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.
Applicant’s amendment to the claims filed on 8/18/2025 in response to the Non-Final Rejection mailed on 4/17/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 39, 41-42, 48-55 are pending and examined on the merits.
Claims 1-38, 40, 43-47 are canceled.
Applicant’s remarks filed on 8/18/2025 in response to the Non-Final Rejection mailed on 4/14/2025 have been fully considered and are not 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/18/2025 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.
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 41-42, 48-55 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 42, 48-55 dependent thereof) recites the limitation "recombined" in line 13. 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 39, 41-42, 48, 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 4/17/2025) {herein Wang} 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} 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 4/17/2025) {herein GE Health}, the instant application, AKTA (2016, cytiva, cited on PTO-892 dated 4/17/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 4/17/2025) {herein Masterflex}, AKTA Valve (2025, Cytiva, cited on PTO-892 dated 4/17/2025) {herein AKTA valve} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 39 to recite ‘mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), from a plurality of different concentrated medium component solutions and recombined together’ and ‘comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
As amended, claims 39, 41-42, 48, 53-54 are drawn to a process for manufacturing a purified protein drug substance comprising a protein of interest, the process comprising the steps 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 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, 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 mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s),from a plurality of different concentrated medium component solutions and recombined together with an aqueous diluent that is a buffer or water, being added into the one or more perfusion bioreactors to maintain a constant culture volume in each of the 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, wherein the first chromatography system comprises a pump having pump speeds; and 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; (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; (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 the purified protein drug substance comprising the protein of interest; wherein: 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; the process automation system stores a first set of control modules to control operation of the one or more single-use perfusion bioreactors; and 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 the pre-set volume range in the single-use surge vessel.
With respect to claims 41, 42, 48, Konstantinov teaches a process 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). 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 to maintain a constant volume in relation to volumes of the culture and fed into a first multi-column chromatography system (MCCS 1) (para 0005 and fi. 1 #27). The mammalian cells 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 concentrated 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 that are 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. Konstantinov further teaches 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 vessel using a peristaltic pump (para 0230). Examiner is interpreting said small surge vessel to be SUSV1 since the harvest from 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 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). 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). 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), fluid volumes and columns of which 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 (Masteflex: page 4). Evidentiary reference of Masterflex is further 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). 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). Examiner is interpreting said components as being automated control strategies which enable the communication between component unit operations such as the bioreactor, filtration system and columns. Furthermore, Examiner is interpreting the Masterflex taught by Konstantinov as having a processor as it is known by those of ordinary skill in the art that processors are essential for controlling the pumps precise operations and integrating it into a fully automated chromatography system. 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. Said purification systems (MCCS1 and MCCS2) comprises equipment that are arranged in a configuration of a production line for the purified protein of interest (fig. 1). Konstantinov further teaches 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).
In an effect to clear the record, Examiner is interpreting the following limitations as not being requirements of the claim ‘if needed, a neutralization system, to obtain a virally inactivated product pool comprising the protein,’ do to the recitation ‘if needed.’ (claim 39). Furthermore, Examiner is interpreting the folloing limitations as not being requirements of the claim ‘(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,’ do to the recitation ‘optional.’
With respect to claims 53-54, 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). Absent evidence otherwise, Examiner is interpreting the third column within the ‘three columns’ taught by Konstatoinov to be a third chromatography system. Konstantinov further teaches that viruses are inactivated by a system consisting of holding the eluate containing recombinant therapeutic protein at a low pH (para 0007). Liquid culture medium obtained from a recombinant cell culture can be filtered or clarified to obtain a liquid culture medium that is substantially free of cells and/or viruses (para 0010). Examiner is interpreting the method of virally inactivating the purified protein at low pH coupled with its subsequent filtering as a viral filtration system.
However, Konstantinov does not teach wherein the fresh sterile liquid culture medium is mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s),from a plurality of different concentrated medium component solutions and recombined together with an aqueous diluent that is a buffer or water… switching the virus-free filtrate into an ultrafiltration/diafiltration system to obtain the purified protein drug substance comprising the protein of interest (claim 39).
With respect to claim 39, Wang teaches a method comprised of an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers for the purification of protein (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.
However, Wang does not teach ultrafiltration (claim 39).
With respect to claim 39, Gefroh teaches an automated facility for filtration is a 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).
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 and Gefroh because Gefroh teaches a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) for sufficient removal of impurities and its virus removal capacity (para 0132). Whereas, 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 and buffer 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, Wang and Gefroh because Gefroh provides the motivation for Konstantinov, to utilize an automated facility with pressure sensors to monitor the pressure within the filters to reduce the likelihood of clogs, leaks and excessive pressure within the filters that could negatively impact appropriate protein separation. In addition, said sensors could provide continuous data to indicate when filters need cleaning or replacement, thereby helping to control flow rates. Furthermore, Konstantinov would be motivated to utilize ultrafiltration, taught by Gefroh, because ultrafiltration would allow for the separation, purification and concentration of proteins from solution based on their size. Whereas, Wang provides the motivation for Konstantinov to utilize a plurality of different concentrated medium components for the purification of protein as said plurality of reservoirs containing different concentrated medium, that are fluidly connected to the bioreactor (fig. 4B #300), would create a temperature-controlled environment (Wang: para 0041) to maintain the activity of the purified protein and would maintain the sterility of the buffers and water. As such, one of ordinary skill in the art would have a reasonable expectation of success that combining the teachings of 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.
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 method of an automated facility for manufacturing purified protein of interest and its uses and methods of making it. Reference of Wang provides the teachings of an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602). Whereas Gefroh teaches an automated facility wherein pressure monitoring of the small-scale pre filters and virus filters was performed with SciPres® (SciLog, Madison, Wis.) pressure sensors and pressure monitor (para 0104) and wherein the filter is for ultrafiltration (para 0007). 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 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 39, 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 39 (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/or Wang and/or Gefroh) teaches an arrangement for feeding whole culture medium to the bioreactor that would require enormous amounts of whole culture medium to be pre-mixed from disparate concentrated components (see, e.g., Applicant's Specification at paragraphs [0416]-[0421]), before being placed in the reservoir feeding into the bioreactor, as shown in Konstantinov's Figure 2.
This argument is found to be not persuasive in view of the modified rejection set forth. Examiner contends that Applicant is not claiming a specific volume (instant application claim39). As such, Examiner contends that the burden of a large volume is not of relevance to the instant application.
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 39.
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 39, 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.
The rejection of claim 49 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 4/17/2025) {herein Wang} 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} (as applied to claims 39, 41-42, 48, 53-54) and Chassot et al. (2006, Braz Dent J, ISBN: 0103-6440, cited on PTO-892 filed 3/20/2024) {herein Chassot} 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 4/17/2025) {herein GE Health}, the instant application, AKTA (2016, cytiva, cited on PTO-892 dated 4/17/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 4/17/2025) {herein Masterflex}, AKTA Valve (2025, Cytiva, cited on PTO-892 dated 4/17/2025) {herein AKTA valve} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 39 to recite ‘mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s), from a plurality of different concentrated medium component solutions and recombined together’ and ‘comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
Previously presented claim 49 is drawn to the process of Claim 39, wherein the first chromatography system is sanitized with a chemical sanitant solution comprising peracetic acid before use.
The teachings of Konstantinov in view of Wang and Gefroh as applied to claims 39, 41-42, 48, 53-54 are set forth in the 103 rejection above.
However, Konstantinov in view of Wang and in further view of Gefroh do not teach the process of Claim 39, wherein the first chromatography system is sanitized with a chemical sanitant solution comprising peracetic acid before use (claim 49).
With respect to claim 49, Chassot teaches a process of using peracetic acid to sanitize resin (abstract), wherein said resin is disinfected with peracetic before utilization (page 120, column 1, paragraph 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 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, Gefroh and Chassot because Chassot teaches a process of using peracetic acid to sanitize resin (abstract). Said resin is disinfected with peracetic before utilization (page 120, column 1, paragraph 2). Gefroh teaches a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) for sufficient removal of impurities and its virus removal capacity (para 0132). Whereas, 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 and buffer 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 the Konstantinov, Wang, Gefroh and Chassot because Chassot provides Konstantinov with the motivation to sanitize the first chromatography system with a chemical sanitant comprising peracetic because Chassot shows it is an effective disinfectant of thermosensitive and porous materials (Chassot: page 118, column 2, paragraph 3) and it is known by those skilled in the art that resin is both thermosensitive and porous. The utilization of said acid for the disinfection of resin before chromatography would save time and resources involved in protein purification by reducing the risk of contamination.
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 method of an automated facility for manufacturing purified protein of interest and its uses and methods of making it. Reference of Wang provides the teachings of an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602). Gefroh teaches an automated facility wherein pressure monitoring of the small-scale pre filters and virus filters was performed with SciPres® (SciLog, Madison, Wis.) pressure sensors and pressure monitor (para 0104) and wherein the filter is for ultrafiltration (para 0007). Whereas Chassot teaches a process of using peracetic acid to sanitize resin (abstract), wherein said resin is disinfected with peracetic before utilization (page 120, column 1, paragraph 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 41-42, 48-55, directly or indirectly depend from Claim 39, and, thus, they contain all the limitations of amended Claim 39, the cited Konstantinov, Wang, Broadley James, GE Health, AKTA, Masterflex, Gefroh, Chassot, Casey 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 Konstantinov, Wang, Broadley James, GE Health, AKTA, Masterflex, Gefroh, Chassot, Casey and/or Khanal teaches the limitations of claims 41-42, 48-55 and provides the motivation for one or ordinary skill in that art to make and use a process for manufacturing a purified protein of interest based on the teachings within the 103 rejection.
The rejection of claim 50 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 4/17/2025) {herein Wang} 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} as applied to claim 39, 41-42, 48, 53-54 and Casey et al (2011, Journal of Membrane Science, cited on PTO-892 dated 4/17/2025) {herein Casey} 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 4/17/2025) {herein GE Health}, the instant application, AKTA (2016, cytiva, cited on PTO-892 dated 4/17/2025) {herein ATKA}, Masterflex (2025, Masterflex Peristaltic Pump Systems, cited on PTO-892 dated 4/17/2025) {herein Masterflex}, AKTA Valve (2025, Cytiva, cited on PTO-892 dated 4/17/2025) {herein AKTA valve} is maintained. The rejection has been modified in view of Applicant’s amendment of claim 39 to recite ‘mixed contemporaneously in less than or equal to 2 minutes of when needed to replace volumes of medium in the perfusion bioreactor(s),from a plurality of different concentrated medium component solutions and recombined together’ and ‘comprising hardware and/or software components configured to execute automated control strategies and enable communication between component unit operations.’
Previously presented claim 50 is drawn to the process of Claim 39, 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.
The teachings of Konstantinov in view of Wang and Gefroh as applied to claims 39, 41-42, 48, 53-54 are set forth in the 103 rejection above.
With respect to claim 50, 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).
However, Konstantinov in view of Wang and in further view of Gefroh do not teach 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 (claim 50).
With respect to claim 50, Casey teaches a process wherein ultrafiltration is mainly utilized for the concentration and purification of protein (page 82, column 1, paragraph 1). Single-pass tangential filtration improves the overall separation and performance of ultrafiltration (page 82, column 1, paragraph 2). The optimum psi is 42.696 (28 psig + 14.696) (page 84, column 2, paragraph 1).
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 and Casey because Casey teaches a process wherein ultrafiltration is mainly utilized for the concentration and purification of protein (page 82, column 1, paragraph 1). Gefroh teaches a system wherein ultrafiltration is employed for the purification of product (para 0004 and 0007) for sufficient removal of impurities and its virus removal capacity (para 0132). Whereas, 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 and buffer 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, Wang, Gefroh and Casey because Casey provides a process for concentrating protein utilizing single pass tangential flow filtration (page 83, column 1, paragraph 1). One would have a reasonable expectation of success since single-pass tangential flow filtration modules consist of internally staged T-series cassettes for creating longer flow paths that result in significantly higher conversion in one pass (Casey: abstract). This eliminates the need for the conventional TFF recirculation loop (Casey: abstract). Konstantinov would be motivated to utilize single-pass tangential because Casey has shown it is effective at concentrating protein (abstract). Furthermore, single-pass tangential filtration improves the overall separation and performance of ultrafiltration (page 82, column 1, paragraph 2) by reducing the adverse effects of the concentration polarization layer (page 82, column 1, paragraph 2). The utilization of said process to concentrate protein would save time and expenses associated with concentrating protein by conventional means such as lyophilization, centrifugation, etc.
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 method of an automated facility for manufacturing purified protein of interest and its uses and methods of making it. Reference of Wang provides the teachings of an automated system (para 0133) comprised of a plurality of reservoirs containing fresh media and buffers (fig. 4B #602). Gefroh teaches an automated facility wherein pressure monitoring of the small-scale pre filters and virus filters was performed with SciPres® (SciLog, Madison, Wis.) pressure sensors and pressure monitor (para 0104) and wherein the filter is for ultrafiltration (para 0007). Whereas Casey teaches a process wherein ultrafiltration is mainly utilized for the concentration and purification of protein (page 82, column 1, paragraph 1). 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 41-42, 48-55, directly or indirectly depend from Claim 39, and, thus, they contain all the limitations of amended Claim 39, the cited Konstantinov, Wang, Broadley James, GE Health, AKTA, Masterflex, Gefroh, Chassot, Casey 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 Konstantinov, Wang, Broadley James, GE Health, AKTA, Masterflex, Gefroh, Chassot, Casey and/or Khanal teaches the limitations of claims 41-42, 48-55 and provides the motivation for one or ordinary skill in that art to make and use a process for manufacturing a purified protein of interest based on the teachings within the 103 rejection.
The rejection of claims 51, 55 under 35 U.S.C. 103