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 .
Status of claims
Claims 1-19, 28-33 and 35 as amended and new claims 38-43 as filed on 9/09/2025 are under examination in the instant office action.
Applicant’s election of a single specie A, (drawn to a condition that is manganese concentration from about 1 nM to about 20,000 nM in a high partial pressure of CO2 condition), in the reply filed on 1/10/2025 (response page 9) is acknowledged.
Thus, claims 20-27 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-8, 10-19, 28-33, 35 as amended and new claims 38-43 remain/are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by WO 2017/021493 (Putics et al).
WO 2017/021493 (Putics et al) discloses a method for modulating glycosylation of a glycoprotein or an antibody produced in a cell culture as intended to influence effector function of the antibody (entire document including page 1, lines 26-28; page 26, line 5). The cited method comprises step of modulating manganese concentration within 2000 nM -100000 nM range (page 5, lines 2-3) which overlaps the presently claimed range. In the cited method a partial pressure CO2 (pCO2) is maintained as high as 90 mmHg during cultivation (page 24, line 15). In the cited method the glycoprotein is recombinant antibody (page 11, lines 21-23) including anti-CD20 antibody (page 13, line 10) including ocrelizumab (page 14, line 6). In the cited method the cells culture comprises eukaryotic cells CHO (page 4, line 18). The cited method is practiced in a bioreactor with a volume up to 20,000L (page 25, lines 20-24).
Thus, as applied to the claimed method, the cited method comprises identical step of modulating the same culture conditions (same concentration Mn range and same pCO2) in the same cell culture with CHO cells as intended for modulating glycosylation of a recombinant glycoprotein including ocrelizumab. Therefore, the final effect with regard to modulating afucosylation (lack of fucose) or fucosylation (degree of and distribution of fucose) of recombinant protein including ocrelizumab is reasonably expected to be the same as claimed as result of practicing the same step of modulating same conditions in the same cell culture expressing same recombinant protein of interest.
Thus, the cited disclosure is considered anticipates claims 1-7, 19, 28-33 and 40-43.
As applied to claim 8, alternative limitation ii): percent of GO (agalactosylated glycoprotein), which is same as disclosed term “GOF” (“non-galactosylated”, see page 32, line 26) in the cited document, is 49-56% (page 30, line 15) and falls within the claimed range.
As applied to claims 10-17: in the cited method a basal medium (page 17, lines 10-15) is supplemented with manganese at the concentration range within 2000 nM -100000 nM as predetermined for optimal conditions for production of antibodies (page 5, lines 2-3). The feeding is done by intermittent supplements (page 19, line 10; page 26, line 26). Thus, adding of manganese in the cited method is the same as encompassed by the claims within the broadest reasonable meaning of the claims.
As applied to claim 18: cell culture pH is about 7.15 for a first period (page 6, line 1; page 18, lines 11-13).
As applied to claim 35: in the cited method manganese concentration is selected, predetermined and/or optimized within a targeted range, and, thus, the cited method comprises step of “assaying” Mn in the culture medium within the broadest menaing of the claims. The cited method clearly comprises step of culturing a host cell culture engineered to express glycoprotein as intended. The pattern of glycosylation is modulated as result of practicing improved feeding with a supplement containing manganese (page 37, lines 20-24) within the broadest menaing of the claims.
As applied to claim 39: in the cited method the recombinant proteins of interest include antibody or antibody fragments including Fv fragment including scFV or single chain antibody molecules and diabodies (page 12, lines 16-20).
Thus, the cited document anticipates the claimed method.
Claim Rejections - 35 USC § 103
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.
Claims 1-8, 10-19, 28-33, 35 as amended and new claims 38-43 remain/are rejected under 35 U.S.C. 103 as being unpatentable over by WO 2017/021493 (Putics et al) and US 9,856,502 (Nair et al).
WO 2017/021493 (Putics et al) discloses a method for modulating glycosylation of a glycoprotein or an antibody produced in a cell culture as intended to influence effector function of the antibody (entire document including page 1, lines 26-28; page 26, line 5). The cited method comprises step of modulating manganese concentration within 2000 nM -100000 nM range (page 5, lines 2-3) which overlaps the presently claimed range. In the cited method a partial pressure CO2 (pCO2) is maintained is high as 90 mmHg during cultivation (page 24, line 15).
The cited WO 2017/021493 (Putics et al) teaches and concludes that feeding a glycoprotein-producing recombinant cell culture with manganese supplementation optimized glycosylation and provided for increase of galactosylation (page 37, lines 20-24) which is decrease of agalactosylation.
But the cited document WO 2017/021493 (Putics et al) does not recognize an optimized glycosylation such as afucosylation.
However, US 9,856,502 (Nair et al) teaches that modulating manganese concentration in a glycoprotein-producing recombinant cell culture provides for reduction of fucosylation (see abstract). Afucosylation was caused by addition of manganese at concentration more than 5 mM (col. 14, lines 59-62); and a gradual increase of afucosylation levels was observed with increase of manganese concentration (col. 15, lines 60-62).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to modulate glycosylation including both decreased agalactosylation and increased afucosylation by modulating manganese concentration in a recombinant glycoprotein-producing cell culture with a reasonable expectation of success in achieving a targeted glycosylation because prior art teaches that feeding a glycoprotein-producing recombinant cell culture with manganese supplementation provides for increase of galactosylation (WO 2017/021493 (Putics et al) ) and that afucosylation is also caused by addition of manganese supplementation (US 9,856,502 (Nair et al)).
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Response to Arguments
Applicant's arguments filed on 9/09/2025 have been fully considered but they are not all found persuasive.
The rejection of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, has been withdrawn in view of claim amendment and applicants’ arguments.
With regard to claim rejection under 35 U.S.C. 102 (a) (1) as being anticipated by WO 2017/021493 (Putics et al) applicant main argument that the cited document states at page 8-9 that the method results in a reduction of afucosylated glycoprotein, and, thus, it teaches away and/or the cited disclosure cannot be anticipatory.
This argument is not found persuasive because the disclosure WO 2017/021493 (Putics et al) is drawn to galactose contents, determination of galactose contents and decrease of non-galactosylated (agalactosylated) isoforms. The cited document is silent about fucosylation (degree of fucose distribution) and/or afucosylation (lack of fucose).
As applied to the claimed method, the cited method comprises identical step of “modulating” the same culture conditions (same concentration Mn range and same pCO2) in the same cell culture with CHO cells as intended for modulating glycosylation of a recombinant glycoprotein including ocrelizumab. Therefore, the final effect with regard to modulating afucosylation (lack of fucose) or fucosylation (degree of and distribution of fucose) of recombinant protein including ocrelizumab is reasonably expected to be the same as claimed as result of practicing the same step of “modulating” same conditions in the same cell culture expressing same recombinant protein of interest.
With regard to claim rejection under 35 U.S.C. 103 as being unpatentable over by WO 2017/021493 (Putics et al) and US 9,856,502 (Nair et al) Applicants argue that the teaching of cited references cannot be combined as to suggest and/or to motivate a skilled artisan to arrive at the claimed invention.
This argument is not found persuasive. Although the cited document WO 2017/021493 (Putics et al) does not explicitly recognize an optimized glycosylation such as afucosylation as result of modulating manganese concentration, the cited US 9,856,502 (Nair et al) teaches that modulating manganese concentration in a glycoprotein-producing recombinant cell culture provides for reduction of fucosylation (see abstract). In particular, the cited US 9,856,502 (Nair et al) discloses that addition of manganese at concentration more than 5 mM (col. 14, lines 59-62) provides for a gradual increase of afucosylation levels with increase of manganese concentration (col. 15, lines 60-62).
With respect to the claimed method it is noted that step of “modulating” culture conditions, including modulating manganese concentration, does not indicate whether modulation refers to increase or to decrease of manganese concentration. Moreover, in the claimed invention the same step of modulating manganese concentration leads to increased afucosylation of proteins (claim 1) including ocrelizumab (claim 7) and also to increased fucosylation of ocrelizumab (claim 40), thereby, to different effects.
No claims are allowed.
Conclusion
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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Vera Afremova
January 7, 2026
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653