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 8/14/2025 in response to the Non-Final Rejection mailed on 4/14/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 43, 45-47, 52-55 are pending and examined on the merits.
Claims 1-42, 44, 48-51 are canceled.
Applicant’s remarks filed on 8/14/2025 and 8/20/2025 in response to the Non-Final Rejection mailed on 4/14/2025 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 7/8/2024 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent Application No. 17/396,725 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/14/2025 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Withdrawn Rejections
The provisional rejection of claims 43, 45-47, 52-55 on the ground of nonstatutory double patenting as being unpatentable over claims 20, 22, 25, 27, 37, 38, 52 of U.S. Patent Application No. 17/396,725 {herein ‘725} is withdrawn in view of Applicant’s submission of a terminal disclaimer over US Application No: 17/396,725 dated 7/8/2024.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The rejection of claims 43, 45-47, 53-54 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 4/14/2025) {herein Wang} and Gefroh et al. (2017, US 2017/0157566 A1, Date Published Jun. 8, 2017, cited on IDS filed 8/8/2021) {herein Gefroh} as evidenced by Broadley James (2024, https://www.broadleyjames.eu/product/single-use-bioreactor-system/, cited on PTO-892 dated 4/14/2025) {herein Broadley James}, GE Heath (2024, https://www.fishersci.at/shop/products/unicorn-start-1-0/15279784, cited on PTO-892 dated 4/14/2025) {herein GE Health}, AKTA (2016, cytiva, cited on PTO-892 dated 4/14/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 4/14/2025) {herein Masterflex}, AKTA Valve (2025, Cytiva, cited on PTO-892 dated 4/14/2025) {herein AKTA valve} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 43 to recite ‘a process automation system (PAS), comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
As amended, claims 43, 45-47, 53 are drawn to an automated facility for manufacturing a purified protein drug substance, the facility comprising: (a) one or more single-use perfusion bioreactors capable of containing a liquid culture medium under conditions that allow cultured mammalian cells in suspension to secrete a protein of interest into the medium for a production cultivation period of at least 10 days; wherein the single-use perfusion bioreactor(s) are adapted to receive fresh sterile liquid culture medium fluidly into each of the perfusion bioreactor(s) in direct relation to volumes of conditioned culture medium that are continuously or periodically removed from each of the perfusion bioreactor(s) as volumes of permeate or cell bleed during the production cultivation period; (b) a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent that is a buffer or water, wherein the plurality of reservoirs is fluidly connected directly to the perfusion bioreactor(s) for delivery of the concentrated culture medium component solutions and aqueous diluent at predetermined ratios directly to the bioreactor(s), or wherein the plurality of reservoirs is indirectly connected to the perfusion bioreactor(s) via an optional mixing vessel, adapted for receiving from the plurality of reservoirs, the concentrated culture medium component solutions and aqueous diluent at predetermined ratios and contemporaneously mixing them together in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), the optional mixing vessel being fluidly connected directly to the perfusion bioreactor(s); (c) a first single-use surge vessel (SUSV1) into which said removed volumes of permeate are automatically and fluidly fed from the one or more single-use perfusion bioreactor(s); (d) a first chromatography system, adapted to automatically and fluidly receive permeate from the SUSV1, whereby the protein is captured in a protein isolate fraction; (e) a low pH or detergent viral inactivation system and, if needed, a neutralization system, adapted to automatically and fluidly receive the protein isolate fraction from the first chromatography system, whereby a virally inactivated product pool comprising the protein is obtained; (f) a holding vessel or a single-use surge vessel, adapted for receiving the virally inactivated product pool; (g) a second chromatography system adapted to fluidly receive the virally inactivated product pool, whereby a purified product pool comprising the protein is obtained; (h) an optional third chromatography system and/or a viral filtration system adapted to fluidly receive the purified product pool comprising the protein from the second chromatography system, whereby a virus-free filtrate comprising the protein is obtained; and (i) an ultrafiltration/diafiltration system adapted to fluidly receive the virus-free filtrate from the second chromatography system or from the third chromatography system and/or the viral filtration system, whereby the purified protein drug substance is obtained; and wherein the automated facility is controlled by a process automation system (PAS), comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations; wherein the PAS is in electronic communication at least with the one or more single-use perfusion bioreactors, with the SUSV1, and with the first chromatography system; wherein the PAS stores a set of control modules to control operation of the one or more single- use perfusion bioreactors; and wherein the PAS stores a set of control modules to control the volumes contained in each of the SUSV1 and the holding vessel or the single-use surge vessel, within pre-set volume range limits.
With respect to claims 43, 45-47, 53, Konstantinov teaches 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). The process comprises culturing mammalian cells that secrete a recombinant therapeutic protein in a perfusion bioreactor (fig. 1, #25) and 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). Bioreactors from Broadley-James Corp were utilized during experimentation (para 0261). Evidentiary reference of Broadley James is cited to demonstrated that said bioreactor is a single-use bioreactor system (page 1). A liquid culture medium typically contains an energy source (e.g., a carbohydrate, such as glucose), essential amino acids ( e.g., the basic set of twenty amino acids plus cysteine ), vitamins and/or other organic compounds required at low concentrations, free fatty acids, and/or trace elements (column 52, lines 17-22). Examiner is interpreting said culture medium to be a concentration medium component as it contains the materials needed for cellular growth. Furthermore, Konstantinov teaches this fluid conduit can include a filter that is capable of removing cells from the liquid culture medium removed from the bioreactor (e.g., ATF cell retention system) (para 0105 and fig 2). Examiner is interpreting the bioreactor of fig.1 (#25) to receive media from the media feed vessel of fig.2. 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). Examiner is interpreting said media is fed through an inlet into the bioreactor since Konstantinov teaches adding substantially the same volume of a second liquid culture medium to the bioreactor (para 0050). 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 vessels 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. 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 if the pump, control the volume dispense and flow rates (page 4). Additionally, operational modes include continuous run, volume dispense, time dispense, batch control and interval/off time in volume and time modes (page 4). Furthermore, integrated sensors monitor fluid pressure and various levels of programming (page 4). As such, Examiner is interpreting the Masterflex Peristaltic Pump System to be synonymous to the claimed PAS, as said pump is able to store protocol information, monitor flow rates and control the volume of fluid dispensed. 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). Said pump controls the operation of the bioreactor, filtration system (examiner interpreted SUSV1) and columns of which Examiner is interpreting as being automated control strategies which enable the communication between component unit operations such as the bioreactor, filtration system and columns. In addition, Examiner is interpreting the bioreactor, filtration system and columns to be first pieces of equipment. A 0.2um filter was added between the bioreactor and the vessel as an additional sterile barrier (para 0230). The liquid culture medium is fed into a first multi-column chromatography system (MCCSl); (ii) capturing the recombinant therapeutic protein in the liquid culture medium 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 (iii) purifying and polishing the recombinant therapeutic protein using the MCCS2, where the eluate from the MCCS2 is a therapeutic protein drug substance; 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). The Masterflex Peristaltic Pump System controls the rate of flow of liquids throughout both column systems (MCCSI and MCCS2) (figs 1 and 9). Examiner is interpreting MCCSI as the first chromatography system. Examiner is interpreting MCCS2 as the second chromatography system. The MCCSl and/or the MCCS2 utilizes at least two chromatography columns (fig. 9). The MCCSl performs the unit operations of capturing the recombinant therapeutic protein and inactivating viruses (para 0006). As such, Examiner is interpreting said system as a viral inactivation system. The reservoir that is used to perform the unit operation of inactivation of viruses can be a 500-mL stir flask with a programmed stir plate (e.g., a stir plate programmed to mix (e.g., periodically mix) (para 0158). The MCCS2 performs the unit operations of purifying and polishing the recombinant therapeutic protein (para 0006). Examiner is interpreting the MCCS2 to be a filtration system since it receives virus free filtrate from MCCS1 and purifies and polishes the recombinant protein. The entire process runs continuously from the liquid culture medium to the eluate from the MCCS2 (para 0010). Unformulated drug substance is captured as the end product (fig. 9). Examiner is interpreting the vessel holding the unformulated drug substance to be a holding vessel. The single PCCS was operated using a control strategy utilizing dynamic UV monitoring (para 0240). A feed stream is processed continuously in an operating PCC system (para 0238). UV detectors can be placed optionally at the inlet of one or more chromatography systems (column 19, line 27-18; fig.1 #7). Examiner is interpreting the UV detector within said system configuration to be different than the first system configuration. The first MCCS can also be equipped with an operating system that utilizes software (e.g., Unicom-based software, G E Healthcare, Piscataway, N.J.) for sensing when a column-switching should occur ( e.g., based upon U V absorbance, volume of liquid, or time elapsed) and affecting (triggering) the column-switching events (column 19, lines 20-26). Examiner is interpreting sensing of column switching based on UV absorbance to be different from the first function, thereby being the second function. Non-limiting examples of recombinant therapeutic proteins that can be produced by the methods provided herein include immunoglobulins (including light and heavy chain immunoglobulins, antibodies, or antibody fragments (e.g., any of the antibody fragments described herein), enzymes (e.g., a galactosidase (e.g., an alpha-galactosidase), myozyme, or Cerezyme), proteins (e.g., human erythropoietin, tumor necrosis factor (TNF), or an interferon alpha or beta), or immunogenic or antigenic proteins or protein fragments (e.g., proteins for use in a vaccine) (para 0126).
Examiner is interpreting the recitations an optional mixing vessel, adapted for receiving from the plurality of reservoirs, the concentrated culture medium component solutions and aqueous diluent at predetermined ratios and contemporaneously mixing them together in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), the optional mixing vessel being fluidly connected directly to the perfusion bioreactor(s), of claim 43; (h) an optional third chromatography system and/or a viral filtration system adapted to fluidly receive the purified product pool comprising the protein from the second chromatography system’ of claim 43 to be limitations that are not requirements of the claims due to the recitation ‘optional.’
However, Konstantinov does not teach a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent that is a buffer or water, wherein the plurality of reservoirs is fluidly connected directly to the perfusion bioreactor(s) for delivery of the concentrated culture medium component solutions and aqueous diluent at predetermined ratios directly to the bioreactor(s), or wherein the plurality of reservoirs is indirectly connected to the perfusion bioreactor(s) via an optional mixing vessel, adapted for receiving from the plurality of reservoirs, the concentrated culture medium component solutions and aqueous diluent at predetermined ratios and contemporaneously mixing them together in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), the optional mixing vessel being fluidly connected directly to the perfusion bioreactor(s) (claim 43).
With respect to claim 43, 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). The plurality of reservoirs containing culture media, PBS (Phosphate Buffer Saline) are fluidly connected to the bioreactor (fig. 4B #300). 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 ‘(b) a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent that is a buffer or water.’ 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).
However, Wang does not teach an ultrafiltration/diafiltration system adapted to fluidly receive the virus-free filtrate from the second chromatography system or from the third chromatography system and/or the viral filtration system, whereby the purified protein drug substance is obtained (claim 43). The product of claim 54, comprising in (h): a third chromatography system and a viral filtration system, adapted to fluidly receive the purified product pool comprising the protein from the second chromatography system, whereby a virus- free filtrate comprising the protein is obtained (claim 54).
With respect to claim 43, Gefroh teaches an automated facility wherein filtration is pressure driven process that uses membranes to separate components in a liquid solution or suspension according to size differences between the components (para 0004). The filtration may be referred to as ultrafiltration (para 0007).
With respect to claim 54, Gefroh teaches an automated facility wherein the second step specified in the connected process schematic is operated in flowthrough mode, and could be either resin-based or membrane-based chromatography (para 0132). This second step is usually the third and last chromatography step for the entire downstream process, however, it may not be required when a two-column process demonstrated sufficient impurity and virus removal capacity (para 0132). Examiner is interpreting the third and last chromatography step to be the third chromatography system.
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 an automated facility for manufacturing a therapeutic protein drug substance that includes 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 and Gefroh because Gefroh teaches a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) and a third chromatography system for its sufficient impurity and virus removal capacity (para 0132). 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).
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, in view of Wang and Gefroh because Gefroh provides the motivation for Konstantinov to incorporate ultrafiltration, a third chromatography system and a plurality of reservoirs for culture medium and buffers into the purification process because doing so, would remove host cell proteins and potentially further reduce the quantity of undesired macormolecules (para 0132) while creating a temperature-controlled environment (Gefroh: para 0041) to maintain the activity of the purified protein. Wang provides the motivation for Konstantinov to utilize an automated system that utilizes a plurality of reservoirs containing fresh media and buffers (fig. 4B #602), wherein the plurality of reservoirs are fluidly connected to the bioreactor (fig. 4B #300) because doing so would create a temperature-controlled region (para 0041) that 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 ordinary skill in the art would have a reasonable expectation of success that combining Konstantinov, Wang and Gefroh 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. In addition, it would reduce the costs associated with protein purification by reducing the likelihood of the purified protein being contaminated with viruses, particulate matter and reduce the likelihood of protein denaturation.
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 and ultrafiltration system 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). Whereas Gefroh provides the teaching of a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) and a third chromatography system for its sufficient impurity and virus removal capacity (para 0132). 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 an automated facility for manufacturing a purified protein drug substance depending on the particular application. It would be routine for one to arrive at the automated facility for manufacturing a purified protein drug substance for the application they intend on using the purified protein of interest as said automated facility 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 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.
This argument is found to be not persuasive in view of the modified rejection set forth. Respectfully, Examiner contends that the recited ‘optional mixing vessel’ is not a requirement of the claim due to the recitation ‘optional.’ As such, Konstantinov’s teaching or lack of teaching ‘mixing’ is not a limitation that is required by Konstantinov. However, in order to practice compact prosecution, 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 cited Wang reference, which pertains to culturing cells adherent to a solid substrate rather than to "cultured cells in suspension," as recited in amended Claim 43, subpart (a), fails to correct the deficiencies of Konstantinov.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Wang is not relied upon to teach ‘cultured cells in suspension.’ 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 Konstantinov teaches ‘the mammalian cell can be a cell that grows in suspension’ (para 0184).
Applicant contends that Wang fails to disclose or suggest a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent structured "for delivery of the concentrated culture medium component solutions and aqueous diluent at predetermined ratios directly to the bioreactor(s)," as recited in Claim 43, subpart (b).
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends Wang teaches the plurality of reservoirs containing culture media, PBS (Phosphate Buffer Saline) are fluidly connected to the bioreactor (fig. 4B #300). 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 ‘(b) a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent that is a buffer or water.’ Absent evidence otherwise, 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).
Applicant contends that nowhere 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 43, subpart (b).
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that the recitation ‘or wherein the plurality of reservoirs is indirectly connected to the inlet into each of the perfusion bioreactor(s) via an optional mixing vessel adapted for receiving from the plurality of reservoirs the concentrated culture medium component solutions and aqueous diluent at predetermined ratios and contemporaneously mixing them together in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), the optional mixing vessel being fluidly connected directly to the inlet into each of the perfusion bioreactor(s)’ in claim 43 of the instant application is not a required limitation due to the recitation ‘or.’ Specifically, the recitation ‘(b) a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent that is a buffer or water, wherein the plurality of reservoirs is fluidly connected to the inlet into each of the perfusion bioreactor(s) directly for delivery of the concentrated culture medium component solutions and aqueous diluent at predetermined ratios directly to the bioreactor(s), or wherein the plurality of reservoirs is indirectly connected to the inlet into each of the perfusion bioreactor(s) via an optional mixing vessel adapted for receiving from the plurality of reservoirs the concentrated culture medium component solutions and aqueous diluent at predetermined ratios and contemporaneously mixing them together in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), the optional mixing vessel being fluidly connected directly to the inlet into each of the perfusion bioreactor(s)’ is interpreted by Examiner as one of two limitations are required by the instant application claim 43, with the limitations being a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent that is a buffer or water, wherein the plurality of reservoirs is fluidly connected to the inlet into each of the perfusion bioreactor(s) directly for delivery of the concentrated culture medium component solutions and aqueous diluent at predetermined ratios directly to the bioreactor(s) OR wherein the plurality of reservoirs is indirectly connected to the inlet into each of the perfusion bioreactor(s) via an optional mixing vessel adapted for receiving from the plurality of reservoirs the concentrated culture medium component solutions and aqueous diluent at predetermined ratios and contemporaneously mixing them together in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), the optional mixing vessel being fluidly connected directly to the inlet into each of the perfusion bioreactor(s). Examiner contends Konstantinov teaches the limitation of ‘a plurality of reservoirs, each adapted for containing a concentrated medium component solution or aqueous diluent that is a buffer or water, wherein the plurality of reservoirs is fluidly connected to the inlet into each of the perfusion bioreactor(s) directly for delivery of the concentrated culture medium component solutions and aqueous diluent at predetermined ratios directly to the bioreactor(s), as stated in the 103 rejection.
Applicant contends that the Masterflex reference also fails to describe or suggest "a process automation system" that "stores a set of control modules to control operation of the one or more single-use perfusion bioreactors," as recited in amended Claim 43, after subpart (i).
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, based on Applicant’s definition of ‘surge vessel’ (The term "surge vessel" means a storage reservoir, mixing vessel, feed tank, or collection vessel (or interchangeably, a "collection tank")) in the specification, Konstantinov does not teach said limitation.
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.
Applicant contends 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."
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, as such is not a required limitation that has to be taught and/or obvious in view of the applied art..
The rejection of claim 52 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 4/14/2025) {herein Wang}, Gefroh et al. (2017, US 2017/0157566 A1, Date Published Jun. 8, 2017, cited on IDS filed 8/8/2021) {herein Gefroh} as applied to claims 43, 45-47, 53-54 and Schofield et al (Date Published: September 28, 2018, biopharma international, cited on PTO-892 dated 4/14/2025) {herein Schofield} as evidenced by Broadley James (2024, https://www.broadleyjames.eu/product/single-use-bioreactor-system/, cited on PTO-892 dated 4/14/2025) {herein Broadley James}, GE Heath (2024, https://www.fishersci.at/shop/products/unicorn-start-1-0/15279784, cited on PTO-892 dated 4/14/2025) {herein GE Health}, AKTA (2016, cytiva, cited on PTO-892 dated 4/14/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 4/14/2025) {herein Masterflex}, AKTA Valve (2025, Cytiva, cited on PTO-892 dated 4/14/2025) {herein AKTA valve} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 43 to recite ‘a process automation system (PAS), comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
Previously presented claim 52 is drawn to the automated facility of Claim 43, comprising in (e): a low pH viral inactivation system and a neutralization system, adapted to automatically and fluidly receive the protein isolate fraction from the first chromatography system, whereby a virally inactivated product pool comprising the protein is obtained.
The teachings of Konstantinov in view of Wang and Gefroh as applied to claims 43, 45-47, 53-54 are set forth in the 103 rejection above.
However, Konstantinov in view of Wang and Gefroh do not teach the automated facility of Claim 43, comprising in (e): a low pH viral inactivation system and a neutralization system, adapted to automatically and fluidly receive the protein isolate fraction from the first chromatography system, whereby a virally inactivated product pool comprising the protein is obtained (claim 52).
With respect to claim 52, Konstantinov teaches fluidly collecting downstream from the first chromatography system a protein isolation faction from automatically switching columns (fig 1. #9, #10, #11) into a fourth column (fig 1. #12) wherein inactivation of viruses can take place (para 0091). Examiner is interpreting the columns (fig 1. #9, #10, #11) as alternate single-use collection vessels as they receive isolated protein from the first column system and deliver it into column 4 (fig 1. #12) for virus inactivation. Viral inactivation takes place in low pH conditions (para 0158).
However, Konstantinov does not teach a neutralization system (claim 52).
With respect to claim 52, Schofield teaches two basic approaches are viable for virus inactivation: a continuous plug flow reactor with in-line pH reduction, hold, and neutralization; and a multi-vessel continuously stirred-tank reactor (CSTR) with in-situ pH reduction, hold, and neutralization (page 2, para 2).
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 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, Gefroh, Schofield because Schofield teaches two basic approaches are viable for virus inactivation: a continuous plug flow reactor with in-line pH reduction, hold, and neutralization; and a multi-vessel continuously stirred-tank reactor (CSTR) with in-situ pH reduction, hold, and neutralization (page 2, para 2). Gefroh teaches a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) along with a third chromatography system for its sufficient impurity and virus removal capacity (para 0132). Wang teaches an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602).
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 Konstantinov, Wang, Gefroh and Schofield because Schofield provides the motivation Konstantinov, in view of Wang and Gefroh to neutralize the purified protein by utilizing a neutralization system as said system is commonly employed by the industry and accepted by the regulatory authorities for the neutralization of viruses (Schofield: page 2, para 3). One of ordinary skill in that art would have a reasonable expectation of success to utilize the neutralization system during protein purification as doing so, in conjunction with the low pH viral inactivation system taught by Konstantinov would result in a purified protein fraction free of viral particles that could inadvertently cause the purified protein to aggregate in solution. Thereby, a low pH protein inactivation and neutralization system during protein purification would reduce the costs associated with protein purification by reducing the likelihood of the purified protein being contaminated with viruses.
One of skill in the art would have a reasonable expectation of success to make and use the claimed viral inactivation system 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). Gefroh provides the teaching of a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) and a third chromatography system for its sufficient impurity and virus removal capacity (para 0132). Whereas Schofield provides the teachings of two basic approaches are viable for virus inactivation: a continuous plug flow reactor with in-line pH reduction, hold, and neutralization; and a multi-vessel continuously stirred-tank reactor (CSTR) with in-situ pH reduction, hold, and neutralization (page 2, para 2). 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.
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 since Claims 45-47, and 52-55, directly or indirectly depend from Claim 43, and, thus, they contain all the limitations of amended Claim 43, the cited Konstantinov, Wang, Gefroh, Broadley James, GE Health, AKTA, Masterflex, Schofield and/or Khanal references also fail to make obvious all the limitations of these claims.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Konstatinov in view of Wang, Gefroh and in further view of Schofield teaches the limitations of claim 52 and provides the motivation for one or ordinary skill in that art to make and use an automated facility for manufacturing a purified protein drug substance (instant application claim 43) based on the teachings within the 103 rejection.
The rejection of claim 55 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 4/14/2025) {herein Wang}, Gefroh et al. (2017, US 2017/0157566 A1, Date Published Jun. 8, 2017, cited on IDS filed 8/8/2021) {herein Gefroh} as applied to claims 43, 45-47, 53-54 and Khanal et al (Date Accepted: 6 April 2018, Wiley Biotechnology Bioengineering, cited on PTO-892 dated 4/14/2025) {herein Khanal} as evidenced by Broadley James (2024, https://www.broadleyjames.eu/product/single-use-bioreactor-system/, cited on PTO-892 dated 4/14/2025) {herein Broadley James}, GE Heath (2024, https://www.fishersci.at/shop/products/unicorn-start-1-0/15279784, cited on PTO-892 dated 4/14/2025) {herein GE Health}, the instant application, AKTA (2016, cytiva, cited on PTO-892 dated 4/14/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 4/14/2025) {herein Masterflex}, AKTA Valve (2025, Cytiva, cited on PTO-892 dated 4/14/2025) {herein AKTA valve} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 43 to recite ‘a process automation system (PAS), comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
Previously presented claim 55 is drawn to the automated facility according to Claim 43, further comprising one or more depth filters or a filtration cart, which operates between the low pH or detergent viral inactivation system and, if needed, the neutralization system, and the second chromatography system, to filter the virally inactivated product pool before it is received by the second chromatography system.
The teachings of Konstantinov in view of Wang and Gefroh as applied to claims 43, 45-47, 53-54 are set forth in the 103 rejection above.
With respect to claim 55, Konstantinov teaches a filter (fig.1 #18) between PCCS1 and PCCS2 (fig 1.)
However, Konstantinov in view of Wang and Gefroh do not teach depth filter or a filtration cart (claim 55).
With respect to claim 55, Khanal teaches depth filtration is widely used in downstream bioprocessing to remove particulate contaminants via depth straining and is therefore applied to harvest clarification and other processing steps (abstract).
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 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, Gefroh, Khanal because Khanal teaches depth filtration is widely used for protein purification in downstream bioprocessing to remove particulate contaminants via depth straining and is therefore applied to harvest clarification and other processing steps (abstract). Gefroh teaches a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) and a third chromatography system for its sufficient impurity and virus removal capacity (para 0132). While Wang teaches an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602).
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, Wang, Gefroh and Khanal because Khanal provides the motivation for Konstatinov, in view of Wang and Gefroh to use depth filtration as depth filtration is widely used in downstream bioprocessing to remove particulate contaminants via depth straining and is therefore applied to harvest, for clarification and other processing steps (abstract). One of ordinary skill in the art would have a reasonable expectation of success to use depth filtration coupled with an automated facility for manufacturing a purified drug substance as depth filtration also removes proteins via adsorption, which can contribute variously to impurity clearance and reduction in product yield (Khanal: abstract). Thereby, utilizing a depth filter during protein purification would reduce the costs associated with protein purification by reducing the likelihood of the purified protein being contaminated with particulate matter.
One of skill in the art would have a reasonable expectation of success to make and use the claimed depth filters because 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). Gefroh provides the teaching of a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) and a third chromatography system for its sufficient impurity and virus removal capacity (para 0132). Whereas Khanal provides the teaching that depth filtration is widely used in downstream bioprocessing to remove particulate contaminants via depth straining and is therefore applied to harvest clarification and other processing steps (abstract). 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.
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 since Claims 45-47, and 52-55, directly or indirectly depend from Claim 43, and, thus, they contain all the limitations of amended Claim 43, the cited Konstantinov, Wang, Gefroh, Broadley James, GE Health, AKTA, Masterflex, Schofield and/or Khanal references also fail to make obvious all the limitations of these claims.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Konstatinov in view of Wang, Gefroh and in further view of Khanal teaches the limitations of claim 55 and provides the motivation for one or ordinary skill in that art to make and use an automated facility for manufacturing a purified protein drug substance (instant application claim 43) based on the teachings within the 103 rejection.
Conclusion
Status of the Claims:
Claims 43, 45-47, 52-55 are pending.
Claims 1-42, 44, 48-51 are canceled.
Claims 43, 45-47, 52-55 are rejected.
No claims are in condition for allowance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS