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 .
Application Status
This action is written in response to applicant’s correspondence received 8 December 2025. Claims 1-17 are currently pending. Accordingly, claims 1-17 are examined herein.
Any rejection or objection not reiterated herein has been overcome by argument. Applicant' s arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. Because no new limitations have been introduced into the independent claims, this action is NON-FINAL.
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.
Claim 11 is 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.
Regarding claim 11, the claim recites that “the induction” is by a small molecule drug, light, cytokine, antibiotic, pH, oxygen level, superoxide, cumate or doxycycline. However, claim 9 (i.e., the claim from which claim 11 depends from) recites the use of two different inducible promoters that are each induced by a unique stimulus. Therefore, it is unclear if claim 11 is further limiting a single inducible promoter of the system described in claim 9 or if claim 11 is limiting both promoters of the system of claim 9 to a single class of inducers or a single molecule selected from cumate or doxycycline.
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.
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.
Claim(s) 1-3 and 6-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chakroborty ("A CRISPR/Cas9-based system for reprogramming cell lineage specification." Stem cell reports 3.6 (2014): 940-947) in view of Hyde (PG Pub No. US 2015/0098954 A1), Shis ("Library of synthetic transcriptional AND gates built with split T7 RNA polymerase mutants." Proceedings of the National Academy of Sciences 110.13 (2013): 5028-5033), and Jusiak ("Engineering synthetic gene circuits in living cells with CRISPR technology." Trends in biotechnology 34.7 (2016): 535-547).
Regarding claim 1, Chakraborty is directed towards a study concerned with endogenous gene activation of a Myod1 gene through the use of a dCas9 comprising a VPR64 domain (i.e., a gene expression activation domain) operably linked at the N-terminus and the C-terminus of the dCas9 protein, termed “VP64dCas9-BFPVP64” (i.e., an inactive CRISPR protein comprising a gene expression activation domain operably linked at the N-terminus of the protein) (pg. 940-941; see Figure 1). Chakraborty teaches that the VP64dCas9-BFPVP64 was able to be placed under the control of a doxycycline-inducible promoter and expressed within mouse embryonic fibroblasts alongside guide RNAs in order to enable robust targeted transactivation of an endogenous Myod1 gene and that the presence of the guide RNAs, expressed from a U6 promoter-driven delivery system, was essential for the transactivation (pg. 940-942; see Figure 1). Chakraborty teaches that transactivated Myod1 can reprogram mouse embryotic fibroblasts into skeletal myocytes (Abstract).
Chakraborty does not teach or suggest that the guide RNA inducible by a second stimulus (Claim 1).
Hyde is drawn towards an invention concerned with modification of DNA in a subject (Abstract). Hyde teaches the use of vector comprising a Cas9 gene under the control of an inducible promoter (i.e., a first promoter that is inducible by a first stimulus) and a guide RNA gene under the control of a separate inducible promoter (i.e., a second promoter that is inducible by a first stimulus) ([0064]; see FIG. 1). Hyde teaches that both the Cas9 gene and the guide RNA can be placed under the control of different tetracycline-inducible promoters such that, in the presence of tetracycline, both the Cas9 protein and the guide RNA are expressed ([0072]-[0073]). Hyde teaches that the inducible promoter may be a pathogen-inducible promoter, a pH-inducible promoter, a temperature-inducible promoter, a magnetic-inducible promoter, light-inducible promoter, or a chemical-inducible promoter ([0040]). Hyde teaches that Cas9 nucleases can be directed to endogenous genomic loci in order to induce edits in a subject’s genome ([0051]). Hyde teaches that the vector may be administered to mammalian tissues (i.e., a mammalian cell) and reside long term in a cell’s nucleus as an epichromosome ([0071]).
Shis is directed towards a study concerned with the development of a synthetic transcriptional AND gate built with split T7 polymerase mutants (Abstract). Shis teaches the use of a genetic AND gate that comprises two different inducible promoters that are inducible by two different inputs such that one of the promoters drives the expression of an N-terminus of a T7 polymerase in the presence of the first input while the other promoter drives the expression of the C-terminus of the T7 polymerase in the presence of a second input (i.e., Shis teaches that two different nucleic acid sequences may be placed under the control of two different promoters such that only in the presence of two inputs will both nucleic acids be expressed and subsequently modulate the expression of a target gene) (pg. 5028-5029, 5032; see Fig. 1 and Fig. 6). Shis teaches that utilizing two different inducible promoters in a synthetic AND gate is advantageous because differences between the on and off states of the output of the AND gates is large, which is a desirable characteristic of transcriptional logic gates that makes them easy to use in larger circuits (pg. 5028).
Jusiak is directed towards a review study concerned with engineering synthetic gene circuits in living cells with CRISPR technology (Abstract). Jusiak teaches that “new methods for inducible circuit activation include expression of gRNAs from inducible promoters as well as activation of the dCas9 protein by light” (pg. 535). Jusiak teaches that a genetic NOT gate had been previously developed wherein an inducible promoter drove gRNA expression in response to a small-molecule input (pg. 541-543; see Figure 3B). Jusiak teaches that, the gRNA, when present, recruited dCas9 to the constitutive promoter of an output gene, inhibiting RNAP binding to the output promoter and, as a result, the output gene was transcribed only in the absence of the input (pg. 541-543; see Figure 3B). Jusiak teaches that the NOT and NOR gates could be layered to build OR and AND gates, thus expanding the number of logical operations that a cell could perform (pg. 541). Jusiak teaches that the output of these circuits can be a protein-coding transgene (pg. 541). Jusiak teaches that such logic circuits could control various phenotypes including bacterial phenotypes, such as biofilm formation, metabolism, and antimicrobial resistance (i.e., Jusiak teaches that CRISPR logic gates can be utilized to edit a target cell) (pg. 541).
Therefore, with regard to the gRNA linked to an inducible promoter, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed second promoter that is inducible and is operably linked to the gRNA because it would have merely amounted to a simple substitution of one promoter that could drive expression of a gRNA for another. Because Hyde teaches the use of an inducible promoter linked to a guide RNA for a similar purpose as Chakraborty, namely the editing of a target nucleic acid in a target cell via the expression of both a Cas9 molecule and a gRNA, then it would have been predictable to have similarly made and used an inducible promoter such that it was linked to the gRNA of Chakroborty and successfully expressed within the target cell of Chakroborty.
Further, with regard to the claimed requirement that the second inducible promoter is inducible by a second stimulus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed invention because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predicable results. Because Jusiak teaches that the prior art was already pursuing CRISPR logic gates for a similar purpose as Chakroborty and Hyde, namely the modulation of a target cell’s phenotype, then it would have been predictable to have similarly used logic gate architecture in the inducible promoters of Chakroborty and Hyde in order to successfully express the VP64dCas9-BFPVP64 and gRNA in a target cell and modify its phenotype. And because Shis teaches that the logic gate architecture of an AND gate was known, namely the linking of two nucleic acids to two different inducible promoters, then it would have been predicable to have used two different inducible promoters in the construct of Chakroborty, Hyde, and Jusiak in order to similarly express the Cas9 and gRNA only in the presence of two inputs because Hyde teaches that both Cas9 molecules and gRNAs can be linked and expressed from many different inducible promoters. And because Shis teaches that utilizing a synthetic AND gate is advantageous because differences between the on and off states of the output of the AND gates is large, one would have been motivated to do so in order to ensure robust inducible expression of the system in the presence of the two inducers and no expression of the system in the absence of said inducers.
Regarding claim 2, Chakraborty teaches that the nucleolytically-inactive CRISPR protein is a dCas9 (pg. 940-941; see Figure 1).
Regarding claim 3, Chakraborty teaches that the system enables robust targeted transactivation of an endogenous Myod1 gene (pg. 940-942; see Figure 1).
Regarding claims 6-8, Chakraborty, Hyde, Shis, and Jusiak renders obvious the transactivation of an endogenous Myod1 gene encoding an endogenous Myod1 protein in a fibroblast.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Chakroborty ("A CRISPR/Cas9-based system for reprogramming cell lineage specification." Stem cell reports 3.6 (2014): 940-947) as applied to claims 1-3 and 6-8 above, and further in view of Wang (Bone 48.3 (2011): 524-532) in view of Hyde (PG Pub No. US 2015/0098954 A1), Shis ("Library of synthetic transcriptional AND gates built with split T7 RNA polymerase mutants." Proceedings of the National Academy of Sciences 110.13 (2013): 5028-5033), and Jusiak ("Engineering synthetic gene circuits in living cells with CRISPR technology." Trends in biotechnology 34.7 (2016): 535-547) as applied to claims 1-3 and 6-8 above, and further in view of Wang (Bone 48.3 (2011): 524-532).
Regarding claim 4, the teachings of Chakroborty, Hyde, Shis, and Jusiak renders obvious claims 1-3 and 6-8 as described above. Chakroborty further teaches that gRNAs can be designed and their ability to deliver the gene expression activation domain to the target and induce expression of the endogenous Myod1 locus tested (pg. 942; see Figure S1D).
Chakroborty in view of Hyde, Shis, and Jusiak does not teach or suggest that the endogenous protein encodes a BMP (Claim 4).
Wang is drawn to a study concerned with the expression of BMP-2 and how its expression correlates to bone healing (Abstract). Wang teaches that endogenous BMP-2 plays a key role in skeletal development, repair, and regeneration in a mouse model (i.e., in a mammalian model) (Abstract). Wang teaches that cells that endogenous BMP-2 plays a critical role in the differentiation of periosteal progenitor cells during bone and skeletal repair in vivo (Abstract; pg. 526). Wang teaches that mesenchymal progenitors expressing endogenous BMP-2 were capable of differentiating into bone forming cells, chondrocytes and osteoblasts, and that the majority of the BMP-2 null cells remained undifferentiated at the site of healing; therefore, expression of the endogenous BMP-2 is essential for the differentiation of the bone progenitor cells in vivo in a mouse model (pg. 531). Wang teaches that stimulation of endogenous BMP-2 expression may represent a more effective approach for enhancing bone repair and regeneration (pg. 531).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed target endogenous encoding a BMP because it would have merely amounted to a simple substitution of one endogenous target gene for another and one target cell for another. Since Chakroborty, Hyde, Shis, and Jusiak teach the use of the inducible system for a similar purpose as Wang, namely targeted gene activation of a target endogenous gene in order to beneficially alter a target cell’s phenotype, then it would have been predictable to have used the inducible system within the cell of Wang in order to induce expression of the endogenous gene encoding a BMP only in the presence of the two inducer molecules. And because Wang teaches that the stimulation of the expression of the endogenous BMP was beneficial, one would have been motivated to do so in order to enhance bone repair and regeneration.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Chakroborty ("A CRISPR/Cas9-based system for reprogramming cell lineage specification." Stem cell reports 3.6 (2014): 940-947) in view of Hyde (PG Pub No. US 2015/0098954 A1), Shis ("Library of synthetic transcriptional AND gates built with split T7 RNA polymerase mutants." Proceedings of the National Academy of Sciences 110.13 (2013): 5028-5033), and Jusiak ("Engineering synthetic gene circuits in living cells with CRISPR technology." Trends in biotechnology 34.7 (2016): 535-547) as applied to claims 1-3 and 6-8 above, and further in view of Duellman ( "dCas9-mediated transcriptional activation of tissue inhibitor of metalloproteinases." Metalloproteinases in medicine (2017): 63-73).
Regarding claim 5, Chakroborty, Hyde, Shis, and Jusiak renders obvious claims 1-3 and 6-8 as described above.
Hyde in view of Shis, Jusiak, and Chakroborty does not teach or suggest that the activation domain is a VPR domain (Claim 5).
Duellman is drawn towards a review study concerned with selective gene activation with dCas9 targeting of a transcriptional activator (Abstract). Duellman teaches that the structure of an N-terminally fused VP64 domain was known in the art to be able to activate gene expression via the targeting of a dCas9 to a gene of interest (pg. 64, 69; see Figure 3). Duellman further teaches that a VPR domain is a construct comprising a VP64 domain linked to p65 and Rta domains that could be operably linked to the C-terminus of a dCas9 protein (pg. 64, 69; see Figure 3). Duellman teaches that the VPR domain could be utilized to transcriptionally activate an endogenous TIMP gene in mouse cells (pg. 70; see Figure 4). Duellman teaches that placing the VP64 domain at the N-terminus of the dCas9 protein did not interfere with nuclear localization of the dCas9 and showed the best fold-induction when compared to C-terminal fusions (pg. 66).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed VPR domain because it would have merely amounted to a simple substitution of one transcriptional activator for another. Since Duellman teaches the use of a VPR domain operably linked to a Cas9 protein for a similar purpose as Chakroborty, Hyde, Shis, and Jusiak, namely the targeted activation of an endogenous gene in a target cell through the use of a transcriptional activation domain, then it would have been predictable to have similarly used the VPR domain of Duellman to induce expression of the target Myod1 gene.
Claims 9-11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Chakroborty ("A CRISPR/Cas9-based system for reprogramming cell lineage specification." Stem cell reports 3.6 (2014): 940-947), Hyde (PG Pub No. US 2015/0098954 A1), Shis ("Library of synthetic transcriptional AND gates built with split T7 RNA polymerase mutants." Proceedings of the National Academy of Sciences 110.13 (2013): 5028-5033), Jusiak ("Engineering synthetic gene circuits in living cells with CRISPR technology." Trends in biotechnology 34.7 (2016): 535-547), and Bowlin (US Patent No. 7,374,774 B2).
Regarding claim 9, the applicable teachings of Hyde in view of Chakroborty, Hyde, Shis, and Jusiak are discussed above as applied to claims 1-3 and 6-8 as described above.
Hyde further teaches that compatible inducible promoters comprise pH-inducible promoters, light-inducible promoters, and chemical-inducible promoters including a cytokine-inducible promoter ([0040], [0042]).
Further, it is noted that the term “electrospun template” is defined in the instant specification as an electrospun substrate that can be used to deliver physiochemical cues to a cell, including a fibroblast cell (Instant specification; pg. 3).
Regarding claim 11, the claim is interpreted as attempting to limit a single promoter within the system of claim 9 such that it is induced by a different inducer when compared to the other claimed promoter.
Chakroborty, Hyde, Shis, and Jusiak does not teach or suggest the use of an electrospun substrate comprising a first agent capable of inducing the first promoter and a second agent capable of inducing the second promoter (Claim 9). Chakroborty, Hyde, Shis, and Jusiak does not teach or suggest that the electrospun substrate is an electrospun template (Claim 10). Chakroborty, Hyde, Shis, and Jusiak does not teach or suggest that the electrospun substrate generates a gradient of growth factors in a cell in contact with the substrate (Claim 13).
Bowlin is drawn to an invention concerned with delivery of substances to a desired location in vivo through the use of electrospun materials (see Abstract; Col. 1, lines 39-40). Bowlin teaches that substances can be released from electro processed materials in response to electrical, magnetic and light based signals in order to deliver various substances in vivo (Col. 12; lines 51-59). Bowlin teaches the use of an electrospun material (i.e., an electrospun substrate) that may contain one or more substances that can be administered to a cell of interest also present within the electrospun material in order to induce cell differentiation in the cells (Col. 39, line 46-50). Bowlin teaches that examples of differentiated cells can include fibroblasts (Col 39; lines 38-43). Bowlin teaches that the substance may be selected from a large list of different chemicals, including doxycycline (i.e., a chemical inducer) and cytokines (Col. 13, lines 52-65; Col. 14, line 52 to Col. 15, line 37). Bowlin teaches that using the electrospun material is advantageous to utilize and deliver compositions to cells because the electrospun material is stable over a long period of time, substantially sterile, and the exact substance composition to be delivered to an individual patient can be prepared and tailored to a specific need shortly before implantation or application (Col. 43, line 60 to Col. 44, line 12). Bowlin teaches that multiple layers of the same or different materials can be deposited on the electrospun material (Col. 30, line 8-14). Bowlin teaches that a gradient of substances can be created along the electrospun material (Col. 30, lines 14-21). Bowlin teaches that the electrospun material may comprise growth factors to stimulate growth and division of target cells (Col. 11, lines 33-42). Bowlin teaches that the growth factors may be fibroblast growth factors (Col. 15, lines 38-41).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed electrospun template because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Because Bowlin teaches the use of an electrospun template for a similar purpose as Chakroborty, Hyde, Shis, and Jusiak, namely the administration of inducer molecules to target cells, then it would have been predictable to have utilized the electrospun template of Bowlin to deliver the first and second inducer molecules to the target cell in order to have greater control over the administration of the inducers through the use of an electrospun template that can be designed to comprise a precise chemical composition. And because Bowlin teaches that the exact substance composition to be delivered to an individual patient can be tailored to a specific need through the use of the template, one would have been motivated to have done used the template to deliver the inducer molecules.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed growth factors present within the electrospun template because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The reasonable expectation of success in using the electrospun template of Bowlin to deliver molecules to the cells of Chakroborty, Hyde, Shis, and Jusiak is discussed above. Therefore, because Bowlin teaches that the template can further comprise fibroblast growth factors, one would have been motivated to have delivered the growth factors to the fibroblast cells of Chakroborty, Hyde, Shis, and Jusiak in order to promote the growth and differentiation of the cells.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chakroborty ("A CRISPR/Cas9-based system for reprogramming cell lineage specification." Stem cell reports 3.6 (2014): 940-947), Hyde (PG Pub No. US 2015/0098954 A1), Shis ("Library of synthetic transcriptional AND gates built with split T7 RNA polymerase mutants." Proceedings of the National Academy of Sciences 110.13 (2013): 5028-5033), Jusiak ("Engineering synthetic gene circuits in living cells with CRISPR technology." Trends in biotechnology 34.7 (2016): 535-547), and Bowlin (US Patent No. 7,374,774 B2), as applied above to claims 9-11 and 13 above, further in view of Sun ("Clonal dynamics of native hematopoiesis." Nature 514.7522 (2014): 322-327) and Motta ("An optogenetic gene expression system with rapid activation and deactivation kinetics." Nature chemical biology 10.3 (2014): 196-202).
Regarding claim 12, Chakroborty, Hyde, Shis, Jusiak, and Bowlin renders obvious claims 9-11 and 13 as described above.
Chakroborty, Hyde, Shis, Jusiak, and Bowlin does not teach or suggest that the cell is genetically modified to express a blue light-inducible sleeping beauty transposon (Claim 12).
Sun is directed towards a study concerned with clonal dynamics of mouse hematopoietic cells (i.e., mammalian cells) (Abstract). Sun teaches the use of a clonal tagging system based on temporally restricted expression of a hyperactive Sleeping Beauty (HSB) transposase, an enzyme that mediates genomic mobilization of a cognate DNA transposon (pg. 322). Sun teaches that in the model, a doxycycline (Dox)-inducible HSB cassette and a single-copy non-mutagenic Tn are incorporated in the mouse genome through gene targeting (pg. 322). Sun teaches that the hyperactive Sleeping Beauty transposase that can have its expression controlled by a doxycycline-dependent transcriptional activator in order to integrate a stable genetic tag for a corresponding cell and its progeny (pg. 322-333; see Figure 1). Sun teaches that the modular nature of the tagging system should enable cell-type-specific transposition, allowing clonal fate tracking of defined cell populations (pg. 326).
Motta is directed towards a study concerned with an optogenetic gene expression system with rapid activation and deactivation kinetics in mammalian cell lines (Abstract). Motta teaches the use of a blue-light inducible transcriptional activator that can induce transcription of a gene of interest in the presence of blue light and will be turned “off” in the presence of darkness (pg. 197). Motta teaches that utilizing light as an inducer of a transcriptional activator is advantageous compared to chemical inducers because chemical inducers are limited by their rate of diffusion (slowing activation), difficult removal (slowing deactivation) and potential off-target effects on normal cellular function (pg. 196). Motta teaches that, in contrast, light is a rapid and nontoxic stimulus that naturally regulates many different cellular processes in diverse settings (pg. 196).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed inducible sleeping beauty transposon because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Because Sun teaches the use of an inducible sleeping beauty transposon that can be utilized to integrate a stable genomic tag into a similar cell as Chakroborty, Hyde, Shis, Jusiak, and Bowlin, namely a mammalian cell, then it would have been predictable to have utilized the inducible sleeping beauty transposon to similarly integrate the genomic tag in the cell of Chakroborty, Hyde, Shis, Jusiak, and Bowlin. And because Sun teaches that the genomic tag can be utilized to track cell fate, and identify both edited target cells and their progeny, one would have been motivated to have utilized the tag in the cells of Chakroborty, Hyde, Shis, Jusiak, and Bowlin in order to identify which fibroblast cells comprise the inducible construct and which do not.
Further, with regard to the blue-light inducible limitation, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed invention because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Because Motta teaches the use of a transcriptional activator for the same purpose as Chakroborty, Hyde, Shis, Jusiak, Bowlin, and Sun, namely the inducible expression of a target nucleic acid of interest in mammalian cells, then it would have been predictable to have utilized the blue-light inducible system of Motta in order to drive the expression of the sleeping beauty transposon, and the subsequent integration of a genomic tag, in the presence of blue light. And because Motta teaches that using blue light as an inducer has many advantages over using chemicals as inducers, one would have been motived to have used blue light as the inducer for the expression and integration of the genomic tag.
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Chakroborty ("A CRISPR/Cas9-based system for reprogramming cell lineage specification." Stem cell reports 3.6 (2014): 940-947), Hyde (PG Pub No. US 2015/0098954 A1), Shis ("Library of synthetic transcriptional AND gates built with split T7 RNA polymerase mutants." Proceedings of the National Academy of Sciences 110.13 (2013): 5028-5033), Jusiak ("Engineering synthetic gene circuits in living cells with CRISPR technology." Trends in biotechnology 34.7 (2016): 535-547), Bowlin (US Patent No. 7,374,774 B2), and Wang (Bone 48.3 (2011): 524-532).
Regarding claim 14, the applicable teachings of Chakroborty, Hyde, Shis, Jusiak, and Bowlin are described above as applied to claims 9-11 and 13.
Chakroborty, Hyde, Shis, Jusiak, and Bowlin does not teach or suggest a method of regenerating tissue (Claim 14). Chakroborty, Hyde, Shis, Jusiak, and Bowlin does not teach or suggest that the endogenous protein is BMP-2 (Claim 14). Chakroborty, Hyde, Shis, Jusiak, and Bowlin does not teach or suggest that induction of both promoters results in tissue regeneration (Claim 15).
The applicable teachings with respect to the Wang reference are described above in the 35 USC 103 rejection of claims 9-11 and 13.
Wang further teaches that endogenous BMP-2 plays a key role in skeletal development, repair, and bone tissue regeneration (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the requirements of the claimed target endogenous encoding a BMP because it would have merely amounted to a simple substitution of one endogenous target gene for another and one target cell for another. Since Chakroborty, Hyde, Shis, and Jusiak teach the use of the inducible system for a similar purpose as Wang, namely targeted gene activation of a target endogenous gene in order to beneficially alter a target cell’s phenotype, then it would have been predictable to have used the inducible system within the cell of Wang in order to induce expression of the endogenous gene encoding a BMP only in the presence of the two inducer molecules. And because Wang teaches that the stimulation of the expression of the endogenous BMP was beneficial, one would have been motivated to do so in order to enhance bone repair and regeneration.
Claims 17 are rejected under 35 U.S.C. 103 as being unpatentable over Chakroborty ("A CRISPR/Cas9-based system for reprogramming cell lineage specification." Stem cell reports 3.6 (2014): 940-947), Hyde (PG Pub No. US 2015/0098954 A1), Shis ("Library of synthetic transcriptional AND gates built with split T7 RNA polymerase mutants." Proceedings of the National Academy of Sciences 110.13 (2013): 5028-5033), Jusiak ("Engineering synthetic gene circuits in living cells with CRISPR technology." Trends in biotechnology 34.7 (2016): 535-547), and Bowlin (US Patent No. 7,374,774 B2), and Wang (Bone 48.3 (2011): 524-532) as applied to claims 14-16 above, as evidenced by Hashimoto (Journal of Orthopaedic Research 25.11 (2007): 1415-1424).
Regarding claim 14, the teachings of Chakroborty, Hyde, Shis, Jusiak, Bowlin, and Wang are described above as applied to claims 14-16.
Chakroborty, Hyde, Shis, Jusiak, Bowlin, and Wang do not teach or suggest that the method generates enthesis (Claim 17).
Hashimoto is drawn to a study concerned with the role that BMP-2 plays in the generation of tendon-to-bone interfaces (Abstract). Hashimoto teaches that the anatomical structure at bone-tendon and bone-ligament interfaces is called the enthesis (Abstract). Hashimoto teaches that expression of BMP-2 successfully regenerates a direct tendon-to-bone enthesis in a mammalian cells (Abstract).
Therefore, it would have been evident to one of ordinary skill in the art before the effective filing date of the claimed invention that the method of Chakroborty, Hyde, Shis, Jusiak, Bowlin, and Wang generates enthesis, as evidenced by Hashimoto. One of ordinary skill would have recognized that the BMP-2 protein described in Hashimoto is the same protein rendered obvious above by Chakroborty, Hyde, Shis, Jusiak, Bowlin, and Wang. Accordingly, it would have been predictable to have generated enthesis via the inducible construct of Chakroborty, Hyde, Shis, Jusiak, Bowlin, and Wang because Hashimoto teaches that the upregulation of BMP-2 results in enthesis in mammalian cells.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-17 have been fully considered and are deemed persuasive. Accordingly, the previously pending rejections under 35 USC 103 have been withdrawn.
Applicant’s arguments with respect to the newly rejected claim(s) 1-17 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Insofar as Applicant’s arguments are applicable to the newly pending 35 USC 103 rejections of record, Applicant has not provided any specific arguments pertaining to the previously utilized Bowlin, Wang, or Hashimoto references. Accordingly, the Bowlin, Wang, and Hashimoto references are interpreted as being drawn to valid prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/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, Neil Hammell can be reached at 571-270-5919. 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.
/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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