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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission has been entered. Applicant indicates on the Request for Continued Examination (RCE) Transmittal, 3/11/2026, that the response of 3/03/2026 be considered.
Claim status
Applicant has amended Claims 1, 17, and 28, and cancelled Claims 31, 34-36, 47, 50-52, 58, and 61-62.
Claims 1, 3, 8-9, 16-17, 28-29 are under consideration.
Election/Restrictions
Applicant’s election of the following invention without traverse in the reply filed on 10/29/2024 has been acknowledged.
Group I, claims 1-3, 8-9, 16-17, 28-29, drawn to a modified cell.
Applicant’s election of the following species has been acknowledged.
Applicant elected SEQ ID NO:3 as the HI locus.
SEQ ID NO:3 is free of the prior art.
Rejoinder
SEQ ID NO: 118 has been rejoined.
SEQ ID NO: 47 is also rejoined.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/24/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Claims 1, 3, 8-9, 16-17, 28-29 are 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 pre-AIA the applicant regards as the invention.
Claim 1 recites the broad recitation a “mammalian cell”, and the claim also recites the cell comprises “SEQ ID NO:1-125”, which is the narrower statement of the limitation as these are all sequences found in C. griseus. Claims 3, 8-9, 16-17, 28-29 are included in the basis of this rejection because none of these claims entirely limit the cell type to C. griseus (albeit Claim 16 does recites a genus of CHO cells in addition to other mammalian cells).A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim 16 contains the trademark/trade name CHOK1SV. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a type of CHO cell and, accordingly, the identification/description is indefinite.
Because this reagent was developed by the manufacturer Lonza at the time of the Applicant’s invention under the trade name CHOK1SV and as a result is proprietary, which means what constitutes as this type of CHO cell can change, and these changes do not need to be disclosed by these companies to the public. Accordingly, the identification of the trade name is indefinite and the applicant is advised to employ a sequence, or biological deposit for this agent.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Specifically, claim 16 draws to an engineered mammalian cell that is either a mouse or human, which does NOT narrow the scope of claim 1 where the mammalian cells is C. griseus (Chinese hamster). Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 3, 8-9, 16-17, 28 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Schuijers et al. (WO2018/111944, filed 12/12/2017), in view of Melville et al. (US2006/0010513, filed 5/11/2005), Land et al., (US2013/0184223, filed 5/20/2011) and Ran et al. (CN108441520, filed 4/4/2018, published 8/24/2018).
SEQ ID NO:118 Embodiments
In regard to claim 1, Schuijers teaches methods and compositions comprising modified mammalian cells comprising a chromosomal modification of a first locus that is within an active genomic compartment of accessible chromatin and within about 30 kb of a topologically associated domain (TAD) boundary, wherein the locus overlaps a region of the cell genome that interacts with an enhancer element (Abstract, [0004-0005, 0009] see Figs. 1 & 2).
In regard to the “HI” locus of claim 1, Applicant has provided no definition of this phrase and Schuijers is directed to a genus of loci that encode cancer related genes capable of undergoing chromosomal integration. Furthermore, in regard to “HI” locus of claims 1 and 3, Schuijers teaches a list of gene loci that are in or adjacent to a TAD boundary and within or proximal to their transcriptional start site ([0009], Table S1). Specifically, in regard to claim 1, Schuijers teaches the human locus of chromosome 12 between 52,461,258-56,466,258 corresponding the to the ATG101 gene of NM_001098673 (see Table S1, p.56, line 21).
Importantly, Melville et al. (US2006) evidences that SEQ ID NO:118 of Claim 1 corresponds to the ATG101 gene of the Chinese hamster (Cricetulus griseus) as shown in the SCORE search 20250204, rnpbm.file, result #2. Thus, Schuijers teaches the “HI” locus of ATG101 on human chromosome 12, which is syngeneic to the claimed “HI” locus of SEQ ID NO:118 in the Chinese hamster.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to have chosen SEQ ID NO:118 as the “HI” locus for modification of a mammalian cell with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because Schuijers teaches the syngeneic locus in human, and also teaches that the cells may also be hamster [0111]. In regard to choosing the ATG101 as the “HI” locus among the genus of loci of Table S1 of Schuijers, Land et al. (US2013) teaches that ATG101 is a target for cancer treatment by the modulation of autophagy (Abstract, see also Claims 1, 7-11 of Land), which would have fulfilled the goals of Schuijers to better understand the regulatory elements that may prove valuable for therapeutically targeting cancer [0006], and a hamster is specifically identified as a nonhuman mammal to be used [0111]. Thus, it would have been predictably obvious to choose the ATG101 locus that corresponded to SEQ ID NO:118 to chromosomally modify.
However, in regard to claim 1, although Schuijers teaches genetic deletion of CTCF binding sites in the “HI” locus by CRISPR/Cas9 genome editing [0008, 0026-0027, 0032, 0154, 0156-0158], and suggests other nucleases that recognize DNA is a site-specific manner [0072], they are silent to recombination target sites (RTS) for a Cre nuclease.
Nevertheless, the chromosomal insertion of two loxP recombination target sites for the conditional deletion of a genomic region by an inducible Cre nuclease was well known in the art. Specifically, Ran teaches modified cells (including human) that used CRISPR/Cas9 to chromosomal insert two loxP sites flanking a genomic region such that the floxed region can be deleted by Cre induction by a small molecule (Abstract of translation, and see Figs. 1, 3, 5 and 6 of Chinese patent document)
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to have combined Cre/loxP sites to flank the CTCF binding sites in the “HI” locus with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because Ran teaches this is an efficient method for floxing a genomic region that can then be conditionally deleted in a temporally controlled manner by the simple addition of 4-OHT (Abstract).
In regard to claims 8 and 9, as stated supra, Ran teaches that two RTS sites are chromosomally integrated in order to “flox” the locus of interest.
In regard to claim 16, as stated above, Schuijer teaches human cells and makes obvious Chinese hamster cells.
In regard to claims 17 and 28, Ran teaches that the loxP integration cassette includes three heterologous genes of interest corresponding to a FRT-neomycin-FRT (Figure 2). Accordingly, it would have been obvious to chromosomally integrate a FRT-neo-FRT cassette as taught by Ran in order to quickly screen for cells that have successfully undergone recombination. Note that Applicant’s specification broadly defines ‘gene’ as a nucleic acid fragment that can act as a regulatory element preceding and following a coding sequence.
In regard to claim 29, as stated supra, Ran teaches that the cells express a site-specific Cre recombinase gene in order to remove the “floxed” the region of interest.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 3/26/2026 are acknowledged.
Applicant argues there is no motivation to choose the claimed HI locus, and the examiner has used improper hindsight to construct the obviousness rejection. Specifically, Applicant argues one who was reading Schuijers is directed to altering expression of genes by methylation using a dCas9 system, and that one would not have combined the epigenetic regulation systems of Schuijers with the Cre/lox system of Ran.
Furthermore, Applicant argues that the inventors have found that the claimed HI loci allow the repeated targeting of a heterologous gene of interest to provide predictable and stable levels.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant's first argument that the preferred embodiments of Schuijers are directed to epigenic regulation, contrary to Applicant’s assertion Schuijers explicitly teaches “CTCF binding site was deleted through CRISPR/Cas9 gene editing” [0027], which controlled expression of the oncogene Myc, and they used “the CRISPR/Cas9 system to delete a 210 bp segment centered on this site in the Chronic Myeloid Leukemia (CML) cell line” [0154]. Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper 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 instant case, the cited prior art discloses the ATG101 gene as being in the claimed genus of HI loci, and provides good reason to choose this gene for modification.
Finally, in regard to Applicant’s arguments that the claimed HI loci allow repeated integrations of a heterologous genes of interest, as a first matter, the repeated integration of heterologous genes is not claimed. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Moreover, the claimed list of 125 HI loci appear to have been generated by bioinformatic muti-dimensional map for the targeted integration of transgenes “with predicted high expression and stability”. Furthermore, the resulting “potential” HI loci discovered by Applicant’s algorithm include enormous ranges of 10,000 bases (+/- 5 kb) per sequence. Moreover, among the genus of HI contemplated, it appears that only a handful of the claimed SEQ ID NOs have actually been shown to support transgene integration above control, and only two SEQ ID NOs have been shown to be comparable to the previously established Fer1L4 HI locus.
New Claim Rejections - 35 USC § 103
Claims 1, 3, 8-9, 16-17, 28 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Weinstein et al. (US 2011/0023147, filed 7/23/2010), in view of Becker et al. (J Biotech, 2011, 156:227-235), Singh et al. (Antiox Redox Signal, 2014, 20:1324-1363) and Troadec et al. (Blood, 2011, 117:5494-5502)
SEQ ID NO:47 Embodiments
In regard to claim 1, Weinstein teaches methods and compositions for the modification of mammalian cells at a genus of loci that are targets for integration of donor polynucleotides [0039, 0056-0064, 0071, 0080-0083]., Specifically, Weinstein teaches a chromosomal modification of a first locus that is within an active genomic compartment of accessible chromatin in the solute carrier family 25 member 37 (Slc25A37) gene (p. 6, Col 1, 3rd to last line). Furthermore, Weinstein teaches the modification is the integration of a Cre recombination target site (RTS) to make a conditional knockout [0021]. Finally, Weinstein teaches the mammalian cell is a hamster, and more particularly a Chinese hamster [0032, 0036, 0037].
Although Weinstein does not teach the sequence of the Chinese hamster Slc25A37 gene, this was a well known sequence, and was taught by Becker et al. (2011), and is 100% identical to SEQ ID NO:47 of instant Application (see SCORE search 2/04/2025, rge.file), which is located in the 3’UTR after the 4th and final exon of the hamster Slc25A37 gene. Thus, it would have been obvious to flank the Slc25A37 gene with a lox site within or overlapping about +/-5 kb of the 4th exon of the hamster gene.
In regard to the disclosed Slc25A37 gene sequence being a high integrating (HI) locus within about 30 kb of a topologically associated domain (TAD) boundary, wherein the locus overlaps a region of the cell genome that interacts with an enhancer element, Applicant has provided no definition of this phrase “HI locus” and as stated supra, Weinstein is directed to the integration of donor polynucleotides at the locus. Furthermore, MPEP 2145, Section II, states that the mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). The court held that granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.). In instant case, Weinstein and Becker teach the sequence of Slc25A37 for integration of a donor nucleic acid, the fact that they do not phrase it as a “HI locus” is immaterial to a case of obviousness.
Finally, in regard to claim 1 as per the motivation to choose the Slc25A37 gene to flox, the review Singh et al. (2014) teaches that Slc25A37 (alias Mfrn1) gene in critical in mitochondrial Fe2+ transport and underlies a variety of neurodegenerative diseases including prion disease (p. 1332, last para., p. 1336-1337, Section E, p. 1339, Fig. 12), which would have been especially relevant to the goal of Weinstein to make and use animal models of human neurodegenerative diseases. In regard to the reasonable expectation of success of doing so, Troadec et al. (2011) teach a floxed Slc25A37 (alias Mfrn1) gene, which when conditionally knocked-out by crossing with Cre drivers leads to a variety of pathophysiological symptoms of Fe2+ dysregulation depending on the Cre driver used (Abstract, Discussion). Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to have combined Cre/loxP sites to flank the Slc25A37 gene with a reasonable expectation of success.
In regard to claims 8 and 9, as stated supra, both Weinstein and Trodec teach that two RTS sites are chromosomally integrated in order to “flox” the locus of interest.
In regard to claim 16, as stated above, Weinstein teaches Chinese hamster cells.
In regard to claims 17 and 28, although Weinstein is silent the integration of a heterologous gene of interest, Troadec teaches that the loxP integration cassette includes three genes of interest corresponding to a FRT-neomycin-FRT (p. 5495, Methods, 1st para.). Accordingly, it would have been obvious to chromosomally integrate a FRT-neo-FRT cassette as taught by Troadec in order to quickly screen for cells that have successfully undergone recombination. Note that Applicant’s specification broadly defines ‘gene’ as a nucleic acid fragment that can act as a regulatory element preceding and following a coding sequence.
In regard to claim 29, as stated supra, Weinstein teaches that the cells express a site-specific Cre recombinase gene in order to remove the floxed the region of interest.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 3/26/2026 are acknowledged and have been addressed supra.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James 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.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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