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 .
Priority
This application claims priority to provisional application 63/383,885. Therefore, it is entitled to the 15th Nov 2022 priority date of the provisional application.
Election/Restrictions
Restriction:
Applicant’s election of Group II (claims 21-25, 28-31, and 33) drawn to a method of expressing a polypeptide of interest, in the reply filed on Jun 10th 2026 is acknowledged.
B. Species Selection:
Applicant’s selection without traverse of:
A. CRISPR-Cas as the endonuclease (claims 21-25, 28-31, and 33);
in the same reply is also acknowledged.
Claims 1-2, 4-7, and 10-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Jun 10th 2026.
Status of Claims
Claims 21-25, 28-31, and 33 are under consideration.
Information Disclosure Statement
The information disclosure statements (IDS) are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because:
the labels for Figures 1 - 3 are preceded by the word "Figure" instead of the abbreviation "FIG."
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Objection - Specification
The disclosure is objected to because of the following:
1. Trade Name:
The use of the terms piggyBac, Maxcyte, and Zeocin, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
2. Sequence Mismatch
The specification bridging pages 15 and 16 states: In certain embodiments, the exogenous nucleotide sequence is integrated at an integration site located within a position selected from nucleotides numbered 1-10,000 bp; 10,000-20,000 bp; and 20,000- 22,904 bp of SEQ ID No. 7. Further, it states something similar at the end of [0066].
However, the sequence listing lists the following for SEQ ID NO: 7:
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Thus, as per the sequence listing, SEQ ID NO 7 only has 3974 nucleotides. It is confusing how, as stated in the specification, the insertion could be in a position 10000-20000 when the referenced sequence is only 3974 nucleotides in length
Either the specification or the sequence listing or both must be corrected.
Appropriate correction is required.
Objection - Claims
Claim 21 recites abbreviations RRS and SOI. Since claim 21 is an independent claim, the abbreviations should be spelt out at first use.
Claim 21 again recites: a) providing a host cell comprising an exogenous nucleotide sequence integrated at a targeted locus of the genome of the host cells, wherein the exogenous nucleotide sequence comprises two RRSs flanking the first selection marker;
But then continues to recite:
b) introducing into the host cells provided in (a) a nucleic acid comprising two RRSs…
Consistent use of parenthesis is recommended.
Claim 24 recites 90% homologous to a sequence... Homologous is not a term of the art used to refer to % similarity in base composition, rather to refer to evolutionary relatedness. “90% identical to a sequence…” would be preferable.
Claim Rejections - 35 USC § 112
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 24, 29, and 31 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 24 recites “at least about 90% homologous to” specific sequences in the contig numbers of Chinese hamster ovary (CHO) cell genomic sequences. “at least about 90%” renders the claims indefinite because although “at least 90%” and “about 90%” are clear, the metes and bounds of “at least about 90%” is not. It is not clear what percent similarity are included in “at least about 90%”. 89% is about 90%, but is not at least 90%. 98% is at least 90%, but not about 90%. Thus, it is not clear if 89% or 98% is included in the range of similarity.
Claim 29 recites “the targeted integration of any of the SOIs is promoted by an exogenous nuclease”. Claim 29 depends from claim 21. Claim 21 recites that one SOI was integrated at a targeted locus, and a second SOI is randomly integrated. Claim 21 recites “e) introducing, via transposon-mediated genomic integration, a second exogenous SOI encoding a second polypeptide of interest and a third selection marker into the genome of the host cell; f) wherein the exogenous nucleotide sequence integrated at a targeted locus of the genome of the host cell is constitutively or inducibly expressed, and the transposon- mediated genomically integrated exogenous SOI is constitutively or inducibly expressed”, indicating that the transposon- mediated genomically integrated exogenous SOI, which is the second SOI, is not integrated by targeting, rather random. Therefore, claim 29 is vague in its recitation of “any”. The specification in [0210] states: Additionally, or alternatively, in certain of embodiments of the host cells of the present disclosure, the targeted integration of the SOIs and selection markers is promoted by an exogenous nuclease. The Example in the disclosure does not mention nuclease. Therefore, it remains unclear what is meant by the “any” when used with a nuclease.
Claim 31 recites “the method of claim 1.” Thus, claim 31 depends from claim 1. 35 CFR 1.75 states “One or more claims may be presented in dependent form, referring back to and further limiting another claim or claims in the same application.” Because claim 31 refers back claim 1, it is a dependent claim of claim 1.
However, claim 31 is directed to the “operation”, per se, of a composition rather than its “structure” and, therefore, is confusing. First, it is unclear whether the above limitation is intended to be directed to a series of steps for the “making” of the composition i.e., a host cell … a targeted integrated exogenous nucleic acid sequence of interest (SOI) to which no steps are recited or to be directed to a series of steps for the “use” of the composition comprising a targeted integrated exogenous nucleic acid sequence of interest (SOI) to which, again, no steps are recited. A claim which claims both an apparatus and the method steps of using the apparatus would be considered indefinite. See MPEP. 2173.05(p).
Accordingly, clarification and appropriate correction for the above limitation recited in the claims is requested.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 21-25, 29-30, and 33 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the Invention
Claim 21 is directed to a method that requires a host cell comprising an exogenous nucleotide sequence integrated at a targeted locus of the host cell. Claim 24 limits the method to certain loci. The specification is broad in its recitation of a host cell.
The broadest reasonable interpretation of the claimed method is a method to produce proteins in a host cell comprising at least two exogenous nucleotide sequences wherein the first sequence is introduced into the host cell by targeted integration (TI) and the second sequence is introduced into the host cell via transposon-mediated genomic integration.
The scope of the invention includes:
#1. CHO cells
# 2.any mammalian cell.
Disclosure of a Complete or Partial structure
However, the specification as filed does not provide an adequate written description of the vast genus of host cells that will have the requisite landing pads with the recited % homology to the recited contigs or SEQ ID NOs that would be commensurate with the breadth of what is claimed.
The Specification in Table 1, [0070], describes 7 examples of a TI host cell with exemplary integration sites. It is not clear what coding sequences were integrated here. The Figures and [0215] in §9.1.3 depict and describe 5 different clones with various integrations (piggyBac alone (PB), with targeted integration alone (TI), simultaneously transfected with targeted integration and piggyBac (TIP), sequentially transfected with targeted integration and with piggyBac two days later (TI+PB), and sequentially transfected with piggyBac and with targeted integration two days later (PB+TI)). However, the Specification fails to disclose the nature of the TI host cell used in the working examples. Rather, the Specification in [0010] states: In certain embodiments, the host cell can be a mammalian host cell. In certain embodiments, the host cell can be a hamster host cell, a human host cell, a rat host cell, or a mouse host cell. In certain embodiments, the host cell can be a CHO host cell, a CHO K1 host cell, a CHO K1SV host cell, a DG44 host cell, a DUKXB-11 host cell, a CHO KiS host cell, or a CHO KiM host cell. The sequence listing and the claimed contigs described as the loci are Chinese Hamster genomic sequences. Thus, the Specification has sufficiently described the sub-genus of CHO TI host cells with integrations sites that are 100% homologous to all of the claimed nucleotide sequences. However, the Specification does not disclose any other TI host cells that have over 90% homology to the recited ranges of nucleotide sequences. In view of the Specification then, it is unpredictable what other host cells would have integration sites with at least 90% identity to all of the claimed nucleotide sequences.
The specification as filed provides a generic description or limiting disclosure of what is encompassed by the claimed invention.
Species not Disclosed
Thus, the inventors only discovered CHO cells as host cells. The specification and prior art of record only provide written support for wherein the host cell for TI or transposon-mediated integration are CHO cells and only the disclosed loci within these cells.
Knowledge from the art
Hertel et al., (Front. Bioengineer. Biotechnol. 10:1010719, 2022, 12 pages; cited on the attached Form PTO-892) disclose “[i]nstability within recombinant CHO cells can occur at any or all of the genome, transcriptome, or proteome level” (p. 2, column 1, bottom) and that even the characteristics of “safe harbors” are “poorly understood and differ substantially between the relatively few known regions…To date, the ongoing efforts to identify additional safe harbor regions in the CHO genome has mostly been conducted via empirical methods” (p. 2, column 2, bottom).
Dahodwala et al. (Curr. Opin. Biotechnol. 60:128-137, 2019; cited on the attached Form PTO-892) disclose “[v]arious mechanisms have been identified as causes of the observed instability, such as gene loss, gene silencing, and increased susceptibility to cellular stresses. Production instability has also been known to arise from distal factors such as increasing apoptosis and global gene changes as well as whole genome/epigenome changes. Unintended and unpredictable gene changes also come with a risk of changing the expression of cellular genes associated with glycosylation, protein folding, proteases and molecular chaperones” (paragraph bridging pp. 129-130).
Based on the evidence of record, one of skill in the art would recognize a need to know the exact genomic integration sites.
Structure/Function Correlation
The feature of the contig that allows for integration of an exogenous sequence seem to be essential for the invention. There is no essential structure of record required for integration sites that would support written description for the genus of host cells that could be used.
The instant specification, fails to describe the host cell adequately. If the host cell is not described, a method of using that host cell cannot be adequately described.
In addition, the prior art and the as-filed specification do not provide written description to allow one of skill in the art to extrapolate from the evidence of CHO cells as shown, to utilization of any other host cell. Particularly so, as the art shows that CHO cells are unique at least with respect to their ability to produce polypeptides. Therefore, one cannot extrapolate from evidence seen with CHO to any other host cell even if having 90% similarity to the loci where insertion is to occur.
Dependent Claims
Claims 22-25, 29-30, and 33 do not limit the scope, structure or sequence of the host cell and are therefore rejected for the same reasons as discussed above for claim 21.
Conclusion of Written Description
The written description requirement for the claimed genus of host cells is not satisfied through sufficient description of a representative number of species. There is substantial variation within the genus of host cells, and the applicant does not describe a sufficient variety of species to reflect the variation within the genus. In view of the lack of description for these species, it is evident that Applicant was not in possession of the full breath of the claimed host cells for producing polypeptides.
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) 21-22, 25, 28-30, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bleck (CA 3180705 A1).
Bleck teaches cells with multiple integration sites and methods of using such cells for protein expression (title, summary of invention). See pertinent para from Summary:
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Bleck teaches that the dock site insertion element is targeted by enzyme selected from the group consisting of an integrase, a recombinase, a nuclease and a nickase (claim 7). Bleck teaches that the docking site sequences may be introduced into the host cells by any suitable genome modification system (page 26, lines 11-12). Various examples of such systems are then provided e.g., integrating vectors (AAV, transposon etc.).
Regarding claim 21, Bleck teaches a method of expressing a polypeptide of interest comprising:
providing a host cell wherein the genome of the host cell comprises any number of integrated docking sites, each docking site comprising at least one dock site insertion element (pg. 2, summary of invention, title). the recombinase dock site insertion element is a Flp Recombination Target (FRT) site (pg. 2, line 15); i.e., a RRS. Each docking site is flanked by exogenous integrating vector sequences, which are viral vector sequences or transposon vector sequences and further comprise a sequence encoding a selectable maker operably linked to a promoter;
b) Bleck teaches the host cells further comprise nucleic acid expression constructs inserted at 1 or more of the docking sites....the nucleic acid expression construct comprises a second (i.e., internal) promoter operably linked to a sequence encoding a protein of interest. …the nucleic acid expression construct further comprises a 5' promoter (or first promoter) operably linked and 5' to a selectable marker (pg. 4, lines 12-28). Bleck teaches the integrated docking sites are independently inserted throughout the genome (of host CHO cell), (claim 165).
c) Bleck teaches the resulting "Dock" cell line can then be transiently co-transfected with a plasmid expressing the transposase, recombinase, integrase, or Cas9 in combination with a transgene plasmid that contains the cognate recognition sequence, the GS selectable marker, and the gene product to be expressed (pg. 55, lines 24-16). In some preferred embodiments, the nucleic acid constructs include a selectable marker. Suitable selectable markers include but are not limited to glutamine synthetase (GS), dihydrofolate reductase (DHFR) and the like (pg. 46, lines 26-28).
d) Bleck teaches selecting cells (Transfection and Selection of Dock Pooled Cell Line pg. 56, line 13 onwards).
Thus, instant steps a-d are met in Bleck’s teachings described above.
Bleck then teach transfecting with a second SOI wherein said second nucleic acid construct includes a selectable marker that is different from the selectable marker in the first nucleic acid construct. Bleck teach repeated rounds of transfection to increase integrations (Several rounds of selection to isolate a high Dock copy number clone were performed, pg. 61, line 9; Examples 2-5; These data also suggest that we have not yet saturated the production capacity of these cells even with approximately 181 copies integrated, pg. 63, lines 10-12). Bleck teach using their system to integrate and express monoclonal antibodies with both heavy and light chains albeit on the same Transgene plasmid (Example 6, pg. 63, line 15 onwards).
Bleck do not specifically teach introducing the second SOI via transposon-mediated genomic integration, nor do they teach a third selection marker in the second exogenous SOI.
However, Bleck suggests that this can be done. See the following from top of pg. 31:
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Further, Bleck had already taught integration via various alternative methods: recombinase or transposase etc. Specifically, Bleck had taught, in some embodiments, the mixtures of different constructs are utilized (pg. 38, line 15).
“It is contemplated that by using mixtures of constructs, some which do not include selectable markers, that higher insertion rates may be achieved.”(Id.);
AND
Claim 80. The host cell line of any one of claims 34 to 79 wherein the nucleic acid expression construct further comprises a nucleic acid sequence encoding a second protein of interest.
Bleck demonstrate their iterative process of integrating SOI results in stable integration and stable expression (pg. 66, last para).
Bleck teach the following gene insertion technologies may be used:
Pg 39:
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to introduce the second SOI via transposon-mediated genomic integration, and that this second exogenous SOI encoding a second polypeptide of interest also includes a third selection marker into the genome of the host cell that already comprised the first SOI, and to select a cell comprising the integrated second exogenous SOI, and to produce the first and second proteins encoded by the multiple integrated nucleic acid sequences. One would have been motivated to, and have a reasonable expectation of success to do so, because: (1) Bleck teaches the need to identify multiple loci for integration sites in CHO-K1 cells that allow for stable, long-term expression of exogenous genes, and the need to produce CHO cells having multiple stable integration sites in order to increase production of a protein encoded by the integrated exogenous sequences; (2) Bleck demonstrates integration is a known and successful method for integrating exogenous genes, expressing the encoded protein and selectable markers, and for identifying multiple integration sites; (3) Bleck teaches the need to produce CHO cells having multiple integration sites in order to increase copy numbers of the genes expressed and to increase yield of the expressed protein; (4) Bleck successfully demonstrates adding new integration sites to CHO cells already comprising integrated sequences in order to increase copy number and yield of the expressed protein; (5) Bleck successfully demonstrates engineering CHO cells to have multiple integration sites with the same or different protein and selection marker expressed; (6) Bleck teaches integration into their CHO cells can be by any means such as transposition, recombination etc. and (7) demonstrates routine methods of selecting for or excluding cells expressing the selectable markers; and demonstrates routine methods of culturing the selected cells to produce and recover the expressed protein.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Bleck recognizes the need for iterative integration of SOI for protein production in CHO cells, and to produce CHO cells comprising multiple stable integration sites in order to engineer CHO cells harboring multiple copies of genes, to result in higher protein production. Bleck provides a platform (engineered CHO cell) that allows for stable integration via many different methods; i.e., targeted e.g., FRT as well as . Bleck demonstrates the known solutions and successful methods for identifying and creating multiple stable integration sites supporting long term expression of exogenous genes via random integration. Bleck demonstrates known methods for adding integration sites to cells that already harbor multiple integrations sites. Bleck successfully demonstrates routine methods for selecting cells by the different or same selectable markers expressed by the multiple integrated nucleic acid sequences, and routine methods for culturing cells to express the encoded proteins, and recover the proteins, such as antibodies.
One of skill in the art could have pursued a transposon-mediated step to introduce another integration site or integrated exogenous sequence encoding a protein and selectable marker by integration into the CHO cells of Bleck that already comprises other integrated sequences encoding protein and selection markers by targeted integration, and to select a cell comprising the additional random integration, and to produce the protein encoded by the multiple integrated nucleic acid sequences with a reasonable expectation of success.
Regarding claim 22, Bleck teaches recovering the first and second polypeptides of interest from the host cell culture (pg. 52, line 16).
Regarding claim 25, Bleck teaches the polypeptides are antibody chains (Example 6).
Regarding claim 28, Bleck teaches the host cell is CHO (claim 94).
Regarding claims 29-30, Bleck teaches their dock sites are preferably used in conjunction with CRISPR gene editing systems wherein the CRISPR gene editing system-compatible nuclease may be a wild-type endonuclease (bridging pgs. 24-25).
Regarding claim 33, Bleck teaches the promoter is a constitutive promoter (Fig. 1).
Thus, Bleck makes obvious instant claims 21-22, 25, 28-30, and 33.
Claims 23- 24 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Bleck (CA 3180705 A1) as applied to claims 21-22, 25, 28-30, and 33 above, and further in view of Ng (WO 2019126634 A2, published June 27, 2019).
The method of claim 21 is discussed above.
Bleck does not teach wherein the first and second SOI are the same (claim 23) or the loci of integration (claim 24) or regulatable promoter (claim 31).
However, before the effective filing date of instant invention, Ng had taught TI CHO cells suitable for the expression of recombinant proteins (Abstract). Ng taught a method of using the taught cells for protein production that includes introducing one or more recombinases that recognize the RRSs (Fig 4; page 7, lines 7-8), followed by selecting TI cells that express the second selection marker to isolate a TI host cell expressing the SOIs (page 7, lines 8-10).
Regarding claim 23, Ng taught the SOIs are antibodies (page 36, lines 7-28) or can be scFvs (page 46, line 20). Ng taught 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 taught the proteins can be the same (pg. 5, line 26).
Regarding claim 24, Ng taught TI CHO cell #4 comprising an integration site at position 79768 of contig NW_003616412.1 (page 101; Table 2).
Regarding claim 31, Ng taught the promoter is regulatable (claims 68-69).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used contig NW_003616412.1 as an integration site of host cell and to have regulated expression of the same SOI/polypeptides of interest in Bleck’s method utilizing host cells that include insertion elements that let DNA integrate into cells by different genome-insertion systems. It would have amounted to utilizing 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 steps in a known method by known means to yield predictable results. The skilled artisan would have predicted that a locus that has been tested can be utilized as a predictable integration site again. The skilled artisan would have been motivated to do so for the purpose of allowing the insertion of any number of sequences of interest, and because Bleck suggests that any number of sequences can be integrated into a specific locus by more than one type of integration method. Regarding the expression of the same protein, one of skill would encode a polypeptide into the first and second SOI to enhance production of that polypeptide. Regarding the regulatable promoter, one of skill would adopt such a promoter in order to gain control over the expression system. Thus, the skilled artisan would have been motivated to incorporate the teachings of Ng into the method taught by Bleck.
Thus, Bleck in view of Ng makes obvious instant claims 23-24 and 31.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
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 21-25, 28-31, and 33 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-15 and 17-23 of U.S. Application No. 17351451 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the US Application also claims a method of expressing a polypeptide using engineered cells overlapping in scope with the instantly claimed method, thus anticipating the instant invention. The US reference application claims the engineered cell is a mammalian, such as hamster, (CHO) cell (claim 18-20) comprising multiple integration sites selected from SEQ ID NO: 1-7, for exogenous nucleic acid sequence (sequence of interest, SOI) encoding selectable markers and proteins of interest that are flanked by RRSs (claim 13), and recovering proteins (claim 14), wherein the first and second polypeptide are the same (claim 15), protein of interest is an antibody, light chain, heavy chain, scFv, or Fc fusion protein (claim 17), wherein the targeted integration of any of the SOIs is promoted by an exogenous nuclease, such as Cas, (claim 21-22) and where expression is controlled by a regulatable promoter (claim 23).
See comparison of the independent claims below:
Preamble
Instant claim 21
Reference 17351451
claim 13
A method of expressing a polypeptide of interest comprising:
a) providing a host cell comprising an exogenous nucleotide sequence integrated at a targeted locus of the genome of the host cell, wherein the exogenous nucleotide sequence comprises two RRSs flanking a first selection marker;
b) introducing into the cell provided in (a) a nucleic acid comprising two RRSs matching the two RRSs of the integrated exogenous nucleotide sequence and flanking a first exogenous SOI encoding a first polypeptide of interest and a second selection marker;
c) introducing a recombinase or a nucleic acid encoding a recombinase, wherein the recombinase recognizes the RRSs;
d) selecting for cells expressing the second selection marker;
e) introducing, via transposon-mediated genomic integration, a second exogenous SOI encoding a second polypeptide of interest and a third selection marker into the genome of the host cell;
f) wherein the exogenous nucleotide sequence integrated at a targeted locus of the genome of the host cell is constitutively or inducibly expressed, and the transposon- mediated genomically integrated exogenous SOI is constitutively or inducibly expressed;
g) selecting for cells expressing the third selection marker; and
h) culturing the host cell under conditions sufficient to express the first and second polypeptides of interest.
a)providing host cells comprising an exogenous nucleotide sequence of interest and a first selection marker integrated at a targeted locus of the genome of the host cells, wherein said targeted locus is at least 95% homologous to a sequence selected from SEQ ID NOs: 1-7, wherein the exogenous nucleotide sequence of interest comprises two RRSs flanking the first selection marker;
b) introducing into the host cells provided in (a) a nucleic acid comprising two RRSs matching the two RRSs of the integrated exogenous nucleotide sequence and flanking a first exogenous SOI encoding a first polypeptide of interest and a second selection marker;
c) introducing into the host cells a recombinase or a nucleic acid encoding a recombinase, wherein the recombinase recognizes the RRSs;
d) selecting for host cells expressing the second selection marker;
e) introducing into the host cells, via random integration, a second exogenous SOI encoding a second polypeptide of interest and a third selection marker into the genome of the host cell;
f) selecting for host cells expressing the third selection marker; and
g) culturing the host cells under conditions sufficient to express the first and second polypeptides of interest wherein each of said first polypeptide of interest and second polypeptide of interest is a single chain antibody, an antibody light chain, an antibody heavy chain, a single-chain Fv fragment (scFv), or an Fc fusion protein; and wherein the targeted integration of the nucleic acid SOI encoding a first polypeptide of interest and a first selection marker was integrated within the targeted locus by an exogenous nuclease.
Limitation f) of instant independent claim is anticipated by claim 23 of the reference application that recites: controlled by a regulatable promoter. The limitation of instant claim 21 e) introducing, via transposon is evidenced by Bazaz (R Bazaz, et al., Sci Rep 12, 3390, 2022) transposition is a random integration process (the random integration activity of piggyBac transposase (PB) … is prevented by the introduced mutations, 4th para of introduction).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Correspondence
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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