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 .
Response to Arguments
Regarding the previous prior art rejection of claim 1, Applicant has amended claim 1 so as to define a method comprising providing a bioreactor containing cultured cells and wherein the method is applied in a cell culture manufacturing procedure.
The Examiner asserts that Ostermeyer reads on providing a bioreactor containing cultured cells, as Ostermeyer discloses maintaining environmental conditions for culturing cells and growing them within the bioreactor (para. 34, 75).
As to the limitation of wherein the method is applied in a cell culture manufacturing procedure, the specific limitation a cell culture manufacturing procedure has been interpreted as a manufacturing procedure wherein cell culturing is used to obtain an end product. It is noted that Applicant’s specification as-filed explicitly recites “a virus antigen manufacturing procedure” rather than “a cell culture manufacturing procedure”. As is understood by those skilled in the art, virus antigen manufacturing procedures involving cell culture comprise growing viruses in host cells and then purifying the virus antigen from the host cells to obtain the virus antigen as the end product; thus the cultured cells participate in the production of virus antigen but are not the end product. Applicant’s specification as-filed does not specify that cells are the final product or that there is any step of harvesting the cells themselves. Therefore, interpreting a cell culture manufacture procedure as a manufacturing procedure wherein cell culturing is used to obtain an end product is consistent with Applicant’s specification.
The Ostermeyer reference reads on a method applied in a cell culture manufacturing procedure, because the method is applied to manufacturing treated water (Abstract, para. 1-9) wherein cell culturing is used to obtain the treated water (Abstract, para. 34, 75, 81).
Therefore, the Examiner maintains that Ostermeyer reads on the newly added limitations of claim 1, as will be discussed in greater detail in the modified grounds of rejection presented below.
Applicant has argued that the Ostermeyer reference does not disclose or suggest dissolving hydrogen for the purpose of improving cell growth, reducing cellular oxidative stress, or providing an antioxidant effect suitable for cell culture. This argument is unpersuasive at is not commensurate in scope with the current pending claims, as the current pending claims do not require the aforementioned effects. Additionally, Ostermeyer discloses providing hydrogen into the culture medium of the bioreactor such that the hydrogen acts as an electron donor (synonymous with an antioxidant), as discussed in the prior Office Action (see pp. 4-5), and the ability of hydrogen gas to improve cell growth, reduce cellular oxidative stress, and/or provide an antioxidant effect suitable for cell cultures is inherent to hydrogen gas, consistent with Applicant’s specification as-filed; therefore, the method of Ostermeyer would necessarily provide the effects noted by applicant.
Regarding the previous rejection of claim 5 under 35 U.S.C. 112(b), Applicant has argued that the claim is not indefinite as the claim has been amended to recite wherein the method is applied in a virus antigen manufacturing procedure, and Applicant asserts that this is a clearly, positively recited limitation. The Examiner agrees. The previous 112(b) rejection is withdrawn, and the Examiner will interpret the phrase wherein the method is applied in a virus antigen manufacturing procedure as limiting.
The claim amendments dated 12/11/2025 have overcome the previous antecedent basis related rejection under 35 U.S.C. 112(b) applied to claim 17.
The claim amendments dated 12/11/2025 have overcome the previous Claim Objections.
The claim amendments dated 12/11/2025 have necessitated a modified grounds of rejection.
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 1-2, 14-17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ostermeyer et al. (US Patent Application Publication 2024/0294410) (already of record) in view of Armiger et al. (US Patent Application Publication 2015/0228996) (already of record).
Regarding claim 1, Ostermeyer et al. discloses an antioxidant culture method (Abstract, para. 81; hydrogen is added to the culture to serve as an antioxidant, see Abstract, para. 84), comprising:
providing a bioreactor containing cultured cells (Abstract, para. 26, 34, 75, 81);
providing an electrolysis-based hydrogen generator (Abstract, para. 18, 27) (Fig. 1, sheet 1 of 2) comprising an anode (para. 29), a cathode (para. 27), and a septum (called membrane) between the anode and cathode (para. 35-36);
connecting the electrolysis-based hydrogen generator and the bioreactor (para. 26-30) (Fig. 1, sheet 1 of 2);
inputting a culture medium of the bioreactor to the cathode (para. 30) (Fig. 1, sheet 1 of 2) and inputting water to the anode (para. 18); and
providing a current to the electrolysis-based hydrogen generator to output a hydrogen from the cathode and dissolve the hydrogen in the culture medium of the bioreactor (Abstract, para. 27-30) (Fig. 1, sheet 1 of 2);
wherein the method is applied in a cell culture manufacturing procedure (the method is applied in a treated water manufacturing procedure wherein cell culture is used to manufacture the treated water, see Abstract, para. 1-9, 75 and 81; reads on a cell culture manufacturing procedure).
Ostermeyer et al. is silent as to the water being pure water.
Armiger et al. discloses a method comprising providing an electrolysis-based hydrogen generator (Abstract, para. 80) having an anode and a cathode (para. 66, 80), inputting a culture medium of a bioreactor to the cathode (para. 80), and inputting water to the anode (para. 80) (Fig. 2, sheet 2 of 9). Specifically, the water inputted to the anode is pure water (para. 80) (Fig. 2, sheet 2 of 9).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the water disclosed by Ostermeyer et al. to be pure water, as Armiger et al. discloses that it was known in the art to use pure water as the water fed to an electrolysis cell, and the skilled artisan would have been motivated to use a water type recognized in the art to be suitable for electrolysis operation; additionally, the skilled artisan would have recognized the advantage in using purified water in order to avoid adverse electrochemical reactions and/or damage to device structure caused by contaminants within the water.
Regarding claim 2, Ostermeyer et al. discloses wherein the hydrogen generated by the electrolysis-based hydrogen generator is provided into the culture medium of the bioreactor, as set forth above, and further discloses wherein the hydrogen is needed for a reaction that occurs within the cell culture (Abstract). Additionally, Ostermeyer et al. discloses providing a current to the electrolysis-based hydrogen generator to generate the hydrogen, as set forth above, and thus Ostermeyer et al. discloses an activation frequency of the current (e.g., current is applied to the generator at least once).
Ostermeyer et al. is silent as to the method further comprising measuring a hydrogen concentration of the culture medium, and raising an activation frequency of the current when the hydrogen concentration is lower than a default value.
Armiger et al. discloses a method comprising generating hydrogen from an electrolysis-based hydrogen generator, as discussed in the rejection of claim 1, above, and further discloses wherein the method comprises raising an activation frequency of the current to arrive at a desired amount of hydrogen production (para. 137).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method disclosed by Ostermeyer et al. to comprise measuring a hydrogen concentration of the culture medium, and raising an activation frequency of the current when the hydrogen concentration is lower than a default value, as the skilled artisan would have been motivated to change an activation frequency of the current based on the produced hydrogen amount, as is known in the art as evidenced by Armiger et al., in order to arrive at a sufficient hydrogen concentration within the culture medium for a desired reaction to occur, as envisioned by Ostermeyer et al.
Regarding claim 14, Ostermeyer in view of Armiger et al. teaches inputting pure water into the electrolysis-based hydrogen generator, as set forth above, and Ostermeyer et al. discloses wherein providing an electrolysis-based hydrogen generator is implemented by connecting an auxiliary equipment with the bioreactor (para. 26-30) (Fig. 1, sheet 1 of 2), wherein the auxiliary equipment comprises:
the electrolysis-based hydrogen generator (para. 26-30), and the culture medium of the bioreactor being inputted into the electrolysis-based hydrogen generator (para. 260-30) (Fig. 1, sheet 1 of 2) and hydrogen gas being outputted from the cathode to the bioreactor (Abstract) (Fig. 1, sheet 1 of 2); and
a power control unit electrically connected with the electrolysis-based hydrogen generator for providing direct current to it (para. 84).
Ostermeyer et al. is silent as to the culture medium of the bioreactor being inputted into the electrolysis-based hydrogen generator via a first pump; a pure water supply end connected with the anode, the pure water in the pure water supply end being inputted into the electrolysis-based hydrogen generator via a second pump; and wherein the power control unit is for controlling the operation of the first pump and the second pump.
However, Armiger et al. discloses a method comprising inputting culture medium of a bioreactor to the cathode of an electrolysis-based hydrogen generator and inputting pure water to the anode of the electrolysis-based hydrogen generator, as set forth in the rejection of claim 1, above; specifically, the method comprises inputting the culture medium via a first pump (para. 80) (Fig. 2, sheet 2 of 9) and providing a pure water supply connected with the anode such that the pure water is inputted via a second pump (para. 80) (Fig. 2, sheet 2 of 9). A computer-controlled pump can be used to achieve a desired flow rate (para. 124). Furthermore, Armiger et al. discloses a power control unit electrically connected with the electrolysis-based hydrogen generator for providing direct current to it and controlling the operation of the pumps (para. 83) (Fig. 3, sheet 3 of 9).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to further modify the method disclosed by Ostermeyer et al. to comprise inputting the culture medium via a first pump and providing a pure water supply end connected with the anode, the pure water in the pure water supply end being inputted into the electrolysis-based hydrogen generator via a second pump, as Armiger et al. discloses that it was known in the art to use such a configuration to deliver culture medium and pure water to an electrolysis-based hydrogen generator in a controlled fashion, and the skilled artisan would have been motivated to use a controllable configuration to ensure a desired amount of culture medium and pure water is delivered to achieve a desired electrochemical reaction. Furthermore, it would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to further modify the power control unit disclosed by Ostermeyer et al. have the configuration disclosed by Armiger et al., i.e., to be for controlling the operation of the pumps as well as in electrical connection with the generator as is already disclosed by Ostermeyer et al., in order to achieve flow rate control according a predetermined program, thereby achieving more detailed control over the electrochemical reaction.
Regarding claim 15, Ostermeyer et al. discloses wherein:
the cathode comprises a first pipeline (12) connected with the bioreactor and used for inputting culture medium of the bioreactor to the cathode (para. 30) (Fig. 1, sheet 1 of 2);
the cathode comprises a second pipeline connected with the bioreactor wherein the second pipeline is used for outputting hydrogen gas (Abstract) (Fig. 1, sheet 1 of 2);
the anode comprises a third pipeline (31) used for inputting water (para. 18) (Fig. 1, sheet 1 of 2); and
the anode comprises a fourth pipeline used for outputting oxygen gas (para. 86).
Furthermore, Ostermeyer et al. in view of Armiger et al. teaches the first pump for inputting culture medium, the second pump for inputting pure water to the anode, and the anode being connected with the pure water supply end; therefore, the prior art combination arrives at the claimed subject matter.
Regarding claim 16, Ostermeyer et al. in view of Armiger et al. teaches the power control unit electrically connected to the electrolysis-based hydrogen generator, as set forth in the rejection of claim 14, above, wherein Armiger et al. discloses the power control unit supplies a negative voltage to the cathode and a positive voltage to the anode (para. 9); thus, the prior art combination necessarily teaches wherein the cathode comprises a cathode contact and the anode comprises an anode contact for receiving voltages via an electrical connection to the power control unit.
Regarding claim 17, Ostermeyer et al. in view of Armiger et al. teaches the power control unit electrically connected to the electrolysis-based hydrogen generator, as set forth in the rejection of claim 14, above, wherein Armiger et al. discloses the power control unit comprises a power supply unit and a controller (para. 9, 83) (Fig. 3, sheet 3 of 9), wherein the power supply unit provides negative voltage to the cathode and positive voltage to the anode under control of the controller (thus the positive electrode of the power supply unit is necessarily electrically connected to an anode contact via the controller and the negative electrode of the power supply unit is necessarily electrically connected to a cathode contact via the controller) (para. 9, 83), and wherein the controller is electrical connected with the first pump (para. 83) (Fig. 3, sheet 3 of 9). Therefore, the prior art combination arrives at the subject matter of claim 17, except for the limitation regarding the controller being electrical connected with the second pump.
However, providing such an electrical connection would require mere duplication of the electrical connection between the controller and the first pump as is already disclosed by Armiger et al. It has been held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced (MPEP §2144.04). It would have been obvious to the skilled artisan to provide an electrical connection between the controller and the second pump in order to achieve the predictable outcome of allowing greater control over water delivery to the generator.
Regarding claim 19, Ostermeyer et al. discloses wherein the electrolysis-based hydrogen generator is a proton exchange membrane fuel cell (para. 26, 78), and the septum is a polymer membrane (para. 85).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ostermeyer et al. (US Patent Application Publication 2024/0294410) (already of record) in view of Armiger et al. (US Patent Application Publication 2015/0228996) (already of record) as applied to claim 1, above, and in further view of Kim et al. (US Patent Application Publication 2016/0032467) (already of record).
Regarding claim 3, Ostermeyer et al. discloses wherein the hydrogen generated by the electrolysis-based hydrogen generator is provided into the culture medium of the bioreactor, as set forth above, and further discloses wherein the hydrogen is needed for a reaction that occurs within the cell culture (Abstract). Additionally, Ostermeyer et al. discloses providing a current to the electrolysis-based hydrogen generator to generate the hydrogen, as set forth above, and thus Ostermeyer et al. discloses an activation frequency of the current (e.g., current is applied to the generator at least once).
Ostermeyer et al. is silent as to wherein an activation frequency of the current is 1 to 3 times per hour for more than 10 minutes each time.
Kim discloses an electrolysis-based hydrogen generator (Abstract, para. 28, 40), wherein an activation frequency of current provided to the generator is 1 time per hour for 20 minutes each time (a current is applied for 20 minutes and thereafter stopped for 40 minutes, in a continuous manner, in other words, current is applied 20 minutes 1 time per hour) (para. 64) in order to produce “high-concentration” hydrogen in water.
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method disclosed by Ostermeyer et al. such that an activation frequency of the current is 1 time per hour for 20 minutes each time (falls within the claim range), as Kim discloses that it was known to use such cycling parameters to produce a high concentration of hydrogen, and the skilled artisan would have been motivated to use parameters recognized in the art to produce a high concentration of hydrogen to ensure that sufficient hydrogen is available to conduct reactions in the cell culture as envisioned by Ostermeyer et al.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Ostermeyer et al. (US Patent Application Publication 2024/0294410) (already of record) in view of Armiger et al. (US Patent Application Publication 2015/0228996) (already of record) as applied to claim 1, above, and in further view of Hu et al. (Molecular hydrogen: A potential radioprotective agent) (already of record).
Regarding claim 4, Ostermeyer et al. discloses providing the hydrogen to the culture medium, as set forth above, and further discloses wherein the hydrogen is needed for a reaction that occurs within the cell culture (Abstract).
Ostermeyer et al. is silent as to wherein a hydrogen concentration of the culture medium ranges from 0.1 to 1.6 ppm.
Hu et al. discloses that it was well known in the art to provide hydrogen to cells to impart a protective effect (p. 1 col. 1 para. 1, p. 5 col. 1 para. 5-7), and further discloses that under normal atmospheric pressure, hydrogen can be dissolved in water for up to around 1.6 ppm (p. 4 col. 1 para. 1).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method disclosed by Ostermeyer et al. such that a hydrogen concentration of the culture medium up to around 1.6 ppm, as Hu et al. discloses that it was known in the art that hydrogen is capable of being dissolved in water up to this limit, and the skilled artisan would have been motivated to provide hydrogen within the culture medium up to the limit hydrogen is capable of dissolving in order to maximize availability of hydrogen for cell culture reactions, as envisioned by Ostermeyer et al. The prior art combination teaches a range of up to about 1.6 ppm which is slightly different than the claim range of 0.1 to 1.6 ppm; nonetheless, it has been held that when the prior art range overlaps or closely approaches the claim range, a prima facie case of obviousness exists. Therefore, the claimed range of 0.1-1.6 ppm does not introduce a patentable distinction over the prior art.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Ostermeyer et al. (US Patent Application Publication 2024/0294410) (already of record) in view of Armiger et al. (US Patent Application Publication 2015/0228996) (already of record) as applied to claim 1, above, and in further view of Hoedemakers et al. (Study of the bubble behavior in alkaline water electrolysis) (already of record).
Regarding claim 13, Ostermeyer et al. discloses applying the current to the electrolysis-based hydrogen generator to generate hydrogen, as set forth above.
Ostermeyer et al. is silent as to wherein the current is a constant current and does not exceed 0.5 ampere.
Hoedemakers et al. discloses an electrolysis-based hydrogen generator wherein a current is applied to generate hydrogen (p. 1 para. 1-3). Hoedemakers et al. discloses wherein a constant current is applied to ensure that hydrogen production is constant (p. 2 para. 2). Additionally, Hoedemakers et al. discloses general conditions for the current applied to an electrolysis-based hydrogen generator (p. 3, entire page) and discloses that increasing the current affects bubble formation within the generator which in turn affects hydrogen generation performance (Abstract, p. 3, entire page).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method disclosed by Ostermeyer et al. such that the current is a constant current, as Hoedemakers et al. discloses doing so in order to ensure constant hydrogen production, and the skilled artisan would have been motivated to provide constant hydrogen production to meet the needs of the cell culture in the bioreactor. As to the limitation of the current not exceeding 0.5 ampere, it has been held that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, when the particular parameter is recognized as a result-effective variable (MPEP §2144.05). Hoedemakers et al. discloses general conditions for the level of the current in amperes and further demonstrates that the current level is a result-effective variable, as set forth above, and therefore it would have been obvious to one of ordinary skill in the art to discover an optimum or workable range for the current level.
Claims 18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Ostermeyer et al. (US Patent Application Publication 2024/0294410) (already of record) in view of Armiger et al. (US Patent Application Publication 2015/0228996) (already of record) as applied to claim 14, above, and in further view of Lee et al. (Hydrogen-rich medium protects mouse embryonic fibroblasts from oxidative stress by activating LKB1-AMPK-FoxO1 signal pathway) (already of record).
Regarding claim 18, Ostermeyer et al. et al. discloses providing the auxiliary equipment and Ostermeyer et al. in view of Armiger et al. teaches wherein the equipment comprises a power control unit for providing current, as set forth above. Armiger et al. discloses measuring an amount of hydrogen produced (para. 80), wherein the electrolysis-based hydrogen generator can be controlled according to an amount of hydrogen measured (para. 137). Ostermeyer et al. discloses wherein the generated hydrogen is needed for a reaction that occurs within the cell culture (Abstract).
The prior art combination is silent as to a hydrogen concentration detector which is arranged in the culture medium in the bioreactor and is connected to the power control unit for measuring the hydrogen concentration of the culture medium and adjusting the power control unit according to a comparison result of the hydrogen concentration of the culture medium and a default value.
Lee et al. discloses a method (Abstract) comprising using a dissolved hydrogen meter to measure the hydrogen concentration of a culture medium (p. 734 col. 1 para. 3).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the equipment disclosed by Ostermeyer et al. to comprise a dissolved hydrogen meter (reads on a hydrogen concentration detector) arranged in the culture medium in the bioreactor for measuring the hydrogen concentration of the culture medium, as Lee et al. discloses it was known in the art to use such a configuration for measuring hydrogen concentration in culture medium, and the skilled artisan would have been motivated to use a known configuration to verify that sufficient hydrogen is available for desired cell culture reactions. Furthermore, it would have been obvious to connect the dissolved hydrogen meter to the power control unit adjusting the power control unit according to a comparison result of the hydrogen concentration of the culture medium and a default value, as Armiger et al. discloses adjusting current based on a measured hydrogen content, and the skilled artisan would have been motivated to use feedback of the hydrogen concentration to adjust current in order to arrive at a desired hydrogen concentration.
Regarding claim 20, Ostermeyer et al. in view of Lee et al. teaches wherein the hydrogen concentration detector is a dissolved hydrogen meter, as set forth above.
Allowable Subject Matter
Claim 5, and accordingly claims 6-12 which depend therefrom, are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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 HOLLY KIPOUROS whose telephone number is (571)272-0658. The examiner can normally be reached M-F 8.30-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Marcheschi can be reached at 5712721374. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HOLLY KIPOUROS/Primary Examiner, Art Unit 1799