DETAILED ACTION
Claims 1-10, 13-15, 22-24, 30-31, and 33 are pending.
Election/Restrictions
Applicant’s election without traverse of group I, claims 1-10, 13-15, and 22-24 in the reply filed on 02/05/2026 is acknowledged.
Claims 30-31 and 33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/05/2026.
Claims 1-10, 13-15, and 22-24 are under examination.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 01/24/2024, 07/16/2024, and 04/01/2025 have been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
1.Claim 13 is 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 13 depends on a cancelled claim. Claim 13 recites “The method of claim 12”, however, claim 12 has been cancelled. Therefore, the limitations of the claims are unknown.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
2.Claims 1-4, 14-15, and 22-24 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Eisenkraetzer et al., (US20180216059A1) (IDS filed on 01/24/2024).
Regarding claim 1, Eisenkraetzer teaches a method of adjusting the pH of a cell culture medium (see [0004] “In case the pH value is outside a desired pH-value range, various parameters of the bioreactors (such as feed rate, aeration rate, temperature, stirring rate or the like) may be adapted to change the state of the bioreactor in a way that the measured pH value in the medium lies within the desired pH value range”), comprising:
obtaining, for the cell culture medium, a functional relationship between a concentration of dissolved carbon dioxide in the cell culture medium and a mole fraction of gaseous carbon dioxide applied to the cell culture medium, and a concentration of net medium acids in the cell culture medium (see [0029] “The concentration of carbon dioxide that is dissolved in a liquid is proportional to carbon dioxide partial pressure (pCO2) in the gas phase and can be calculated using respective proportional factors. Proportional factors depend on the liquid and temperature as well as pressure.”, see [0039] “Ratio of all species carbon dioxide (H2CO3*), bicarbonate HCO3 − and carbonate CO3 2− can be calculated”, see [0050] “pH is then computed according to pH=−log(1.01479E-06)=5.99.”, see [0056] “The medium-specific relation is specific for the medium M1 of the first tank and indicates a relation between the pH value of the medium M1 and a respective fraction of CO2 gas in a gas volume when said medium is in pH-CO2 equilibrium state with said gas volume and lacks a cell culture.”. Eisenkraetzer’s method of calculating the ratios meet the claimed functional relationship.);
adding carbonate salt or bicarbonate salt to the cell culture medium to obtain a desired carbonate salt or bicarbonate salt concentration in the cell culture medium (see [0065] “the medium may be a bicarbonate buffer that is free of any other substances (except the bicarbonate) which have an impact on the pH-CO2 equilibrium.”, see [0302] “Ham's F-12K (Kaighn's) Medium uses a sodium bicarbonate buffer system (2.5 g/L).”); and
determining, using a charge balance model, an amount of strong acid or strong base to be added to the cell culture medium to adjust the pH of the cell culture medium to a desired pH, wherein the charge balance model is based on at least the functional relationship between the concentration of dissolved carbon dioxide in the cell culture medium and the mole fraction of gaseous carbon dioxide applied to the cell culture medium, the concentration of net medium acids in the cell culture medium, the desired carbonate salt or bicarbonate salt concentration in the cell culture medium, and the desired pH (The desired pH is the functional relationship between the concentration of dissolved carbon dioxide applied to the cell culture medium. see [0039] – [0040] “Ratio of all species carbon dioxide (H2CO3*), bicarbonate HCO3- and carbonate CO32- can be calculated… KS1= [H+] [HCO3-]/[H2CO3]”, see [0050] “pH is then computed according to pH=−log(1.01479E-06)=5.99.”, see [0051] – [0055] “The CO2 concentration in the gas phase can be computed based on bicarbonate concentration and pH…First, the amount of CO2 dissolved in water (aq) under normal atmosphere of pressure is computed…After having determined [CO2(aq)] (equation 10) and Ks1 (equation 5)…the formula…equation 11…Can be resolved for computing the pH value”, see [0301] “the control unit 132 may be operable to increase or decrease the influx of liquids having an impact on the pH value, e.g. may increase or decrease the influx of a citric acid or of a 1M NaOH solution and/or may increase or decrease CO2 gas influx for modifying the pH value in the medium of a bioreactor.”, thus the model calculations of Eisenkraetzer meets the charge balance model limitation).
Regarding claim 2, Eisenkraetzer teaches adding the determined amount of strong acid or strong base to the cell culture medium, thereby making a pH-adjusted cell culture medium (see [0301] “the control unit 132 may be operable to increase or decrease the influx of liquids having an impact on the pH value, e.g. may increase or decrease the influx of a citric acid or of a 1M NaOH solution and/or may increase or decrease CO2 gas influx for modifying the pH value in the medium of a bioreactor.”).
Regarding claim 3, Eisenkraetzer teaches the carbonate salt or the bicarbonate salt is sodium carbonate or sodium bicarbonate (see [0302] “Ham's F-12K (Kaighn's) Medium uses a sodium bicarbonate buffer system (2.5 g/L).”).
Regarding claim 4, Eisenkraetzer teaches supplementing the cell culture medium with one or more ionic compounds (see [0065] “For example, the medium may be a bicarbonate buffer that is free of any other substances (except the bicarbonate) which have an impact on the pH-CO2 equilibrium. “), wherein the charge balance model is further based on the concentration of the one or more ionic compounds (see [0039] – [0040] “Ratio of all species carbon dioxide (H2CO3*), bicarbonate HCO3- and carbonate CO32- can be calculated… KS1= [H+] [HCO3-]/[H2CO3]”, see [0050] “pH is then computed according to pH=−log(1.01479E-06)=5.99.”, see [0051] – [0055] “The CO2 concentration in the gas phase can be computed based on bicarbonate concentration and pH…First, the amount of CO2 dissolved in water (aq) under normal atmosphere of pressure is computed…After having determined [CO2(aq)] (equation 10) and Ks1 (equation 5)…the formula…equation 11…Can be resolved for computing the pH value”, see [0301] “the control unit 132 may be operable to increase or decrease the influx of liquids having an impact on the pH value, e.g. may increase or decrease the influx of a citric acid or of a 1M NaOH solution and/or may increase or decrease CO2 gas influx for modifying the pH value in the medium of a bioreactor.”).
Regarding claim 14, Eisenkraetzer teaches wherein the concentration of net medium acids in the cell culture medium is modeled in the charge balance model as a function of temperature (see claim 1 of Eisenkraetzer).
Regarding claim 15, Eisenkraetzer teaches wherein the concentration of net medium acids in the cell culture medium is modeled in the charge balance model as a function of pH and temperature (see claim 1 of Eisenkraetzer).
Regarding claim 22, Eisenkraetzer teaches adjusting the pH of a cell culture medium according to the method of claim 1 (see [0193] “The parameters are obtained e.g. by manually, automatically or semi-automatically performing the following steps: adjusting samples of the medium M1 lacking the cell culture to multiple different pH values, thereby letting the samples reach pH-CO2 equilibrium with the gas volume above the medium in the respective sample…”, see [0200]), and
culturing cells in the pH-adjusted cell culture medium (see [0004], see claim 10 of Eisenkraetzer).
Regarding claim 23, Eisenkraetzer teaches wherein the cells are mammalian cells (see [0208] “According to embodiments, the cells of the cell cultures are prokaryotic or eukaryotic cells, in particular mammalian cell culture cells.”).
Regarding claim 24, Eisenkraetzer teaches wherein cells are Chinese hamster ovary (CHO) cells (see [0329] “the project could be to grow CHO cells (Chinese hamster ovary cells) over 14 days in the cell culture medium M1 under optimal or nearly optimal cell growth conditions until a cell density of about 100×105 cells/milliliter is reached.”).
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.
3.Claims 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Eisenkraetzer et al., as applied to claims 1-4, 14-15, and 22-24 above, and in view of Rossler et al., "Temperature: A simple parameter for process optimization in fed-batch cultures of recombinant Chinse hamster ovary cells". Enzyme and Microbial Technology Vol. 18, Issue 6, pages 423-427. 1996. https://doi.org/10.1016/0141-0229(95)00121-2.
The teachings of Eisenkraetzer as applied to claims 1-4, 14-15, and 22-24 are discussed in the 35 UCS 102 rejection above.
Eisenkraetzer does not teach the use of amino acids, sodium hydroxide, or hydrochloric acid.
Regarding claims 5-6, Rossler teaches the ionic compound comprising one or more ammino acids and wherein the amino acids comprise glutamine, asparagine, or glutamic acid (see page 424 “Amino acids were derived with o-phthalaldehyde (OPA) and analyzed by high-performance liquid chromatography (HPLC).”, see page 425 “It is well known that glutamine is a major energy source for CHO cells9 and that the built-up ammonia can reduce or stop growth. Ammonia, which is produced predominantly from glutamine by glutaminase activity”, see page 427 “Because it is also known that aspargine could be used instead of glutamine, this is another possible way.”).
Regarding claims 7-8, Rossler teaches the strong base being sodium chloride and the strong acid being hydrochloric acid (see page 424 “The dissolved oxygen tension of the medium was controlled at 50% saturation with 02 and the pH was maintained at 7.2 by hydrochloric acid and the addition of sodium hydroxide using the system control loops.”).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to combine the method of adjusting the pH of a cell culture medium taught by Eisenkraetzer with the addition of amino acids, sodium chloride, and hydrochloric acid taught by Rossler. Rossler provides motivation by teaching that it is well known that glutamine is a major energy source for CHO cells and that the built-up ammonia can reduce or stop growth (see page 425). Rossler provides further motivation by teaching that while glutamine can be expensive, it is known that asparagine can be used instead of glutamine (see page 427). Rossler provides motivation by teaching that hydrochloric acid and sodium hydroxide can help maintain pH levels (see page 424). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
4.Claims 9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Eisenkraetzer et al., (US20180216059A1) (IDS filed on 01/24/2024), as evidenced by Volcke et al., Calculation of PH and Concentration of Equilibrium Components during Dynamic Simulation by Means of a Charge Balance. Universiteit Gent Department of Applied Mathematics, Biometrics and Process Control. 2005.
Eisenkraetzer teaches the limitations of claim 1 as discussed in the 35 USC 102 rejection above. Eisenkraetzer does not teach the explicit equations of claims 9 and 13.
The equation of claim 9 is the charge balance model, claim 13 uses the charge balance model as a function with pH. Charge balance models are well known and used in the art.
Volcke teaches the use of charge balance models and charge balance models that has the function of pH (see pages 1-7) (instant claims 9 and 13).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to perform the methods as taught by Eisenkraetzer, with the charge balance model equations to arrive at the instantly claimed method. It would have been prima facia obvious to one of skill in the art to reasonably optimize the charge balance model equations to balance functional relationships (such as pH or temperature) in order to keep the cell environment optimal for growth and the health of the cells. Volcke teaches that the charge balance model that includes the function of pH has been known and used in the art (see pages 1-7). One of ordinary skill in the art would routinely optimize the charge balance model equations used in order to obtain the optimal environment (such as desired pH or temperature, for example) for each cell, depending on the cell type being cultured.
5.Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Eisenkraetzer et al., (US20180216059A1) (IDS filed on 01/24/2024), as evidenced by Volcke et al., Calculation of PH and Concentration of Equilibrium Components during Dynamic Simulation by Means of a Charge Balance. Universiteit Gent Department of Applied Mathematics, Biometrics and Process Control. 2005, as evidenced by Buytendyk, F J et al. “A Study of the System Carbonic Acid, Carbon Dioxide and Water: Determination of the True Dissociation-constant of Carbonic Acid.” The Biochemical journal vol. 21,3 (1927): 576-84. doi:10.1042/bj0210576.
The teachings of Eisenkraetzer and Volcke as it pertains to claims 9 and 13 are discussed in the 35 USC 103 rejection above.
Eisenkraetzer does not teach the explicit equation of claim 10.
The equation of claim 10 uses the carbonic acid dissociation equation. Carbonic acid dissociation equations are well known and used in the art.
Buytendyk teaches the use of the carbonic acid dissociation (see page 577, see page 580-581, see page 583) (instant claim 10).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to perform the methods as taught by Eisenkraetzer, with the carbonic acid dissociation equation to arrive at the instantly claimed method. It would have been prima facia obvious to one of skill in the art to reasonably optimize the carbonic acid dissociation equation in order to determine the desired pH. One of ordinary skill in the art would use the carbonic acid dissociation equation in order to determine the type of acid that should be used for the specific culture medium and predict the pH of a cell culture medium. Buytendyk teaches the carbonic acid dissociation equation is known and used in the art (see page 577). The carbonic acid dissociation equation is widely known and used in the art of cell culturing. One of ordinary skill in the art would routinely optimize the carbonic acid dissociation equation used in order to obtain the optimal environment (such as desired pH or temperature, for example) for each cell, depending on the cell type being cultured.
Conclusion
No claim is allowed.
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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678