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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5 June 2026 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 5 June 2026. Claims 1-2, 6, 8, 10-14, 16, 20, 22-23, 25-26, 30-33, 39-40, and 42-46 are currently pending. Claims 14, 16, 20, 22- 23, 25-26, 30-33, 39-40, and 42-46 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1-2, 6, 8, and 10-13 are examined herein. The restriction requirement mailed 2 April 2025 is still deemed proper. Applicant's elected Group I without traverse in the reply filed 2 July 2025.
Any rejection or objection not reiterated herein has been overcome by amendment.
Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the
claims in condition for allowance for the reasons that follow.
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 2, 6, 8, and 10-11 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.
Regarding claim 2, the claim recites “two transcription factors consisting of a first gRNA targeting a first transcription factor of […] and a second gRNA targeting a second transcription factor of […]” (see Claim 2). As currently written, the claimed phrase “two transcription factors consisting of” appear to be referring to the two claimed gRNA molecules and not the claimed genes present within the claims. It is unclear if the claimed two transcription factors are referring to the two claimed gRNA molecules, as is currently written, or if the claim is intended to encompass two gRNAs targeting two transcription factors consisting of the claimed genes.
Regarding claim 10, the claim recites that the gRNA targets or comprises a sequence from the claimed SEQ ID NOs: 38-97 (see Claim 10). However, claim 2 (i.e., the claim from which claim 10 depends on) recites a first and second gRNA. Thus, it is unclear which gRNA claim 10 is referring to with respect to the claimed SEQ ID NOs.
Regarding claims 6, 8, and 11, as the claims are ultimately dependent on claim 2 and do not rectify the currently outstanding 35 USC 112(b) rejection above, the claims are also rejected under 35 USC 112(b).
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.
Claims 2, 6, 8, and 10-11 are 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.
Regarding claim 2, the claim is directed towards a system for increasing expression of a neuronal-specific gene through the use of gRNAs targeting two transcription factors and a fusion protein that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity (see Claim 2) .
Accordingly, the claims are interpreted as reciting a system that must possess the function of increasing the expression of the claimed genes while utilizing a fusion protein that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would leave one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP 2163. A claimed genus may be satisfied through sufficient descriptions of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with known or disclosed correlation between function and structure. MPEP 2163(3)a(II). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
As the claims currently recite, as described above, the claim is directed towards a system that must possess the function of increasing the expression of the claimed genes while utilizing a fusion protein that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity. While claiming a structure by a function is not prohibited, there must be sufficient structure-function relationship described in the specification such that the claimed genus was represented by a representative number of species or the teachings of the specification, or, the prior art can be used support a well-known structure-function relationship.
In the instant case, the instant specification does not support the claimed structure-function relationship that utilizing the claimed fusion protein that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity would predictably result in the increased expression of a neuronal-specific gene. Further, the prior art does not support a clear, well-defined, and predictable structure-function relationship between contacting the claimed genes with a polypeptide having methylase activity, or transcriptional repression activity, and having the function of increasing the expression of the genes.
Prior Art
Prior to the effective filing date of the claimed invention, the prior art provides evidence that contacting the claimed SOX2, RUNX3, SOX9, GATA6, and FOXA1 genes with a polypeptide that has methylase activity (i.e., increasing the methylation of the claimed genes) results in the genes’ decreased expression. Additionally, the prior art provides evidence that utilizing a fusion protein that comprises a Cas protein and a polypeptide domain that has transcriptional repression activity or methylase activity results in the decreased expression of the claimed genes.
Regarding the state of the art surrounding the contacting of the claimed genes with a polypeptide that has methylase activity, Maehara ("SOX2-silenced squamous cell carcinoma: a highly malignant form of esophageal cancer with SOX2 promoter hypermethylation." Modern Pathology 31.1 (2018): 83-92) is drawn towards a study concerned with SOX2 hypermethylation and teaches that hypermethylation of the promoter region is a critical epigenetic event leading to SOX2 silencing (Abstract). Maddipoti ("Epigenetic Silencing of the RUNX3 Gene by Promoter Hypermethylation in Patients with Acute Myeloid Leukemia." Blood 112.11 (2008): 3341) is drawn towards a study concerned with RUNX3 silencing and teaches that hypermethylation of a RUNX3 promoter resulted in the downregulation of the gene’s expression (Abstract). Cheng ("Methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma." Genome biology 16.1 (2015): 42) is drawn towards a study concerned with SOX9 silencing and teaches that SOX9 expression is silenced through promoter DNA methylation (pg. 4). Wu ("Aberrant JAK/STAT signaling suppresses TFF1 and TFF2 through epigenetic silencing of GATA6 in gastric cancer." International journal of molecular sciences 17.9 (2016): 1467) is drawn towards a study concerned with GATA6 silencing and teaches that low GATA6 methylation demonstrated a higher level of protein expression (i.e., the methylation of GATA6 results in the decreased expression of GATA6) (pg. 5-6). Gong ("FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer." Oncogene 34.39 (2015): 5012-5024) is drawn towards a study concerned with FOXA2 repression and teaches that FOXA1 expression is silenced through promoter DNA hypermethylation (pg. 5013).
Therefore, a thorough review of the prior art demonstrates that increasing the methylation status at the claimed genes results in their downregulated expression. Accordingly, the prior art does not provide evidence that contacting the claimed genes with a polypeptide that ahs methylase activity would predictably result in the increased expression of the genes, as claimed.
Additionally, the prior art teaches that contacting a gene of interest with a fusion protein comprising a Cas protein and a polypeptide that has transcriptional repression activity results in the reduced expression of the gene of interest. Dominguez ("Beyond editing: repurposing CRISPR–Cas9 for precision genome regulation and interrogation." Nature reviews Molecular cell biology 17.1 (2016): 5-15) is drawn towards a study concerned with repurposing CRISPR proteins for genomic expression regulation (Abstract). Dominguez teaches that fusing a dCas9 to a transcriptional repressor resulted in increased repression efficiency of a gene that the dCas9 targeted through the use of its gRNA molecules (pg. 7).
Thus, a thorough review of the prior art demonstrates that contacting a gene of interest with a Cas protein fused to a polypeptide having transcriptional repression activity results in its downregulated expression. Accordingly, the prior art does not provide evidence that contacting the claimed genes with a fusion protein that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity would have predictably resulted in the increased expression of the claimed genes.
Therefore, the prior art does not support a clear, well-defined, and predictable structure-function relationship between the contacting of the claimed genes with a fusion protein that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity and the increased expression of a neuronal-specific gene.
Working Examples
With regard to working examples, the specification provides little evidence on the possession of a sufficient number of species of fusion proteins as claimed which possess the function as claimed. The instant specification does not describe the use of a fusion protein that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity and a resultant increased expression of the claimed genes.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would recognize that the instant specification does not provide adequate written description for the entirety of the claimed genus of fusion proteins that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity or methylase activity and the function of being able to increase the expression of the claimed genes.
Conclusion
The specification does not identify a structure-function relationship between the claimed fusion proteins that comprises a Cas protein, zinc finger protein, or a TALE protein and a polypeptide domain that has transcriptional repression activity and the function of the increased expression of the claimed neuronal-specific genes. Further, the closet prior art shows that prior to the effective filing date of the claimed invention that contacting the claimed genes with polypeptides comprising a domain that has methylase activity or transcriptional repression activity results in the decreased expression of the claimed genes. Taken together, the skilled artisan would not have reasonably concluded at the time of the invention that applicant was in possession of the invention as claimed. Thus, claim 2 is rejected under 35 U.S.C. 112(a).
Regarding claims 6, 8, and 10-11, as they are ultimately dependent on claim 2 and do not rectify the written description rejection described above, the claims are also rejected under U.S.C. 112(a).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 and 12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ejarque ("Neurogenin3 cooperates with Foxa2 to autoactivate its own expression." Journal of Biological Chemistry 288.17 (2013): 11705-11717).
Regarding claims 1 and 12, it is noted that the instant specification teaches that the singular form “a” includes plural references ([0007]). Thus, the claims are interpreted as encompassing multiple polynucleotides and multiple vectors encoding the claimed transcription factors.
Regarding claims 1 and 12, Ejarque is drawn towards a study concerned with how NEUROG3 cooperates with FOXA2 and FOXA1 to autoactivate its own expression (Abstract). Ejarque teaches that when FOXA2 and NEUROG3 are coexpressed from different vectors (i.e., “a” vector and “an” isolated polynucleotide as defined by the instant specification) within embryonic pancreas cells, FOXA2 individually transactivated the NEUROG3 promoter (pg. 11710-11711; see Figure 4). Ejarque teaches that FOXA2 and FOXA1 are both equally capable of potentiating the autoactivation of NEUROG3 in in vitro luciferase assays, and in vivo, Foxa1 functions at later stages of endocrine differentiation (pg. 11713). Ejarque teaches that FOXA1, expressed from a different vector when compared to the vector encoding NEUROG3 (i.e., “a” vector and “an” isolated polynucleotide as defined by the instant specification), also synergistically cooperates with NEUROG3 in autoactivating the NEUROG3 promoter in transient transfection assays in mPAC and NIH3T3 cells (Fig. 6A and 6B), thus demonstrating that FOXA1, like FOXA2, can regulate Neurog3 promoter activity (pg. 11713-11714; see Figure 6). Ejarque teaches that positive autoregulation of NEUROG3 can provide several functional advantages to the control of cell fate determination by NEUROG3 (pg. 11715). Ejarque teaches that because of the crucial role of Neurog3 in endocrine cell differentiation, it is expected that multiple direct and indirect positive and negative feedback loops can be utilized to cooperate to control Neurog3 gene expression (pg. 11716).
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) 2, 6, and 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (PG Pub No. US 2021/0254049 A1, filed 19 April 2019) in view of Carcagno ("Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain." The Journal of Neuroscience 34.46 (2014): 15223-15233).
Regarding claim 2, it is noted that the claim is drawn to a system for increasing expression of a “neuronal-specific gene” (see line 1 of claim 2). Because the claim does not expressly require that the system must increase the expression of a gene present within a neuronal cell’s genomic sequence, the claim is interpreted as a system intended for increasing expression of at least one of the claimed target genes wherein the genes themselves are defined as “neuronal-specific”.
Regarding claims 2, 6, and 11, Wang is drawn to an invention concerned with identifying targets involved in cell differentiation via the use of complexes that each include a catalytically- deactivated DNA binding protein, a guide RNA that guides the complex, and one or more effector domains may be introduced into stem cells to cause at least one of the stem cells to differentiate into a target phenotype (Abstract). Wang teaches the use of a target NEUROG3 gene that can be activated by a CRISPR system in iPSCs via a guide RNA ([0068]; see FIG. 8). Wang teaches that the CRISPR system can comprise a fusion protein comprising a dCas9 (i.e., a first polypeptide domain) that can initiate expression of transcription factors via the use of transcriptional activation domain (i.e., a second polypeptide domain) that results in the differentiation of a stem cell ([0014], [0021], [0024]). Wang teaches that NEUROG3 is a genetic target that was identified as one of many genetic targets most likely to yield beta cell- specification of cell fate ([0176]-[0177]). Wang teaches the use of an mRNA (i.e., an isolated polynucleotide) encoding a fusion protein that includes a dCas9 protein and a transcriptional regulator that can target and activate expression of the transcription factors ([0024]). Wang additionally teaches that SOX2 is a known gene marker for iPSC pluripotency and trilineage potential ([0158]-[0159]).
Wang does not teach or suggest the use of a second gRNA comprising a gRNA that targets SOX2 (Claims 2 and 6).
Carcagno is drawn towards a study concerned with how the expression of NEUROG3 in the spinal cord induces the correct specification of p3-derived neurons (Abstract). Carcagno teaches that coexpressing NEUROG3 alongside SOX2 in the spinal cord is beneficial because NEUROG3 expression in the ventral spinal cord is limited to the ventricular zone, which can be successfully indicated by colabeling the cells with the progenitor cell marker Sox2 (pg. 15225; see Figure 2E).
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 modified the method of Wang such that SOX2 expression was increased alongside NEUROG3 expression because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Carcagno teaches the expression of only SOX2 alongside NEUROG3 allowed for the marking of the progenitor cells present within the ventricular zone, one of ordinary skill in the art would have expected that increasing the expression of SOX2 alongside NEUROG3 to have successfully resulted in the expression of both proteins in order to mark the cells which comprise the NEUROG3 protein. Additionally, because Wang already teaches that SOX2 is a known marker that can be utilized in iPSCs to mark pluripotency, one of ordinary skill in the art would have expected that increasing SOX2 expression through the use of a second gRNA would have predictably resulting in the marking of the iPSCs cells comprising an increased expression of NEUROG3.
Regarding claim 10, for the purposes of examination the claim is interpreted as limiting only one of the two claimed gRNAs of claim 2. Wang teaches the use of an sgRNA comprising a polynucleotide sequence that has 100% identity to the claimed SEQ ID NO: 40 and targets NEUROG3 ([0189; see SEQ ID NO: 22 in Table 4 and in previously attached sequence alignment).
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (PG Pub No. US 2021/0254049 A1, filed 19 April 2019) in view of Carcagno ("Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain." The Journal of Neuroscience 34.46 (2014): 15223-15233) as applied to claims 2, 6, and 10-11 above, and further in view of Beucher ("The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice." PloS one 7.5 (2012): e36449).
Regarding claim 8, Wang in view of Carcagno renders obvious claims 2, 6, and 10-11 as described above. Wang further teaches that the fusion protein may comprise a corepressor ([0023]). Wang teaches that the fusion proteins may be utilized to repress genes that encode proteins involved in cell differentiation such that the cell is differentiated into a specific target phenotype ([0031]).
Wang in view of Carcagno does not teach or suggest that the second polypeptide domain has transcription repression activity when the first transcription factor is NEUROG3 and the second transcription factor is FOXA1 (Claim 8).
Beucher is drawn towards a study concerned with how the transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice (Abstract). Beucher teaches that enteroendocrine subtype specification is controlled by endocrine progenitors expressing Neurog3 then Pax4 and Arx such that the cells can be differentiated into different endocrine cells selected from Gast, GlP, Nts, Sct, CCK, GLP1, Sst, and 5-HT cells (pg. 9; see Figure 8). Beucher teaches that Arx represses Foxa1/Foxa2 expression (pg. 9). Beucher teaches that Foxa1 and Foxa2 promote the differentiation of GLP1 and Somatostatin- (Sst-) expressing cells (i.e. expression of Foxa1 (pg. 2). Beucher teaches that Foxa1 expression is increased in Arx-deficient small intestine and colon cells (pg. 8; see Figure 7). Beucher teaches that Arx represses Foxa1 and Foxa2 in endocrine progenitors, both genes being subsequently activated in L-cells to control terminal differentiation (i.e., through the repression of Foxa1, the terminal differentiation of the progenitor cells can be controlled) (pg. 9).
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 modified the gRNAs of Wang in view of Carcagno such that one of the gRNAs targeted Foxa1 because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Wang teaches that the dCas9 fusion proteins can be utilized to repress genes of interest, one would have expected repressing Foxa1 in the cells of Beucher using the fusion protein to have resulted in the successful control over the differentiation of the endocrine progenitors. Additionally, because Wang teaches that the gRNAs can be designed to target genes responsible for cell differentiation, one would have expected targeting the repressor fused to the dCas9 of Wang to have successfully resulted in the repression of Foxa1 within the endocrine progenitors of Beucher.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 2, 6, 8, and 10-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 26, 28-29, and 34 of copending Application No. 18/180,718 (reference application) in view of Wang (PG Pub No. US 2021/0254049 A1, filed 19 April 2019), Carcagno ("Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain." The Journal of Neuroscience 34.46 (2014): 15223-15233), and Beucher ("The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice." PloS one 7.5 (2012): e36449).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 2, 6, 8, and 10, copending claim 1 claims a composition for treating leukemia, the composition comprising: a Cas9 protein or a fusion protein, wherein the fusion protein comprises two heterologous polypeptide domains, wherein the first polypeptide domain comprises a Cas9 protein and the second polypeptide domain has an activity selected from the group consisting of transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, nuclease activity, nucleic acid association activity, methylase activity, and demethylase activity; and at least one guide RNA (gRNA) that targets the Cas9 protein to a regulatory element of a target gene (i.e., a polynucleotide encoding a protein) selected from MYB and SREBF1. Copending claim 34 claims a method of modifying growth in a cell comprising modifying the expression of different transcription factors.
Copending claims 1 and 34 do not claim the use of a gRNA targeting neuronal-specific transcription factors selected from NEUROG3 and SOX2 (Claims 2, 6). Copening claims 1 and 34 do not claim that the first transcription factor is NEUROG3 and the second transcription factor is FOXA1 (Claim 8). Copending claims 1 and 34 do not claim the use of a gRNA that comprises a polynucleotide sequence selected from SEQ ID NO: 40 (Claim 10).
The applicable teaching of Wang, Carcagno, and Beucher are discussed above as applied to claims 2, 6, 8, and 10-11 as described above.
Therefore, regarding claim 2, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending method such that SOX2 expression was increased alongside NEUROG3 expression because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Carcagno teaches the expression of only SOX2 alongside NEUROG3 allowed for the marking of the progenitor cells present within the ventricular zone, one of ordinary skill in the art would have expected that increasing the expression of SOX2 alongside NEUROG3 to have successfully resulted in the expression of both proteins to mark the cells which comprise the NEUROG3 protein. Additionally, because Wang already teaches that SOX2 is a known marker that can be utilized in iPSCs to mark pluripotency, one of ordinary skill in the art would have expected that increasing SOX2 expression using a second gRNA would have predictably resulting in the marking of the iPSCs cells comprising an increased expression of NEUROG3.
Therefore, regarding claims 2, 6, and 10, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute at least one of the copending claimed gRNAs for a gRNA comprising the claimed SEQ ID NO: 40 that targets NEUROG3, as described by Wang, and another gRNA for a gRNA targeting SOX2, as rendered obvious by Wang in view of Carcagno above because it would have amounted to a simple substitution of one known element for another to obtain predictable results. Because both the copending claims and Wang in view of Carcagno teach the targeting and modulation of the expression of genes of interest via a CRISPR complex that is guided to the target gene via the use of at least one gRNA, one would have expected modifying the copending claims to the instantly claimed target genes to have successfully resulted in modulation of the claimed genes’ expression levels.
Therefore, regarding claim 8, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending gRNAs such that the gRNAs targeted NEUROG3 and FOXA1 because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Wang teaches that the dCas9 fusion proteins can be utilized to repress genes of interest, one would have expected repressing Foxa1 in the cells of Beucher through the use of the fusion protein to have resulted in the successful control over the differentiation of the endocrine progenitors. Additionally, because Wang teaches that the gRNAs can be designed to target genes responsible for cell differentiation, one would have expected targeting the copending repressor fused to the copending dCas9 to have successfully resulted in the repression of Foxa1 within the endocrine progenitors of Beucher.
Regarding claims 11-13, copending claims 26 and 28-29 recite identical limitations.
Claims 2, 6, 8, and 10-13 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 26-29, and 31 of copending Application No. 18/279,996 in view of Wang (PG Pub No. US 2021/0254049 A1, filed 19 April 2019), Carcagno ("Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain." The Journal of Neuroscience 34.46 (2014): 15223-15233), and Beucher ("The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice." PloS one 7.5 (2012): e36449).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 1-2, 8, and 10, copending claim 1 claims a composition for treating leukemia, the composition comprising: a Cas9 protein or a fusion protein, wherein the fusion protein comprises two heterologous polypeptide domains, wherein the first polypeptide domain comprises a Cas9 protein and the second polypeptide domain has an activity selected from the group consisting of transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, nuclease activity, nucleic acid association activity, methylase activity, and demethylase activity; and at least one guide RNA (gRNA) that targets the Cas9 protein to a regulatory element of a target gene (i.e., a polynucleotide encoding a protein) selected from MYB and SREBF1. Copending claim 31 claims a method of modulating the expression of different transcription factors.
Copending claims 1 and 31 do not claim the use of a gRNA targeting neuronal-specific transcription factors selected from NEUROG3 and SOX2 (Claims 2, 6). Copending claims 1 and 31 do not claim that the first transcription factor is NEUROG3 and the second transcription factor is FOXA1 (Claim 8). Copending claims 1 and 31 do not claim the use of a gRNA that comprises a polynucleotide sequence selected from SEQ ID NO: 40 (Claim 10).
The applicable teaching of Wang, Carcagno, and Beucher are discussed above as applied to claims 2, 6, 8, and 10-11 as described above.
Therefore, regarding claim 2, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending method such that SOX2 expression was increased alongside NEUROG3 expression because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Carcagno teaches the expression of only SOX2 alongside NEUROG3 allowed for the marking of the progenitor cells present within the ventricular zone, one of ordinary skill in the art would have expected that increasing the expression of SOX2 alongside NEUROG3 through the use of the copending proteins to have successfully resulted in the expression of both proteins to mark the cells which comprise the NEUROG3 protein. Additionally, because Wang already teaches that SOX2 is a known marker that can be utilized in iPSCs to mark pluripotency, one of ordinary skill in the art would have expected that increasing SOX2 expression using a second gRNA would have predictably resulting in the marking of the iPSCs cells comprising an increased expression of NEUROG3.
Therefore, regarding claims 6 and 10, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute at least one of the copending claimed gRNAs for a gRNA comprising the claimed SEQ ID NO: 40 that targets NEUROG3, as described by Wang, and another gRNA for a gRNA targeting SOX2, as rendered obvious by Wang in view of Ko above. A person of ordinary skill in the art would have had a reasonable expectation of success because both the copending claims and Wang in view of Ko teach the targeting and modulation of the expression of genes of interest via a CRISPR complex that is guided to the target gene via the use of at least one gRNA.
Therefore, regarding claim 8, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending gRNAs such that the gRNAs targeted NEUROG3 and FOXA1 because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Wang teaches that the dCas9 fusion proteins can be utilized to repress genes of interest, one would have expected repressing Foxa1 in the cells of Beucher through the use of the fusion protein to have resulted in the successful control over the differentiation of the endocrine progenitors. Additionally, because Wang teaches that the gRNAs can be designed to target genes responsible for cell differentiation, one would have expected targeting the copending repressor fused to the copending dCas9 to have successfully resulted in the repression of Foxa1 within the endocrine progenitors of Beucher.
Regarding claims 11-13, copending claims 26-29 recite identical limitations.
Claims 2, 6, 8, and 10-11 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 44-46 of copending Application No. 18/840,832 in view of Wang (PG Pub No. US 2021/0254049 A1, filed 19 April 2019), Carcagno ("Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain." The Journal of Neuroscience 34.46 (2014): 15223-15233), and Beucher ("The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice." PloS one 7.5 (2012): e36449).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 1-2, 8, and 10, copending claim 1 claims a composition for modulating T cells, the composition comprising a modulator of a gene, wherein the gene is selected from RREB1, MYB, and KLF2. Copending claim 5 claims that the modulator comprising a DNA targeting composition comprising a Cas9 protein or a fusion protein, wherein the fusion protein comprises two heterologous polypeptide domains, wherein the first polypeptide domain comprises a Cas9 protein and the second polypeptide domain has an activity selected from transcription activation activity, transcription repression activity, nuclease activity, transcription release factor activity, histone modification activity, nucleic acid association activity, methylase activity, and demethylase activity; and at least one guide RNA (gRNA) that targets the Cas9 protein to the gene or a regulatory element thereof.
Copending claim 1 not claim the use of a gRNA targeting neuronal-specific transcription factors selected from NEUROG3 and SOX2 (Claims 2, 6). Copending claim 1 does not claim that the first transcription factor is NEUROG3 and the second transcription factor is FOXA1 (Claim 8). Copending claim 1 does not claim the use of a gRNA that comprises a polynucleotide sequence selected from SEQ ID NO: 40 (Claim 10).
The applicable teaching of Wang, Carcagno, and Beucher are discussed above as applied to claims 2, 6, 8, and 10-11 as described above.
Therefore, regarding claim 2, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending method such that SOX2 expression was increased alongside NEUROG3 expression because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Carcagno teaches the expression of only SOX2 alongside NEUROG3 allowed for the marking of the progenitor cells present within the ventricular zone, one of ordinary skill in the art would have expected that increasing the expression of SOX2 alongside NEUROG3 through the use of the copending proteins to have successfully resulted in the expression of both proteins to mark the cells which comprise the NEUROG3 protein. Additionally, because Wang already teaches that SOX2 is a known marker that can be utilized in iPSCs to mark pluripotency, one of ordinary skill in the art would have expected that increasing SOX2 expression using a second gRNA would have predictably resulting in the marking of the iPSCs cells comprising an increased expression of NEUROG3.
Therefore, regarding claims 6 and 10, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute at least one of the copending claimed gRNAs for a gRNA comprising the claimed SEQ ID NO: 40 that targets NEUROG3, as described by Wang, and another gRNA for a gRNA targeting SOX2, as rendered obvious by Wang in view of Ko above. A person of ordinary skill in the art would have had a reasonable expectation of success because both the copending claims and Wang in view of Ko teach the targeting and modulation of the expression of genes of interest via a CRISPR complex that is guided to the target gene via the use of at least one gRNA.
Therefore, regarding claim 8, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending gRNAs such that the gRNAs targeted NEUROG3 and FOXA1 because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Wang teaches that the dCas9 fusion proteins can be utilized to repress genes of interest, one would have expected repressing Foxa1 in the cells of Beucher through the use of the fusion protein to have resulted in the successful control over the differentiation of the endocrine progenitors. Additionally, because Wang teaches that the gRNAs can be designed to target genes responsible for cell differentiation, one would have expected targeting the copending repressor fused to the copending dCas9 to have successfully resulted in the repression of Foxa1 within the endocrine progenitors of Beucher.
Regarding claim 10, copending claim 7 claims the use of a gRNA that comprises a sequence with 100% identity with the claimed SEQ ID NO: 38 (see SEQ ID NO: 94 in previously attached sequence alignment).
Regarding claims 11-13, copending claims 44-46 recite identical limitations.
Response to Arguments
Applicant's arguments filed 5 June 2026 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments pertain to the previously utilized Wang reference, Applicant has not provided any arguments pertaining to the combination of Wang with Carcagno or Beucher as described in the rejections of record above. Thus, the arguments pertaining to the previously recited 35 USC 102 and 103 rejections of record are found moot.
Applicant alleges that the provisional double patenting rejections of record should be withdrawn as each of the copending US patent applications have a later filing date than the present application (Remarks; pg. 12).
This argument is not found persuasive because the provisional double patenting rejections of record are not the only remaining rejections of record. Thus, the provisional double patenting rejections of record above over the copending applications are upheld.
Conclusion
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights