DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 19 August 2025 have been entered. Claims 2-16 were previously pending in the application. No claims have been cancelled and no new claims have been added by Applicant. Claims 2-16 are currently pending in the application. Claim 2 is an independent claim.
The following election of species remains in effect in the instant application: B4galt2 is additionally inactivated. Claims 5-13 remain withdrawn from consideration as being directed to a nonelected species.
Claims 2-4 and 14-16 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a DIV of U.S. Application No. 15/534,735, filed 09 June 2017, now U.S. Patent No. 10,858,671, which is a 371 pf PCT/DK2015/050391, filed 11 December 2015, claims priority to U.S. Provisional Application Nos. 62/091,056, filed 12 December 2014, and 62/193,403, filed 16 July 2015.
Thus, the earliest possible priority for the instant application is 12 December 2014.
Specification
The objection to the specification of the disclosure for:
the Brief Description of the Drawings does not recite a description of each panel of every figure;
the use of the term “biostynthic” in the specification page 26 line 27; and
the use of the term “RNeasy” and “Amaxa”, which are a trade name or a mark used in commerce;
is withdrawn in view of the amendment to the specification adding specific descriptions of Figure 13 panel A4 and Figure 18 panels A and B, correcting the spelling of biosynthetic, and adding appropriate marks to “RNeasy” and “Amaxa”.
Claim Objections
The objection to amended and previously presented claims 2-4 and 14-16 for reciting recite abbreviations without first writing out the terms for which the abbreviations stand, is withdrawn over amended and previously presented claims 2-4 and 15-16 and maintained over amended claim 14 in view of the amendments to claims 2-4, 14, and 16 writing out the terms for which the abbreviations stand. Although claim 14 writes out the terms for CHO, HEK293, and HUVEC, the term for HKB has not been written out. Appropriate correction is required.
Amended claim 2 is newly objected to because of the following informalities: amended independent claim 2 recites “beta-1,4-galactosyltransferase 1 (B4galt3)”, which appears to be a typographical misspelling of “beta-1,4-galactosyltransferase 3 (B4galt3)”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The rejection of amended and previously presented claims 2-4 and 14-16 under 35 U.S.C. 103 as being unpatentable over Lin et al. (WO2015/134488A1: Priority to 03/04/2014), in view of Rossomando et al. (WO2013013013A2) and Lo et al. 1998, Glycobiology, 8(5), 577-526, is maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended the claims to write-out the abbreviated terms, but has not altered the scope of the claims. Therefore, Applicants amendments do not overcome a finding of obviousness.
Applicant argues that the specific combination of deactivation of B4galt1 and B4galt3 is surprising and unpredictable in causing a nearly complete loss of galactosylation of N-glycans, such as presented in Figures 1D, 10, 17, and 21 as well as Figure 36, compared to Figure 22, of the instant Application. However, this is not agreed.
Note that Figure 1D shows glycoprofiling peaks for a zinc finger nuclease (ZFN) knockout (KO) screen in CHO cells using human EPO as a reporter in WT, single B4galt(1-4) KO, double B4galt1/2 KO, and double B4galt1/3 KO cells, which shows substantial loss of galactosylation in single KO for B4galt1, with lower levels of galactosylation loss for single KOs of B4galt2 and B4galt3. Additionally, Figure 1D shows increased loss of galactosylation for the B4galt1/2 KO compared to B4galt1 alone, with a nearly complete loss of galactosylation in the B4galt1/3 KO.
Figure 10 shows glycoprofiling of EPO produced in CHO-GS WT cells and mutant cells which do not comprise any B4galt inactivations.
Figure 17 shows glycoprofiling with KO of B4galt1/2/3/4 genes showing that B4galt1 KO produced substantial partial loss of galactosylation, that each of B4galt2 and Bgalt3 single KOs showed low levels of galactosylation loss, that B4galt1/2 double KO produced increased galactosylation loss compared to either single (-1 or -2) KO, that B4galt1/3 produced nearly complete loss of galactosylation, and that B4galt1/2/3 triple KO results in essentially complete loss of galactosylation. Page 78 of the specification indicates that Figure 17 presents data for CHO-GS cells using EPO as a reporter molecule [lines 24-30].
Figure 21A shows immunofluorescence cytology with a monoclonal antibody to LacNAc, where WT, single B4galt1-4 KOs, double Brgalt1/2 KO, and triple B4galt1/2/4 KO all show cells with stronger staining compared to the B4galt1/3 panel. The description for Figure 21 does not indicate the cell line nor the target.
Figure 22 shows glycoprofiling peaks of IgG produced in CHO wildtype (WT), B4galt1 knockout (KO), fut8 KO, and B4galt1/fut8 double KO, which shows essentially complete loss of the galactosylation for the indicated target with each of the B4galt1 KO and the B4galt1/fut8 double KO cells.
Additionally, Figure 36 further shows glycoprofiling peaks of IgG produced in CHO Mgat2 KO, St3gal4/6 KO, and cosmc/B4galt1/B4galt3/fut8 quadruple KO, which shows essentially complete loss of the galactosylation for the indicated target with cosmc/B4galt1/B4galt3/fut8 quadruple KO cells.
Therefore, as presented in the instant specification, the extent of loss of galactosylation with deletion of B4galt genes varies with the specific cell type and target assessed. Whereas loss of galactosylation of EPO in CHO cells or CHO-GS cells was maximal with a double mutation of B4galt1/3 KO (Figure 1D), complete loss of galactosylation of an IgG in CHO cells was achieved with the single KO of B4galt1 (Figure 22).
It is noted that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
The scope of the claims as written is not commensurate with the data presented as evidence of unexpected results in that independent claim 1 recites a mammalian cell wherein the galactosylation genes B4galt1 and B4galt3 are inactivated in the cell. Therefore, the claims as written and elected are distinct from the evidence used to support the assertion of surprising and unexpected results in that the evidence as presented includes the KO of B4galt1 alone or the double KO of B4galt1 and B4galt3 only in CHO cells or CHO-GS cells and only for EPO and a single IgG target. Note that the evidence as presented actually shows a complete loss of galactosylation with just the deletion of B4galt1 in the absence of further inactivation of B4galt3 for the IgG target in CHO cells (Figure 22).
Lin teaches that galactosyltransferases, such as B4galT1/2/3/4/5/6/7, add a galactose residue in a beta 1,4 linkage to a GlcNAc residue of an N-linked glycan [0035]. Lin also teaches cell lines in which all copies of at least one of the galactosyltransferase genes are inactivated [0035].
Additionally, Lo teaches that B4galT1 and B4galt3 are highly expressed in a wide range of human tissue types, whereas B4galt5 is lowly expressed in a wide range of human tissue types, and B4galt2, B4galt4, and B4galt6 are only expressed in a few human tissue types tested, which Lo teaches is consistent with observations in mice [column 12 ¶ 3-4, Figure 6]. Therefore, an ordinarily skilled artisan would expect that the degree of loss of galactosylation from combinations of B4galt genes would depend on the cell type used, and the corresponding expression levels of the B4galt genes within the utilized cell types in the absence of B4galt gene inactivation. Further, given that B4galt1 and B4galt3 are the highest expressing B4galt variants, and that they are the 2 most ubiquitously expressed B4galt variants, an ordinarily skilled artisan at the time of filing the instant application would have expected that inactivation of both B4galt1 and B4galt3 would result in nearly complete loss of galactosylation in mammalian cell lines with a reasonable expectation of success.
As such, Applicant’s arguments do not overcome a finding of obvious under 35 U.S.C. 103 over Lin, Rossomando, and Lo, and the rejection of record is maintained.
Double Patenting
The provisional rejection of amended and previously presented claims 2-4 and 14-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 19, 21-23, and 67-68 of copending Application No. 16/300,196, hereafter referred to as the ‘196 application, is maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended the claims to write-out the abbreviated terms, but has not altered the scope of the claims. Therefore, Applicants amendments do not overcome the provisional rejection on the ground of nonstatutory double patenting over the ‘196 application.
Applicant has not provided any arguments traversing the rejection, and as such, Applicant’s arguments have not been found persuasive in overcoming the provisional rejection on the ground of nonstatutory double patenting over the ‘196 application.
Applicant has not filed a terminal disclaimer, and as such has not overcome the provisional rejection on the ground of nonstatutory double patenting over the ‘196 application in view of any terminal disclaimer.
Accordingly, the provisional rejection on the ground of nonstatutory double patenting over the ‘196 application is maintained.
Conclusion
No claim is 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 Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634