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 .
Support for the amendments is within the instant application specification.
Examiner acknowledges Applicant’s Remarks dated 8/20/2025 regarding the typographical error of “Multiflex,” which is intended to recite “Multiplex.” Corrections to the term are within the ‘Response to Remarks.’
Applicant’s amendment to the claims filed on 8/7/2025 in response to the Non-Final Rejection mailed on 5/8/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 1, 3-8, 13-19, 48-51, 53-54, 56-58 are pending and examined on the merits.
Claims 2, 9-12, 20-47, 52, 55 are canceled.
Applicant’s remarks filed on 8/7/2025 and 8/20/2025 in response to the Non-Final Rejection mailed on 5/8/2025 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
The terminal disclaimer filed on 6/2/2024 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent Application No. 17/396,727 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/7/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objection
The objection to claim 15 because of the following informalities: the incorrect number of limitations within claim 15 is withdrawn in view of Applicant’s amendment of claim 15 to correct the numbering issue.
New 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.
Claims 1, 3-8, 13-19, 48-51, 53-54, 56-58 are newly 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. The new rejection is necessitated by Applicant’s recitation of ‘"automated control strategies" and “component unit operations” in claim 20 of the instant application.
Claim 1 (claims 3-8, 13-19, 48-51, 53-54, 56-58 dependent thereof) recites the limitation "recombined" in line 9. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of the plurality of the different concentrated medium component solutions being ‘combined’ in order for them to be ‘recombined.’ It is suggested that Applicant amend the claim to recite ‘combined.’ Appropriate correction is suggested.
RESPONSE TO REMARKS: This argument is found to be moot in view of the new rejection. Examiner contends that there is no prior recitation of the plurality of different concentrated medium component being ‘combined’ in order for them to be ‘recombined.’ Appropriate correction is suggested.
Maintained 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 rejection of claims 1, 4-8, 15-19, 48, 54 under 35 U.S.C. 103 as being unpatentable over Konstantinov et al (2017, US 2017/0218012 A1, Date published: Aug. 3, 2017, cited on IDS filed 8/8/2021) {herein Konstantinov} in view of Wang et al (US 2019/0002815 A1, Date Published: Jan. 3, 2019, cited on PTO-892 dated 5/8/2025) {herein Wang} as evidenced by Broadley James (2024, https://www.broadleyjames.eu/product/single-use-bioreactor-system/, cited on PTO-892 filed 3/20/2024) {herein Broadley James}, GE Heath (2024, https://www.fishersci.at/shop/products/unicorn-start-1-0/15279784, cited on PTO-892 dated 5/8/2025) {herein GE Health}, AKTA (2016, cytiva, cited on PTO-892 dated 5/8/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 5/8/2025) {herein Masterflex} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 1 to recite ‘in less than or equal to 2 minutes of when needed to replace volumes of medium’ and ‘comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
As amended, claims 1, 4-8, 15-19, 48, 54 are drawn to a process for manufacturing a purified protein of interest, the process comprising the step of: (a) culturing mammalian cells in suspension in one or more single-use perfusion bioreactors comprising a liquid culture medium under conditions that allow the cells to secrete the protein into the liquid culture medium for a production cultivation period of at least 10 days, wherein, periodically or continuously, during the production cultivation period, fresh sterile liquid culture medium is added into the one or more perfusion bioreactors, being mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium, from a plurality of different concentrated medium component solutions and recombined together with an aqueous diluent that is a buffer or water, to maintain a constant culture volume in each of the perfusion bioreactor(s), in direct relation to volumes of the culture that are continuously or periodically removed from each of the perfusion bioreactor(s) as volumes of permeate or cell bleed, wherein the fresh sterile liquid culture medium is added to the one or more perfusion bioreactor(s): (i) by injecting the plurality of different concentrated medium component solutions at fixed ratios relative to one another, directly into the perfusion bioreactor(s), while the aqueous diluent is also added to the perfusion bioreactor(s) at varied ratio(s) relative to the plurality of different concentrated component solutions; or (ii) by injecting the plurality of different concentrated medium component solutions and the aqueous diluent at fixed ratios relative to one another, directly into the perfusion bioreactor(s); or (iii) by injecting the plurality of different concentrated medium component solutions and the aqueous diluent, at fixed ratios relative to one another, into a mixing chamber wherein fresh sterile liquid culture medium is mixed contemporaneously before being added to each perfusion bioreactor(s); and wherein the removed volumes of permeate are automatically and fluidly fed from the one or more single-use perfusion bioreactor(s) into a single-use surge vessel and thence into a first chromatography system, whereby the protein is collected in a protein isolate fraction; and (b) switching the protein isolate fraction into a low pH or detergent viral inactivation system and, if needed, a neutralization system, to obtain a virally inactivated product pool comprising the protein, wherein: (i) a process automation system, comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations, is in electronic communication at least with the one or more single-use perfusion bioreactors and the single-use surge vessel; (ii) the process automation system stores a first set of control modules to control operation of the one or more single-use perfusion bioreactors; and (iii) an automated controller comprising a detector is used to measure the fluid volume in the single-use surge vessel, and a processor varies the pump speeds of the first chromatography system to maintain a pre-set volume range in the single-use surge vessel.
With respect to claims 1, 4-6, Konstantinov teaches a process wherein protein is purified via an automated facility for manufacturing a therapeutic protein drug substance (para 0003 and 0004). The process comprises culturing mammalian cells that secrete a recombinant therapeutic protein in a perfusion bioreactor (fig. 1, #25) that contains a liquid culture medium, where a volume of the liquid culture medium that is substantially free of cells is continuously or periodically removed from the perfusion bioreactor and fed into a first multi-column chromatography system (MCCS 1) (para 0005 and fi. 1 #27). The mammalian cell can be a cell that grows in suspension (para 0184). Said bioreactor can have a volume of 500L (para 0182). Culturing of the cells present in the bioreactor includes periodic or continuous removal of the first liquid culture medium and at the same time or shortly thereafter adding substantially the same volume of a second liquid culture medium to the bioreactor (para 0050). Konstantinov further teaches that in some examples of fed-batch culture, the second liquid culture medium is a concentrated form of the first liquid culture medium (para 0051). Konstantinov defines a fed-batch bioreactor as a bioreactor that contains a plurality of cells in a first culture medium (para 0051). As such, it would be obvious to one of ordinary skill in the art that a concentrated culture medium could also be utilized in perfusion bioreactor as said bioreactor also contains a plurality of cells in a first culture medium for protein purification. The production cultivation period was for at least 10 days (para 0215). Bioreactors from Broadley-James Corp were utilized during experimentation (para 0261). Evidentiary reference of Broadley James is cited to demonstrate that said bioreactor is a single-use bioreactor system (page 1). Examiner is interpreting said single use bioreactor to be part of the first chromatography system. Once the culture reached specific cell density, cell-bleeding methods were initiated to maintain cell density at a steady state (para 0223). The harvest from the bioreactor/ATF was pumped into a disposable bag serving as a small surge vessel using a peristaltic pump (para 0230). Examiner is interpreting said small surge vessel to be SUSVI. The volume of the bioreactor was pumped into a vessel (fig 1 #27) using a Masterflex peristaltic pump (para 0230). Said pump control the rate of flow of liquids from the bioreactor to the filtration system (fig. 1 #27) and throughout the columns systems (figs 1 and 9). Evidentiary reference of Masterflex is cited to demonstrate that Masterflex Peristaltic Pump Systems are automated and allow for the storage of standard protocols to store information on the continuous operation of the pump, control the volume dispense and flow rates (page 4). Examiner is interpreting the Masterflex Peristaltic Pump Systems to automatically and fluidly feed from one single use perfusion bioreactor into a single-use surge vessel in an uninterrupted flow as the fluids are moving through the system. Furthermore, the evidentiary reference of Masterflex is cited to demonstrate that Masterflex Peristaltic Pump System is comprised of hardware and software components to execute automated control strategies such as standard protocol (page 2, 4). Additionally, Examiner is interpreting the Masterflex Peristaltic Pump Systems to be in electronic communication with the single use perfusion bioreactor taught by Konstantinov as it is able to control the flow rate/speed of the purification system from the single use bioreactor to the surge vessels through an intuitive digital touchscreen (Masterflex: page 4). The pump speed can be customized from low flow pumps to high flow pumps (page 3). Examiner is interpreting the Masterflex pump to have a processor since it is able to control the flow rate/speed of the purification system and store protocols which contains preset limitations for controlling the functionality of the purification system. Examiner is interpreting the Masterflex Peristaltic Pump System to be synonymous to the claimed PAS, as said pump is able to store protocol information for the purification system, monitor/detect flow rates and control the volume of fluid dispensed within the single use surge vessels and column system (Konstantinov: fig, 1 #20). Examiner is interpreting the ability of the Masterflex Peristaltic Pump System to store protocols and vary the rate of flow/speed of the pump as being synonymous with it varying the pump speed throughout the purification system, including the first, second and an optional third chromatography system and maintaining pre-set volume ranges throughout the chromatography system including the single use surge vessels. Said pump controls the operation of the bioreactor, by detecting/monitoring the filtration system (examiner interpreted SUSV1) and columns. The liquid culture medium then can be fed (loaded) into the first MCCS (para 0147). Examiner is interpreting ‘loaded’ to being synonymous to injected. Next, the recombinant therapeutic protein within the liquid culture medium is captured using the MCCSl, where the eluate of the MCCSl containing the recombinant therapeutic protein is continuously fed into a second multi-column chromatography system (MCCS2); and the recombinant protein is purified and polished using the MCCS2, where the eluate from the MCCS2 is a protein of interest; and where the process is integrated and runs continuously from the liquid culture medium to the eluate from the MCCS2 that is the therapeutic protein drug substance (para 0005). Examiner is interpreting said recitation to be the collection of the protein isolate fraction. In addition, Konstantinov teaches a process of switching the protein isolates into a low pH system to inactivate the viruses (para 0006). Evidentiary evidence of the instant application recites ‘a neutralization system to obtain a virally inactivated product pool comprising the protein (Instant Application Specification: para 00031). Examiner is interpreting the viral inactivation process to encompass a neutralization system since the viruses are inactivated during the process taught by Konstantinov and would therefore result in a virally inactivate pool comprising the protein.
With respect to claim 7, Konstantinov discloses the claimed invention except for two, three, four, five, or six single-use perfusion bioreactors. It would have been inherent to one having ordinary skill in the art at the time the invention was made to adjust the number of bioreactors utilized for experimentation based on the amount of isolated protein desired, since it has been held that the provision of adjustability, where needed, involves only routine skill in the art. In re Stevens, 101 USPQ 284 (CCPA 1954). Konstantinov teaches a process wherein bioreactors were operated in perfusion mode (para 0258). Examiner is interpreting the plural recitation of ‘bioreactors’ to be at least two bioreactors.
With respect to claim 8, Konstantinov teaches a process wherein the bioreactor can have a volume of 500L (para 0182).
With respect to claim 15, Konstantinov teaches a process wherein the volume of the bioreactor was pumped into a vessel (fig 1 #27) using a Masterflex peristaltic pump (para 0230). Said pump controls the rate of flow of liquids from the bioreactor to the filtration system (fig. 1 #27) and throughout the column systems (figs 1 and 9). Examiner is interpreting the Masterflex peristaltic pump to control the operation of the feed tank since it controls the rate of flow of liquids from the bioreactor to the filtration system. Examiner is interpreting the feed tanks as the bioreactor and surge vessels since protein from said tanks are fed into the column filtration system. Evidentiary evidence of Masterflex is cited to demonstrated that Masterflex Peristaltic Pump Systems are automated and allow for the storage of standard protocols to store information on the continuous operation of the pump, control the volume dispensed and flow rates (page 4). Examiner is interpreting the storage of protocols to be synonymous to storing a second and third set of control modules to control the operation of the feed tanks since it is well known in the art that protocols are a set of directions to perform an experimental task. Examiner is interpreting the Masterflex Peristaltic Pump Systems to automatically and fluidly feed from one single use perfusion bioreactor into a single-use surge vessel. Additionally, Examiner is interpreting the Masterflex Peristaltic Pump Systems to be in electronic communication with the single use perfusion bioreactor taught by Konstantinov as it is able to control the flow rate/speed of the purification system from the single use bioreactor to the surge vessels through an intuitive digital touchscreen (Masterflex: page 4). The pump speed can be customized from low flow pumps to high flow pumps (page 3). Examiner is interpreting the Masterflex pump to have a processor since it is able to control the flow rate/speed of the purification system and store protocols which contains preset limitations for controlling the functionality of the purification system. Examiner is interpreting the Masterflex Peristaltic Pump System to be synonymous to the claimed PAS, as said pump is able to store protocol information for the purification system, monitor/detect flow rates and control the volume of fluid dispensed within the single use surge vessels and column systems (Konstantinov: fig, 1 #20). Examiner is interpreting the ability of the Masterflex Peristaltic Pump System to store protocols and vary the rate of flow/speed of the pump as being synonymous with it varying the pump speed throughout the purification system, including the first, second and an optional third chromatography system and maintaining pre-set volume ranges throughout the chromatography system including the single use surge vessels. Said pump controls the operation of the bioreactor, by detecting/monitoring the filtration system (examiner interpreted SUSV1) and columns. Furthermore, Konstantinov teaches the single-use bioreactor is configured to the PCCS system (fig.1). Examiner is interpreting the configuration taught by Konstantinov to be ‘logically configured’ since said configuration allows for the purification of protein as the bioreactor is connected to multiple feed tanks (fig.1).
With respect to claim 16, Konstantinov teaches a method wherein a system including at least a bioreactor, a first MCCS, and a second MCCS can be disposed on a single skid (para 0114). Systems may include a first MCCS and a second MCCS disposed on a single skid, or the entire system disposed on a single skid (para 0114). The two PCCS used in this study were a custom modified AKTA (GE Healthcare, Piscataway, N.J.) capable of running up to four columns (para 0265). Each system was equipped with five UV monitors (UV-900), three pumps (P-900), multiple valves (PV-908, SV-903), one pH and one conductivity meter (pH/C-900), and Unicorn-based custom software (GE Healthcare, Piscataway, N.J.) (para 0265). In systems that utilize more than one skid, the skids can be designed to fit together (e.g., fit together via a latch, turn-key, Screw, or clamp device) (para 0116). Evidentiary evidence of GE Heath recites that the Unicorn-based custom software is a software program ran on computer that allows for the real-time monitoring of protein purification and the automatic collection of said proteins (page 1). Evidentiary evidence of the instant application recites ‘skid’ is a unit operation configured to communicate by hard-wiring or wireless computer (para 00096). Examiner is interpreting the computer used to run the Unicorn-based custom software includes a plurality of communication interfaces to electronically couple the at least one single-use perfusion bioreactor to a plurality of pieces of portable equipment since it requires hard-wiring or wireless communication to function alongside the PCCS.
With respect to claim 17, Konstantinov teaches a process wherein the volume of the bioreactor was pumped into a vessel (fig 1 #27) using a Masterflex peristaltic pump (para 0230). Said pump controls the rate of flow of liquids from the bioreactor to the filtration system (fig. 1 #27) and throughout the columns systems (figs 1 and 9). Examiner is interpreting the Masterflex peristaltic pump to control the operation of the feed tank since it controls the rate of flow of liquids from the bioreactor to the filtration system. Said pump controls the operation of the bioreactor, by detecting/monitoring the filtration system (examiner interpreted SUSV1) and columns. Examiner is interpreting the detecting/monitoring of the filtration system by the Masterflex peristaltic pump to be synonymous with the PAS detecting the components of the purification system and monitoring its functionality. Evidentiary evidence of Masterflex is cited to demonstrated that Masterflex Peristaltic Pump Systems are automated and allow for the storage of standard protocols to store information on the continuous operation of the pump, control the volume dispense and flow rates (page 4). Examiner is interpreting the Masterflex Peristaltic Pump Systems to be coupled to/in electronic communication with the single use perfusion bioreactor taught by Konstantinov as it is able to control the flow rate/speed of the purification system from the single use bioreactor to the surge vessels through an intuitive digital touchscreen (Masterflex: page 4). Additionally, the Masterflex Peristaltic Pump System (Examiner interpreted PAS) is able to monitor fluid pressure (page 4, column 1). The pump speed can be customized from low flow pumps to high flow pumps (page 3). Examiner is interpreting the Masterflex Peristaltic Pump System to be synonymous to the claimed PAS, as said pump is able to store protocol information for the purification system, monitor/detect flow rates and control the volume of fluid dispensed within the single use surge vessels and column systems (Konstantinov: fig, 1 #20). Examiner is interpreting the ability of the Masterflex Peristaltic Pump System to store protocols and vary the rate of flow/speed of the pump as being synonymous with it varying the pump speed throughout the purification system, including the first, second and an optional third chromatography system and maintaining pre-set volume ranges throughout the chromatography system including the single use surge vessels. Additionally, examiner is interpreting the third chromatography system to be a third set of control modules. Said pump controls the operation of the bioreactor, by detecting/monitoring the filtration system (examiner interpreted SUSV1) and columns. Furthermore, Konstantinov teaches the single-use bioreactor is configured to the PCCS system (fig.1). Examiner is interpreting the configuration taught by Konstantinov to be ‘logically configured’ since said configuration allows for the purification of protein as the bioreactor is connected to multiple feed tanks (fig.1).
With respect to claim 18, Konstantinov teaches a method wherein a media feed vessel is attached to a bioreactor (fig 1). Examiner is interpreting the media feed vessel to be a mixing vessel since the media is added to the bioreactor from said vessel. The system also includes a bioreactor, a first MCCS, and a second MCCS that can be disposed on a single skid (para 0114). Systems may include a first MCCS and a second MCCS disposed on a single skid, or the entire system disposed on a single skid (para 0114). The two PCCS used in this study were a custom modified AKTA (GE Healthcare, Piscataway, N.J.) capable of running up to four columns (para 0265). Each system was equipped with five UV monitors (UV-900), three pumps (P-900), multiple valves (PV-908, SV-903), one pH and one conductivity meter (pH/C-900), and Unicorn-based custom software (GE Healthcare, Piscataway, N.J.) (para 0265). In systems that utilize more than one skid, the skids can be designed to fit together (e.g., fit together via a latch, turn-key, Screw, or clamp device) (para 0116). Evidentiary evidence of GE Heath recites that the Unicorn-based custom software is a software program ran on computer that allows for the real-time monitoring of protein purification and the automatic collection of said proteins (page 1). Evidentiary evidence of the instant application is cited to demonstrated that ‘skid’ is a unit operation configured to communicate by hard-wiring or wireless computer (para 00096). Examiner is interpreting the computer used to run the Unicorn-based custom software includes a plurality of communication interfaces to electronically couple the at least one single-use perfusion bioreactor to a plurality of pieces of portable equipment since it requires hard-wiring or wireless communication to function alongside PCCS. In addition, Examiner is interpreting the Unicorn-based custom software are a PAS since it is able to control the protein purification system.
With respect to claim 19, Konstantinov teaches a method wherein the recombinant therapeutic human enzyme is produced over a 70 day period (para 0252).
With respect to claim 48, Konstantinov teaches a process of continuously producing therapeutic protein substances utilizing continuous systems (para 0004).
With respect to claims 54, Konstantinov teaches a method wherein the recombinant therapeutic human enzyme was produced in a bioreactor continuously over a 70-day period (para 0252).
However, Konstantinov does not teach the process of claim 1, (i) by injecting the plurality of different concentrated medium component solutions at fixed ratios relative to one another, directly into the perfusion bioreactor(s), while the aqueous diluent is also added to the perfusion bioreactor(s) at varied ratio(s) relative to the plurality of different concentrated component solutions; or (ii) by injecting the plurality of different concentrated medium component solutions and the aqueous diluent at fixed ratios relative to one another, directly into the perfusion bioreactor(s); or (iii) by injecting the plurality of different concentrated medium component solutions and the aqueous diluent, at fixed ratios relative to one another, into a mixing chamber wherein fresh sterile liquid culture medium is mixed contemporaneously before being added to each perfusion bioreactor(s); and wherein the removed volumes of permeate are automatically and fluidly fed from the one or more single-use perfusion bioreactor(s) into a single-use surge vessel and thence into a first chromatography system, whereby the protein is collected in a protein isolate fraction (claim 1).
With respect to claim 1, Wang teaches an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602). The plurality of reservoirs are fluidly connected to the bioreactor (fig. 4B #300 and para 0064). It is known by those of ordinary skill in the art that PBS is a buffer. As such, Examiner is interpreting the reservoirs containing PBS to be the same as Applicant’s recited ‘a plurality of different concentrated medium component solutions and recombined together with an aqueous diluent that is a buffer.’ Wang further teaches the fresh media and buffers are mixed contemporaneously, at the same time, within the media container (incubator) before being added directly into each perfusion bioreactor (fig. 4B #300 and para 0062, 0064). The system can contain a control system or pump (para 0066). Examiner is interpreting the process of adding the fresh media and buffers from the media container to the bioreactors as the same as the fresh media and buffers being injected into the bioreactors as the fresh media and buffers are transported via tubing into the media container which is connected directly to the culture chambers of the device (fig. 4B #602, #300). Although the references of Konstantinov, in view of Wang do not explicitly teach the limitation of claim 1 (mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium), MPEP 2144.05 states"[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05 IIA)." One of ordinary skill would desire to optimize the time at which sterile liquid medium is added to one or more perfusion bioreactors depending on the particular application. It would be routine for one to arrive at the time in which to replace the sterile medium within the bioreactor for the application they intend on using the purified protein of interest. Therefore, the above invention would have been prima facie obvious. As such, Examiner in interpreting Wang to teach said limitation with the teaching of ‘gravity can drive the flow of liquids from the storage vessels into the reservoir or sub-reservoirs’ (para 0064) and ‘the system could also contain a control system’ (para 0066) as being mechanisms of replacing the medium with fresh medium as needed.
A pump is used to control the flow of media and buffer and may be automated (para 0037). Examiner is interpreting the utilization of an automated process for the flow of media and buffers to be within set ratios as the automated process since said process must be programmed to deliver a set amount of fluids. Said system may be used for harvesting protein from cells (para 0112).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the teachings of Konstantinov et al of a process of an automated facility for manufacturing a therapeutic protein drug substance that include providing a liquid culture medium containing a recombinant therapeutic protein that is substantially free of cells (para 0004) over the course of at least 30 days (para 0065 and 0108) or combine the teachings of Wang because Wang
teaches an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602). The plurality of reservoirs containing culture media, PBS (Phosphate Buffer Saline) are fluidly connected to the bioreactor (fig. 4B #300).
One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability, and would be motivated to combine the teachings of Konstantinov, and Wang because Wang provides a process of creating a temperature-controlled environment (Wang: para 0041) to maintain the activity of the purified protein and a process wherein an automated system utilizes a plurality of reservoirs containing fresh media and buffers (fig. 4B #602) and wherein the plurality of reservoirs are fluidly connected to the bioreactor (fig. 4B #300). Konstantinov would be motivated to incorporate a process of protein purification with a plurality of different reservoirs for buffers, as taught by Wang, as doing so would maintain the sterility and environment of the buffers and water within the plurality of different reservoirs. As such, one of ordinary skill in the art would have a reasonable expectation of success that combining the teachings of Konstantinov and Wang would help to preserve the media and buffers and would reduce the likelihood of invertedly causing the protein of interest to denature due to improper culturing conditions.
One of skill in the art would have a reasonable expectation of success to make and use the claimed plurality of reservoirs containing fresh media and buffers because Konstantinov provides the basic automated facility for manufacturing purified protein of interest and its uses and methods of making it. Reference of Wang provides the teachings an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602). Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
MPEP 2144.05 states"[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05 IIA)." One of ordinary skill would desire to optimize a process for manufacturing a purified protein of interest depending on the particular application. It would be routine for one to arrive at the process for manufacturing a purified protein of interest for the application they intend on using the purified protein of interest as said process is well known in the art based on the teachings of Konstantinov and Wang. Therefore, the above invention would have been prima facie obvious.
RESPONSE TO REMARKS: Beginning on p. 7 of Applicant’s remarks, Applicant contends that the rejection has been addressed by amendment. In summary, Applicant contends that the cited Konstantinov alone-- or in any combination of Konstantinov and/or Gefroh with Wang, a reference that pertains to culturing cells adherent to a solid substrate rather than to culturing mammalian cells in suspension.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends Wang was utilized to teach a plurality of reservoirs with PBS (see 103 rejection), of which Examiner is interpreting as being the same as Applicant’s recited ‘aqueous diluent that is a buffer’ since it is known by those of ordinary skill in the art that PBS is a buffer. Examiner contends that the mammalian cell can be a cell that grows in suspension (Konstantinov: para 0184).
Applicant contends that In Konstantinov, "mixing" refers to the exchange of fresh whole medium for medium spent occurring due to perfusion, and any discussion of fixed ratios in Konstantinov refers to "loading" in chromatography operations (e.g., MCCS or PCCS), not to the ratio of culture medium concentrate solutions being injected into the bioreactor. Applicant contends Applicant's Specification uses the words "injection" or "injecting" to refer to the addition of concentrated medium components and/or aqueous diluent to the bioreactor(s). (See, Applicant's Spec., e.g., at paragraphs [0065], [0145], [0267], [0302]-[0304], [0420]-[0421], [0423]). Where at page 7 of the Office Action, the "Examiner is interpreting said single use bioreactor to be part of the first chromatography system," the Examiner has grossly conflated two clearly separate unit operations without any rational basis, as would be recognized by any person of ordinary skill in the art of biologics manufacturing processes.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that contrary to Applicant’s assertion that ‘mixing’ (taught by Konstantinov) refers to exchange of fresh whole medium for spent medium, Konstantinov teaches PCCS1 and PCCS2 as a ‘mixing’ device (para 0267). Examiner contends that the term ‘mixing’ taught by Konstantinov has the same definition as is commonly known in the industry.
Applicant contends that the phrase "mixed contemporaneously" means that the concentrated medium components and diluent are mixed together to make fresh culture medium, only within a few seconds or minutes (<2minutes) of when needed to replace volumes of medium that are removed from each of the perfusion bioreactor(s), either as volumes of permeate or cell bleed. Applicant contends that for greater clarity, Applicant has herein amended independent Claim 1, subpart (a), to distinctly incorporate and recite limitations from paragraph [000144], "...being mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium, from a plurality of different concentrated medium component solutions and recombined together with an aqueous diluent that is a buffer or water." Applicant contends that no-where in Wang is it disclosed or suggested that culture medium is mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium, from a plurality of different concentrated medium component solutions and recombined together with an aqueous diluent that is a buffer or water," as recited in amended Claim 1, subpart (a).
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Wang teaches the plurality of reservoirs are fluidly connected to the bioreactor (fig. 4B #300 and para 0064). The fresh media and buffers are mixed contemporaneously, at the same time, within the media container (incubator) before being added directly into each perfusion bioreactor (Konstantinov: fig. 4B #300 and para 0062, 0064). Examiner contends that although the references of Konstantinov, in view of Wang do not explicitly teach the limitation of claim 1 (mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium), MPEP 2144.05 states"[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05 IIA)." One of ordinary skill would desire to optimize the time at which sterile liquid medium is added to one or more perfusion bioreactors depending on the particular application. It would be routine for one to arrive at the time in which to replace the sterile medium within the bioreactor for the application they intend on using the purified protein of interest. Therefore, the above invention would have been prima facie obvious. Furthermore, Examiner contends that the limitation ‘in less than or equal to 2 minutes of when needed to replace volumes of medium’ is unclear as the breadth of the claim encompasses any point at which columns of medium need to be replaced. As such, Examiner in interpreting Wang to teach said limitation with the teaching of ‘gravity can drive the flow of liquids from the storage vessels into the reservoir or sub-reservoirs’ (para 0064) and ‘the system could also contain a control system’ (para 0066) as being mechanisms of replacing the medium with fresh medium as needed.
Applicant contends that Konstantinov and Wang fail to disclose or suggest other limitations recited in amended Claim 1, e.g., "being mixed contemporaneously...by injecting the plurality of different concentrated medium component solutions at fixed ratios relative to one another directly into the perfusion bioreactor(s)...,"
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Wang teaches an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602). The plurality of reservoirs are fluidly connected to the bioreactor (fig. 4B #300). A pump is used to control the flow of media and buffer and may be automated (para 0037). Examiner is interpreting the utilization of an automated process for the flow of media and buffers to be within set ratios as the automated process must be programmed to deliver a set amount of fluids. Said system may be used for harvesting protein from cells (para 0112). Examiner contends that Applicant has not provided any evidence that the pump taught by Wang does not provide set ratios of media and buffers to the bioreactor from a plurality of reservoirs.
Applicant contends that the Examiner has misinterpreted the nature of the "Masterflex Peristaltic Pump System, employed by Konstantinov, to be synonymous to the claimed PAS." Applicant contends the Masterflex pump itself does not know to change the pump speed setting-- without a human operator or a PAS providing it the input signal to make a change in setpoint.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends the recitation “a process automation system, comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations” is not limited to changing the pup speed setting. The breadth of the claim encompasses any control strategy. As such, Examiner contends that the Masterflex Pump taught by Konstantinov teaches the claim limitation of “automated control strategies” as said pump controls the rate of flow of liquids from the bioreactor to the filtration system (Konstantinov: fig. 1 #27) and throughout the columns systems (Konstantinov: figs 1 and 9).
Applicant contends that the Masterflex reference also fails to describe or suggest "a process automation system" that "stores a first set of control modules to control operation of the one or more single-use perfusion bioreactors," as recited in amended Claim 1, subpart (b).
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Masterflex Peristaltic Pump Systems are automated and allow for the storage of standard protocols to store information on the continuous operation if the pump, control the volume dispense and flow rates (page 4). Examiner contends that the ‘standard protocols’ as interpreted to include a set of control modules to control operation of the one or more single-use perfusion bioreactors as it is known by those of ordinary skill in the art that protocols, in the scientific field, are sets of instructions for which the experiments are ran.
Applicant contends that Konstantinov, employing the Masterflex pump system, merely teaches that the surge vessel acts as a flow break and allows volume to surge up and down passively, not "to maintain a pre-set volume range in the single-use surge vessel," as recited in Claim 1, subpart (b), in reference to Applicant's Specification, paragraph [0193].
This argument is found to be not persuasive in view of the modified rejection set forth. Respectfully, Examiner requests that Applicant provide the evidence of said argument. Examiner contends that said argument is not within the primary reference of Konstantinov.
Applicant contends that any mention of "automation" by Konstantinov refers to either perfusion operation, or automated switching of columns, not surge vessels. Applicant contends that Konstantinov fails to disclose or suggest a single-use surge vessel under automated control.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Konstantinov teaches the harvest from the bioreactor/ATF was pumped into a disposable bag serving as a small surge vessel using a peristaltic pump (para 0230). Examiner is interpreting said small surge vessel to be SUSV1 since the harvest form the bioreactor/ATF is pumped into it. Examiner contends that the ‘disposable bag’ is the same as a storage reservoir and/or collection vessel as both result in the holding of materials. The volume of the bioreactor was pumped into a vessel (fig 1 #27) using a Masterflex peristaltic pump (para 0230).
The rejection of claims 3, 13-14, 49-51, 53, 56-58 under 35 U.S.C. 103 as being unpatentable over Konstantinov et al (2017, US 2017/0218012 A1, Date published: Aug. 3, 2017, cited on IDS filed 8/8/2021) {herein Konstantinov} in view of Wang et al (US 2019/0002815 A1, Date Published: Jan. 3, 2019, cited on PTO-892 dated 5/8/2025) {herein Wang} as applied to claims 1, 4-8, 15-19, 48, 54 and in further view of Gefroh et al. (2017, US 2017/0157566 A1, Date Published Jun. 8, 2017, cited on IDS filed 8/8/2021) {herein Gefroh} and in further view of Casey et al (2011, Journal of Membrane Science, cited on PTO-892 dated 5/8/2025) {herein Casey}, Chassot et al. (2006, Braz Dent J, ISBN: 0103-6440, cited on PTO-892 filed 3/20/2024) {herein Chassot} and Khanal et al (Date Accepted: 6 April 2018, Wiley Biotechnology Bioengineering, cited on PTO-892 dated 5/8/2025) {herein Khanal} as evidenced by Broadley James (2024, https://www.broadleyjames.eu/product/single-use-bioreactor-system/, cited on PTO-892 filed 3/20/2024) {herein Broadley James}, GE Heath (2024, https://www.fishersci.at/shop/products/unicorn-start-1-0/15279784, cited on PTO-892 dated 5/8/2025) {herein GE Health}, the instant application, AKTA (2016, cytiva, cited on PTO-892 dated 5/8/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 5/8/2025) {herein Masterflex} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 1 to recite ‘in less than or equal to 2 minutes of when needed to replace volumes of medium’ and ‘comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
Previously presented claim 3 is drawn to the process of Claim 1, further comprising the steps of: (c) introducing the virally inactivated product pool into a second chromatography system to obtain a purified product pool comprising the protein; (d) switching the purified product pool comprising the protein into an optional third chromatography system and/or a viral filtration system to obtain a virus-free filtrate comprising the protein; and (e) switching the virus-free filtrate into an ultrafiltration/diafiltration system to obtain a composition comprising the purified protein of interest.
Previously presented claim 13 is drawn to the process of Claim 3, wherein the first chromatography system comprises a pump having pump speeds; and wherein one or more of steps (b), (c), (d), or (e) is performed automatically and fluidly in an uninterrupted flow from the previous step, and wherein a surge vessel is employed between one or more steps, and a processor varies the pump speed in a subsequent step to regulate a pre-set volume range of the surge vessel preceding the subsequent step.
Original claim 14 is drawn to the process of Claim 13, wherein in-line or in-vessel conditioning of pH and/or conductivity load is performed between the one or more of steps (b), (c), (d), or (e).
Previously presented claim 49 is drawn to the process of Claim 1, wherein the first chromatography system is sanitized with a chemical sanitate solution comprising peracetic acid before use.
Previously presented claim 50 is drawn to the process of Claim 3, wherein the ultrafiltration/diafiltration system comprises a single pass tangential flow filtration (SPTFF), and the operating pressure of the SPTFF is controlled in a range of 0.25 psi to 60 psi.
Previously presented claim 51 is drawn to the process of Claim 3, wherein the ultrafiltration/diafiltration system comprises inline depth filtration (ILDF), and the operating pressure of the ILDF is controlled in a range of 0.25 psi to 60 psi.
Previously presented claim 53 is drawn to the process of Claim 3, wherein the process is conducted in a continuous format.
Previously presented claim 56 is drawn to the process of Claim 3, wherein the first chromatography system is sanitized with a chemical sanitate solution comprising peracetic acid before use.
Previously presented claim 57 is drawn to the process of Claim 6, wherein the first chromatography system is sanitized with a chemical sanitate solution comprising peracetic acid before use.
Previously presented claim 58 is drawn to the process according to Claim 3, further comprising the step of filtering the virally inactivated product pool by one or more depth filters or a filtration cart, between the low pH or detergent viral inactivation system and, if needed, the neutralization system, and the second chromatography system.
The teachings of Konstantinov in view of Wang as applied to claims 1, 4-8, 15-19, 48, 54 are set forth in the 103 rejection above.
With respect to claim 3, Konstantinov teaches a process wherein the purification of protein by MCCSl or the MCCS2, or both, involves column switching (para 0006). The process involves three columns to perform the unit operation of capturing the recombinant therapeutic protein from the liquid culture medium (para 0007). It is noted that the recitation of “to obtain a virus-free filtrate” is a “product-by-process” claim limitations. MPEP 2113 states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentabili