DETAILED ACTION
This action is in reply to papers filed 11/19/2025.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230084201A1, Published 3/16/2023.
Election/Restriction
Applicant’s election of Group I (claims 1-17) in the reply filed on 11/19/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 2-13 and 18-21 are cancelled. Claims 22-33 are new and depend on elected claims 13 and 17. Accordingly, claims 1, 14-17 and 22-33 are pending and examined herein.
Claim Objections
Claim 17 is objected to because of the following informalities: Claim 17 is drawn to a method of producing the non-human animal model of claim 14, wherein the method comprises, inter alia, providing a system. Claim 14 is drawn to a non-human animal model comprising the system of claim 1. At issue here is that claim 17 recites the phrase “providing a system”. Since claim 17 depends from claim 14 and claim 14 requires “the system” of claim 1, claim 17 should either recite “providing the system” or “providing the system of claim 14” or something similar. As currently presented, claim 17 requires two systems- the system of claim 14, which is the system of claim 1, and- because of the use of the article ‘a’- claim 17’s own system.
Appropriate correction is required.
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Osterwalder, Marco. (“Genome-wide identification of Hand2 target regions in mouse embryos using dRMCE, a new genetic tool.” Dissertation. (2012); Ref. 10 in IDS filed 9/8/2022).
Regarding claim 1, Osterwalder discloses embryonic stem cells were co-transfected with the pDIRE and pDREV-1 plasmids (i.e. ‘a system’; Pg. 43, bottom half of page), wherein pDREV-1 plasmid does not comprise a promoter (Pg. 47, Fig. 4C; Pg. 111, para. 2), comprises a polyadenylation signal upstream from a transgene of interest (H2B-Venus), paired recombinase recognition sites (loxP and FRT); and wherein the pDIRE plasmid comprises two genes encoding recombinases cre and flp (Pg. 36, Fig. 1B; Pg. 37, Fig. 1B description; Pg. 110, para. 1). In the paragraph bridging Pg. 98 and Pg. 99, Osterwalder discloses the dMRCE (pDIRE and pDREV-1) technology enables directed and highly efficient replacement of the target region with orthologous or paralogous genes, epitope or fluorescent tags, and single or multiple mutations into endogenous genes of interest. Osterwalder adds that this is very important for in vivo biochemical studies and the generation of ES cell and mouse models with direct relevance to human diseases (see also pg. 203+ of Osterwalder). In a particular teaching, Osterwalder discloses use of dRMCE to re-engineer the Hand2 conditional allele. Continuing, Osterwalder adds that their results indicate that Hand2 interacts with Gli3 and Tbx regulatory sites in limb buds and binds to a minimal ZRS element associated with human point mutations that cause polydactyly (Pg. 9-10).
Accordingly, Osterwalder anticipates the claimed invention.
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) 14-17 and 22-33 are rejected under 35 U.S.C. 103 as being unpatentable over Osterwalder, Marco. (“Genome-wide identification of Hand2 target regions in mouse embryos using dRMCE, a new genetic tool.” Diss. Verlag nicht ermittelbar, 2012; Ref. 10 in IDS filed 9/8/2022) as applied to claim 1 and further in view of Fahrenkrug et al. (PgPub US20150067898A1, Published 3/5/2015), Michaelis et al. (J Vis Exp. 2014 Aug 23;(90):51802.) Trono et al. (PgPub US20130115692A1, Published 5/9/2013; Ref. 10 in IDS filed 9/8/2022), Economides et al. (PgPub US20030084468A1, Published 1/13/2003; Ref. 11 in IDS filed 9/8/2022), Davis et al. (PgPub US20100077495A1 , Published 3/25/2010; Ref. 12 in IDS filed 9/8/2022) and Chen et al. (Cell Stem Cell. 2015 Aug 6; 17(2): 233–244.; Ref. 26 in IDS filed 9/8/2022).
The teachings of Osterwalder are relied upon as detailed above. Specifically, and with regards to claim 17, (in-part), Osterwalder teaches embryonic stem cells were co-transfected with the pDIRE and pDREV-1 plasmids (i.e. ‘a system’; Pg. 43, bottom half of page), wherein pDREV-1 plasmid does not comprise a promoter (Pg. 47, Fig. 4C; Pg. 111, para. 2), comprises a polyadenylation signal upstream from a transgene of interest (H2B-Venus), paired recombinase recognition sites (loxP and FRT); and wherein the pDIRE plasmid comprises two genes encoding recombinases cre and flp (Pg. 36, Fig. 1B; Pg. 37, Fig. 1B description; Pg. 110, para. 1). In the paragraph bridging Pg. 98 and Pg. 99, Osterwalder teaches the dMRCE (dual Recombinase Mediated Cassette Exchange, that is pDIRE and pDREV-1) technology enables directed and highly efficient replacement of the target region with orthologous or paralogous genes, epitope or fluorescent tags, and single or multiple mutations into endogenous genes of interest . Osterwalder adds that this is very important for in vivo biochemical studies and the generation of ES cell and mouse models with direct relevance to human diseases (see also pg. 203+ of Osterwalder). In a particular teaching, Osterwalder teaches use of dRMCE to re-engineer the Hand2 conditional allele. Osterwalder adds that their results indicate that Hand2 interacts with Gli3 and Tbx regulatory sites in limb buds and binds to a minimal ZRS element associated with human point mutations that cause polydactyly (Pg. 9-10) (as in claim 27 and claim 35).
However, Osterwalder fails to teach a non-human animal model comprising the system of claim 1 (as in claim 14).
Before the effective filing date of the claimed invention, Fahrenkrug et al. sought to combine the efficiency of oligo HDR for delivery of small insertions (e.g., LoxP sites) and the large cargo capacity of recombinase mediated cassette exchange (RMCE) for site specific integration of transgenes. Fahrenkrug teaches the recombinase-mediated cassette exchange (RMCE) process allows for systematic, repeated modification of higher eukaryotic genomes by targeted integration. This result is achieved with RMCE by the clean exchange of a preexisting gene cassette for an analogous cassette carrying the gene of interest (GOI) (Pg. 7, para. 52). As a proof-of-concept, Applicants simultaneously transfected primary fibroblasts with four components: 1) SRY TALENs 2) an oligo with homology to SRY that includes two RMCE (as in claim 15) compatible loxP sites 3) a RMCE compatible transgene and 4) a source of Cre recombinase. Fahrenkrug teaches their results showed that it was possible to simultaneously provide the TALENS, HDR template containing loxP site, a transgene of interest flanked by loxP, and a Cre-recombinase mRNA resulting in RMCE mediated recombination into a TALEN targeted locus (Pg. 7, para. 53).
Fahrenkrug teaches embodiments of the invention include a method of making a genetically modified animal (as in claim 14 and claim 17 (in-part)), such as a mouse (as in claim 16 (Pg. 9,para. 68), wherein said method comprising exposing embryos or cells to an mRNA encoding a TALEN, with the TALEN specifically binding to a target chromosomal site in the embryos or cells, cloning the cells in a surrogate mother or implanting the embryos in a surrogate mother, with the surrogate mother thereby gestating an animal that is genetically modified without a reporter gene and only at the TALEN targeted chromosomal site (Pg. 12, para. 90).
Michaelis et al. teach the generation of transgenic animals is time-consuming, cost-intensive and quite elaborate. Michaelis attributes this to the required long breeding process for generating and maintaining the transgene over the generations. Additionally, the genetic manipulation of the entire organism by the transgenic or knockout approach is prone to cause physiological impairments when targeting genes with essential functions in multiple regions. To remedy this, Michaelis teaches transfection of a living mouse with plasmid constructs. After observing a sufficient filling of the tissue by the plasmid, the organ in the living mouse is electroporated (as in claim 17). Michaelis teaches this protocol can be employed for delivering DNA- or RNA- constructs into living mice in order to (over)express or knock down genes, facilitating in vivo gene function analysis. Furthermore, it is suitable for studying reporter constructs or putative gene regulatory elements. Thus, the main advantages of the electroporation technique Michaelis notes are fast performance in combination with low effort as well as the moderate technical equipment and skills required compared to alternative techniques (Abstract; Pg. 1 ‘Introduction’).
However, none of Osterwalder, Fahrenkrug or Michaelis teach wherein the promoter-less donor vector further comprises a post-transcriptional regulatory element (as in claim 22 and claim 28), wherein said post-transcriptional regulatory element is WPRE (as in claim 24 (in-part) and as in claim 30 (in-part).
Before the effective filing date of the claimed invention, Trono et al. taught safe, highly efficient, and very potent for expressing transgenes for human gene therapy (Abstract). In one embodiment, Trono teaches for vectors that do not have strong promoters, inserting other regulatory elements such as the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) (as in claim 22, as in claim 28, as in claim 24, in-part, and as in claim 30, in-part) (Pg. 6, para. 47). Trono teaches WPRE is positioned within the vector so as to be included in the RNA transcript of the transgene, but outside of stop codon of the transgene translational unit. Trono adds that the inclusion of WPRE is a useful tool for stimulating and enhancing gene expression of desired transgenes (Pg. 8-9, para. 78).
However, none of Osterwalder, Fahrenkrug, Michaelis and Trono teach wherein the promoter-less donor vector further comprises a polyadenylation signal downstream from the transgene (as in claim 23 and claim 29) or that the promoter-less donor vector comprises: PGK polyadenylation signal (pA); trimerized SV40pA; the transgene or the polynucleotide encoding the RNA; loxP and flippase recognition target (FRT); a rabbit beta-globin pA (as in claim 24 and claim 30).
Before the effective filing date of the claimed invention, Economides et al. taught
a DNA targeting vector designed for targeting a protected transgene cassette (which, in this particular example, lacks an exogenous promoter) into the ROSA26 locus. Regarding claim 24, and claim 30, Economides teaches the DNA targeting vector comprises, inter alia, a promoter-less selection cassette containing SA-loxP-EM7-neo-4×polyA-loxP, wherein SA is a splice acceptor sequence, the two loxP sites are the locus of recombination sites derived from bacteriophage P1, the neomycin (neo) phosphotransferase transgene, and 4×polyA which is a polyadenylation signal engineered by linking in tandem the polyadenylation signal of the mouse phosphoglycerate kinase gene (PGKpA) (PGK polyadenylation signal), three copies of a 254 bp BamHI fragment containing both early and late polyadenylation signals of Simian Virus 40 (tpA) (trimerized SV40pA). This set of polyadenylation signals is referred to as 4×pA. The two loxP sites are in cis with respect to each other, in order to accommodate Cre-mediated excision rather than inversion of the floxed sequences. After the second loxP site, a LacZ open reading frame (ORF) has been engineered, followed by a rabbit β-globin polyA (βgl pA) (Pg. 14, para. 429) (as in claim 23 and claim 29). At Pg. 18, para. 467, Economides adds that the reasoning behind using multiple polyadenylation signals is to ensure that transcription of the gene of interest (neo transgene) will not extend into a gene that is driven by an exogenous promoter. Examiner notes that Economides does teach loxP and FRT recombination sites (Pg. 18, para. 469).
However, none of Osterwalder, Fahrenkrug, Michaelis, Trono and Economides teach a polynucleotide encoding RNA (as in claim 1 and claim 17, in the alternative), wherein the RNA is siRNA (as in claim 26, claim 32) or shRNA (as in claim 26, claim 33).
Before the effective filing date of the claimed invention, Davis et al. taught inducible expression system that incorporate a recombination system (Pg. 8, para. 100). Davis adds that, a polynucleotide of interest whose expression is under control of an inducible promoter is not limiting. For example, a polynucleotide of interest encodes a regulatory RNA molecule (as in claim 1, in the alternative, and as in claim 17) such as siRNA (as in claim 26 and claim 32) and shRNA (as in claim 27 and claim 33) (Pg. 11, para. 123-126). Davis explains that a molecule capable of effecting RNAi (e.g., shRNA), such that expression of the nucleic acid sequence targeted by the regulatory RNA molecule is “knocked down” in the presence of the inducing agent provides a mechanism for regulated gene expression, and in particular, for conditional knock-down of target nucleic acid sequences (Pg. 12, para. 138).
And although Davis fails to teach the RNA molecule is sgRNA (as in claim 8), before the effective filing date of the claimed invention, Chen et al. taught an efficient two-step strategy to generate induced knock-out human embryonic stem cells by combining CRISPR/Cas9-mediated genome editing with the Flp/FRT and Cre/LoxP system (as in claim 25 and claim 31). Chen adds that they found that “dual-sgRNA targeting” (as in claim 26 and claim 34) is critical for bi-allelic knock-in of FRT sequences to flank the exon within a gene of interest in one step (Pg. 3, para. 1)
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 Osterwalder, wherein Osterwalder teaches the dMRCE technology as a means of gene editing endogenous genes of interest, wherein said dMRCE comprises a promoter-less vector, with the teachings of Trono et al., wherein Trono teaches the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) enhances gene expression of desired transgenes in vectors that do not contain strong promoters, with a reasonable expectation of success. That is one of ordinary skill in the art would have found it prima facie obvious to include the WPRE in the promoter-less vector in order to increase transgene expression. Additionally, upon reading the teachings of Economides et al., the skilled artisan would have been sufficiently motivated to include, inter alia, the trimerized SV40pA in the promoter-less vector of Osterwalder because Economides teaches the inclusion of multiple polyA sites ensures a stop of transcription in the promoter-less plasmid. Furthermore, using the dMRCE technology of Osterwalder, the skilled artisan would have found it prima facie obvious to substitute the gene of interest in Osterwalder with siRNA or shRNA, as taught by Davis, or sgRNA, as taught by Chen, in order to provide a conditional means of dissecting endogenous gene functions and biological processes in cells in a temporal manner.
Finally, one of ordinary skill in the art would have found it prima facie obvious to combine all of these elements in order to develop an animal disease model in which transgenes are (1) expressed throughout the model, as taught in Fahrenkrug, or (2) expressed in specific tissues, as taught in Michaelis.
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.
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.
Claims 1, 14-17 and 22-33 and rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11466290. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Independent claim 1 is drawn to a system, comprising: a promoter-less donor vector, comprising a polyadenylation signal or transcription stop element upstream from a transgene or RNA, the transgene or RNA, and paired recombinase recognition sites; and one expression vector, comprising two genes encoding recombinases specific to the paired recombinase recognition sites, or two expression vectors, the first expression vector comprising one gene encoding a first recombinase that is specific to one of the paired recombinase recognition sites, and the second expression vector comprising one gene encoding a second recombinase that is
specific to the other of the paired recombinase recognition sites. Claim 14 is drawn to a animal model comprising the system of claim 1. Claim 17 is drawn to a method of producing the animal model of claim 14.
Claim 1 of U.S. Patent ‘290 is drawn to a system, comprising: a promoter-less donor vector, comprising four polyadenylation signals (pAs) upstream from a transgene or a polynucleotide encoding an RNA, the transgene or the polynucleotide encoding the RNA, wherein the transgene or the polynucleotide encoding RNA comprises a disease associated mutation, and paired recombinase recognition sites selected from loxP, flippase recognition target (FRT), Vlox and its derivatives, Slox and its derivatives, Rox and its derivatives, or attb, wherein the transgene or polynucleotide encoding the RNA is in between the paired recombinase recognition sites; and one expression vector, comprising two genes encoding recombinases specific to the paired recombinase recognition sites, or two expression vectors, the first expression vector comprising one gene encoding a first recombinase that is specific to one of the paired recombinase recognition sites, and the second expression vector comprising one gene encoding a second recombinase that is specific to the other of the paired recombinase recognition sites.
It is clear that all the elements of the application claims are to be found in patent claims (as the application claims fully encompasses patent claims). The difference between the application claims and the patent claims lies in the fact that the patent claim includes many more elements and is thus much more specific. For example, patent claims limit the paired recombinase recognition sites to be selected from loxP, flippase recognition target (FRT), Vlox and its derivatives, Slox and its derivatives, Rox and its derivatives, or attb. Thus the invention of claims of the patent is in effect a “species” of the “generic” invention of the application claims. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993). Since application claims is anticipated by claims of the patent, it is not patentably distinct from claims of the patent.
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632