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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 26 September 2025.
APPLICANT’S ELECTION
Applicants’ election without traverse of Group I (Claims 1-13; drawn to a method for treatment of a cell culture medium) in the reply filed on 26 September 2025 is acknowledged. Claims 14-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
CLAIMS UNDER EXAMINATION
Claims 1-18 are pending. Claims 1-13 have been examined on their merits.
PRIORITY
Provisional Application 63/010,536, filed on 15 April 2020, is acknowledged.
REJECTIONS:
Claim Rejections - 35 USC § 112
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.
Claim 8 is rejected 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 claims contain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 8 recites the cysteine derivative is “L-cysteine mixed disulphides or various peptides”. The specification lacks written description because it does not provide guidance to determine all of the possible various peptides that would provide the claimed effect.
A consideration of the four corners of the specification does not reflect that applicants have actually invented the claimed invention, since the specification does not permit the skilled artisan to visualize or recognize all of the members of the genus being utilized in the claimed method.
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.
Claims 1-4, 6, 8-10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Nishiuch et al. (cited in IDS; Cytotoxicity Of Cysteine IN Culture Media. In Vitro. Volume 12(9) 1976: 635-638) in view of Ritacco et al. (Cell culture Media for Recombinant Protein Expression in Chinese Hamster Ovary (CHO) Cells: History, Key Components, and Optimization Strategies. Biotechnol Prog., 2018, Vol. 34 (6) pages 1407-1426).
Nishiuch et al. teach 1 mM cysteine is highly toxic to cultured mammalian (eukaryotic) cells (Abstract; page 636, left column, last paragraph). This toxicity was eliminated completely by preincubation of the media at 37°C for 24 hours before use (Abstract; page 637, left column first paragraph). Media containing cysteine was incubated at 37°C without cells (page 637, left column, third paragraph). Said temperature is interpreted to be a condition suitable for inoculation. The art teaches media is in a tube (vessel) (page 636, left column, second paragraph).
The art is silent regarding the presence of one or more redox trace metals in media.
Ritacco teaches most cell culture media contain non-essential amino acids, including cysteine (page 1411, right column, 6th paragraph). The art teaches cysteine is a special nonessential amino acid in monoclonal antibody production The formation of disulfide bridges between sulfhydryl groups on cysteine residues supports the folding of tertiary and quaternary structure of both CHO cell structural proteins and recombinant antibody product (page 1412, left column, fourth paragraph). A drop in cysteine can result in loss of titer in monoclonal antibody product (same cited section).
Ritacco teaches trace metal elements play critical roles in the regulation of metabolic pathways (page 1413, right column, first paragraph). The art teaches iron is widely recognized as a necessary component in chemical defined media (page 1413, right column, third paragraph). In CHO cell culture media, iron impacts glycosylation microheterogeneity of product (Table 2). Manganese, molybdenum, selenium and vanadium are known to be required for cell culture, and are included in most media (page 1413, right column)]. In CHO cell culture media, these metals increase production of active substances, improve galactosylation, enhance cell growth and protect cells from oxidative stress (see Table 2).
Table 1 discloses media that contains cysteine copper and iron (F12 and DMEM/F12 media).
It would have been obvious to use a redox active trace metal in a media used to grow mammalian cells. Nishiuch cultures mammalian cells and Ritacco teaches trace metals are known to be required for cell culture. One would have been motivated to use trace metals in a media used to culture cells that express recombinant proteins since Ritacco teaches trace metals improves cell growth, increases production and protects cells. One would have had a reasonable expectation of success since Ritacco teaches cysteine and trace metals can be used together in a media. Therefore claim 1 is rendered obvious.
Nishiuch teaches MEM-10BS media is supplemented with SH compounds by adding concentrated solutions of the compounds to the media immediately before use (see page 636, left column, second paragraph). The media is incubated without cells for 24 hours before use (page 637, left column, first sentence). Therefore the art is interpreted to teach addition in the vessel, when the vessel is under conditions suitable for inoculation. It would have been obvious to add the trace elements taught by Ritacco at the same time. One would do so to prepare the media for subsequent inoculation with cells after holding the media for 24 hours. The MPEP teaches selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (See 2144.04). Therefore claim 2 is rendered obvious.
Nishiuch teaches 1mM cysteine in a culture media held for 24 hours before inoculation (supra). Therefore claim 3 is included in this rejection.
The MPEP teaches selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (See 2144.04). Therefore claim 4 is rendered obvious.
The specification states “a “bioreactor” is an in vitro culture system that has been designed to initiate, maintain and direct cell growth in a well-defined and tightly controlled culture environment ([0145]). The vessels taught by the prior art are interpreted to be a bioreactor. Claim 6 is included in this rejection.
Ritacco teaches iron is used at 10-110 µm (Table 2).
Ritacco teaches S-sulfocysteine is a replacement cysteine source and antioxidant in CHO cell culture media (page 1412, right column, fourth paragraph). Therefore claim 8 is included in this rejection.
Nishiuch teaches 1mM cysteine in a culture media held for 24 hours (supra). Therefore claim 9 is included in this rejection.
Ritacco teaches trace metal include iron, manganese, molybdenum, selenium and vanadium (supra). Therefore claim 10 is included in this rejection.
Nishiuch cultures mammalian cells (supra). Therefore claim 13 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Nishiuch in view of Ritacco as applied to claim 10 above, and further in view of Hunter's Trace Elements (from Hunter et al., Proc. Am. Philos. Soc. 94: 152-170 (1950); document created 2015).
Claim 10 is rejected on the grounds set forth above. The teachings of the prior art are reiterated.
Ritacco teaches trace metals are used to culture cells. The art teaches 10-110 µm iron, 0.001-0.1 µm molybdenum, 0.4-40 µm manganese and 0.8-100 µm copper (see Table 2). The art does not explicitly teach the trace elements are provided as a solution. The specification does not define the term “about”. Therefore the concentration taught by the art is interpreted to read on the claim limitation.
Hunter teaches a composition comprising trace elements. The composition is a solution. The composition contains copper, iron, molybdenum and manganese.
It would have been obvious to prepare the trace elements taught by Ritacco as a solution. Ritacco teaches trace metals and Hunter teaches trace metals are prepared as a solution. The skilled artisan would use a trace element solution when adding it to a liquid culture medium. One would have had a reasonable expectation of success since Hunter teaches trace metals can be prepared in a solution. One would have expected similar results since both references are directed to trace elements. Therefore claim 11 is rendered obvious as claimed.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Nishiuch in view of Ritacco as applied to claim 1 above, and further in view of Place et al. (Limitations of oxygen delivery to cells in culture: An underappreciated problem in basic and translational research. Free Radic Biol Med. 2017 Dec;113:311-322).
Claim 1 is rejected on the grounds set forth above. The teachings of the prior art are reiterated.
Nishiuch teaches a pH of 6.8-7.0 (see page 636, left column, first paragraph). The art teaches a temperature of 37°C (supra). The art is silent regarding the % oxygen.
Place teaches the gaseous oxygen percentage that occupies the atmosphere of a typical cell culture incubator is 18.6% oxygen (see page 5, first paragraph).
It would have been obvious to use 18.6% oxygen. One would have been motivated to do so since Nishiuch cultures cells and Place teaches 18.6% oxygen is used for cell culture. One would have had a reasonable expectation of success since Place teaches 18.6% can be used for cell culture. One would have expected similar results since both references are directed to cell culture. Therefore claim 12 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653