DETAILED ACTION
This action is in reply to papers filed 3/6/2026. Claims 1-21 are pending and examined herein.
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230292720A1, Published 9/21/2023.
Withdrawn Claim Objections
The objection to claim 13 is withdrawn in view of Applicant’s amendment.
Maintained Claim Rejections
The 103 (a) rejection of claims 1-21 as being unpatentable over Jalil et al. (Stem Cell Reports. 2021 Dec 14), Prather et al. (PgPub US20170035035A1, Published 2/9/2017), Ban et al. (PgPub US20130210150A1, Published 8/15/2013) and Ma et al. (Cytotechnology. 2013 Oct 16;66(6):967–978.) is maintained. Applicant’s arguments will be addressed following maintained rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-21 remain rejected under 35 U.S.C. 103 as being unpatentable over Jalil et al. (Stem Cell Reports. 2021 Dec 14), Prather et al. (PgPub US20170035035A1, Published 2/9/2017), Ban et al. (PgPub US20130210150A1, Published 8/15/2013) and Ma et al. (Cytotechnology. 2013 Oct 16;66(6):967–978.). The rejection is copied below for Applicant’s convenience.
Jalil describes a highly efficient method for simultaneous (as in claim 1a, claim 13a and claim 21a) base editing and reprogramming of fibroblasts (as in claim 8 and claim 18, in-part) employing a CRISPR-Cas9 (as in claim 14) adenine base editor (as in claim 1a and claim 2) (Abstract). Specifically, Jalil developed an efficient RNA-based delivery system for A⋅T to G⋅C conversion in patient-derived primary fibroblasts employing ABEmax. Jalil combined this approach with episomal vector reprogramming (as in claim 4 and claim 14), creating a fast and robust method for simultaneous derivation of hiPSC lines and specific point mutation correction in a single straightforward procedure (Pg. 3064, Col. 2, last paragraph). After the electroporation of patient-derived primary fibroblasts with the episomal reprogramming vectors, the mRNA ABEmax construct and the single-guide RNA (sgRNA; which binds to the ABE and defines the genomic target to be modified) (as in claim 5 and claim 16, in-part), Jalil notes that their method generated hundreds of monoclonal colonies. Sanger sequencing of the 120 individual colonies showed that 96.7% carried the desired A-to-G edit on the targeted position (Figure 1D) (as in claim 1b, claim 13b and claim 21b) (Pg. 3066, Col. 2, last paragraph).
However, Jalil et al. fails to teach genetically editing non-human somatic cells.
Before the effective filing date of the claimed invention, Prather taught targeted deletion of CD163 (as in claim 12, claim 13 and claim 21) (Pg. 39, para. 372) in pig (as in claim 10, claim 11, claim 13, claim 18 and claim 21a) cells after transfection with CRISPR/Cas9 and donor DNA (Pg. 10, para. 109; Pg. 3, para. 29). Specifically, Prather teaches complete (as in claim 9) deletion of exon 7 of the CD163 gene (as further in claim 16 and as in claim 19) (Pg. 44, para. 397). Prather teaches when CRISPR/Cas9 components designed to target CD163 were introduced into presumptive zygotes (Pg. 33, para. 364), targeted modification of the genes in the subsequent blastocysts was observed. When individual blastocysts were genotyped for mutation of CD163, specific mutations were found in all the embryos (100% GE efficiency) (as in claim 1 c-d, claim 13 c-d, and claim 21 c-d) (Pg. 39, para. 372). Prather teaches infection of the wild type pigs showed histopathology consistent with PRRS including interstitial edema with the infiltration of mononuclear cells (FIG. 10). However, in stark contrast there was no evidence for pulmonary changes in the CRISPR derived (as in claim 7) Null (CD163−/−) pigs (as in claim 20 and claim 21e) (Pg. 42-43, para. 389).
However, neither Jalil et al. nor Prather et al. teach the reprogramming factors comprises Klf4, c-Myc, Nanog, Oct4, Sox2 and SV40 large T antigen (as in claim 3).
Before the effective filing date of the claimed invention, and with regards to claim 3 and claim 15, Ban et al. taught a composition for use in gene delivery for induction of a pluripotent stem cell, which comprises a Sendai virus vector into which the KLF gene, OCT gene, and SOX gene are found therein (as in claim 6, in-part and as in claim 17, in-part) (Abstract). Ban adds that this composition is used in combination with a different Sendai virus vector inserted with the c-MYC gene (Pg. 2, para. 26). Moreover, Ban teaches other genes can be further combined to the above-described combination of genes to increase the efficiency of induction of reprogramming, wherein such a gene is the SV40 large T antigen (as in claim 6, in-part and as in claim 17, in-part). Ban also teaches NANOG (as in claim 6, in-part and as in claim 17, in-part) can be included in the reprogramming composition(Pg. 13, para. 104). Note that Ban teaches cells to be reprogrammed are derived from pigs (Pg. 14, para. 108).
Ma teaches that although forced expression of the transcription factors Oct4, Sox2, Klf4 and Nanog can revert fibroblasts to a state of pluripotency (Pg. 975, Col. 2), it is largely unknown how Oct4, Sox2, Klf4 and Nanog lead to changes in the cell state (Pg. 968, Col. 2, para. 1) ). To this end, Ma teaches that in order to systematically investigate the function of the four transcription factors, they collected data on proteins reported to have regulatory or binding relationships with Oct4, Sox2, Klf4 and Nanog, and constructed an interaction network (Fig. 11). Ma teaches many proteins were identified to interact with Oct4, Sox2 and Klf4; however, Nanog, only interacts with three known factors (Oct4, Sox2 and Klf4) (Pg. 975, Col. 1-Col. 2). As such, it would have been prima facie obvious to include Nanog in the first Sendai vector in Ban et al, as further in claim 6 and as further in claim 17.
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Jalil et al., wherein Jalil teaches simultaneously reprogramming and genetically editing fibroblasts, with the teachings of Prather et al., wherein Prather teaches genetically editing pig cells with a CRISPR/Cas9 nuclease such that porcine reproductive and respiratory syndrome virus is inhibited in offspring of CRISPR/Cas9 nuclease derived pigs, with the teachings of Ban et al., wherein Ban teaches a method of reprogramming pig fibroblasts into induced pluripotent stem cells, with a reasonable expectation of arriving at the claimed invention. That is, one of ordinary skill in the art would have found it prima facie obvious to use the CRISPR/Cas9 protocol of Prather and the pig iPSCs of Ban et al., in the simultaneous genetic engineering and reprogramming method of Jalil et al., with a reasonable expectation of arriving at the claimed invention. The skilled artisan would have been motivated to make such substitutions in order generate disease-resistant pigs.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Applicant’s Arguments/Response to Arguments
Applicant argues: Applicant argues Jalil describes a highly efficient method for simultaneous base editing and reprogramming of fibroblasts employing a CRISPR-Cas9 adenine base editor. Jalil applies this approach to generate gene-edited hiPSCs from skin biopsies of four patients carrying a Finnish-founder pathogenic point mutation in either NOTCH3 or LDLR genes. Jalil's method produces gene-edited hiPSC monoclonal lines for research and therapies. See Abstract and page 3071, right column, lines 5-6. However, Jalil nowhere describes non-human somatic cells. Jalil is not relevant to breeding animals. Jalil does not teach or suggest reprograming and gene-editing non-human somatic cells for breeding animals. Jalil is silent about how to improve precision of gene edition for breeding non-human animals. Jalil provides no pointers to achieve the present invention.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. At the outset, Examiner did not cite Jalil for teaching non-human somatic cells. See para. 9 above. Nevertheless, Examiner disagrees with Applicant’s argument regarding Jalil not providing pointers to achieve the claimed invention. Indeed, as admitted by Applicant, Jalil describes a highly efficient method for simultaneous base editing and reprogramming of fibroblasts employing a CRISPR-Cas9 adenine base editor. Step (a) of claim 1 is drawn to gene editing non-human mammalian somatic cells to induce a gene edition of interest and simultaneously reprograming the cells to reprogram into induced pluripotency stem cells (iPSCs), so as to produce a plurality of gene-edited iPSC candidates. Jalil teaches simultaneously reprograming non-human somatic cells to reprogram into induced pluripotency stem cells and gene-editing said cells. There is nothing in Jalil that would dissuade one of ordinary skill in the art from applying Jalil’s method to non-human somatic cells.
Indeed, Jalil teaches their combined approach created a fast and robust method for simultaneous derivation of hiPSC lines and specific point mutation correction in a single straightforward procedure. Jalil adds that starting from a patient skin biopsy, their approach quickly yielded tens of genetically corrected hiPSC monoclonal lines with an efficiency consistently above 96%. Jalil notes that the previous studies in the art employing SpCas9 achieved simultaneous reprogramming and DSB-dependent gene editing, which is particularly powerful in generating knockouts. However, Jalil further notes that by replacing SpCas9 with the ABEmax and improving the delivery efficiency, the simple DBS-free method presented by Jalil and colleagues significantly improves the implementation and efficacy of base editing in hiPSC reprogramming and facilitates their use for research, biobanking, and future therapeutic applications (see Jalil at paragraph bridging Pgs. 3064-3066). Insofar as Jalil suggests their method provides an improvement over the art of making knockouts, the use of non-human somatic cells in the method of Jalil would have been prima facie obvious.
Applicant argues: Prather teaches nothing about precise gene edition in breeding animals. Prather does not teach or suggest simultaneous reprograming and gene-editing carried out in non-human animal somatic cells and subsequent subcloning and genotyping conducted at the in vitro cell stage to obtain non-human animal precisely gene-edited induced pluripotency stem cells (iPSCs) which are then used in somatic nuclear transfer (SCNT) to generate a precisely gene-edited nonhuman animal embryo and a resultant gene-edited non-human animal as described in the present invention. Jalil in combination with Prather do not achieve the present invention.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. At the outset, Examiner did not cite Prather for teaching simultaneous reprograming and gene-editing carried out in non-human animal somatic cells and subsequent subcloning and genotyping conducted at the in vitro cell stage to obtain non-human animal precisely gene-edited induced pluripotency stem cells (iPSCs) which are then used in somatic nuclear transfer (SCNT) to generate a precisely gene-edited nonhuman animal embryo and a resultant gene-edited non-human animal.
Rather, Prather was/is cited for teaching the claimed targeted deletion of in pig cells after transfection with CRISPR/Cas9 and donor DNA.
Applicant argues: Ban describes Sendai virus vectors in which genes that encode reprograming factors for inducing pluripotent stem cells are incorporated in a specific order, compositions comprising these vectors for gene delivery to be used in the induction of pluripotent stem cells, and uses thereof. Ban describes the origin of the animals where the cells are to be reprogramed is not particularly limited, and includes mammals such as humans and non-human primates (monkeys and such), rodents such as mice and rats, and non-rodents such as bovine, pigs, and goats. See paragraph [0108]. Ma describes bioinformatic analysis of the four transcription factors Oct4, Sox2, Klf4 and Nanog used to induce pluripotent stem cells. Still, Ban and Ma are not relevant to breeding animals. Ban and Ma do not teach or suggest reprograming and gene-editing nonhuman somatic cells for breeding animals. Ban and Ma teach nothing about precise gene edition in breeding animals. Ban and Ma do not teach or suggest simultaneous reprograming and gene editing carried out in non-human animal somatic cells and subsequent subcloning and genotyping conducted at the in vitro cell stage to obtain non-human animal precisely gene-edited induced pluripotency stem cells (iPSCs) which are then used in somatic nuclear transfer (SCNT) to generate a precisely gene-edited non-human animal embryo and a resultant gene-edited nonhuman animal as described in the present invention.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. At the outset, Examiner did not cite Ban and Ma for teaching reprograming and gene-editing nonhuman somatic cells for breeding animals.
Indeed, Ban et al. was/is cited for teaching a composition for use in gene delivery for induction of a pluripotent stem cell, which comprises a Sendai virus vector into which the claimed KLF gene, OCT gene, and SOX gene are found therein. Ban also teaches the claimed SV40 large T antigen and the claimed NANOG as factors found in reprogramming composition for reprogramming cells derived from pigs.
Ma was/is cited for teaching Nanog only interacts with three known factors (Oct4, Sox2 and Klf4) and therefore providing a reason to include Nanog in the first Sendai vector in Ban et al, as claimed.
The Courts have consistently held 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).
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632