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 10 December 2025. 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 Claims 14, 16, 20, 22-23, 25-26, 30-33, 39-40, and 42-46 are withdrawn from prosecution as being drawn to non-elected subject matter.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, claims 1-2, 6, 8, and 10-13 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 § 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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1 and 12-13 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ko (US Patent No. 10,836,997 B2, filed 9 March 2016).
Regarding claims 1 and 12, Ko is directed towards an invention concerned with differentiating a pluripotent stem cell of mammalian origin into a desired cell type by induction of expression of transcription factors (Abstract). Ko teaches the use of a pluripotent stem cell inducer that comprises an mRNA present within a vector encoding one or more transcription factors (i.e., Kop teaches the use of an isolated polynucleotide that encodes one or more transcription factors) (Col. 9, lines 46-52). Ko teaches that a human pluripotent stem cell may be differentiated into a nerve cell present in the hypothalamus via the use of the introduction of transcription factors NEUROG3 and SOX2 into the human pluripotent stem cell (Col. 34, line 32-67; see Example 8).
Regarding claim 13, Ko teaches that the pluripotent stem cell may be isolated (Col. 12, liens 15-26; see Fig. 2).
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, 8, 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 Ko (US Patent No. 10,836,997 B2, filed 9 March 2016).
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 ([0024]).
Wang does not teach or suggest the use of a second gRNA targeting a second transcription factor of SOX2 (Claims 2 and 6).
However, one of ordinary skill in the art would have considered the teachings of Ko as both references are common fields of endeavor pertaining to the differentiation of stem cells.
The applicable teachings of Ko are discussed above as applied to claims 1 and 12-13.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Wang such that a second gRNA that targets and upregulates SOX2 was utilized, as described by Wang. A person of ordinary skill in the art would have been motivated to do so in order to differentiate the stem cell of Wang via the upregulation of two transcription factors known to be able to differentiate pluripotent stem cells into specific nerve cells, as described by Ko. A person of ordinary skill in the art would have had a reasonable expectation of success because Wang teaches that the CRIPR system can be utilized to upregulate a transcription factor of interest and Ko teaches that upregulating NEUROG3 and SOX2 resulted in the successful differentiation of stem cells into a desired nerve cell type.
Regarding claim 8, Wang 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]).
Ko teaches that NEUROG3 is required to differentiate a stem cell into a nerve cell (Col. 34, line 32-67; see Example 8). Ko teaches that FOXA1 is a transcription factor that is required to differentiate a stem cell into a liver cell (Col. 13, lines 1-7) or a trachea cell (Col. 44, lines 15-19; see Example 35). Ko further teaches that there are many different cell types that do not require the expression of either NEUROG3 or FOXA1, including but not limited to skeletal muscle cells, skin cells, ovary cells, adrenal gland cells, salivary gland cells, among many others (Col. 33 to Col. 44; see Examples 6-7, 9-18, and 20-35).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gRNAs that target fusion proteins comprising a dCas9 that is linked to a corepressor such that the target NEUROG3 and FOXA1, as described by Ko. A person of ordinary skill in the art would have been motivated to do so in order to prevent the differentiation of the stem cells into nerve or liver cells. A person of ordinary skill in the art would have had a reasonable expectation of success because Wang teaches that corepressors may be recruited to transcription factors of interest in order to prevent their expression to generate a specific stem cell phenotype while Ko teaches that NEUROG3 and FOXA1 were known transcription factors that were associated with specific phenotypes of differentiated stem cells.
Regarding claim 10, 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).
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 1-2, 6, 8, and 10-13 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) and Ko (US Patent No. 10,836,997 B2, filed 9 March 2016).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1-2, 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 nucleic acid encoding NEUROG3 and SOX2 (Claim 1). Copending claims 1 and 34 do not claim the use of a gRNA targeting a first neuronal-specific transcription factor selected from NEUROG3 and SOX2 (Claims 2, 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).
However, one of ordinary skill in the art would have considered the teachings of Ko and Wang as both references are common fields of endeavor pertaining to the use of CRISPR methods for targeting genes of interest and the regulation of transcription factors.
The Applicable teaching of Ko and Wang are discussed above as applied to claims 1-2, 6, 8, and 10-13 above.
Therefore, regarding claim 1, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the nucleic acid rendered obvious above by Wang in view of Ko such that the expression of two transcription factors NEUROG3 and SOX2 are modulated. A person of ordinary skill in the art would have been motivated to do so in order to differentiate stem cells into a desired cell type. 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 modulation of transcription factors in a target cell of interest.
Therefore, regarding claims 2, 6, 8, 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.
Regarding claims 11-13, copending claims 26 and 28-29 recite identical limitations.
Claims 1-2, 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) and Ko (US Patent No. 10,836,997 B2, filed 9 March 2016).
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 nucleic acid encoding NEUROG3 and SOX2 (Claim 1). Copending claims 1 and 31 do not claim the use of a gRNA targeting a first neuronal-specific transcription factor selected from NEUROG3 and SOX2 (Claims 2, 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).
However, one of ordinary skill in the art would have considered the teachings of Ko and Wang as both references are common fields of endeavor pertaining to the use of CRISPR methods for targeting genes of interest and the regulation of transcription factors.
The Applicable teaching of Ko and Wang are discussed above as applied to claims 1-2, 6, 8, and 10-13 above.
Therefore, regarding claim 1, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the nucleic acid rendered obvious above by Wang in view of Ko such that the expression of two transcription factors NEUROG3 and SOX2 are modulated. A person of ordinary skill in the art would have been motivated to do so in order to differentiate stem cells into a desired cell type. 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 modulation of transcription factors in a target cell of interest.
Therefore, regarding claims 2, 6, 8, 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.
Regarding claims 11-13, copending claims 26-29 recite identical limitations.
Claims 1-2, 8, and 10-13 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).
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 does not claim the use of a nucleic acid encoding NEUROG3 and SOX2 (Claim 1). Copending claim 1 not claim the use of a gRNA targeting a first neuronal-specific transcription factor selected from NEUROG3 and SOX2 (Claims 2, 8). Copending claim 1 not claim the use of a gRNA that comprises a polynucleotide sequence selected from SEQ ID NO: 40 (Claim 10).
However, one of ordinary skill in the art would have considered the teachings of Ko and Wang as both references are common fields of endeavor pertaining to the use of CRISPR methods for targeting genes of interest and the regulation of transcription factors.
The Applicable teaching of Ko and Wang are discussed above as applied to claims 1-2, 6, 8, and 10-13 above.
Therefore, regarding claim 1, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the nucleic acid rendered obvious above by Wang in view of Ko such that the expression of two transcription factors NEUROG3 and SOX2 are modulated. A person of ordinary skill in the art would have been motivated to do so in order to differentiate stem cells into a desired cell type. 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 modulation of transcription factors in a target cell of interest.
Therefore, regarding claims 2, 6, 8, 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.
Regarding claim 10, copending claim 7 claims the use of a gRNA that comprises a sequence with 100% identity to 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 10 December 2025 have been fully considered but they are not persuasive.
It is noted that Applicant’s arguments are directed towards the previously pending 35 USC 102, 102, 112(d), and 103 rejections of record, filed 10 September 2025. As Applicant’s amendments have necessitated the newly filed 35 USC 102 and 103 rejections above, Applicant’s arguments are not found persuasive as they are not directed towards the currently pending 35 USC 102 and 103 rejections of record.
Regarding Applicant's request to hold the nonstatutory double patenting rejections in abeyance, the request is denied per MPEP 804. The rejections will remain in place until they are overcome by amendment, terminal disclaimer, or otherwise. Future requests to hold the rejections in abeyance will likewise be denied.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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).
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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.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636