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 .
DETAILED ACTION
Amendments
In the reply filed on 02/24/2026, Applicant has amended claim 2 and newly canceled claims 37-38.
Claim Status
Claims 1-2, 11, 15-17, 20-21, 25 and 29-36 are pending.
Claims 21, 25 and 29-36 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election of Group I, drawn to a genetically modified mammalian cell comprising a transgene at a sustained transgene expression locus, and species of RPL13A locus were made without traverse in the reply filed on 02/19/2025.
Claims 1-2, 11, 15-17 and 20 are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 2 and 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for insufficient antecedent basis is withdrawn in light of Applicant’s amendment to claim 2 to recite “the transgene”.
Maintained Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 11, 15-17 and 20 stand rejected under 35 U.S.C. 103 as being unpatentable over Elefanty et al., (WO 2016/074016. Cited in IDS 04/03/2023) in view of Lo et al., (BioTechniques. 2017;62(4):165-174. Prior art of record) and Freed et al., (PLoS ONE. 2008; 3(1): e1422. P. 1-12. Prior art of record).
Claim 1 is directed to a human pluripotent stem cell (PSC) comprising a transgene inserted at a RPL13A locus in the genome wherein the transgene is expressed at a detectable level in the PSC and cells differentiated from the PSC, wherein the cells differentiated from the PSC include dopaminergic neurons, microglial cells or cardiomyocytes. It is noted that the limitation “wherein the transgene is expressed at a detectable level in … cells differentiated from the PSC, wherein the cells differentiated from the PSC include dopaminergic neurons, microglial cells or cardiomyocytes” does not limit the structure of the claimed product “a human PSC”, thus this wherein clause does not provide patentable weight in determining patentability of the claimed product. Claim 1 is reasonably interpreted as a human PSC comprising a transgene inserted at a RPL13A locus in the genome wherein the transgene is expressed at a detectable level in the PSC and the PSC is capable of differentiating into dopaminergic neurons, microglial cells or cardiomyocytes.
Elefanty teaches a human embryonic stem cell (p. 11, line 40 – p. 12, line 4, see Elefanty claims 15-16, and see Examples 3-4 and 12-13) comprising a vector comprising an exogenous nucleic acid (i.e., a transgene) and homologous sequences of a constitutively expressed gene and a translation interruption-reinitiation signal that is capable of replacing the stop codon of the constitutively expressed gene (see Elefanty claim 1 in p. 42), so that the vector is incorporated into the genome sequence at the constitutively expressed gene locus to express the exogenous nucleic acid in the cell (see Elefanty claim 18 in p. 43, see Fig 1 for an exemplary insertion of a transgene into the GAPDH locus and see Examples 3-4 in p. 33 for detection of transgene expression in hESCs). Elefanty teaches the hESC is capable of differentiating into cells like endothelial cells (see Examples 4 and 8), cardiomyocytes (NKX2-5GFP+ cells, see Example 13, and Fig 26A and legend in p. 7, para 1) and dopaminergic neurons (tyrosine hydroxylase (TH)+ neurons, see Example 13, and Fig 26B and legend in p. 7, para 1). Thus, Elefanty teaches a human PSC comprising a transgene inserted at a constitutively expressed gene locus in the genome wherein the transgene is expressed at a detectable level in the PSC and the PSC is capable of differentiating into dopaminergic neurons, endothelial cells and cardiomyocytes. Elefanty nevertheless teaches the transgene is expressed at a detectable level in cells differentiated from the PSC including dopaminergic neurons, endothelial cells or cardiomyocytes (see Examples 4 and 13 as discussed above).
However, Elefanty teaches the constitutively expressed genes (also referred to as housekeeping genes, see p. 3, para 1) comprise genes such as ribosomal protein RPLP1 and RPLP0 and others known to the person skilled in the art (p. 10, para “constitutively expressed genes”), but is silent on an RPL13A gene locus.
Lo teaches generating stable cell lines for protein production by integrating transgenes into a housekeeping gene locus, e.g., the human ribosomal protein L13A (RPL13A) gene locus, such that transgene expression is driven by the endogenous RPL13A promoter to ensure consistent and predictable expression of the recombinant protein (e.g., abstract and p. 168, last para.). Lo teaches the transgene is expressed at a detectable level in the cells for >15 passages (see Fig 1D and legend, and second to the last page, lower half of the middle column). Lo teaches transgenes inserted at the RPL13A locus are expressed at a lower but more consistent average level (p. 170, end of middle col., see Fig 2D and legend cited as “moderate and tight expression levels”). Regarding cell types, Lo teaches “human cell lines were chosen for validation in this study due to their broader applicability to other human cells, such as human induced pluripotent stem cells” (p. 166, last para.), thus suggests human induced pluripotent stem cells (i.e., a human PSC) can be used in RPL13A locus insertion.
Regarding RPL13A expression in human PSCs, Freed teaches gene expression profiling on hESCs and dopaminergic neurons derived thereof (e.g., abstract). Freed teaches RPL13A is one of the most-highly expressed genes commonly expressed in undifferentiated hESCs and dopaminergic neuronal cells (see Table 3, col. “Common Genes”, 1st row “Ribosomal proteins”). Thus, Freed teaches RPL13A is highly expressed in hESCs as well as dopaminergic neurons derived from hESCs.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the human PSC comprising a transgene inserted at a constitutively expressed gene locus disclosed by Elefanty, by choosing an RPL13A locus as taught by Lo and suggested by Freed with a reasonable expectation of success. Since Elefanty suggests other housekeeping gene loci known to the person skilled in the art may be chosen (p. 10, para “constitutively expressed genes”), since Lo reduces to practice inserting a transgene at the RPL13A locus such that the transgene is driven by the endogenous RPL13A promoter to achieve consistent and tight expression in the cells that may be applicable to human induced pluripotent stem cells (see above), and sine Freed teaches RPL13A is highly expressed in hESCs and dopaminergic neurons derived thereof (see Table 3, indicating the endogenous RPL13A promoter is active in human PSCs), one of ordinary skill in the art would have had a reason to choose the RPL13A locus as the site to insert the transgene into the human PSC genome of Elefanty in order to achieve consistent and tight expression of the transgene as suggested by Lo. One of ordinary skill in the art would have had a reasonable expectation of success in doing so since Freed teaches RPL13A is highly expressed in hESCs as well as the derivative cells such as dopaminergic neurons.
With respect to claim 2, directed to the expression level of the transgene not changing, it is noted that this wherein clause is directed to a limitation that simply expresses the intended result of inserting the transgene at the RPL13A locus, but does not limit the structure of the claimed human PSC. Thus, the wherein clause does not provide any patentable weight in determining the patentability of the claimed product. See MPEP 2111.04 (I). Elefanty nevertheless teaches the transgene is expressed in cells differentiated from the PSC including dopaminergic neurons, endothelial cells or cardiomyocytes (see Examples 4 and 13 as discussed above). Lo specifically teaches that all transgenic cells maintained their fluorescence for >15 passages (second to the last page, lower half of the middle column).
With respect to claim 11 directed to the PSC being a human ESC or human iPSC, as stated supra, Elefanty teaches the human PSC includes an embryonic stem cell or induced pluripotent stem cell (p. 11, line 40 – p. 12, line 1, see Elefanty claims 15-16, and see Examples 4 and 13 for human embryonic stem cells).
With respect to claim 15 directed to the transgene being inserted into the 3’ UTR of the RPL13A locus, Elefanty teaches inserting the transgene into the 3' UTR of the constitutively expressed gene locus (e.g., the 3’ UTR of the GAPDH locus, p. 11, para 3, see Fig 1). Lo teaches the transgene cassette is inserted after the last exon 10 of the human RPL13A genomic locus (see Fig 1B and legend), thus teaches the transgene is inserted into the 3’ UTR of the RPL13A gene locus.
With respect to claim 16 directed to the transgene sequence being linked in frame to a RPL13A gene sequence through a coding sequence for a self-cleaving peptide, Elefanty teaches a self-cleaving 2A peptide is used to link the C-terminus of the constitutively expressed gene (e.g., GAPDH gene) with the transgene (p. 3, para 4, see Fig 1 and reference claim 3). Lo teaches the transgene is linked in frame to the RPL13A gene with a protein quantitation reporter (PQR) that is an optimized self-cleaving viral P2A peptide (see e.g., p. 166, last para and see Fig 1B).
With respect to claim 17 directed to the transgene encoding a therapeutic protein or a safety switch signal, it is noted that the specification defines a safety switch signal as that can be used to stop proliferation of the genetically modified cells when their presence in the patient is not desired, such as a suicide gene like a thymidine kinase (TK) gene (see specification [0066]). Elefanty teaches the transgene encodes a polypeptide that is lacking or non-functional in a subject having a genetic disease (p. 26, para “Methods of treatment”, thus teaches a therapeutic protein). Furthermore, Elefanty specifically teaches a Myc:ER transgene that promotes proliferation only in the presence of 4-OHT (see e.g., Examples 8 and 12, equivalent to a safety switch signal). Elefanty also teaches the transgene encodes a suicide gene, optionally encoding thymidine kinase (see Elefanty claim 11). Lo teaches the transgene includes a foreign gene for producing recombinant protein pharmaceuticals for clinical use (p. 165, last sentence in left col).
With respect to claim 20 directed to a pharmaceutical composition comprising the dopaminergic neurons or cardiomyocytes derived from the human PSC and a pharmaceutically acceptable carrier, as stated supra, Elefanty teaches differentiating the human PSC into dopaminergic neurons or cardiomyocytes and the transgene is expressed in those differentiated cells (see Example 13 as discussed above). Elefanty teaches cells comprising the exogenous nucleic acid can be used in a medicament for treating a disease or disorder in a subject (e.g., p. 27, para. 3-5), and teaches pharmaceutically acceptable carriers suitable for the formulations of pharmaceutical compositions (p. 26, para 1). Thus, Elefanty suggests a pharmaceutical composition comprising the dopaminergic neurons or cardiomyocytes derived from the human PSC and a pharmaceutically acceptable carrier.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 02/24/2026 are acknowledged.
Applicant firstly argues that (A) there is no reasonable expectation of success to combine the cited references to arrive at the claimed PSC (Remarks, p. 6-9).
Applicant’s arguments have been fully considered but they are not persuasive. The detailed response is listed as follows.
In response to Applicant’s argument that Elefanty only provides a single example of introducing a GAP-Trap vector at the GAPDH locus in hESCs and achieving expression throughout differentiation, that does not enable the use of any housekeeping gene (HKG) as a locus for achieving transgene expression throughout differentiation (Remarks, p. 7, para 1), as a first matter, Applicant is reminded that as explained in the prior action, the limitation “wherein the transgene is expressed at a detectable level in … cells differentiated from the PSC, wherein the cells differentiated from the PSC include dopaminergic neurons, microglial cells or cardiomyocytes” does not limit the structure of the claimed product “a human PSC”, thus this wherein clause does not provide patentable weight in determining patentability of the claimed product. Claim 1 is reasonably interpreted as a human PSC comprising a transgene inserted at a RPL13A locus in the genome wherein the transgene is expressed at a detectable level in the PSC and the PSC is capable of differentiating into dopaminergic neurons, microglial cells or cardiomyocytes. Therefore, the argued limitation of “a locus for achieving transgene expression throughout differentiation” is not required in the instant claim.
Furthermore, Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Elefanty teaches a human PSC comprising a transgene inserted at a locus of a constitutively expressed gene and teaches the constitutively expressed genes comprise a list of genes such as ribosomal protein RPLP1 and RPLP0 and others known to the person skilled in the art (p. 10, para “constitutively expressed genes”). The only difference between Elefanty and the instant invention is that Elefanty is silent on RPL13A gene locus. Prior art Lo is cited to teach targeting a transgene into RPL13A gene locus in a human cell to achieve consistent expression of the transgene (p. 170, end of middle col., see Fig 2D and legend cited as “moderate and tight expression levels”), and prior art Freed is cited to teach RPL13A is one of the most-highly expressed genes commonly expressed in undifferentiated hESCs and dopaminergic neuronal cells (see Table 3, col. “Common Genes”, 1st row “Ribosomal proteins”). Thus, one of ordinary skill in the art would have had a reason to combine the teachings of Lo and Freed to choose RPL13A gene locus as the target site to incorporate the transgene into the human PSC of Elefanty to achieve detectable transgene expression in the PSC with a reasonable expectation of success.
In response to Applicant’s argument that Synnergren et al. evidences that not all HKGs are stably expressed in differentiating hESCs and “As a result, this teaching in Synnergren provides serious doubts that any HKG could be used as a locus for achieving transgene expression throughout differentiation” (originally emphasized by Applicant), and that Synnergren et al. teaches that RPL13A is actually not a suitable locus for sustained transgene expression during PSC differentiation due to its highly variable expression, thus one of ordinary skill in the art would not select RPL13A with any reasonable expectation of success (Remarks, p. 7 and p. 9), as stated supra, the argument that “achieving transgene expression throughout differentiation” is not required in the instant claims. Furthermore, one of ordinary skill in the art would have immediately expected that Synnergren’s teaching of not all HKGs are stably expressed in differentiating hESCs does not support the argument that whether any HKG could be used as a targeting locus. This is evidenced by the fact that although Synnergren suggests GAPDH locus or RPL13A locus has highly variable expression as argued by Applicant (the variations of RPL13A being 21-30 and GAPDH being higher 72-103, see Table 1), this teaching does not dissuade one of ordinary skill in the art, such as Elefanty, from using GAPDH locus as a targeting site in human PSC and achieving transgene expression throughout differentiation. Similarly, one of ordinary skill in the art would likely not be dissuaded from using RPL13A locus as well.
In response to Applicant’s argument that two papers (Klatt et al. 2020 and Ordovas et al. 2015) both teach AAVS1 targeting leads to unacceptably variable transgene expression during differentiation (Remarks, p. 7-8), as stated supra, the argument that “transgene expression during differentiation” is not required in the instant claims. Furthermore, one of ordinary skill in the art would not be dissuaded from using RPL13A locus as a target site because of Klatt and Ordovas’ teaching of AAVS1 locus.
Applicant additionally argues that (B) there is no motivation to combine the cited references to arrive at the claimed PSC (Remarks, p. 9-10).
Applicant’s arguments have been fully considered but they are not persuasive. The detailed response is listed as follows.
In response to Applicant’s argument that Lo uses a HEK293T cell line cell that has unique, extensive, and synthetic genomic transformations but does not suggest anything about PSCs and their subsequent differentiation into dopaminergic neurons, microglial cells, or cardiomyocytes, and one of ordinary skill in the art would simply not turn to the teachings of Lo to identify a locus for stable gene expression in PSCs and cells differentiated from PSCs (Remarks, p. 9-10), Applicant is reminded that a 35 U.S.C. § 103 based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, as stated supra, Elefanty already teaches a human PSC comprising a transgene inserted at a locus of a constitutively expressed gene and suggests a list of constitutively expressed genes (p. 10, para “constitutively expressed genes”). The only difference between Elefanty and the instant invention is that Elefanty is silent on RPL13A gene locus. Lo is cited to teach targeting a transgene into RPL13A gene locus in a human cell to achieve consistent expression of the transgene (p. 170, end of middle col., see Fig 2D and legend cited as “moderate and tight expression levels”), and prior art Freed is further cited to teach RPL13A is one of the most-highly expressed genes commonly expressed in undifferentiated hESCs and dopaminergic neuronal cells (see Table 3, col. “Common Genes”, 1st row “Ribosomal proteins”). Thus, one of ordinary skill in the art would have had a reason to combine the teachings of Lo and Freed to choose RPL13A gene locus as the target site to incorporate the transgene into the human PSC of Elefanty to achieve detectable transgene expression in the PSC with a reasonable expectation of success.
In response to Applicant’s argument that Lo is referring to human cell lines generally for the validation study and further points out that the "broader applicability" to PSCs does not relate to the specific instance of cell differentiation from PSCs, which is an essential element of the presently claimed cells (Remarks, p. 9-10), similarly as stated supra, the argument regarding “the specific instance of cell differentiation from PSCs” is not required in the instant claims.
Applicant finally argues that (C) the cited references fail to teach each and every element of the claimed PSCs (Remarks, p. 10-11).
Applicant’s arguments have been fully considered but they are not persuasive. The detailed response is listed as follows.
In response to Applicant’s argument that Freed’s NCAM+ cells that have RPL13A expression in Table 3 are neuronal precursors, and the teachings in Freed do not relate to differentiated dopaminergic neurons (Remarks, p. 10), as a first matter, the argument that “the transgene is expressed at a detectable level in… cells differentiated from the PSC, wherein the cells differentiated from the PSC include dopaminergic neurons, microglial cells, or cardiomyocytes” is not required in the instant claims.
Furthermore, Freed indeed teaches dopaminergic neurons are differentiated from hESCs (see e.g., p. 3, right col, “Results”, para 1, teaching TH-positive cells are first detected at days 10-12). Additionally, Freed teaches using FACS to sort PSA-NCAM+ cells at day 14 (see e.g., p. 3, right col, “Results”, para 3), and teaches “expression of four neuronal markers (TH, Lmx1b, Pitx3 and TrkB) was detected in sorted cells (Fig. 1F).” (p. 3, right col, last full para, also see Fig 1F). Freed clearly teaches “Remarkably, the gene for TH, a marker of mature dopaminergic neurons … is known to be expressed in the sorted cell population (Fig. 1F and 2A)” (p. 4, right col, last para). In summary, Freed teaches at least a portion of the sorted NCAM+ cells that have RPL13A expression are mature dopaminergic neurons as evidenced by the expression of neuronal markers such as TH. Therefore, Freed teaches the RPL13A promoter is active in hESCs and the cells differentiated from the hESCs, such as PSA-NCAM+ cells. Since at least a portion of Freed’s NCAM+ cells are mature dopaminergic neurons, the RPL13A promoter is likely to be active in the mature dopaminergic neurons as well.
In response to Applicant’s argument that nowhere in Freed are microglial cells or cardiomyocytes even mentioned (Remarks, p. 10), Applicant is reminded that the instant claim recites “wherein the cells differentiated from the PSC include dopaminergic neurons, microglial cells, or cardiomyocytes”, in which the cell types are separated by a conjunction “or”, thus only one cell type is required for examination.
In response to Applicant’s argument that Freed also shows PPIA is commonly expressed between hESCs and NCAM+ cells, while the present application shows PPIA is unsuitable for transgene expression because of its highly variable expression (Remarks, p. 11), Applicant is reminded that Freed is cited to suggest RPL13A is expressed in hESCs and NCAM+ neurons, thus makes obvious the RPL13A promoter is active in human PSCs and cells differentiated from the PSC. Therefore, whether or not a PPIA gene locus is suitable for transgene expression does not negate the teaching of Freed regarding RPL13A.
In summary, Applicant’s arguments are not persuasive, and thus the prior rejection is maintained.
Maintained Provisional Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 11, 15-17 and 20 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 173-174, 178, 182-183, 228 and 230 of copending Application No. 17/923,358 (‘358) in view of Lo et al., (BioTechniques. 2017;62(4):165-174. Prior art of record) and Freed et al., (PLoS ONE. 2008; 3(1): e1422. P. 1-12. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims, especially claims 228 and 230, recite an engineered iPSC comprising a genomic modification comprising an insertion of an exogenous knock-in cassette within an endogenous coding sequence of a GAPDH in the iPSC’s genome, the gene product of interest is e.g., a CAR, wherein the gene product of interest is expressed from the endogenous promoter of GAPDH. The cell is for use as a medicament or for use in the treatment of a disease (copending claim 183).
However, the copending application is silent on the iPSC being from human, nor teach a RPL13A gene locus for transgene insertion.
Lo teaches integrating transgenes into a housekeeping gene locus, e.g., the human ribosomal protein L13A (RPL13A) gene locus, such that transgene expression is driven by the endogenous RPL13A promoter to ensure consistent and predictable expression of the recombinant protein (e.g., abstract and p. 168, last para.). Lo teaches the transgene is expressed at a detectable level in the cells for >15 passages (see Fig 1D and legend, and second to the last page, lower half of the middle column). Lo teaches transgenes inserted at the RPL13A locus are expressed at a lower but more consistent average level (p. 170, end of middle col., see Fig 2D and legend cited as “moderate and tight expression levels”). Regarding cell types, Lo teaches “human cell lines were chosen for validation in this study due to their broader applicability to other human cells, such as human induced pluripotent stem cells” (p. 166, last para.), thus suggests human induced pluripotent stem cells (i.e., a human PSC) can be used.
Regarding RPL13A expression in human PSCs, Freed teaches gene expression profiling on hESCs and dopaminergic neurons derived thereof (e.g., abstract). Freed teaches RPL13A is one of the most-highly expressed genes commonly expressed in undifferentiated hESCs and dopaminergic neuronal cells (see Table 3, col. “Common Genes”, 1st row “Ribosomal proteins”). Thus, Freed teaches RPL13A is highly expressed in hESCs as well as dopaminergic neurons derived from hESCs.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the iPSC comprising a transgene inserted at a GAPDH locus recited in the copending application, by substituting with a RPL13A locus in a human cell as taught by Lo and suggested by Freed with a reasonable expectation of success. Since Lo reduces to practice inserting a transgene at the RPL13A locus such that the transgene is driven by the endogenous RPL13A promoter to achieve consistent and tight expression in the human cells that may be applicable to human induced PSCs (see above), and sine Freed teaches RPL13A is highly expressed in hESCs and dopaminergic neurons derived thereof (Table 3, indicating the endogenous RPL13A promoter is active in human PSCs), one of ordinary skill in the art would have had a reason to substitute with a RPL13A locus as the site to insert the transgene into a human PSC in order to achieve consistent and tight expression of the transgene. One of ordinary skill in the art would have had a reasonable expectation of success in doing so since Freed teaches RPL13A is highly expressed in hESCs as well as the derivative cells such as dopaminergic neurons.
Since the instant application claims are obvious over cited application claims, in view of Lo and Freed, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 02/24/2026 are acknowledged.
Applicant requests that the double patenting rejections be held in abeyance until allowable subject matter is identified. Applicant further argues that the provisional nonstatutory double patenting rejection should be the only remaining rejection in the application thus the rejection should be withdrawn (Remarks, p. 11).
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804.I.B.1. Furthermore, as stated supra, the prior 103 rejection is maintained, thus the provisional nonstatutory double patenting rejection is not the only remaining rejection, and therefore is maintained.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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