4 domain (Hirai, Int J Dev Biol. 2010;54(11-12):1589-96)(Hirai, Page 4, Second Complete Paragraph; Hirai, Page 5, Second Complete Paragraph).
Given that this potent activator can transcribe a target with 100 fold higher efficiency than another activator domain it is not a surprising result that the synthetic transcription factors claimed have nearly double the activating activity of wild type transcription factors. Therefore, applicant’s arguments are not found to be persuasive and the rejections of record are maintained.
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.
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 and 3 are newly rejected under 35 U.S.C. 103 as being unpatentable over Mojzita (WO2017144777), Published August 31, 2017, in view of Xu, BMC systems biology 9.Suppl 1 (2015) as evidenced by Chain A, Matching-Type Protein A-1-Protein-NCBI, Published May 22, 2024, and Boddupalli (WO2018022574), published February 1, 2018.
Claim 1 has been amended to recite a single synthetic transcription factor comprising one of two specific sequences, SEQ ID NOS: 7 and 22. These sequences encode the following sequences the MATAL1 DNA binding domain – SV40 Nuclear Localization Signal – VP16 Activation domain (SEQ ID NO: 7) and the TF1α DNA binding domain – SV40 Nuclear Localization Signal – VP16 Activation Domain (SEQ ID NO: 22) (Specification, Page 9, Lines 2-3; Specification, Page 14, Lines 6-7; Specification, Page 6, Paragraph 0034; Specification, Page 3, Paragraphs 0013 and 0018; Specification, Page 5, Paragraph 0028). While claim 3 has been amended to recite the synthetic transcription factor of claim 1, having the sequence of SEQ ID NO: 7.
With respect to claim 1, Mojzita (WO2017144777) teaches that synthetic transcription factors are artificial proteins which comprise the following elements: a DNA-binding protein, a nuclear localization signal, and a transcription activation domain (Mojzita, Page 10, Lines 1-3). Mojzita also provides examples an example of a synthetic transcription factor which comprises a DNA-binding domain linked to the Sv40 NLS and the VP16 transcription activation domain (Mojzita, Page 17, Lines 21-23).
With respect to claim 1, Mojzita does not teach an artificial transcription factor comprising a MATAL1 or TF1α DNA Binding Domain.
With respect to claim 1, Xu teaches that MATa1 proteins are members of the homeodomain superfamily of DNA-binding proteins, and that these proteins contact the DNA with a homeodomain DNA binding domain (Xu, Page 7, Column 1, Second Full Paragraph). Importantly, Chain A, Matching-Type Protein A-1-Protein-NCBI provides evidence of an inherent characteristic of the MATa1 protein of Xu, specifically, Chain A, Matching-Type Protein A-1-Protein-NCBI demonstrates that MATa1 from brewer’s yeast has 100% sequence identity to the MATAL1 DNA binding domain sequence described in the specification and provided in instant SEQ ID NO: 28, see figure 1 below. Therefore, it is clear that the DNA binding domain claimed in SEQ ID NO: 7 is the homeodomain binding domain from the yeast MATA1 protein.
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Figure 1: Description of alignment between the MATAL1 sequence of instant SEQ ID NO: 28 and the Chain A, Mating-Type Protein A-1 from brewer’s yeast.
With respect to claim 1, Boddupalli teaches a transcription factor which comprises a heterologous chimeric polypeptide comprising a transcriptional transactivator domain (AD), a DNA binding domain (DBD) that recognizes a target associated with a protein or polypeptide of interest and a Group H nuclear receptor ligand binding domain (LBD) (Boddupalli, Page 54, Paragraphs 000245-000246). Boddupalli also provides a list of DNA binding domains that can be used in these transcription factors including the plant homeodomain families of DNA binding domains.
Given the teachings of Mojzita, Xu as evidenced by Chain A, Matching-Type Protein A-1-Protein-NCBI and Boddupalli it would have been obvious to arrive at the sequence of instant SEQ ID NO: 7, which the instant specification makes clear is comprised of the MATAL1 DNA binding domain operatively linked to the SV40 NLS and the VP16 activation domain.
This would have been obvious because Mojzita and Boddupalli are both drawn to synthetic transcription factors and provide examples of the structures of these proteins and also provide examples of the different elements which should be used to produce these proteins, while Xu and Chain A, Mating-Type Protein A-1-Protein-NCBI make clear that the MATAL1 DNA binding domain is a homeodomain DNA binding domain.
Specifically, Mojzita teaches a transcription factor that appears to differ from the sequence of SEQ ID NO: 7 only in the specific DNA binding domain used, while Boddupalli suggests the use of the homeodomain DNA binding domain and Xu and its evidence demonstrate that the MATAL1 binding domain is the homeodomain DNA binding domain.
At the time of filing it would have been obvious to the ordinary artisan to modify the synthetic transcription factor of Mojzita to replace the DNA-binding protein of Mojzita with the DNA binding protein of Xu as evidenced by Chain A, Mating-Type Protein A-1-Protein-NCBI, thereby using the homeodomain DNA binding domain in this synthetic transcription factor as taught by Boddupalli. This would have been obvious because as taught in Mojzita and Boddupalli synthetic transcription factors are assemblies of specific components and in the case of instant SEQ ID NO: 7 this sequence is simply a combination of known elements and in fact even the use of the specific individual components found in SEQ ID NO: 7 is taught in the Mojzita and Boddupalli references.
Given the state of the art with respect to synthetic transcription factors combining the teachings of the references would have been obvious because the references are drawn to synthetic transcription factors and their uses, particularly synthetic transcription factors and synthetic promoters. Therefore, arriving at the claimed sequences is simply a design choice made by combining known elements in a certain order.
Given the state of the prior art with respect to synthetic transcription factors and the fact that the domains included in the sequence of SEQ ID NO: 7 are known in the prior art it would have been obvious to make and try all of the different combinations of these elements to arrive at a library having varied expression pattern and strength and therefore any combination of these elements would have been obvious. Similarly the ordinary artisan would have been motivated to arrive at the claimed sequence because it would have been obvious to try all of the different combinations of DNA binding domains, nuclear localization signals and activation domains in order to produce a synthetic transcription factor having optimal qualities. This would have been obvious to try because there are a finite number of identified elements which make up a synthetic transcription factor (DNA binding domain, NLS and Activation domain) and combining them would lead to predictable results (levels of expression at specific targets) with a high expectation of success given the state of the art. Therefore, one of ordinary skill in the art would have found it obvious to try all of the these combinations and further would have been motivated to do so in order to produce a synthetic transcription factor having optimal characteristics, including level of transcription and ability to bind to target loci.
Therefore, claim 1 is rejected as obvious under Mojzita in view of Xu as evidenced by Chain A, Matching-Type Protein A-1-Protein-NCBI and Boddupalli.
With respect to claim 3, Mojzita , Xu, Chain A, Matching-Type Protein A-1-Protein-NCBI and Boddupalli collectively teach all of the limitations of claim 1 taught above, including the sequence of SEQ ID NO: 7 (See above).
Claim 4 is newly rejected under 35 U.S.C. 103 as being unpatentable over Mojzita (WO2017144777), Published August 31, 2017, in view of Hong, Elife 7 (2018) as evidenced by Gat1p [Saccharomyces cerevisiae] Protein-NCBI, Published December 16, 2022.
Claim 4 has been amended to recite a single synthetic transcription factor comprising the specific sequence of SEQ ID NO: 22. This sequences encodes the following sequence TF1α DNA binding domain – SV40 Nuclear Localization Signal – VP16 Activation Domain (SEQ ID NO: 22) (Specification, Page 9, Lines 2-3; Specification, Page 14, Lines 6-7; Specification, Page 6, Paragraph 0034; Specification, Page 3, Paragraphs 0013 and 0018; Specification, Page 5, Paragraph 0028).
With respect to claim 4, Mojzita (WO2017144777) teaches that synthetic transcription factors are artificial proteins which comprise the following elements: a DNA-binding protein, a nuclear localization signal, and a transcription activation domain (Mojzita, Page 10, Lines 1-3). Mojzita also provides examples an example of a synthetic transcription factor which comprises a DNA-binding domain linked to the Sv40 NLS and the VP16 transcription activation domain (Mojzita, Page 17, Lines 21-23).
With respect to claim 1, Mojzita does not teach an artificial transcription factor comprising a TF1α DNA Binding Domain.
With respect to claim 1, Hong teaches the GAT1 protein is a transcriptional activator that is involved in an incoherent type-1 feedforward loop to control the expression of the high affinity ammonium transporter gene, MEP2 in yeast (Hong, Abstract). Hong further teaches the GAT1 DNA binding domain and teaches that this domain is an evolutionary hotspot under certain selection conditions that represents an opportunity to modify the target of the GAT1 transcription factor and the binding efficiency of these proteins to their targets (Hong, Abstract; Hong, Page 11, Third Complete Paragraph). Therefore, Hong teaches that the GAT1 protein and the GAT1 DNA binding domain is well known in the art.
Importantly, Gat1p [Saccharomyces cerevisiae] Protein-NCBI provides evidence of an inherent characteristic of the GAT1 protein of Hong, specifically, Gat1p [Saccharomyces cerevisiae] Protein-NCBI demonstrates that GAT1p from brewer’s yeast has 100% sequence identity to the TF1α DNA binding domain sequence described in the specification (Specification, Page 14, Paragraph 0056). Therefore, it is clear that the DNA binding domain claimed in SEQ ID NO: 22 is the DNA binding domain of GAT1p.
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Figure 2: Description of alignment between the DNA binding domain sequence of instant SEQ ID NO: 22 and the Gat1p protein from Brewer’s Yeast.
Given the teachings of Mojzita and Hong as evidenced by Xu as evidenced Gat1p [Saccharomyces cerevisiae] Protein-NCBI it would have been obvious to arrive at the sequence of instant SEQ ID NO: 22, which the instant specification makes clear is comprised of the TF1α DNA binding domain operatively linked to the SV40 NLS and the VP16 activation domain.
This would have been obvious because Mojzita is drawn to synthetic transcription factors and provides examples of the structures of these proteins and also provides examples of the different elements which should be used to produce these proteins, while Hong and Gat1p [Saccharomyces cerevisiae] Protein-NCBI teach the DNA binding domain of the yeast Gat1p protein.
Specifically, Mojzita teaches a synthetic transcription factor that appears to differ from the sequence of SEQ ID NO: 22 only in the specific DNA binding domain used, while Hong and its evidence demonstrate that the Tf1α binding domain is the Gat1p DNA binding domain and is well known and studied in the art.
At the time of filing it would have been obvious to the ordinary artisan to modify the synthetic transcription factor of Mojzita to replace the DNA-binding protein of Mojzita with the DNA binding protein of Hong as evidenced by Gat1p [Saccharomyces cerevisiae] Protein-NCBI, thereby using the Gat1p DNA binding domain in this synthetic transcription factor. This would have been obvious because as taught in Mojzita synthetic transcription factors are assemblies of specific components and in the case of instant SEQ ID NO: 22, this sequence is simply a combination of known elements.
Given the state of the art with respect to synthetic transcription factors combining the teachings of the references would have been obvious because the references are drawn to synthetic transcription factors and their uses, particularly synthetic transcription factors and synthetic promoters. Therefore, arriving at the claimed sequences is simply a design choice made by combining known elements in a certain order.
Further, given that the domains included in the sequence of SEQ ID NO: 22 are known in the prior art it would have been obvious to make and try all of the different combinations of these elements to arrive at a library having varied expression pattern and strength and therefore any combination of these elements would have been obvious. Similarly the ordinary artisan would have been motivated to arrive at the claimed sequence because it would have been obvious to try all of the different combinations of DNA binding domains, nuclear localization signals and activation domains in order to produce a synthetic transcription factor having optimal qualities. This would have been obvious to try because there are a finite number of identified elements which make up a synthetic transcription factor (DNA binding domain, NLS and Activation domain) and combining them would lead to predictable results (levels of expression at specific targets) with a high expectation of success given the state of the art. Therefore, one of ordinary skill in the art would have found it obvious to try all of the these combinations and further would have been motivated to do so in order to produce a synthetic transcription factor having optimal characteristics, including level of transcription and ability to bind to target loci.
Therefore, claim 4 is rejected as obvious under Mojzita in view of Hong as evidenced by Gat1p [Saccharomyces cerevisiae] Protein-NCBI.
Conclusion
Claims 1 and 3-4 are rejected.
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.
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/BRIAN JAMES SULLIVAN/Examiner, Art Unit 1663
/WEIHUA FAN/Examiner, Art Unit 1663