DETAILED ACTION
Status of Application, Amendments, And/Or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment of 09 September 2025 has been entered in full. Claims 7, 11-15, and 17 are canceled. Claims 1-6, 8-10, 16, and 18-23 are under examination.
Withdrawn Objections And/Or Rejections
The substitute specification provided with the amendment of 09 September 2025 (entered) is in compliance with the sequence rules, thus resolving the issues raised at pp. 2-5 of the previous Office action (mailed 09 June 2025).
The rejection of claims 8-10, 12-15, and 17-20 under 35 U.S.C. 102(a)(1) as being anticipated by Maier et al. as set forth at pp. 6-7 of the previous Office action (mailed 09 June 2025) is withdrawn in view of the amended and canceled claims (as per the amendment received 09 September 2025).
The rejection of claims 8-10 and 18-20 under 35 U.S.C. 102(a)(1) as being anticipated by Orvar et al. as set forth at p. 7 of the previous Office action (mailed 09 June 2025) is withdrawn in view of the amended and canceled claims (as per the amendment received 09 September 2025).
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) 1-3, 5, 6, 8-10, 19, 20, 22, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fukuda et al. (2019, Biotechnol. Progress 35:e2820; https://doi.org/10.1002/btpr.2820; pp.1-8) in view of Beatson et al. (2011, Biotechnol. And Bioengineer. 108(11):2759-2764; of record), Liu et al. (2019, Cell. & Mol. Bio. Lett.; https://doi.org/10.1186/s1168-019-0171-z, pp. 1-12; of record), and Heavner et al. (US 7,521,206 B2; issued 21 April 2009).
The rejection is maintained for reasons of record. However, in view of the amended and newly submitted claims received 09 September 2025, the rejection is repeated below, modified slightly to address the new claim limitations.
Fukuda et al. teach a method of for producing a target biologic which is an antibody, the method comprising culturing a CHO cell line in which host cell proteins were knocked out using the CRISPR/Cas9 system, wherein the knocked out host cell proteins were known to be harmful contaminants, and wherein expression of the target biologic in the knockout cells yielded a better, less immunogenic product. Fukuda et al. also teach a composition comprising the target biologic. See abstract, last paragraph of Introduction, and Discussion sections.
Fukuda et al. do not teach a CHO cell line in which TGFβ1 is knocked out. However, Beatson et al. teach that CHO cells naturally produce TGFβ1 which is immunologically active on human cells including profound undesired immunological effects. See abstract, last two paragraphs before Materials and Methods section. Liu et al. describe a cell line that has had TGFβ1 knocked out, thus providing the methodology and reagents required to make a CHO cell line in which TGFβ is knocked out; i.e., there is a deletion of the nucleotides encoding TGFβ1. Liu et al. teach that there is no detectable TGFβ1 in the cells. See abstract, Materials and Methods from p. 2 to p. 3, Figure 2.
Fukuda et al. also do not teach a specific vector comprising a gene encoding a target biologic. However, Heavner et al. teach a CHO cell line transformed with a vector encoding a therapeutically useful recombinant antibody. See abstract, paragraph bridging col. 3-4, first paragraph of col. 17, col. 20 li. 11 to col. 21 li. 58, Example 1.
Therefore, it would have been obvious to one of ordinary skill in the art at the time the application was effectively filed to modify the method for producing a target biologic in a CHO cell line in which an undesirable host cell protein is knocked out, as well as the resulting composition comprising the target biologic, as taught by Fukuda et al. by using a TGFβ1 knockout CHO cell line as suggested by Beatson et al. as well as reagents and methods taught by Liu et al. and Heavner et al. with a reasonable expectation of success. The motivation to do so would have been found in the warnings of Beatson et al. that the presence of host cell TGFβ1 in the therapeutic protein prep was active in humans and caused undesirable immunological reactions, and the teachings of the other references providing reagents and methodology to make and use a CHO cell line with host TGFβ1 knocked out to produce a composition comprising a therapeutically useful antibody free of contaminating TGFβ1.
Applicant’s arguments (pp. 8-9, remarks received 09 September 2025) have been fully considered but are not found to be persuasive for the following reasons.
Applicant argues that the references teach away from the claimed invention. Specifically, Applicant urges that Beatson points to TGFβ1 as a master regulator of cell proliferation and health. Applicant also references the instant specification as teaching that TGFβ1 is important to cell proliferation and health, and thus knocking out the TGFβ1 gene in CHO cells was expected to negatively impact the cells. Applicant contends that Liu supports this in teaching that the proliferation of the TGFβ1 knockout cell was significantly lower than for the control group, and that the lack of TGFβ1 inhibited proliferation of cartilage cells. Applicant concludes that these teachings away from the claimed invention would not have provided the ordinary skilled artisan with a reasonable expectation of success.
This has been fully considered but is not found to be persuasive. Beatson recognizes that the natural production of TGFβ1 in CHO cells is immunologically active on human cells including profound undesired immunological effects. See abstract, last two paragraphs before Materials and Methods section. Thus, even though the ordinary skilled artisan may have surmised that proliferation rates may have been reduced in TGFβ1 knockout cells, they also would have recognized that the lack of TGFβ1 in the final preparation of a recombinant protein produced by a TGFβ1 knockout cell would have been a valuable feature. Knowing that the knockout cells may have had a lower proliferation rate would have suggested to the ordinary skilled artisan that a larger cell culture may have been necessary to make up for the reduced proliferation rates. It is noted that a reduced proliferation rate can be addressed in an altered experimental design. If the TGFβ1 knockout resulted in cell fatality, that would have been a valid teaching away from the claimed invention.
Claim(s) 1-4, 6, 8-10, 16, 18-20, 22, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fukuda et al. (2019, Biotechnol. Progress 35:e2820; https://doi.org/10.1002/btpr.2820; pp.1-8) in view of Beatson et al. (2011, Biotechnol. And Bioengineer. 108(11):2759-2764; of record), Liu et al. (2019, Cell. & Mol. Bio. Lett.; https://doi.org/10.1186/s1168-019-0171-z, pp. 1-12; of record), and Wang et al. (US 6,150,328; issued 21 November 2000).
The rejection is maintained for reasons of record. However, in view of the amended and newly submitted claims received 09 September 2025, the rejection is repeated below, modified slightly to address the new claim limitations.
As discussed above, Fukuda et al. teach a method of for producing a target biologic which is an antibody, the method comprising culturing a CHO cell line in which host cell proteins were knocked out using the CRISPR/Cas9 system, wherein the knocked out host cell proteins were known to be harmful contaminants, and wherein expression of the target biologic in the knockout cells yielded a better, less immunogenic product. Fukuda et al. also teach a composition comprising the target biologic. See abstract, last paragraph of Introduction, and Discussion sections.
Fukuda et al. do not teach a CHO cell line in which TGFβ1 is knocked out. However, Beatson et al. teach that CHO cells naturally produce TGFβ1 which is immunologically active on human cells including profound undesired immunological effects. See abstract, last two paragraphs before Materials and Methods section. Liu et al. describe a cell line that has had TGFβ1 knocked out, thus providing the methodology and reagents required to make a CHO cell line in which TGFβ is knocked out; i.e., there is a deletion of the nucleotides encoding TGFβ1. Liu et al. teach that there is no detectable TGFβ1 in the cells. See abstract, Materials and Methods from p. 2 to p. 3, Figure 2.
Fukuda et al. also do not teach a specific vector comprising a gene encoding a target biologic. However, Wang et al. teach a CHO cell line transformed with a vector encoding therapeutically useful recombinant proteins, human BMP-2 and human BMP-4, which are TGFβ superfamily members. See abstract, paragraph bridging col. 4-5, Examples V and VI.
Therefore, it would have been obvious to one of ordinary skill in the art at the time the application was effectively filed to modify the method for producing a target biologic in a CHO cell line in which an undesirable host cell protein is knocked out, as well as the resulting composition comprising the target biologic, as taught by Fukuda et al. by using a TGFβ1 knockout CHO cell line as suggested by Beatson et al. as well as reagents and methods taught by Liu et al. and Wang et al. with a reasonable expectation of success. The motivation to do so would have been found in the warnings of Beatson et al. that the presence of host cell TGFβ1 in the therapeutic protein prep was active in humans and caused undesirable immunological reactions, and the teachings of the other references providing reagents and methodology to make and use a CHO cell line with host TGFβ1 knocked out to produce a composition comprising human BMP-2 and/or human BMP-4 free of contaminating TGFβ1.
Applicant’s arguments (p. 9, remarks received 09 September 2025) have been fully considered but are not found to be persuasive for the following reasons.
Applicant repeats the argument that the references teach away from the claimed invention since knocking out the TGFβ1 gene resulted in reduced cell proliferation rates. This has been fully considered but is not found to be persuasive for the reasons provided above.
Claim(s) 1-3, 6, 8-10, 16, and 18-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fukuda et al. (2019, Biotechnol. Progress 35:e2820; https://doi.org/10.1002/btpr.2820; pp.1-8) in view of Beatson et al. (2011, Biotechnol. And Bioengineer. 108(11):2759-2764; of record), Liu et al. (2019, Cell. & Mol. Bio. Lett.; https://doi.org/10.1186/s1168-019-0171-z, pp. 1-12; of record), and Green et al. (2013, PLoS ONE 8(3):e58395; doi:10.1371/journal.pone.0058395; pp. 1-11).
Fukuda et al. teach a method of for producing a target biologic, the method comprising culturing a CHO cell line in which host cell proteins were knocked out using the CRISPR/Cas9 system, wherein the knocked out host cell proteins were known to be harmful contaminants, and wherein expression of the target biologic in the knockout cells yielded a better, less immunogenic product. Fukuda et al. also teach a composition comprising the target biologic. See abstract, last paragraph of Introduction, and Discussion sections.
Fukuda et al. do not teach a CHO cell line in which TGFβ1 is knocked out. However, Beatson et al. teach that CHO cells naturally produce TGFβ1 which is immunologically active on human cells including profound undesired immunological effects. See abstract, last two paragraphs before Materials and Methods section. Liu et al. describe a cell line that has had TGFβ1 knocked out, thus providing the methodology and reagents required to make a CHO cell line in which TGFβ is knocked out; i.e., there is a deletion of the nucleotides encoding TGFβ1. Liu et al. teach that there is no detectable TGFβ1 in the cells. See abstract, Materials and Methods from p. 2 to p. 3, Figure 2.
Fukuda et al. also do not teach a specific vector comprising a gene encoding a target biologic. However, Green et al. teach a CHO cell line transformed with a vector encoding a therapeutically useful recombinant protein, human Wnt3a. See abstract, Figure 1, p. 2 “Engineering Wnt-producing iCHO cell lines.” Green et al. teach that recombinant production of hWnt3a is desirable because Wnt signaling pathways are among the most important and most complex described in developmental biology (p. 1).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the application was effectively filed to modify the method for producing a target biologic in a CHO cell line in which an undesirable host cell protein is knocked out, as well as the resulting composition comprising the target biologic, as taught by Fukuda et al. by using a TGFβ1 knockout CHO cell line as suggested by Beatson et al. as well as reagents and methods taught by Liu et al. and Green et al. with a reasonable expectation of success. The motivation to do so would have been found in the warnings of Beatson et al. that the presence of host cell TGFβ1 in the therapeutic protein prep was active in humans and caused undesirable immunological reactions, and the teachings of the other references providing reagents and methodology to make and use a CHO cell line with host TGFβ1 knocked out to produce a composition comprising human Wnt3a free of contaminating TGFβ1.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ELIZABETH C. KEMMERER whose telephone number is (571)272-0874. The examiner can normally be reached M-F 6:30-3.
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/ELIZABETH C. KEMMERER/ Primary Examiner, Art Unit 1674
/ECK/
22 September 2025