DETAILED ACTION
Status of the Claims
Claims 1-30 are currently pending and are the subject of this Office Action.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 08/18/2023 and 11/07/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 3 and 9 are objected to because of the following informalities: claims 3 and 9 do not end with a period. As per MPEP 608.01(m), each claim must begin with a capital letter and end with a period.
Claim Rejections – 35 U.S.C. 103(a)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 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.
Hoellerbauer et al. and Lee et al.
Claims 1-30 are rejected under 35 U.S.C. 103 as being unpatentable over Hoellerbauer et al. (Cancer Reports, 2020, 3:e1269, doi.org/10.1002/cnr2.1269, cited in IDS of 08/18/2023) in view of Lee et al. (ACS Synth. Biol., 2016, 5:1211−1219) and as evidenced by Kim et al. (Appl. Microbiol. Biotechnol., 2012, 93:917-930).
Regarding claim 1, Hoellerbauer discloses a method of producing a cell comprising edits at two or more target loci:
combining two or more guide RNAs (gRNAs) capable of directing CRISPR/Cas9-mediated indel formation at respective target loci with Cas9 protein to form a ribonucleoprotein complex (RNP);
(b) serially transfecting a population of cells with the RNP until at least about 10% indel formation is achieved at each target locus (“nucleofected TERT-immortalized NSC-CB660 cells with pools of 3 sgRNAs for each gene, in four successive rounds of nucleofection spaced 1 week apart” as per the 2.3. RNP nucleofection generates dramatic protein loss in cell pools section on p. 6 and/or Fig. 3).
Regarding the limitation (c) isolating a cell comprising edits at two or more target loci by single cell cloning of the cell from the population of serially transfected cells, Hoellerbauer notes that for their methods, “[t]he deletion efficiency decreases as the size of the desired deletion increases, meaning that single-cell clones may need to be created to study larger deletions” (e.g., as per the 4. DISCUSSION section on pp 11-12). Therefore, it would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to perform single cell cloning as per Hoellerbauer, at least in the case of larger deletions. One of ordinary skill in the art would have been motivated to do so since Hoellerbauer explicitly suggests such a step in some cases.
Regarding claims 2, 8, 18, and 21, Hoellerbauer discloses the above, wherein the population of cells is serially transfected with the RNP until at least about 20% indel formation is achieved at each target locus (e.g., as per Fig. 3).
Regarding claims 3, 9, and 19, which recites a ratio of moles of RNP to number of transfected cells between about 0.1 pmol per 106 cells to about 5 pmol per 106 cells, it is noted that Hoellerbauer discloses the use of 1.5 x 105 to 2.5 x 105 cells with 1.875-60 pmol of RNP complex (e.g., as per the Supplementary Protocol and/or Fig. 1) and explicitly states that “The number of cells to use should be empirically determined for your cell type” as per the Supplementary Protocol on p. 4. Further, Applicant is directed to In re Aller, Lacey, and Hall, 105 USPQ 233 (C.C.P.A. 1955), where the court found
"More particularly, where the general conditions
of a claim are disclosed in the prior art, it is
not inventive to discover the optimum or workable
ranges by routine experimentation."
Routine optimization is not considered inventive and no evidence has been presented that the selection of the ratio of RNPs to cells was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art.
Regarding claims 4, 10, and 20, Hoellerbauer discloses the above, wherein three or more gRNAs capable of directing CRISPR/Cas9-mediated indel formation at respective target loci are combined with Cas9 protein to produce RNPs and the RNPs are serially transfecting into a population of cells until at least about 10% indel formation is achieved at each target locus (e.g., as per Fig. 3).
Regarding claims 6, 12, and 23, Hoellerbauer discloses the above, wherein the two or more gRNAs capable of directing CRISPR/Cas9-mediated indel formation at respective target loci are identified via an efficiency screen comprising transfecting a population of cells with a population of RNPs, where each RNP comprises a gRNA capable of directing CRISPR/Cas9-mediated indel formation at a target locus; and sequencing the target loci to identify gRNAs based on their efficiency in directing CRISPR/Cas9-mediated indel formation (e.g., pre-validation of sgRNAs as per p. 11, right column).
Regarding claim 7, Hoellerbauer discloses a host cell composition, wherein the host cell comprises edits at two more target loci, wherein the edits are the result of combining two or more gRNAs capable of directing CRISPR/Cas9- mediated indel formation at respective target loci with Cas9 protein to form an RNP; serially transfecting a population of cells with the RNP until at least about 10% indel formation is achieved at each target locus; and isolating the host cell comprising edits at two or more target loci by single cell cloning of the host cell from the population of serially transfected cells (“nucleofected TERT-immortalized NSC-CB660 cells with pools of 3 sgRNAs for each gene, in four successive rounds of nucleofection spaced 1 week apart” as per the 2.3. RNP nucleofection generates dramatic protein loss in cell pools section on p. 6 and/or Fig. 3).
However, it is noted that the Hoellerbauer reference is silent on the limitation of the cell being a CHO cell, as set forth in claims 5, 11, 22, and 25-26, and the cell composition comprising “a nucleic acid encoding a non-endogenous polypeptide of interest” such as an antibody or fragment thereof, as set forth in claims 7, 13-16, and 27-30, and further isolating the polypeptide of interest, as set forth in claims 17 and 24.
Lee similarly discloses methods of “DNA-free RNA-guided Cas9 nuclease mediated genome editing facilitates the rational design of the CHO cell genome for efficient production of high quality therapeutic proteins” such as monoclonal antibodies (e.g., as evidenced by Kim cited by Lee), as per the Abstract.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to express non-endogenous proteins such as monoclonal antibodies in CHO cells as per Lee as evidenced by Kim, using the serial CRISPR-Cas9 RNP transfection method as per Hoellerbauer. One of ordinary skill in the art would have been motivated to do so since Hoellerbauer teaches an increased transfection efficiency as a result of successive nucleofections when targeting multiple loci (e.g., as per 2.3. RNP nucleofection generates dramatic protein loss in cell pools section on p. 6 and/or Fig. 3). CHO cells have been extensively studied and engineered with respect to several genes, as evidenced by reviews from Henry et al. (Biotechnology and Bioengineering, 2020, 117:1187-1203), Xu et al. (Pharm. Bioprocess., 2015, 3(4):285-292), and Wang et al. (Biotechnology and Bioengineering, 2018, 115:1378-1393) to name a few.
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since such serial CRISPR-Cas9 RNP transfection/nucleofection was well within reach of the skilled artisan.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
12,286,619 B2
Claims 7-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,286,619 B2 (the ‘619 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the rejected claims of the present invention would be anticipated and/or rendered obvious by the subject matter in the claims of the reference patent.
The claims of the ‘619 patent disclose a CHO cell composition with edits at least two loci and including a non-endogenous nucleic acid encoding an antibody or antigen-binding portion thereof.
Note that present claims 7-16 recite the limitation of a host cell composition produced as the result of specific steps and is therefore a product-by-process claim. Note that as per MPEP § 2113, “product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps”. The same MPEP section states that “‘even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.’ In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). The claims of the ‘619 patent teach all the limitations implied by the recited process steps and therefore meets all of the structural limitations of the claimed product except for the product-by-process limitations and thus would either anticipate or render obvious the claimed host cell composition. Thus, the specific process limitations of the rejected claims do not do not distinguish the claimed invention from the reference patent in accordance with MPEP § 2113. One of ordinary skill would expect the product to be the same no matter how it was synthesized and/or prepared.
12,098,365 B2
Claims 7-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,098,365 B2 (the ‘365 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the rejected claims of the present invention would be anticipated and/or rendered obvious by the subject matter in the claims of the reference patent.
The claims of the ‘365 patent disclose a CHO cell composition with edits at least two loci and including a non-endogenous nucleic acid encoding an antibody or antigen-binding portion thereof.
Note that present claims 7-16 recite the limitation of a host cell composition produced as the result of specific steps and is therefore a product-by-process claim. Note that as per MPEP § 2113, “product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps”. The same MPEP section states that “‘even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.’ In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). The claims of the ‘619 patent teach all the limitations implied by the recited process steps and therefore meets all of the structural limitations of the claimed product except for the product-by-process limitations and thus would either anticipate or render obvious the claimed host cell composition. Thus, the specific process limitations of the rejected claims do not do not distinguish the claimed invention from the reference patent in accordance with MPEP § 2113. One of ordinary skill would expect the product to be the same no matter how it was synthesized and/or prepared.
Conclusion
No claims are allowed.
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/JEREMY C FLINDERS/
Primary Examiner, Art Unit 1684