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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/09/2026 has been entered.
Status of claims
Claims 1-8, 10-33, 35 and 38-43 as amended on 7/09/2026 are currently pending.
Applicant’s election of a single species A or a (drawn to a condition that is manganese concentration range about 1 nM-200nM (as originally recited in the claims) including about 1nM-1000 nM (as presently amended) in a high partial pressure of CO2 condition), in the reply filed on 1/10/2025 (response page 9) has been acknowledged.
Thus, claims 20-27, as whole, were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species (b through i) and the subject matter of generic claims 1, 32, 33 and 35 as drawn to non-elected species (b through i) was withdrawn from further consideration pursuant to 37 CFR 1.142(b).
Claims 1-8, 10-19, 28-33, 35 and 38-43 as amended on 7/09/2026 are under examination in the instant office action (as drawn to the elected species A).
Claim Rejections - 35 USC § 112
Indefinite
Claims 1-8, 10-19, 28-33, 35 and 38-43 as amended are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rendered indefinite by the newly inserted phrase “supplementing” in the context of the claim which has only one active step of “modulating one or more…parameters”. It is uncertain whether phrase “supplementing” is intended as another active step of adding additional manganese to a common culture medium or whether concentration 1-1000nM is a final manganese concentration in the cell culture medium. If the recited concentration range is final, then, it is unclear what is “modulating”.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: a relationship between “modulating” and “supplementing”.
Claim 10 recites the limitation "the modulation of the Mn concentration” in the method of clam 1. There is insufficient antecedent basis for this limitation in the claims because claim 1 (elected species or parameter a), does not recite “modulation of the Mn” but “supplementing” with Mn which is uncertain as explained above. The recited concept about “selecting raw materials” to modulate Mn concentration is unclear. Besides, modulating is a broader concept/limitation than “supplementing” with 1-1000nm Mn as recited in claim 1. “Modulating” does not have a concentration range and is an unlimited “broad” range for any changes. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim 11 recites the limitation "the modulation of the Mn concentration” in the method of clam 1. There is insufficient antecedent basis for this limitation in the claim. Further, claim 11 is unclear about “leached Mn” in the lack of definitions.
Claim 12 is also uncertain about concept/limitation “leached Mn” because (i) a generic filter is not a source of Mn, (ii) “a medium preparation” is not a source of Mn at the very least as claimed. Neither “hold” or “a culture vessel” might be reasonably considered as a source of Mn.
Claim 13 recites the limitation "the culture medium” in the method of claim 1. There is insufficient antecedent basis for this limitation in the claim 1 which solely recites “a cell culture” or “the cell culture” but not “a culture medium”. A cell culture and a cell culture medium are different entities. A medium comprises nutrients intended for a cell culture. A cell culture comprises cells and not necessarily a medium with nutrients.
Claim 14 recites the limitation "the culture medium” in the method of claim 1. There is insufficient antecedent basis for this limitation in the claim 1 which solely recites “a cell culture” or “the cell culture” but not “a culture medium”.
Claim 14 also recites the limitation drawn to “a production stage” in claim 1. There is insufficient antecedent basis for this limitation in the claim 1 which does not recite “culturing” cells as intended for production.
Claim 15 recites the limitation "the culture medium” in the method of claim 1. There is insufficient antecedent basis for this limitation in the claim 1 which solely recites “a cell culture” or “the cell culture” but not “a culture medium”.
Claim 17 recites the limitation "the culture medium” in the method of claim 1. There is insufficient antecedent basis for this limitation in the claim 1 which solely recites “a cell culture” or “the cell culture” but not “a culture medium”.
Claim 18 recites the limitation "the modulation of the Mn concentration” in the method of clam 1. There is insufficient antecedent basis for this limitation in the claims because claim 1 does not recite “modulation” but “supplementing” with which is uncertain as explained above. Further, relationship between steps of “modulation” Mn and employing pH of 6.1-7.3 is unclear, particularly in view that the recited pH range is a common pH for mammalian cell culture. A structural relationship between “modulation” Mn and using common pH is unclear.
Further, claim 18 recites limitation drawn to treatment HTST. There is insufficient antecedent basis for this limitation in the claims.
Claim 19 recites the limitation drawn to harvesting glycoprotein at 5-20 days of cell culture. There is insufficient antecedent basis for this limitation in the claim 1 which does not recite “culturing” cells as intended for production and harvest. Claim 1 contains one step of “modulating” one parameter.
Claim 31 recites limitation “the volume” for the cell culture of method of claim 1. There is insufficient antecedent basis for this limitation in the claims because there is no “a volume” in the claims neither for a cell culture nor for a medium nor for a cell vessel, if any are/would be employed.
Claim 32 is directed to a method of making a product that is a cell culture medium with Mn 1-1000 nM. However, the only active step in a method of making this product is a step of “modulating”. It is unclear what is “modulating” in the method for making a culture medium with Mn 1-1000 nM since the method of making must result in a final product with a final structure and contents.
Claim 32 is rendered indefinite by its “wherein “ clauses encompassing “glycosylation” of a protein of interest which would require a culturing of a cell culture producing a protein of interest. However, claim 32 is directed to a method of making a medium but not a method of producing a protein. Claim 32 does not recite cells for making a cell culture medium. Even if this limitation is an intended effect, the langue of the claim is confusing and raises to a doubt.
Claim 33 is indefinite because it is directed to a product which is “modulated” (claim 33, line 3). The product must have final structure and contents which appear to be intended as: 1) a cell expressing a protein, and 2) a medium with MN 1-1000 nM as recited in the claim. Thus, it is unclear what is “modulated” in a final product.
Claim 35 is rendered indefinite by reciting 0% of afucosylation level in a method for afucosylation of protein because method resulting in zero effects has no result/effect towards which it is intended. The language of the claim raises to a doubt what is practiced.
Claim 41 recites the limitation "said culture medium” in the method of claim 40. There is insufficient antecedent basis for this limitation in the claims because claim 40 solely recites “a cell culture” or “said cell culture” but “a culture medium”.
Claim 42 recites the limitation "said medium” in the method of claim 40. There is insufficient antecedent basis for this limitation in the claims because claim 40 solely recites “a cell culture” or “said cell culture” but “a medium”.
Clams 41 and 42 are unclear with regard to “medium hold” in the lack of definitions about what is “medium hold”.
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 1-6, 8, 13-19, 28-31 and 35-39 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by US 2017/0362625 (Leiske et al).
The cited document US 2017/0362625 (Leiske et al) teaches a method for manipulating fucosylated glycan content in a cell culture expressing the glycoprotein, wherein the method comprises step of culturing the cell culture in a medium with manganese(Mn) in concentration 50-1000 nM manganese and pH about 7, and step harvesting the glycoprotein, wherein the level of afucosylated glycan increases (par. 0009, 0075). The cited document US 2017/0362625 (Leiske et al) teaches that Mn had a significant impact on the afucosylation level (0157), that the level of afucosylated glycan increases by 1.3% over the base value (0158). The cited method provides for about 4.5-6.6 % of afucosylated glycoprotein (table 2). The modulation of level of pCO2 is monitored (0149); and it would be “high” within the broadest meaning of the claims or no specific meaning. (Notes: in view of specification high and low pCO2 ranges are overlapping, see published application par. 0036-0037). In the cited method of US 2017/0362625 (Leiske et al) the glycoprotein is a recombinant protein such as antibody including chimeric, humanized or human antibody (par. 0024) including anti-CD-20 antibody (0143) including various known antibodies (par. 0143 at col.11). The glycoprotein is harvested upon 17 days (0148). The cell culture is CHO cells (0022). The cell culture is in a bioreactor or chamber of about 3L (0147).
Thus, the cited document US 2017/0362625 (Leiske et al) anticipates claims 1-6, 8, 13-19, 28-31, 35-39.
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 and 38-43 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0362625 (Leiske et al) in view of WO 2017/021493 (Putics et al).
The cited document US 2017/0362625 (Leiske et al) is relied upon as explained above for the teaching of a method for manipulating fucosylated glycan content in a cell culture expressing the glycoprotein, wherein the method comprises step of culturing the cell culture in a medium with manganese(Mn) in concentration 50-1000 nM manganese and pH about 7, and step harvesting the glycoprotein, wherein the level of afucosylated glycan increases (par. 0009, 0075). In the cited method the modulation of pCO2 level is monitored (0149); and it would be “high” within the broadest meaning of the claims. But the document is silent about specific value of pCO2.
However, the cited WO 2017/021493 (Putics et al) teaches a method for manipulating glycosylation of glycoprotein in a cell culture CHO expressing the glycoprotein, wherein the method comprises step of culturing the cell culture in a medium with manganese (Mn), while monitoring a common for mammalian cell culture level of carbon dioxide within the range for pCO2 being as high as 90mmHg (entire document including page 24, line 14-15).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to monitor a common for mammalian cell culture or CHO cell culture level of carbon dioxide up to 90mmHg disclosed by Putics in the method of US 2017/0362625 (Leiske et al) with a reasonable expectation of success in manipulating glycosylation of glycoprotein in mammalian cell culture or CHO because this range is commonly established in the prior art for optimized and growth and glycoprotein production by mammalian cells including CHO cells. 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.
Further, with regard to claims 7 and 38, In the cited method of US 2017/0362625 (Leiske et al) the glycoprotein is a recombinant protein such as antibody including chimeric, humanized or human antibody (par. 0024) including anti-CD-20 antibody (0143) including rituximab (par. 0143 at col.11) produced by mammalian cell culture including CHO. But it is silent about production of anti-CD-20 antibody ocrelizumab. However, the cited WO 2017/021493 (Putics et al) teaches a method for manipulating glycosylation of glycoprotein in a cell culture CHO expressing the glycoprotein, wherein the glycoproteins includes anti-CD-20 antibody including rituximab and ocrelizumab (page 14, lines 6 and 18).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to produce glycoproteins or anti-CD-20 antibody ocrelizumab by the method of US 2017/0362625 (Leiske et al) with a reasonable expectation of success in producing and manipulating glycosylation of glycoprotein in mammalian cell culture or CHO because the mammalian cell culture including CHO has been known and used in the prior art for producing glycoproteins including various anti-CD-20 antibodies including rituximab and ocrelizumab as taught by Putics 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 7/09/2026 with respect to the claims as amended on 7/09/2026 have been considered but are moot because of new grounds of rejections.
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Vera Afremova
September 15, 2026
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653
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