DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on February 18, 2026 have been received and entered. Claims 1, 26, 33, 43-45, 47, 56, 66, have been amended, while claims 4, 9, 12-13, 17-25, 27-31, 34-39, 41-42, 46, 48-55, 57-65. have been canceled. Claims 67 and 68 are newly added. Claims 1-3, 5-8, 10, 11, 15, 16, 26, 32, 33, 40, 43-45, 47, 56, 66-67 and 68 are pending in the instant application.
Election/Restrictions
Applicant’s election of claims 1-3, 5-8, 10-11, 15-17, 19-21, 24, 26, 32-33, 40, 43-44 and 45 (group I) in the reply filed on October 19, 2021 was acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 47, 56 and 66 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on October 19, 2021.
Priority
This application is a 371 of PCT/IB2018/000232 filed on 02/17/2018, which claims priority from US provisional application 62/460,420 filed on 02/17/2017.
Claims 1-3, 5-8, 10, 11, 15, 16, 26, 32, 33, 40, 43-45, 67-68 are under consideration.
New & maintained-Claim Rejections - 35 USC § 112 -in modified form
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 1-3, 5-8, 10, 11, 15, 16, 26, 32, 33, 40, 43-45, 67 are 68 are rejected in modified form 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.
In the instant case, the recitation of limitation “.wherein a gene of interest located between the two RTS is expressed in NL1 or NL2 and is stable for at least one generation.” (claims 1, 43-45) is considered new matter. Applicants point to example 4 of the specification and for the specific support showing that CHOKISV GS-KO cells stably expressed the gene of interest after growth in a 8-day batch culture, i.e., samples were taken at 2, 4 and 8 days. As one having ordinary skill in the art would recognize, subculturing a pool of cells necessarily produces a new generation of cells. As shown in Example 4, the resulting sub cultured batch culture exhibits stable expression of the gene of interest. However, indicated portion of the specification fails to provide support for recitation two RTS is expressed in NL1 or NL2 and is stable for at least one generation. It is emphasized that sub cultured batch culture exhibiting stable expression of the gene of interest does not support “stable for at least one generation”. The cited portion explicitly provide supports for “subculture cell exhibits stable expression of the gene of interest or stable for one generation. It is emphasized that recitation of at least one generation encompasses any number of generations including more than one (eg. 50 70, 100, 250 generations or more). There is not support for cell being stable for at least one generation.
There is no explicit or implicit support for the limitation of stably expressing the gene of interest for at least one generation. Recitation of at least 1 generation is open ended and read on gene of interest is stably expressed indefinitely (emphasis added). Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of the claimed CHOKISV GS KO cells, as claimed. In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for the claimed CHOKISV GS KO cells, wherein a gene of interest expressed in NL1 or NL2 and is stable for at least one generation. The specification provide direct support to a gene of interest expressed in NL1 or NL2 locus and is stable for one generation. Claims 1-3, 5-8, 10, 11, 15, 16, 26, 32, 33, 40, are included in the rejection because they directly or indirectly depend from the rejected base claim. This is a new matter rejection.
Response to arguments
Applicant disagree with the rejection arguing support for the amended limitation on page 70, example 4, phase 3 for the explicit support. Applicant assert that one having ordinary skill in the art would recognize, a "subculture" is a transfer of the cells to fresh media, i.e., a cell passage, which creates new generations of cells, i.e., at least one generation of cells. Moreover, as noted in this example, the difficult to express protein etanercept exhibited good expression thus demonstrating stability after at least one generation. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is emphasized that recitation of at least 1 generation is open ended and breadth of the claims read on gene of interest is stably expressed indefinitely (emphasis added). The specification explicitly provide supports for “subculture cell exhibits stable expression of the gene of interest” (ie stable for one generation). The recitation fails to support stability of gene expression beyond 1 generation. As stated in previous office action, Feary et al (Biotechnology Progress, 2021, 1-12) teaches that instability of gene expression is likely due, in part, to a loss of integrated gene of interest [mAb gene] copies (Table 2). It is further disclosed that some instability is to be expected due the genomic plasticity of CHO cells (see page 9, col. 2, last para. and table 2). Feary further discloses direct repeats of plasmid sequences can result in the formation of DNA loops and dimerization with concomitant loss or gain of genetic material. Additionally, large plasmids have a higher probability of containing potentially unstable regions (see page 10, col. 1, para. 2). Further, Cabera et al (Cell Syst. 2022 Dec 21;13(12):950-973 and references therein) reported transgene silencing, defined as the loss of expression over time, persists as an obstacle for engineering primary cells (abstract). In view of foregoing teaching in art, it is apparent that the stability of expression is not directly dependent to the CHOK1SV doubling time but rather to the genetic and epigenetic robustness of the integration site and selection system. There is no explicit or implicit support for the limitation of stably expressing the gene of interest for at least one generation as recitation of at least is open ended and read on gene of interest expressed indefinitely as discussed in the body of the rejection.
Examiner’s note: Should applicant amend the independent claims by inserting the phrase “stably” in between terms “is” and expressed” and deleting the phrase “stable for at least one generation “, instant rejection may be overcome pending further consideration.
Withdrawn -Double Patenting
Claims 1-3, 5-8, 10, 11, 15, 16, 20, 21, 26, 32, 33, 40, 43-44 and 45 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No.11781116 and Rance et al (WO/2013/190032, 12/27/2013) for the reasons of record. Applicant’s amendments to the claims obviates the basis of the rejection.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kawabe (Cytotechnology 64:267-79 (2012) teaches scFv-Fc producer cells using an accumulative gene integration system.
deVree (Nature Biotechnology, 20014, 32(10), 1019-1025) teaches that targeted locus amplification can be used to uncover insertion sites and sequences of integrated transgenes.
Povey et al (Journal of Biotechnology 184 (2014) 84–93) teach early in the cell line construction process whereby the resulting mass spectrometry data are used to predict the phenotype of mammalian cell lines at larger culture scale using a PartialLeast Squares Discriminant Analysis (PLS-DA) model. Using MALDI-ToF mass spectrometry, a library of mass spectrometry fingerprints was generated for individual cell lines at the 96 deep well plate stage of cell line development.
Lewis et al (nature Biotechnology, 2013, 31, 759-765) teaches value of the hamster genome as the reference upon which CHO cells can be studied and engineered for protein production.
THIS ACTION IS MADE FINAL. 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.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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