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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 8-11, 17, 29-38, 73 and 76-77 in the reply filed on 18 March 2026 is acknowledged. Claims 1, 8-11, 17, 29-38, 41, 73 and 76-77 are pending. Claim 41 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1, 8-11, 17, 29-38, 73 and 76 are pending and being examined on the merits.
Priority
The current application is a 371 PCT of US2021/056174 filed 10/22/2021 which claims priority to application 63/105,007 filed 10/23/2020.
Information Disclosure Statement
The information disclosure statement filed 12/11/2023 has been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 30 and 31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 30 and 31 recite “The polypeptide of claim 1 or 2”, Claim 2 is cancelled. It is unclear how theses claims can depend from a cancelled claim.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 11 is directed to the polypeptide according to claim 1, fused to a first binding member of a heterodimer or to a second binding member of a heterodimer, wherein the first binding member binds to a second binding member of the heterodimer, wherein the first binding member comprises an amino acid sequence at least 75% identical to the amino acid sequence of SEQ ID NO:2 and the second binding member comprises an amino acid sequence at least 75% identical to the amino acid sequence of SEQ ID NO:3, wherein the N-terminus or the C-terminus of the NBD is fused to the first or the second binding member. Because SEQ ID NO: 2 is 72 amino acids in length and SEQ ID NO: 3 is 74 amino acids in length, the claim encompasses proteins differing from SEQ ID NO: 2 and 3 by approximately 18 amino acid residues as well as nucleic acids encoding such variants. The claim therefore encompasses a substantial genus of undisclosed protein and nucleic acid species.
The specification discloses SEQ ID NO: 2 and 3 as well as numerous positively charges variants and several exemplary linker constructs [00185-00190; 218-229] but does not disclose a representative number of species falling within the claimed 75%-identity genus. The specification further fails to identify conserved residues, permissible substitution sites, consensus motifs, mutagenesis data, structure-function relationships, or other common structural characteristics sufficient to demonstrate possession of the claimed genus. Nor does the specification provide representative variant sequences spanning the breadth of the claimed genus.
The unpredictability of amino acid substitutions in proteins was well known in the art. For example, Bowie (Bowie et al., Science, 247:1306-1310 (1990)), demonstrated that amino acid substitutions may be tolerated at certain positions while substantially affecting structure or function at other positions [see pg. 247].
Accordingly, in view of the limited amount of guidance provided by the specification and the art, one of ordinary skill in the art would conclude that Applicant was not in possession of the claimed invention.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a polypeptide where the first binding member is SEQ ID NO: 2 with a Q31K or Q31K/E20R substitution and the second binding member is SEQ ID NO: 3, does not reasonably provide enablement for a polypeptide where the first and second binding member is 75% identical to SEQ ID NO: 2 and 3, respectively. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention
Claim 1 broadly encompasses a polypeptide where the first and second binding member is 75% identical to SEQ ID NO: 2 and 3, respectively. Because SEQ ID NO: 2 is 72 amino acids in length and SEQ ID NO: 3 is 74 amino acids in length, the claim encompasses proteins differing from SEQ ID NO: 2 and 3 by approximately 18 amino acid residues as well as nucleic acids encoding such variants. The claim therefore covers a substantial number of undisclosed variants.
State of the Art
The art recognized that amino acid substitutions are not uniformly tolerated throughout a protein sequence. Bowie et al., Science 247:1306-1310 (1990), reported that some amino acid positions accommodate numerous substitutions whereas other positions tolerate few substitutions and that patterns of conservation and variation are related to the local environment of each residue [see pg. 247]. Accordingly, one of ordinary skill in the art would not be able to predict, without substantial experimentation, which of the numerous variants encompassed by the claim possess the characteristics attributed to the disclosed protein.
Breadth of the claims
Claim 11 recites, inter alia, wherein the first binding member comprises an amino acid sequence at least 75% identical to the amino acid sequence of SEQ ID NO:2 and the second binding member comprises an amino acid sequence at least 75% identical to the amino acid sequence of SEQ ID NO:3.
Guidance of the Specification
The specification discloses SEQ ID NO: 2 and 3 as well as numerous positively charges variants and several exemplary linker constructs [00185-00190; 218-229] but does not disclose a representative number of species falling within the claimed 75%-identity genus. The specification further fails to identify conserved residues, permissible substitution sites, consensus motifs, mutagenesis data, structure-function relationships, or other common structural characteristics sufficient to demonstrate possession of the claimed genus. Nor does the specification provide representative variant sequences spanning the breadth of the claimed genus.
Experimentation Required
Accordingly, a person of ordinary skill in the art seeking to practice the full scope of the claimed invention would be required to generate numerous sequence variants and experimentally evaluate each variant for heterodimerization. Such testing would include expression of variant proteins, and binding assays. The amount of experimentation required is substantial because the specification provides insufficient guidance for predicting which substitutions will preserve the disclosed biological functions throughout the full scope of the claimed genus. The need for extensive screening and characterization of numerous variants constitutes undue experimentation under the factors set forth in In re Wands, 858 F.2d 731 (Fed. Cir. 1988).
The Supreme Court has further explained that a specification must enable the full scope of the claimed genus. See Amgen Inc. v. Sanofi. Because the present disclosure requires substantial screening to identify operative members of the claimed genus that retain the disclosed binding and signaling activities, the specification does not enable the full scope of claim 11.
Claim 76 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 76 is directed a method of modulating expression of an endogenous gene in a cell, the method comprising: contacting the cell with the polypeptide according to according to claim 1, wherein the polypeptide is conjugated to a heterologous functional domain, and wherein the polypeptide penetrates the cell membrane and wherein the nucleic acid binding domain (NBD) of the polypeptide binds to a target nucleic acid sequence present in the endogenous gene and the heterologous functional domain modulates expression of the endogenous gene. The claim therefore encompasses virtually every endogenous gene and every heterologous functional domain capable of modulating expression.
The specification discloses NBD comprising positively charged RUs conjugated to a positively charged first member of a heterodimer pair and KRAB conjugated to a positively charged second member of the heterodimer pair are transported across cell membrane and targeted to bind the TIM3 gene promoter, repressing TIM3 expression in a dose-dependent manner, thereby demonstrating TIM3 repression, specific RU combinations, specific positively charged heterodimer domains, and specific functional domains [Fig. 1, 0008, 00355]. The specification fails to provide a representative species spanning all target genes, all transcriptional activators, all repressors, and all DNA modifying proteins.
Keung (Keung, Albert J., et al. Nature Reviews Genetics 16.3 (2015): 159-171. (Year: 2015)) teach that the activity of engineered transcriptional regulators is highly dependent upon genomic context, chromatin state, target-site selection, and effector-domain identity, such that successful modulation of gene expression generally requires empirical optimization of both the DNA-binding component and the recruited functional domain. Likewise, Perez (Perez-Pinera, Pablo, et al. Nature methods 10.3 (2013): 239-242) demonstrate that different transcriptional effector domains exhibit substantially different regulatory activities at different endogenous loci. Accordingly, the prior art teaches that the mere fusion of a DNA-binding domain to a heterologous functional domain does not predictably result in modulation of expression of an endogenous gene across the full scope of possible target genes and functional domains.
Accordingly, in view of the limited amount of guidance provided by the specification and the art, one of ordinary skill in the art would conclude that Applicant was not in possession of the claimed invention.
Claim 76 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of modulating expression of an endogenous TIM-3 gene comprising contacting the cell with TL8188_Q31K_3x37A or TL8188_ Q31K,E20R_3X37A, wherein the polypeptide is conjugated to a KREB functional domain, does not reasonably provide enablement the method as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention
Claim 76 is directed a method of modulating expression of an endogenous gene in a cell, the method comprising: contacting the cell with the polypeptide according to according to claim 1, wherein the polypeptide is conjugated to a heterologous functional domain, and wherein the polypeptide penetrates the cell membrane and wherein the NBD of the polypeptide binds to a target nucleic acid sequence present in the endogenous gene and the heterologous functional domain modulates expression of the endogenous gene. The claim therefore encompasses virtually every endogenous gene and every heterologous functional domain capable of modulating expression.
State of the Art
Keung (Keung, Albert J., et al. Nature Reviews Genetics 16.3 (2015): 159-171. (Year: 2015)) teach that the activity of engineered transcriptional regulators is highly dependent upon genomic context, chromatin state, target-site selection, and effector-domain identity, such that successful modulation of gene expression generally requires empirical optimization of both the DNA-binding component and the recruited functional domain. Likewise, Perez (Perez-Pinera, Pablo, et al. Nature methods 10.3 (2013): 239-242) demonstrate that different transcriptional effector domains exhibit substantially different regulatory activities at different endogenous loci. Accordingly, the prior art teaches that the mere fusion of a DNA-binding domain to a heterologous functional domain does not predictably result in modulation of expression of an endogenous gene across the full scope of possible target genes and functional domains.
Breadth of the claims
Claim 76 recites, inter alia, a method of modulating expression of a gene…wherein the polypeptide penetrates the cell membrane and wherein the NBD of the polypeptide binds to a target nucleic acid sequence present in the endogenous gene and the heterologous functional domain modulates expression of the endogenous gene.
Guidance of the Specification
The specification discloses NBD comprising positively charged RUs conjugated to a positively charged first member of a heterodimer pair and KRAB conjugated to a positively charged second member of the heterodimer pair are transported across cell membrane and targeted to bind the TIM3 gene promoter, repressing TIM3 expression in a dose-dependent manner, thereby demonstrating TIM3 repression, specific RU combinations, specific positively charged heterodimer domains, and specific functional domains [Fig. 1, 0008, 00355]. The specification fails to provide a representative species spanning all target genes, all transcriptional activators, all repressors, all DNA modifying proteins.
Experimentation Required
Accordingly, a person of ordinary skill in the art seeking to practice the full scope of the claimed invention would be required to engage in extensive screening and characterization to determine which of the vast number of heterologous functional domains encompassed by the claim actually modulate expression at a given endogenous gene.
The Supreme Court has further explained that a specification must enable the full scope of the claimed genus. See Amgen Inc. v. Sanofi. Because the present disclosure requires substantial screening to identify operative members of the claimed genus that retain the function, the specification does not enable the full scope of claim 76.
Claim Rejections - 35 USC § 103
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.
Claims 1, 8-10, 37 and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2012/0270273 A1) in view of Wender (Wender et al. PNAS 97.24 (2000): 13003-13008) and Langedijk (Langedijk et al. Molecular diversity 8.2 (2004): 101-111).
Regarding claims 1, 8-9, and 73, Zhang teach methods useful in the construction of designer transcription activator-like effector (dTALE) polypeptides [abstract]. Zhang teach a sequence encoding the monomer units of a TALE polypeptide of SEQ ID NO: 60; or a sequence encoding the monomer units of SEQ ID NOs: 174 [0008; Table 2]. Zhang teach that the tandem repeats (also referred to herein as monomer units) that are generally each 33, 34, or 35 amino acids in length and comprise 3 monomer units [0072, 0086, SEQ ID NO: 60]. SEQ ID NO: 174 of Zhang is 98% identical to SEQ ID NO: 1. Zhang teaches expression vectors encoding the TALE polypeptides for use in modulating gene expression [0005].
Zhang does not teach where the polypeptide comprises one or both of the following amino acid substitutions relative to SEQ ID NO: 1: E20R/K/H and Q31K/R/H.
Regarding claim 10, Zhang teaches 8 to 39 repeat units [0086].
Regarding claim 37, Zhang teaches the TALE binding to the promoter [0221].
Wender teaches that removal of lysine and arginine from peptides reduces their cellular internalization [pg. 13005, bridging paragraph from col. 1 to col. 2] while peptides with multiple arginine residues had enhanced cellular uptake [pg. 13005, col. 2, para 2, abstract].
Langedijk teaches that a peptide where Glu was replaced with Arg in the middle of the molecule showed a three times higher translocation activity [pg. 103, last paragraph – pg. 104, first paragraph].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the TALE repeat unit of Zhang by introducing positively charged amino acid substitutions, such as lysine, arginine, or histidine for negative/neutral amino acids. One of ordinary skill would be motivated to make the modification in order to increase the net positive charge of the TALE protein and thereby improve intracellular delivery of the programmable DNA-binding protein, with a reasonable expectation of success because positively charged amino acid residues were known to promote cellular internalization.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2012/0270273 A1) in view of Wender (Wender et al. PNAS 97.24 (2000): 13003-13008) and Langedijk (Langedijk et al. Molecular diversity 8.2 (2004): 101-111) as applied to claim 1 and further in view of Chen (WO 2020093043).
The teachings of Zhang, Wender, and Langedijk are discussed above as applied to claim 1 and similarly apply to claim 11.
Zhang, Wender, and Langedijk do not teach where the polypeptide is fused to a first binding member of a heterodimer or to a second binding member of a heterodimer, wherein the first binding member binds to a second binding member of the heterodimer, wherein the first binding member comprises an amino acid sequence at least 75% identical to the amino acid sequence of SEQ ID NO:2 and the second binding member comprises an amino acid sequence at least 75% identical to the amino acid sequence of SEQ ID NO:3, wherein the N-terminus or the C-terminus of the NBD is fused to the first or the second binding member.
Chen teaches designed heterodimer proteins, monomeric polypeptides capable of forming heterodimer proteins, protein scaffolds including such polypeptides, and methods for using the heterodimer proteins [abstract]. Chen teaches that heterodimeric interaction specificity between two DNA strands, and between protein and DNA, is often achieved by varying side chains or bases coming off the protein or DNA backbone— for example, the side chains of protein contacting DNA in TALEN-DNA complexes [pg. 1, para 3]. Chen teaches monomers fused to DNA binding or transcriptional activation domains dimerize to function in vivo [pg. 97, para 3]. Chen teaches the heterodimer polypeptide domains comprising SEQ ID NOs: 306 and 306 which are 100% identical to SEQ ID NOs: 2 and 3.
It would have been obvious to one of ordinary skill in the art to experiment with using heterodimer binding domains linked to the NBD and functional domains of the polypeptides as taught and suggested by Zhang, Wender, and Langedijk because as taught by Chen, the two heterodimer polypeptides function in vivo, furthermore, an artisan of ordinary skill would have readily appreciated that different functional domains could be expressed with the same NBD.
Claims 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2012/0270273 A1) in view of Wender (Wender et al. PNAS 97.24 (2000): 13003-13008) and Langedijk (Langedijk et al. Molecular diversity 8.2 (2004): 101-111) as applied to claim 1 and further in view of Ostertag (US 2018/0187185 A1).
The teachings of Zhang, Wender, and Langedijk are discussed above as applied to claim 1 and similarly apply to claims 30 and 31.
While Zhang teaches a sequence encoding an N-terminal domain that is at least 70% identical to the amino acid sequence of an N-terminal domain sequence from a transcription activator-like effector (TALE) polypeptide from a bacterium of the genus Xanthomonas, or a fragment thereof, such that the sequence encoding the N-terminal domain is 5' of the sequence encoding the nucleic acid binding domain of the dTALE polypeptide; a sequence encoding a C-terminal domain that is at least 70% identical to the amino acid sequence of a C-terminal domain from a transcription activator-like effector (TALE) polypeptide from a bacterium of the; Zhang, Wender, and Langedijk do not teach wherein the NBD comprises an N-cap domain comprising the amino acid sequence SEQ ID NO: 184 and a C-cap domain comprising the amino acid sequence SEQ ID NO: 185.
Ostertag teaches an exemplary Xanthomonas-TALE-Clo051 (XTC) [0062; Fig. 3; 145]. Ostertag teaches that a N and C terminal domains of Xanthomonas TAL DNA-binding domain comprising SEQ ID NO: 28 and SEQ ID NO: 34 [0151 and 0154] that are 100% identical to SEQ ID NO: 184 and 185, respectively [144-148].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to substitute the N and C terminal domains of Zhang with SEQ ID NO: 28 and SEQ ID NO: 34 of Ostertag. The modification amount to a simple substitution on one known Xanthomonas TAL DNA-binding domains for another.
Claims 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2012/0270273 A1) in view of Wender (Wender et al. PNAS 97.24 (2000): 13003-13008) and Langedijk (Langedijk et al. Molecular diversity 8.2 (2004): 101-111) as applied to claim 1 and further in view of Gaiko (Gaiko, Kathrine. "Developing TALE Proteins as a Biosensor for Detecting Pathogen Specific Double-Stranded DNA." (2019)).
The teachings of Zhang, Wender, and Langedijk are discussed above as applied to claim 1 and similarly apply to claims 32 and 33.
While Zhang teaches dTALE polypeptide can then be isolated from the cells by an appropriate purification scheme using a purification tag [0152], Zhang, Wender, and Langedijk do not teach a positive poly-histidine tag.
Gaiko teach optimization of the TALE purification process to yield high concentrations of the protein by using a two-column purification technique with His tag [abstract; pg. 22].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the polypeptide as taught and suggested by Zhang, Wender, and Langedijk to contain a poly-histidine tag for the advantage of facilitating high yield purification of the recombinant protein. One of ordinary skill would have a reasonable expectation of success because polyhistidine tags were a routine and well-established purification tool that permitted rapid purification using immobilized affinity chromatography and were shown to be useful for TALE purification.
Claims 34 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2012/0270273 A1) in view of Wender (Wender et al. PNAS 97.24 (2000): 13003-13008) and Langedijk (Langedijk et al. Molecular diversity 8.2 (2004): 101-111) as applied to claim 1 and further in view of Hovig (US 2011/0171184 A1)
The teachings of Zhang, Wender, and Langedijk are discussed above as applied to claim 1 and similarly apply to claims 34 and 35.
While Zhang teaches using a mammalian nuclear localization signal (NLS) and the synthetic transcription activation domain VP64 on the TALE encoding construct [0212; Fig. 1C], Zhang, Wender, and Langedijk do not teach using SEQ ID NO: 173, a positively charged nuclear localization sequence.
Hovig teaches a method for introducing peptide nucleic acid (PNA) molecules into the cytosol, preferably the nucleus of a cell [abstract]. Hovig teaches using PKKKRKV as a NLS signal in attempts to direct PNA to the cell nucleus where the effect was shown to be highly dependent on the NLS sequence [0018].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the polypeptide as taught and suggested by Zhang, Wender, and Langedijk to contain PKKKRKV as a NLS signal for the advantage of mediating nuclear transport. One of ordinary skill would have a reasonable expectation of success since PKKKRKV as a NLS signal were a routine and well-established purification tool that permitted nuclear transport of proteins.
Claims 36, 38, and 76-77 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 2012/0270273 A1) in view of Wender (Wender et al. PNAS 97.24 (2000): 13003-13008) and Langedijk (Langedijk et al. Molecular diversity 8.2 (2004): 101-111) as applied to claim 1 and 37 and further in view of Anderson (Anderson et al. Immunity 44.5 (2016): 989-1004)
The teachings of Zhang, Wender, and Langedijk are discussed above as applied to claim 1 and 37 and similarly apply to claims 36, 38 and 76-77.
Regarding claims 36, 38, and 76, Zhang teaches that dTALE polypeptides can be used to modulate transcription of endogenous genes, 4 additional dTALE polypeptides were engineered to directly activate transcription of the pluripotency transcription factors, Sox2, Klf4, c-Myc, and Oct4 [0067, 0221]. Zhang teaches using a mammalian nuclear localization signal (NLS) and the synthetic transcription activation domain VP64 on the TALE encoding construct [0212; Fig. 1C]. Zhang teach that the dTALE polypeptide binding sites were selected from the proximal 200 bp promoter region of each gene [0221]. Zhang, Wender, and Langedijk do not teach wherein the NBD of the polypeptide binds to a region of the TIM3 gene, PD-L1 gene, PDCDl gene, CTLA4 gene, or LAG3 gene.
Anderson teach that TIM-3 and LAG-3 are well-known inhibitory immune checkpoint regulators, and that modulation of their repression was a recognized immunotherapy strategy [pg. 989, col. 1, para 2 – pg. 996, col. 1, para 1].
Regarding claim 77, Zhang teach modulation of transcription from the genome [0005, 0222].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the polypeptide as taught and suggested by Zhang, Wender, and Langedijk where the NBD of the polypeptide binds to the promoter region of the TIM-3 or LAG-3 gene. One of ordinary skill would be motivated with a reasonable expectation of success because promoter targeting, as taught in Zhang was a way to modulate the expression of endogenous genes and these genes were well-known immunoregulatory targets.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: SEQ ID NO: 8 and 181 are free of the art.
Claims 17 and 29 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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