DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on October 31, 2025 has been entered.
Application Status
Applicant’s amendments filed October 31, 2025, amending claim 18 is acknowledged. Claim 18 was only amended to fix claim dependency such that it depends from claim 14, in accordance to the interpretation in the previous office action (page 3). Claims 14-16, 18-22 and 24-30 are pending and under examination.
The amendment to claim 18 overcomes the §112(b) rejection in the previous office action.
Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Interpretation
As indicated in the office action mailed November 12, 2024 (page 5), “incompatible RRSs” is interpreted as “heterospecific RRSs” such that the four RRSs can’t recombine with each other, but can be recognized by the same type of recombinase, e.g., four heterospecific Lox sites that can each be recognized by a Cre recombinase.
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.
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 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over Ng (WO 2019126634 A2, published June 27, 2019). This is a maintained rejection.
Regarding claims 25-26, step a), Ng teaches TI CHO cells suitable for the expression of recombinant proteins (Abstract). Ng teaches TI CHO cell #4 comprising an integration site at position 79768 of contig NW_003616412.1 (page 101; Table 2). Ng teaches three RRS sites integrated in the targeted integration site of host #4 as illustrated in Figure 4 (page 104, lines 10-15). Ng teaches the three RRS sites, RRS1, RRS2 and RRS3 only recombine with other RRS1, RRS2 and RRS3 sites (Fig 4) and are therefore heterospecific (i.e., incompatible) (page 58, ¶1). Ng teaches in a single embodiment a T1 CHO cell with an exogenous sequence integrated at nucleotides 69303-79768 of NW_003616412.1, wherein the exogenous sequence comprises three heterospecific RRSs (pages 80-83, exemplary embodiment A2/A12/A13/A17/A24). Regarding step b), Ng also teaches introducing into the cell two vectors, wherein each vector comprises two RRSs that match either RRS1/RRS3 or RRS3/RRS2 (i.e., two RRSs matching two of the incompatible RRSs in the integrated exogenous nucleotide sequence) (Fig 4; page 7, lines 2-7). Ng also teaches the two vectors comprise a SOI and/or a different selectable marker flanked by the two RRSs (Fig 4; page 7, lines 5-7). Regarding step c), Ng also teaches introducing one or more recombinases that recognize the RRSs (Fig 4; page 7, lines 7-8). Regarding d), Ng also teaches selecting TI cells that express the second selection marker to isolate a TI host cell expressing the SOIs (page 7, lines 8-10). Ng teaches the SOIs are antibodies (page 36, lines 7-28). Ng teaches individual SOIs encoding heavy and light chain sequences can be integrated into a single exogenous nucleic acid sequence present at a single integration site (page 36, lines 23-26).
Ng does not teach in a single embodiment, the TI CHO cell #4 with four or more incompatible RRSs and introducing a third vector with an SOI and/or selection markers.
However, Ng also teaches the exogenous nucleotide sequence can comprise four, five, six, seven or eight RRSs (page 32, line 17-18). Ng teaches there are at least 16 different (i.e., incompatible) RRSs (page 32, lines 25-29). Ng also teaches the cells and method of the invention can be used to integrate/insert four or more sequences of interest (SOIs) into a locus to increase the cell’s production titer (page 2, lines 25-28; page 39, lines 9-12).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have included a fourth heterospecific RRS in the NW_003616412.1 position 79768 integration site of host cell #4 and to have added a third recombination vector harboring either a third SOI or an additional selection marker to the obvious TI CHO cell comprising four RRSs in Ng’s RCME method. It would have amounted to adding a known RRS in a known site that is known to comprise RRSs in a known cell by known means to yield predictable results and a simple duplication of parts (i.e., the vector) and steps in a known method by known means to yield predictable results. The skilled artisan would have predicted that a fourth RRS could be added that was heterospecific to the first three because Ng teaches that four or more RRSs can be added to an integration site and there are 16 different RRSs to choose from. The skilled artisan would have been motivated to do so for the purpose of allowing the insertion of three or more sequences of interest, and because Ng suggests that four or more RRSs and three or more SOIs can be integrated into a specific locus. Regarding the third vector, “A mere duplication of parts has no patentable significance unless a new and unexpected result is produced” MPEP 2144.04. In this case, Ng suggests that additional RRSs and additional SOIs can be integrated into a single locus, which the skilled artisan would understand requires a third vector with the RRSs that recognize RRS3 and an RRS4. Thus, the addition of another vector of those disclosed in Ng would result in a third integrated antibody gene, which would be an expected result. The skilled artisan would have been motivated to do so to increase the antibody titer of the producing CHO cell as taught in Ng.
Regarding claim 27, Ng teaches the RRS are recognized by a Cre recombinase, a FLP recombinase, a Bxb1 integrase, and a fC31 integrase (page 43, lines 8-11).
Regarding claim 28, Ng teaches the SOIs can be scFvs (page 46, line 20).
Regarding claim 29, Ng teaches the vectors are plasmids (page 103, line 14).
Regarding claim 30, Ng teaches that a TI host cell comprises at least one exogenous nucleotide sequence integrated at one or more integration sites in the genome of the TI host cell (page 31, lines 28-30). Ng teaches additional high-productive integration sites (Table 2).
It would have been obvious to one skilled in the art to have chosen an additional site integration site from Ng’s Table 2 and introduced the obvious exogenous nucleic acid with four RRSs. It would have amounted to the simple duplication of parts of an obvious variant of Ng’s integrated exogenous nucleic acid. “A mere duplication of parts has no patentable significance unless a new and unexpected result is produced” MPEP 2144.04. In this case, Ng suggests that additional exogenous nucleic acid sequences can be integrated into additional loci in the genome. Because Ng teaches specific additional sites, the addition of another landing pad at those sites would result in the claimed starting cell of (a), which would be an expected result. The skilled artisan would have been motivated to do so because 1) Ng suggests it, and 2) to increase the antibody titer of the producing CHO cell as taught in Ng.
Claims 14-16, 18-22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Ng (WO 2019126634 A2, published June 27, 2019) as applied to claims 25-30 above, and further in view of Turan (Turan et al., Journal of Molecular Biology (2011), 407: 193-221). This is maintained rejection.
The teachings of Ng are recited above and applied as for claims 25-30. Briefly regarding claims 14 and 20, Ng regarding a T1 CHO-K1M host cell with three integrated heterospecific RRSs at position 69303-79768 of NW_003616412.1 (pages 80-83, exemplary embodiment A2/A12/A13/A17/A24). Ng also teaches b) introducing into the cell two vectors each comprising two RRSs that match two sequentially oriented RRSs in the integrated landing pad and that flank a SOI (Fig 4; page 7, lines 2-7). Ng also teaches one of the vectors comprises a selectable marker flanked by the two RRSs (Fig 4; page 7, lines 2-7). Ng also teaches c) introducing one or more recombinases that recognize the RRSs (Fig 4; page 7, lines 7-8). Ng also teaches d) selecting TI cells that express the second selection marker to isolate a TI host cell expressing the SOIs (page 7, lines 8-10). Ng also teaches e) culturing the cell under conditions suitable for expressing the SOI and recovering the polypeptide of interest therefrom (page 7, lines 15-17). Ng also teaches a variety of possible selection markers such that the skilled artisan could choose three different selection markers from the list (page 5, lines 1-4). Ng teaches “the third selection marker can be different from the first and second selection markers” (sentence spanning pages 4-5). Ng teaches the third selection marker can be GFP (page 5, lines 7-8).
The obviousness of adding a fourth heterospecific RRS to the landing pad of Ng and including a third vector comprising a third SOI to the host cell with a 4-RRS landing pad is recited above for claim 25.
Ng does not teach that all the introduced vectors comprise a selection marker and that each selection marker is distinct from at least one other selection marker flanked by a different pair of RRSs.
Turan teaches methods of RMCE, which can use Flp and Cre recombinases (Title, Abstract). Turan teaches “multiplexing RMCE” is a strategy enabling two or more modifications in parallel using multiple heterospecific (i.e., incompatible RRSs) (page 205, ¶4). Turan teaches that multiplexing can use both Flp and Cre sites (page 215, ¶6). Turan teaches that during multiplexing multiple vectors are introduced and each one can carry a selectable marker (Figure 7). Turan teaches that the selectable marker in the first vector is GFP and the other selectable marker in the second vector is RFP (i.e., the selectable markers are different from each other) (Figure 7). Turan also teaches an additional two selection markers already included in the genome that are distinct from GFP and RFP; thus Turan teaches four unique selection markers (Figure 7).
Regarding claims 14 and 20, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have included a second and third unique selection marker in the second and third introduced vectors in the RMCE method of Ng. It would have amounted to adding known genetic marker genes to known vectors by known means to yield predictable results. The skilled artisan would have predicted that Ng’s additional vectors could include a selection markers thar are distinct from each other because Turan teaches each vector used in a multiplex RMCE method having a selection marker, while both Ng and Turan each teach at least 4 different selection markers that can be used. The skilled artisan would have been motivated to do so for the purpose of screening for all three cassette integrations simultaneously and to increase the recovery efficiency of clones in which all three recombination events occurred.
Regarding clams 15 and 21, Ng teaches the RRSs are recognized by a Cre recombinase, a FLP recombinase, a Bxb1 integrase, and a fC31 integrase (page 43, lines 8-11).
Regarding claims 16 and 22, Ng teaches the SOIs can be scFvs (page 46, line 20).
Regarding claims 18, Ng teaches the TI host cell #4 is a CHO K1M host cell (page 101, line 6-9).
Regarding claims 19 and 24, Ng teaches the vectors are plasmids (page 103, line 14), as recited above for claim 29.
Response to Arguments - §103
Applicant argues that Examiner’s position that increasing the copy number of a transgene increases the titer of the recombinant protein in a predictable manner is incorrect. Applicant provides evidence from an article published in 2024 that gene copy number does not always correlate with transgene expression and argues that based on this data there was not a reasonable expectation of success of increasing antibody titer by introducing a fourth RRS and a third vector (Remarks, pages 7-9). Applicant cites FIGs 23A and 24A in Ng to demonstrate that adding copies of antibody light chains (LCs) does not necessarily increase antibody titer (page 9, last ¶). These arguments have been fully considered but are not persuasive because obviousness does not require an absolute expectation of success, only a reasonable expectation of success. “Conclusive proof of efficacy is not required to show a reasonable expectation of success.” MPEP 2143.02. As explained in the previous office action, it was common knowledge in the art of therapeutic protein production in CHO cells that increased transgene copy number generally correlated with increased protein titer. Ng even explicitly states “increasing copy number to HLL-HL (five SOIs) or HLL-HLHL (seven SOIs) can provide for an increase in titer and/or specific productivity.” (page 39, lines 20-21). In the previous office action, Examiner provided evidence in a review article published in 2010 by Cacciatore, who teaches that a standard method in the art is to increase the copy number of the transgene integrated in the genome for the purpose of increasing expression of the transgene and production of the protein of interest (Cacciatore et al., Biotechnology Advances (2010), 28: 673-681; Section 2.2; of record). Additionally, the data cited by Applicant in the 2024 article by Lee demonstrates that at least from 2 to 3 to 4 and up to 5 copies, there is a general increase in titer when additional gene copies are provided (Lee et al., Biotechnology Progress (2024), 40:e3433). The claims are not limited to any number of light or heavy chain copies that are in each of the “sequences of interest”. Ng teaches in each cassette there could be a single heavy chain (HC) or single LC coding sequence, or both a HC and LC coding sequence (Fig 21). An additional RRS and additional vector/cassette as rendered obvious in the method above would increase Ng’s HC/LC copy number from 1 or 2, to 2 or 3, which according to Lee and Cacciatore would be reasonably predicted to increase antibody titer. As such, the skilled artisan would have reasonably expected at the effective filing date of the claimed invention, that increasing the SOI copy number, and mAb gene copy number specifically, by one copy up to 5 copies would increase the recombinant protein titer.
Applicant argues that Ng does not suggest the inclusion of a third vector to facilitate the integration of an exogenous gene in a “secondary locus”. Instead, Ng merely suggests integration at a single locus (Remarks, page 10, ¶2). This argument has been fully considered but is not persuasive because the features upon which applicant relies (i.e., a secondary locus) are not recited in most of the rejected claims. 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). All of the claims require that the exogenous sequence is integrated within “a site” and at “a predetermined locus [singular]” in the CHO genome and that the “exogenous sequence” or “at least a single exogenous sequence” comprises the 4+ RRSs. Thus, the claims require the 4+ RRSs, which are the landing pad for the three cassettes, to be at the same locus. Although the claims can encompass additional RRS landing pads at a secondary site, as shown in FIG. 7 of the Drawings, a secondary site is not a requirement in most of the claims. Only claim 30 requires “at least two exogenous nucleic acids incorporated at predetermined loci [plural]”. The claims are interpreted as encompassing the structure depicted in FIG. 5, which would require at least 4 RRSs to be in the same locus.
Regarding Applicant’s arguments as they apply to claim 30, they are still unpersuasive because Ng teaches multiple loci that are amenable to integration and expression of an exogenous sequence. As indicated in the rejection above “A mere duplication of parts has no patentable significance unless a new and unexpected result is produced” MPEP 2144.04. In this case, Ng suggests that additional exogenous nucleic acid sequences can be integrated into additional loci in the genome. Because Ng teaches specific additional sites, the addition of another landing pad at those sites would result in the claimed starting cell of (a), which would be an expected result. The skilled artisan would have been motivated to do so because 1) Ng suggests it, and 2) to increase the antibody titer of the producing CHO cell as taught in Ng.
Applicant appears to argue that the claimed invention provides surprising results because as shown in FIG. 8A, the addition of a 3rd HLL cassette (1x HC and 2x LC coding sequences) provides more than the expected increase in titer (Remarks, page 10, ¶2). This argument has been fully considered, but is not persuasive because the proffered evidence is not commensurate in scope with the claims. Fig 8A is the result of “two site” integration method, in which the first site only contains 3 RRSs (depicted in FIG. 7) and not 4 RRSs. See Example 3, Specification pages 41-42. As indicated in the previous paragraph, the claims are interpreted as drawn in FIG. 5, where at least four RRSs are integrated at a single site. Figure 9A appears to contain data from the 2-vector vs 3-vector strategies that are claimed. From the data in Fig 9A, there is a less than expected increase of ~ 1.5x mAb production when 2-copies vs 3-copies of the HC and LC genes are incorporated in the CHO genome. Therefore, it does not appear that the claimed invention provides unexpected results compared to Ng’s 2-vector strategy with the obvious inclusion of a 3rd vector to integrate a 3rd copy of the SOI at a single locus.
Applicant argues that Turan does not remedy the deficiencies of Ng (Remarks, page 10, ¶2-3). This argument has been fully considered but is not persuasive because a prima facie case of obviousness is established for claims 20-25 for the reasons set for in the §103 rejections of record and the response to Applicant’s arguments in paragraphs 29-32 above.
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.
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Claims 14-16, 18-22 and 24-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-84 of U.S. Patent No. 12129480 in view of Ng (WO 2019126634 A2, published June 27, 2019) and Turan (Turan et al., Journal of Molecular Biology (2011), 407: 193-221). This is a maintained rejection.
Patented claims 1-2 recite a TI host cell comprising an exogenous nucleotide sequence integrated at an integration site within a locus is at least about 90% homologous to a sequence selected from 41190-45269 of NW_006874047.1 (SEQ ID NO: 8), nucleotides 63590-207911 of NW_006884592.1 (SEQ ID NO: 9), nucleotides 253831-491909 of NW_006881296.1 (SEQ ID NO: 10), nucleotides 69303-79768 of NW_003616412.1 (SEQ ID NO: 11), nucleotides 293481- 315265 of NW_003615063.1 (SEQ ID NO: 12), nucleotides 2650443-2662054 of NW_006882936.1 (SEQ ID NO: 13), and nucleotides 82214-97705 of NW_003615411.1 (SEQ IDNO: 14); or (b) sequences within 3,000 base pairs from nucleotide 45269 of NW_006874047.1 (SEQ ID NO: 8), nucleotide 207911 of NW_006884592.1 (SEQ ID NO: 9), nucleotide 491909 of NW_006881296.1 (SEQ ID NO: 10), nucleotide 79768 of NW_003616412.1 (SEQ ID NO: 11), nucleotide 315265 of NW_003615063.1 (SEQ ID NO: 12), nucleotide 2662054 of NW_006882936.1 (SEQ IDNO: 13),and nucleotide 97705 of NW_003615411.1 (SEQ ID NO: 14). Patented claims 18-19 recite wherein the TI host cell is a mammalian host cell including a hamster host cell. Patented claims 20-22 recite wherein the exogenous nucleotide sequence comprises at least two recombination recognition sequences (RRSs) recognized by a recombinase including Cre recombinase, an FLP recombinases. Patented claims 23-29 recite the exogenous nucleic acid comprises a third heterospecific RRS, wherein two selection markers, one or two SOIs, and a IRES operably linked to a third selection marker are in between the heterospecific RRSs. Patented claims 30 and 32 recite the SOIs are antibody light chains, heavy chains or scFVs. Patented claim 66 recites a method for expressing two polypeptides of interest comprising a) providing the cells of patented claim 1-2, (b) introducing into the cell provided in a) a first vector comprising two RRSs matching the first and the third RRS on the integrated exogenous nucleotide sequence and flanking at least one first exogenous SOI and at least one second selection marker; (c) introducing into the cell provided in a) a second vector comprising two RRSs matching the second and the third RRS on the integrated exogenous nucleotide sequence and flanking at least one second exogenous SOI; (d) introducing one or more recombinases, or one or more nucleic acids encoding one or more recombinases, wherein the one or more recombinases recognize the RRSs; and (e) selecting for TI cells expressing the second selection marker to thereby isolate a TI host cell expressing the first and second polypeptides of interest.
The patented claims do not recite the host cells comprising a fourth heterospecific RRS or a third vector (all claims), wherein each vector comprises a selection marker that is different from at least one other selection marker (claims 14-16, 18-22 and 24). The patented claims do not recite specific CHO cells (claim 18).
The teachings of Ng are recited above in paragraphs 10, 12, 14-17 and 20 and incorporated here. The teachings of Turan are recited above in paragraph 23 and incorporated here.
Regarding claims 14-16, 18-22 and 24-30, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have included an additional RRS to the patented CHO cell with the integrated landing pad and a selection marker in the second and third introduced vectors in the patented RMCE method. It would have amounted to adding a known RRS in a known site that is known to comprise RRSs in a known cell by known means to yield predictable results and to have additionally added known genetic marker genes to known vectors by known means to yield predictable results. The skilled artisan would have predicted that a fourth RRS could be added that was heterospecific to the first three patented RRSs because Ng and Turan both teach that four or more RRSs can be added to a genome and there are 16 different RRSs to choose from. The skilled artisan would have been motivated to do so for the purpose of allowing the insertion of three or more sequences of interest, and because Ng suggests that four or more RRSs and three or more SOIs can be integrated into a specific locus. The skilled artisan would have also predicted that an additional vector with a selection marker could be added to the patented method because Turan teaches each vector used in a multiplex RMCE method having a selection marker. The skilled artisan would have been motivated to do so for the purpose of screening for all three cassette integrations simultaneously and to increase recovery efficiency of clones in which all three recombination events occurred.
Regarding claim 18, it also would have been obvious to have used CHO K1M cells because Ng teaches 1) that such CHO cells have RRSs landing pads integrated at the patented and instantly claimed sites, and 2) multiplexed RMCE is operational in those cells.
Claims 14-16, 18-22 and 24-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 89-91 of copending Application No. 18883322 in view of Ng (WO 2019126634 A2, published June 27, 2019) and Turan (Turan et al., Journal of Molecular Biology (2011), 407: 193-221). This is a maintained rejection.
Copending claim 89 recites a method for expressing two polypeptides of interest comprising:(a) providing a TI host cell comprising an exogenous nucleotide sequence integrated at a site within a locus of the genome of the host cell, wherein the locus is at least about 90% homologous to a sequence selected from contig NW_006874047.1 (SEQ ID NO: 8),contig NW_006884592.1 (SEQ ID NO: 9), contig NW_006881296.1 (SEQ ID NO: 10),contig NW_003616412.1 (SEQ ID NO: 11), contig NW_003615063.1 (SEQ ID NO: 12), contig NW_006882936.1 (SEQ ID NO: 13), and contig NW_003615411.1 (SEQ ID NO:14), wherein the exogenous nucleotide sequence comprises a first and a second RRS flanking at least one first selection marker, and a third RRS located between the first and the second RRS, and all the RRSs are heterospecific; (b) introducing into the cell provided in a) a first vector comprising two RRSs matching the first and the third RRS on the integrated exogenous nucleotide sequence and flanking at least one first exogenous SOI and at least one second selection marker; (c) introducing into the cell provided in a) a second vector comprising two RRSs matching the second and the third RRS on the integrated exogenous nucleotide sequence and flanking at least one second exogenous SOI; (d) introducing one or more recombinases, or one or more nucleic acids encoding one or more recombinases, wherein the one or more recombinases recognize the RRSs; and (e) selecting for TI cells expressing the second selection marker to thereby isolate a TI host cell expressing the first and second polypeptides of interest.
The copending claims do not recite the host cells comprising a fourth heterospecific RRS in the genome of the host cell or introducing a third vector (all claims) wherein each vector comprises a selection marker that is different from at least one other selection marker (claims 14-16, 18-22 and 24). The copending claims types of recombinases (claims 15, 21, and 27). The copending claims do not recite specific SOIs (claims 16, 22 and 28) or specific CHO cell types (claim 18). The copending claims do not recite types of vectors (19, 24, and 29).
The teachings of Ng are recited above in paragraphs 10, 12, 14-17 and 20 and incorporated here. The teachings of Turan are recited above in paragraph 23 and incorporated here.
Regarding claims 14-16, 18-22 and 24-30, the obviousness of having included an additional RRS to the copending CHO cells with the integrated landing pad and having included selection markers in the second and third introduced vectors in the copending RMCE method is recited above in paragraph 39 and incorporated here.
Regarding claim 18, the obviousness of having used CHO K1M cells is recited above in paragraph 40 and incorporated here.
Regarding claims 15, 21 and 27, it would have been obvious to one skilled in the art to have specifically used Cre and FLP recombinases because Ng teaches that such recombinases can be used to introduce transgenes into RRS-containing landing pads via an RMCE method.
Regarding claims 16, 22 and 28, it would have been obvious to one skilled in the art to have specifically included antibody light and heavy chains as the SOIs in the copending method because Ng teaches that antibody light and heavy chains can be produced in CHO cells and the genes encoding them can be integrated into the CHO genome via an RMCE method.
Regarding claims 19, 24 and 29, it would have been obvious to one skilled in the art to have specifically used plasmids as the vectors to integrate the SOI in the copending method because Ng teaches that plasmids can be used to introduce transgenes into RRS-containing landing pads via an RMCE method.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments - NSDP
Applicant argues that the ‘480 patent is a national stage application of the applied Ng reference and the ‘322 copending application is a continuation of the ‘480 patent. Applicant argues for the reasons argued against the §103 rejections, the examined claims are nonobvious over the patented and copending claims (Remarks, pages 11-12). This argument has been fully considered but is not persuasive for the reasons explained above in paragraphs 29-32.
Conclusion
No claims are allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Examiner, Art Unit 1635