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 08/15/2025, Applicant has newly canceled claims 1-5, 15-20 and 31-50, and added new claims 51-67.
Election by Original Presentation
Newly submitted claim 56 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
Applicant’s species election filed 09/14/2023 stated “erythroid progenitor cells” as the elected species of the starting cells.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 56 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
Claim Status
Claims 51-67 are pending.
Claims 56 is withdrawn.
Claims 51-55 and 57-67 are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/15/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
New Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 55 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 55 recites the limitation "the PBMCs" in line 1. There is insufficient antecedent basis for this limitation in the claim because the base claim 53 recites the starting cells being erythroid progenitor cells but is silent on PBMCs. It is recommended to change its dependency to be dependent on claim 54. It is examined as so.
New 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 51-52, 57-60 and 62-67 are rejected under 35 U.S.C. 103 as being unpatentable over Su et al (PLoS ONE. 2013; 8(5): e64496, p. 1-10. Cited in IDS 01/31/2023) in view of Yoshioka et al (PLoS ONE. 2017; 12(7): e0182018, p. 1-17. Cited in IDS 01/31/2023), Gavathiotis et al (US Patent No: 11,382,898 B2, effectively filed 06/01/2017. Prior art of record) and Dowdy et al (US Patent No: 10,370,646 B2. Cited in IDS 01/31/2023).
With respect to claim 51, Su teaches a method of obtaining a population of iPSCs from starting cells of a hematopoietic lineage (title, abstract). Su teaches introducing to the starting cells, e.g., peripheral blood mononuclear cells (PBMNCs) and CD3-/19- PBMNCs, an expression construct encoding BCL-xL and 4 additional reprogramming factors, i.e., Yamanaka factors OCT4, SOX2, MYC and KLF4 (“OS+MK+B”. See abstract, p. 3, left col, last para, from line 5, also see Fig 3A), and culturing the starting cells to allow expression of BCL-xL, OCT4, SOX2, MYC and KLF4 proteins, thereby inducing the starting cells and their progeny to reprogram into iPSCs (p. 3, left col, last para, from line 5 from bottom, also see Fig 3B).
However, Su uses episomal DNA plasmids for introducing reprogramming factors but is silent on a VEEV RNA expression construct which comprises VEEV nsP1, nsP2, nsP3 and nsP4 genes and directs expression of the reprogramming factors.
Yoshioka teaches a method of obtaining a population of iPSCs comprising introducing to the starting cells an RNA replicon of Venezuelan Equine Encephalitis (VEE) virus containing genes encoding non-structural proteins of VEE virus nsP1, nsP2, nsP3 and nsP4, and reprogramming factors as a polycistronic synthetic self-replicative RNA (srRNA) (abstract and p. 2, para 2, see Fig 1A). Yoshioka teaches the nsP1, nsP2, nsP3 and nsP4 are RNA replicases that enable self-replication of the construct and a single srRNA transfection results in extended expression of reprogramming factors (abstract, p. 2, para 2, see Fig 1A). Yoshioka teaches RNA-based iPSCs approach, i.e., the VEEV RNA expression construct srRNA, avoids potential integration problems associated with DNA-based approaches and is inherently safer for future clinical applications compared to episomal DNA plasmids (end of p. 1 – p. 2, para 1).
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 method of obtaining iPSCs from a hematopoietic lineage comprising introducing BCL-xL and additional reprogramming factors OCT4, KLF4, SOX2 and MYC via episomal DNA plasmids disclosed by Su, by substituting the episomal DNA plasmids with a VEEV RNA expression construct comprising VEEV nsP1, nsP2, nsP3 and nsP4 RNA replicases directing expression of reprogramming factors taught by Yoshioka with a reasonable expectation of success. Since Yoshioka teaches RNA-based iPSCs approach, i.e., the VEEV RNA expression construct srRNA, avoids potential integration problems associated with DNA-based approaches and is inherently safer for future clinical applications compared to episomal DNA plasmids (end of p. 1 – p. 2, para 1), one of ordinary skill in the art would have had a reason to substitute Su’s episomal DNA plasmids with Yoshioka’s VEEV RNA expression construct to improve the safety of the reprogramming approach for future clinical applications as taught by Yoshioka (end of p. 1 – p. 2, para 1).
However, Su and Yoshioka do not teach the amino acid sequences of BCL-xL and the additional reprogramming factors OCT4, KLF4, SOX2 and MYC.
Regarding the sequence of BCL-xL, Gavathiotis teaches BCL-xL is an anti-apoptotic BCL-2 family member (col 1, line 54-55). The sequence in Gavathiotis’s SEQ ID NO: 4 is 100% identical to the instant SEQ ID NO: 1 (see SCORE search 06/09/2023, -1.rai file, result #14).
PNG
media_image1.png
532
510
media_image1.png
Greyscale
Regarding the sequences of OCT4, KLF4, SOX2 and MYC, Dowdy, an issued US patent from the authors of Yoshioka et al, teaches a method of obtaining iPSCs by introducing a VEEV RNA expression construct encoding reprogramming factors including OCT4, KLF4, SOX2 and MYC (col 1, Summary, see Fig 1A). The sequence of OCT4 in Dowdy’s SEQ ID NO: 4 comprises a sequence that is 100% identical to the sequence of instant SEQ ID NO: 3 (see SCORE search 06/09/2023, -3.rai file, result #13), related to claim 51 (a)(i). The sequence of KLF4 in Dowdy’s SEQ ID NO: 8 comprises a sequence that is 100% identical to the sequence of instant SEQ ID NO: 5 (see SCORE search 06/09/2023, -5.rai file, result #10), related to claim 51 (a)(ii). The sequence of SOX2 in Dowdy’s SEQ ID NO: 6 comprises a sequence that is 100% identical to the sequence of instant SEQ ID NO: 7 (see SCORE search 06/09/2023, -7.rai file, result #12), related to claim 51 (a)(iii). The sequence of c-MYC in Dowdy’s SEQ ID NO: 10 comprises a sequence that is 100% identical to the sequence of instant SEQ ID NO: 9 (see attached above), related to claim 51 (a)(iv).
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 method of obtaining iPSCs by introducing a VEEV RNA expression construct encoding BCL-xL and additional reprogramming factors OCT4, KLF4, SOX2 and c-MYC to the starting cells PBMCs disclosed by Su and Yoshioka, by choosing the sequence of BCL-xL as taught by Gavathiotis and the sequences of OCT4, KLF4, SOX2 and c-MYC as taught by Dowdy with a reasonable expectation of success. Since Gavathiotis teaches the BCL-xL sequence belongs to an anti-apoptotic family (col 1, line 54-55) which is the mechanism of improving reprogramming as taught by Su (p. 5, right col, para 1), and since Dowdy has reduced to practice the sequences of OCT4, KLF4, SOX2 and c-MYC with biological functions of inducing iPSCs (Dowdy, col 1, Summary), one of the ordinary skill in the art would have had a reason to use the sequence of BCL-xL as taught by Gavathiotis and the sequences of OCT4, KLF4, SOX2 and c-MYC as taught by Dowdy in the method of Su and Yoshioka in order to successfully generate iPSCs (Dowdy, col 1, Summary). Furthermore, the successful cloning and sequencing of the cDNA encoding a known protein (i.e. BCL-xL, OCT4, KLF4, SOX2 and c-MYC) is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
With respect to claim 52 directed to the starting cells being peripheral blood mononuclear cells, Su teaches the starting cells are peripheral blood mononuclear cells (PBMNCs) and CD3-/19- PBMNCs (abstract, p. 3, left col, last para, line 5, see Fig 3A).
Claim 57 is directed to the coding sequences for BCL-xL and reprogramming factors being separated by a coding sequence for a 2A peptide or an IRES. Claim 58 is directed to the coding sequences being under the control of a common promoter. Claim 59 is directed to the common promoter being a 26S promoter.
Regarding the coding sequences being separated by a 2A peptide or an IRES, Su teaches a 2A peptide is used to link two genes (p. 7, left col, para 3), and Yoshioka teaches a 2A sequence and an IRES are used to separate the reprogramming factors (see Fig 1A green bars showing 2A peptide and purple bars showing IRES), thus teach claim 57. Regarding the sequences being under control of a common promoter, a 26S promoter, Su teaches the genes are under control of a common promoter (p. 7, left col, para 3), and Yoshioka teaches the sequences of the reprogramming factors are under control of a common promoter, a 26S promoter (see the red bar at the beginning of the transgenes in Fig 1A showing a 26S promoter), thus teach claims 58 and 59.
Accordingly, one of ordinary skill in the art would have used a 2A sequence or an IRES separating BCL-xL and the additional reprogramming factors and would have used a common promoter, i.e., a 26S promoter, to control the transcription of the reprogramming factors as taught by both Su and Yoshioka with a reasonable expectation of success. One of the ordinary skill in the art would have had a reason to do so in order to achieve balanced expression of BCL-xL and the reprogramming factors to enhance the induction efficiency as taught by Su (p. 2, “Results” para 1). One of ordinary skill in the art would have chosen a 26S promoter since Yoshioka has reduced to practice a 26S promoter in the VEEV RNA expression construct.
Claim 60 is directed to the VEEV RNA expression construct comprising the coding sequences of reprogramming factors in a defined 5’ to 3’ order.
Yoshioka teaches a VEEV srRNA expression constructs comprising Yamanaka factors OCT4, KLF4, SOX2 and c-MYC and in combination with other reprogramming factors for testing in a define order. Yoshioka teaches when there are 5 reprogramming factors (i.e., Yamanaka factors plus a 5th reprogramming factor) in the construct, the 5th reprogramming factor is inserted either before the cMyc or after the cMyc (see modified Fig 1A attached). Yoshioka teaches in one scenario the sequences are arranged in a 5’ to 3’ order: (a) a coding sequence for the Oct4, (b) a coding sequence for a 2A peptide, (c) a coding sequence for the KLF4, (d) a coding sequence for a 2A peptide, (e) a coding sequence for the Sox2, (f) an IRES, (g) a coding sequence for the 5th reprogramming factor, (h) a coding sequence for a 2A peptide, and (i) a coding sequence for the c-Myc (see Fig 1A “5F: OKS-iGM”, also attached in the bottom row below), thus teaches the 5’ to 3’ order in claim 60.
PNG
media_image2.png
131
994
media_image2.png
Greyscale
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 method of obtaining iPSCs by introducing a VEEV RNA expression construct encoding Yamanaka factors OCT4, KLF4, SOX2 and c-MYC plus a 5th reprogramming factor BCL-xL to the starting cells PBMCs disclosed by Su in view of Yoshioka, Gavathiotis and Dowdy, by choosing the 5’ to 3’ order of the reprogramming factors as taught by Yoshioka with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to choose the 5’ to 3’ order as taught by Yoshioka because Yoshioka has reduced to practice the construct with the taught order to achieve a balanced expression of the reprogramming factors to induce efficient reprogramming (see Fig 1B for expression and Fig 2 “5F-srRNA” for reprogramming).
With respect to claims 62-67 directed to the VEEV RNA expression construct not directing expression of a GLIS1 protein, a p53 dominant negative protein, or a Lin28 protein, and the only reprogramming factors encoded by the VEEV RNA expression construct being BCL-xL, OCT4, KLF4, SOX2 and c-MYC, as stated supra, Su teaches introducing to the starting cells the combination of 5 reprogramming factors BCL-xL plus OCT4, SOX2, MYC and KLF4 (“OS+MK+B”. See abstract, p. 3, left col, last para, also see Fig 3A), related to claims 62-67. Yoshioka makes obvious a substitution with a VEEV RNA expression construct comprising VEEV nsP1, nsP2, nsP3 and nsP4 RNA replicases directing expression of the reprogramming factors (see above).
Accordingly, one of ordinary skill in the art would have appreciated that the method of obtaining iPSCs suggested by Su in view of Yoshioka, Gavathiotis and Dowdy would have comprised introducing to the starting cells a combination of 5 reprogramming factors BCL-xL plus OCT4, SOX2, MYC and KLF4 encoded by the VEEV RNA expression construct, such that the VEEV RNA expression construct does not direct expression of a GLIS1 protein, a p53 dominant negative protein, or a Lin28 protein, and the only reprogramming factors encoded by the VEEV RNA expression construct are BCL-xL, OCT4, KLF4, SOX2 and c-MYC.
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 08/15/2025 are acknowledged.
Applicant first argues the StemCell Erythroid Progenitor Reprogramming kit (“Stemcell kit”) cited by the examiner in the response incorporates the reprogramming vector from the Epi5 kit which contains mutant p53 dominant negative protein so the effective reprogramming of erythroid progenitor cells requires strong suppression of p53 expression and knockdown of p53 activity was considered to be critical for efficient reprogramming evidenced by Fu et al (Remarks, p. 6-8).
Applicant’s argument has been fully considered but it is not persuasive. Applicant is reminded that the citation of Stemcell kit in the response in the prior action is to demonstrate higher efficiency of reprogramming is obtained in erythroid progenitors as compared to that in PBMCs, to rebut the argument and declaration that the claimed method (using erythroid progenitors) results in a higher efficiency of reprogramming than the method of Su (using PBMCs). Thus, the mechanisms of this effective reprogramming of erythroid progenitor cells, whether being through suppression of p53 activity in Stemcell kit or through expression of BCL-xL in the claimed method, do not negate Examiner’s response that the reprogramming efficiency obtained in erythroid progenitor cells (i.e. the claimed method) cannot be compared to that obtained in PBMCs (i.e., the method of Su).
Applicant further argues there is no explanation why one of skill in the art would select Su’s reprogramming factor combination to begin with, out of a “sea of prior art” in the iPSC reprogramming field. The sole rationale underlying selection of Su is hindsight guided by Applicant’s disclosure (Remarks, 10-11), and there is nothing in the cited art suggests that VEEV would be suitable for delivering reprogramming factors to hematopoietic cells, other than fibroblasts taught by Yoshioka (remarks, p. 12, para 2).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to selecting Su based upon hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Su clearly teaches inclusion of BCL-XL together with Yamanaka factors (OCT4, SOX2, MYC, and KLF4) increases the efficiency of reprogramming adult peripheral blood mononuclear cells (“the most readily available source”) by approximately 10-fold and Su aims to generate integration-free iPSCs from adult peripheral blood for potential applications in iPSC banking, disease modeling and regenerative medicine (see abstract). Therefore, one of ordinary skill in the art would have had ample reasons to select Su’s method, comprising a combination of Yamanaka factors OCT4, SOX2, MYC, and KLF4 together with inclusion of BCL-xL to effectively reprogram adult PBMCs into iPSCs for potential applications in iPSC banking, disease modeling and regenerative medicine.
In response to nothing in the cited art suggesting that VEEV would be suitable for delivering reprogramming factors to hematopoietic cells, in the prior Office action (p. 11-12) regarding previous claim 5 directed to electroporating the VEEV RNA expression construct, prior art Diener teaches delivery of RNA into cells of a hematopoietic lineage is commonly performed by electroporation and RNA electroporation enables efficient protein expression in cells (p. 997, right col, para 2-3), thus, Diener teaches that electroporating an RNA, such as a VEEV RNA construct into cells of a hematopoietic lineage was a well-known and highly successful technique. Furthermore, Yoshioka’s VEEV RNA expression construct comprises VEEV nsP1, nsP2, nsP3 and nsP4 that are RNA replicases and a viral subgenomic RNA promoter 26S promoter to direct expression of reprogramming factors (see Fig 1A of Yoshioka and prior Office action, p. 8), one of ordinary skill in the art would have had a reasonable expectation of success in introducing a VEEV RNA construct into hematopoietic cells, e.g., by electroporation, and in obtaining replication of the construct by RNA replicases VEEV nsP1-nsP4, as well as expression of the reprogramming factors directed by the 26S promoter in the hematopoietic cells.
Applicant finally argues the claimed method achieves highly efficient reprogramming with unexpected synergistic results (Remarks, p. 12, last para, also referring to Tomishima Declaration at paragraphs 15-17). Specifically, Applicant argues that the examiner ignores that (1) Su teaches lentiviral vector results in 200-fold more efficient reprogramming than other vectors; (2) Su teaches extrachromosomal vector has reduced reprogramming efficiency compared to lentiviral vector; (3) Stemcell kit uses p53 inhibitor and EBNA that are critical for efficiency of reprogramming; (4) the claimed method achieves (a) a comparable reprogramming efficiency to lentiviruses which were supposed to be 200-fold more effective than other vectors; (b) an improved reprogramming efficiency relative to Stemcell/Epi5 kit without the need to use a mutant p53 and (c) a reprogramming efficiency that is 8-fold greater than Yoshioka’s preferred “5F” VEEV construct containing GLIS1 (Remarks, p. 12-14).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to the unexpected synergistic results, as a first matter, MPEP 716.02(d), states that unexpected results must be commensurate in scope with the claimed invention. In instant case, the purported unexpected results presented by the Applicant were studies performed in (1) erythroid progenitor cells or T cells, and (2) with reprogramming factors arranged in a specific order separated by specific 2A peptides and IRES. This is not commensurate in scope with the claimed genus of method of obtaining iPSCs from any cell type of a hematopoietic lineage comprising introducing reprogramming factors that are arranged in any order driven by any number of promoters or separated by any polycistronic expression mechanism. Furthermore, regarding the synergistic result, prior Office action (p. 31) has stated “it is noted that merely comparing a VEEV vector comprising BCL-XL (OKS-iBM) to an episomal control vector without BCL-xL (Epi5, see Fig 5B) does not support the statement that the combination of a VEEV vector and BCL-XL has a “synergistic” benefits without proper controls.”
In response to the examiner ignoring the teaching of Su and Stemcell kit, it is noted that Su’s teaching regarding lentiviral vector and Stemcell kit’s using p53 inhibitor and EBNA, do not negate Su’s teaching of obtaining integration-free iPSCs from hematopoietic cells by a combination of 5 reprogramming factors OCT4, KLF4, SOX2, c-MYC and BCL-xL using an episomal vector.
In response to the claimed method achieves (a) a comparable reprogramming efficiency to lentiviruses, this seems to refer to Dr. Tomishima’s declaration that the absolute number of reprogrammed iPSCs by the claimed method (>700 colonies per 1 x 106 erythroid progenitor cells) (Declaration para 29, see Example 2 and Fig 5B in specification) is comparable to the reprogramming efficiency of Su’s lentiviral vector (~700 colonies per 1x106 PBMCs) (see Remarks, p. 13, para (1), and Su, Fig 1B “OS+BCL-XL” showing ~70/105 PBMCs). It is noted that since these experiments use different starting cells (erythroid progenitor cells in the claimed method versus PBMCs in Su) and since Su teaches PBMCs inherently have a lower reprogramming efficiency that the efficiency of adult blood cells is 100-fold lower than reprogramming of CD34+ hematopoietic progenitor cells (Su, p. 2, left col, last para), the results in the claimed method cannot be compared to that in Su’s lentiviral method.
In response to the claimed method achieves (b) an improved reprogramming efficiency relative to Stemcell/Epi5 kit without the need to use a mutant p53, this is not persuasive because Su does not use a mutant p53. Furthermore, Su specifically teaches “In others, the use of 7 factors (… OSK+LIN28+MYCL1+TP53 shRNA+EBNA1) leads to the generation of 5-10 iPSC colonies from 1 ml of PB. [39,42] In comparison, with only 5 factors (OS+MK+BCL-XL), we have achieved significantly higher reprogramming efficiency: 20-30 iPSC colonies from 1 ml of PB” (Su, end of p. 4 – beginning of p. 5). It is noted that the 7 factors (OSK+LIN28+MYCL1+TP53 shRNA+EBNA1) is comparable to Stemcell/Epi5 kit (see Remarks, p. 6-7 for the components in Epi5 kit). Thus, Su teaches the combination of 5 factors has an improved reprogramming efficiency relative to Stemcell kit without the need to use a mutant p53.
In response to the claimed method achieves (c) a reprogramming efficiency that is 8-fold greater than Yoshioka’s preferred “5F” VEEV construct containing GLIS1, this is not persuasive because Su uses the claimed combination of 5 reprogramming factors but does not use a GLIS1. Thus, the argument is not based on comparative data to Su.
In summary, Applicant’s arguments are not persuasive. As necessitated by amendment, new grounds of rejections have been made over Su in view of Yoshioka, Gavathiotis and Dowdy as discussed above.
Claims 52-55 are rejected under 35 U.S.C. 103 as being unpatentable over Su et al (PLoS ONE. 2013; 8(5): e64496, p. 1-10. Cited in IDS 01/31/2023) in view of Yoshioka et al (PLoS ONE. 2017; 12(7): e0182018, p. 1-17. Cited in IDS 01/31/2023), Gavathiotis et al (US Patent No: 11,382,898 B2, effectively filed 06/01/2017. Prior art of record) and Dowdy et al (US Patent No: 10,370,646 B2. Cited in IDS 01/31/2023), as applied to claim 51 above, and further in view of Manian et al (Stem Cell Research. 2018; 29: 148–151. Prior art of record).
As stated supra, Su in view of Yoshioka, Gavathiotis and Dowdy teach a method of obtaining iPSCs by introducing a VEEV RNA expression construct encoding BCL-xL and 4 additional reprogramming factors to the starting cells PBMCs. Regarding the starting cells, Su teaches peripheral blood mononuclear cells (PBMNCs) and CD3-/19- PBMNCs (See abstract, p. 3, left col, last para, from line 5, also see Fig 3A). Su teaches PBMNCs are a mixed population containing lymphoid cells and myeloid cells as well as 0.01–0.1% CD34+ hematopoietic stem/progenitor cells (HSCs) (p. 2, left col, para 1).
However, Su, Yoshioka, Gavathiotis and Dowdy are silent on the starting cells being erythroid progenitor cells in claims 52-54, nor teach the erythroid progenitor cells are obtained by culturing PBMCs in the presence of EPO, SCF and IL-3 in claims 54-55.
Manian teaches a method of obtaining iPSCs from starting cells erythroid progenitor cells (title, abstract), related to claims 52-54. Manian teaches the erythroid progenitor cells are obtained by culturing PBMCs in the presence of 2 U/ml erythropoietin, 50 ng/ml stem cell factor and 10 ng/ml IL-3 (p. 149, right col, para “Expansion of erythroid progenitors), related to claims 54-55. Manian teaches cultured erythroid progenitor cells have high genome integrity and are used to generate safe iPSCs for disease modelling and clinical applications (p. 148, right col, last para), and teaches the cultured cells are highly homogenous for erythroid progenitor cells (see Fig 1A, 90% cells are CD71+ and 72% are CD235+).
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 method of obtaining iPSCs by introducing a VEEV RNA expression construct encoding BCL-xL and the 4 additional reprogramming factors to the starting cells PBMCs suggested by Su in view of Yoshioka, Gavathiotis and Dowdy, by substituting with erythroid progenitor cells obtained by culturing PBMCs in the presence of erythropoietin, stem cell factor and IL-3 as taught by Manian with a reasonable expectation of success. Since Manian teaches cultured erythroid progenitor cells have high genome integrity and are highly homogenous that can be used to generate safe iPSCs for disease modelling and clinical applications (p. 148, right col, last para and Fig 1A), one of the ordinary skill in the art would have had a reason to use erythroid progenitor cells obtained by culturing PBMCs as taught by Manian in the method of Su in view of Yoshioka, Gavathiotis and Dowdy in order to generate safe iPSCs from highly homogenous hematopoietic lineage cells for disease modelling and clinical applications (Manian, p. 148, right col, last para, see also “iPSC-based therapies” of Su in Abstract).
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 08/15/2025 are acknowledged and have been discussed above.
Claim 61 is rejected under 35 U.S.C. 103 as being unpatentable over Su et al (PLoS ONE. 2013; 8(5): e64496, p. 1-10. Cited in IDS 01/31/2023) in view of Yoshioka et al (PLoS ONE. 2017; 12(7): e0182018, p. 1-17. Cited in IDS 01/31/2023), Gavathiotis et al (US Patent No: 11,382,898 B2, effectively filed 06/01/2017. Prior art of record) and Dowdy et al (US Patent No: 10,370,646 B2. Cited in IDS 01/31/2023), as applied to claims 51 and 60 above, and further in view of Wikipedia (“2A peptides – Wikipedia”, published 03/21/2021, downloaded on 10/1/2025, p. 1-3, downloaded from https://en.wikipedia.org/w/index.php?title=2A_peptides&oldid=1013371903).
With respect to the sequences recited in claim 61, as stated supra, Gavathiotis makes obvious the BCL-xL protein comprising SEQ ID NO: 1, and Dowdy makes obvious the OCT4 comprising SEQ ID NO: 3, the KLF4 comprising SEQ ID NO: 5, the SOX2 comprising SEQ ID NO: 7, and the c-MYC comprising SEQ ID NO: 9.
However, Su, Yoshioka, Gavathiotis and Dowdy are silent on the OCT4 comprising SEQ ID NO: 4 in claim 61 (b).
It is noted that the instant SEQ ID NO: 4 comprises 380 amino acids, of which amino acids 1-360 are 100% identical to the instant SEQ ID NO: 3, i.e., the OCT4 sequence taught by Dowdy.
Regarding the amino acids 361-380 of instant SEQ ID NO: 4 that are directed to a T2A peptide sequence, Dowdy teaches in the OKS-iM RNA replicon (i.e., the VEEV RNA expression construct that Yoshioka is based on), the OCT4 protein is fused to a T2A peptide sequence (“OCT4-T2A-KLF4” see e.g., col 5, line 54, and col 14, lines 5-6). Regarding a T2A peptide sequence, Wikipedia teaches T2A peptide has a sequence of (GSG) EGRGSLL TCGDVEENPGP (p. 1, Table) in which the linker “GSG” on the N-terminal of a 2A peptide helps with efficiency (p. 1, the paragraph above the Table). It is noted that the T2A sequence taught by Wikipedia is 100% identical to the amino acids 361-380 of instant SEQ ID NO: 4 (see below).
PNG
media_image3.png
105
576
media_image3.png
Greyscale
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 VEEV RNA expression construct encoding OCT4 fused to a 2A peptide suggested by Su in view of Yoshioka, Gavathiotis and Dowdy, by choosing a T2A that fused to OCT4 as suggested by Dowdy and choosing the sequence of T2A with a GSG linker taught by Wikipedia with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since Dowdy has reduced to practice a VEEV construct comprising OCT4 fused to a T2A (see e.g., col 5, line 54) and since Wikipedia teaches the sequence of T2A and teaches the linker “GSG” on the N-terminal of a 2A peptide helps with efficiency (p. 1, the paragraph above the Table). One of ordinary skill in the art would have appreciated that by fusing OCT4 to a T2A with a GSG linker, the OCT4 protein would have comprised the sequence of instant SEQ ID NO: 4.
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 08/15/2025 are acknowledged and have been discussed above.
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 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).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631