DETAILED ACTION
Applicant’s response filed 4/24/2026 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Claims 1-3, 5-6, 8-9, 12, 16, 18-24, 26-28, and 30 of the claim set filed 4/24/2026 are pending. Claims 4, 7, 10-11, 13-15, 17, 25, and 29 are cancelled. Claims 8-9 ,21-22, and 30 are withdrawn. Thus, claims 1-3, 5-6, 12, 16, 18-20, 23-24, and 26-28 are being examined on the merits herein.
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 .
Objection(s)/Rejection(s) Withdrawn
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
RE: Claims 1-3, 12, 16, 18 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Roy (WO 2018/075940 A1, published 4/26/2018; IDS filed 12/22/2021; cited in the Incoming Written Opinion of the International Searching Authority filed 6/10/2021).
Applicant amended claims 1 and 16 to now require: measuring, using at least one sensor, automatically introducing a volume effective to treat the cells for cell therapy of at least one additive… the volume effective of the at least one additive determined and introduced by a controller operatively connected to the at least one sensor in response to the determined cell state.
Roy does not teach the newly added limitations and as such the previously filed rejections are withdrawn. However, Applicant amendment has necessitated new grounds of rejection, as set forth below.
RE: Claims 5-6, 19-20, 24, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Roy in view of Janas (Janas, et al., BioProcess International (2015), Perfusion’s Role in Maintenance of High-Density T-Cell Cultures, retrieved on 1/20/2026 from https://www.bioprocessintl.com/bioreactors/perfusion-s-role-in-maintenance-of-high-density-t-cell-cultures; PTO 892).
For the reasons discussed above, the obviousness rejection over Roy is withdrawn, and thus the obviousness rejections of the dependent claims (i.e., the obviousness rejections of claims 5-6 and 19-20) that are based on the same basis are likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection, as set forth below.
In regards to independent claim 24, Roy and Janas do not teach of the newly amended claim limitations and thus the previously filed rejections of independent claim 24 and dependent claims 26-28 are withdrawn. However, Applicant amendment has necessitated new grounds of rejection, as set forth below.
New ground(s) of Rejection, necessitated by Amendment
Restriction/Election
Applicant amended the instant application 4/24/2026 and added new claim 30 drawn to “wherein the at least one additive is a transducing agent.” Said claim is drawn to a non-elected species. Per Applicant remarks filed 10/23/2024, Applicant elected species I, which pertains to wherein the additive is the pH control element.
Thus, claim 30 is withdrawn as being drawn to a non-elected species.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 12, 16, 18 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Roy in view of Welch (Welch, et al., Lab Chip (2014) 14:1191-1197; PTO 892) and Naciri (Naciri, et al., Cytotechnology (2008) 57: 245-250; PTO 892).
In regards to claims 1 and 16, Roy teaches immunotherapy using adoptive T cell transfer (ACT) is a highly promising approach in treating cancers, infectious and autoimmune diseases, as well as for transplantation associated problems (p1, lines 22-25).
Briefly, Roy teaches a method of expanding, activating, and/or transfecting suspension cells, the method comprising: obtaining a blood sample from a patient; isolating suspension cells from the blood sample; introducing the suspension cells to a bioreactor comprising a porous microcarrier; activating the suspension cells; expanding the suspension cells; optionally transfecting the suspension cells; preparing the suspension cells for transfusion into the patient; and transfusing the suspension cells into the patient (p5, lines 23-28).
Thus, Roy teaches a method of treating cells for cell therapy.
In regards to a perfusion chamber, Roy teaches of microcarriers used in combination with modem bioreactors to create 3D niches. Roy teaches the high surface density of these microcarriers encourage high cell density and efficient signaling, while cytokine requirements, media usage, and bioreactor footprint are reduced (p22, Example 1). Roy teaches the bioreactor comprises a closed bioreactor and an open bioreactor with the closed bioreactor comprising a stirred-type bioreactor, a bag bioreactor and a perfusion bioreactor (p5, lines 1-5). In some embodiments of the present disclosure, stirred-tank type ambrTM micro-bioreactor systems (TAP Biosystems) that allow bioprocess optimization at microscale (10- 15 ml) are used, mimicking the core characteristics of classical bioreactors, but with reduced use of media and growth factors.
Thus, Roy teaches a perfusion chamber and further teaches a perfusion chamber with a working volume of 10-15 mL, i.e., a volume of 50 mL or less.
In regards to introducing a media comprising at least about 3x10^6 cells/mL (i.e., claim 1) into a perfusion chamber having a volume of 50 mL or less, Roy teaches a cell culture media with a cell density of 2.5x10^6 cells/mL (p29, lines 5-8). Examiner notes the sole difference between the cell density of Roy and the instant application comprises only the routine optimization of cell density. Said optimization would have been obvious and well-within the purview of the ordinarily skilled artisan at the time of filing. Examiner notes Roy teaches a smaller working volume, i.e., 10-15 mL, as compared to the larger working volume, i.e., 50 mL or less, of the instant application. As Roy uses a smaller volume, so does Roy use a slightly lesser cell density. Additionally, Examiner notes Roy teaches microcarriers allow for high density cell culture; typically, about two orders of magnitude higher cell densities (up to 2x 108 cells/mL, compared to 2-3x 106/mL cells without microcarrier) (p12, lines 10-22).
As a POSITA will appreciate, cell density is a result effective variable based on multiple parameters such as volume size, time spent in culture, the type of cells used, etc. Absent any teaching of criticality or unexpected results by the Applicant, it would be obvious that one of ordinary skill in the art would recognize that cell density is a result effective variable and Examiner notes that the optimization of cell density/concentration would have been prima facie obvious to one of ordinary skill in the art at the time of filing. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[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) (see MPEP 2144.05).
Thus, Roy teaches a method of treating cells for cell therapy, via the use of a small volume, high cell density microcarrier based perfusion system.
In regards to withdrawing cell waste and byproducts from the perfusion chamber, Roy teaches of frequent media exchanges which inherently consists of withdrawing cell waste and byproducts from the perfusion chamber (p13, lines 24-26).
The method of Roy does not employ an automated sensor to detect and control changes in pH, etc. However, Roy provides motivation to automate said microcarrier based perfusion system. Roy teaches of eventually providing automated monitoring of culture parameters of oxygen, pH, etc (p12, lines 5-9).
In regards to measuring, via using at least one sensor, at least one parameter of the cells or the media, the at least one parameter selected from pH, as well as in regards to automatically introducing a volume effective to treat the cells for cell therapy of at least one additive selected from a pH control agent, the volume effective of the at least one additive determined and introduced by a controller operatively connected to the at least one sensor, Examiner offers the teachings of Welch.
Welch teaches of microfluidics and lab-on-a-chip applications. Welch teaches of real-time feedback control of pH within microfluidics using integrated sensing and actuation. Welch teaches said microfluidic system which applies engineering feedback principles to control pH, does so with a high degree of precision. Welch further teaches of real-time control of pH through the feedback-controlled stepping of 0.14 pH increments in both the increasing and decreasing direction and that the system converges to the pH setpoint within approximately 20 seconds of a step change. Welch additionally notes the integration of feedback theory into a microfluidic environment is a necessary step for achieving complete control over the microenvironment (Abstract). Additionally, Welch teaches this system is an improvement over any other microfluidic feedback system to control pH because of the fast response time, easy integration into microfluidics, and the ability to adjust the setpoint of the device in real time. Welch teaches unlike other microfluidic pH systems which employ indicator dyes with a limited sensitivity range, the device of Welch is capable of operating over a large range of pH without modification. Further, the device incorporates straightforward manufacturing of both sensors and control structures which will allow for easy integration into more complex microfluidic systems for a variety of applications (p1196, last paragraph).
The system of Welch was designed for feedback-controlled regulation of pH within a microfluidic structure. Welch teaches of a sensor continuously monitoring the pH of the solution with a discrete readout circuit. The output of the readout circuit is read by a data acquisition (DAQ) device that transmits the data to a computer running MATLAB. MATLAB performs a control algorithm and specifies a signal which the DAQ outputs to operate pneumatic microfluidic valves. The valves control the flow and therefore the mixing of two different solutions, i.e., reagents, i.e., pH control agents, within the microfluidics. Changes in the flow of each solution allow for active control over the pH of the mixed solution exposed to the pH sensor (Fig 1, p1192, point 2).
Welch teaches accurate generation of pH buffers is a necessity for both research and commercial applications. The control of pH within microfluidics is becoming increasingly important as applications of cell culture expand. The pH is a key physiochemical property in the cell microenvironment and constant monitoring and control of it is critical to maintenance of cell culture at the microscale (p1191, 3rd paragraph).
Thus, Welch teaches of microfluidics and lab-on-a-chip applications utilizing automated control of perfusion in regards to pH. Thus, Welch teaches of perfusing cells by measuring, using at least one sensor, at least one parameter of the cells or the media, the at least one parameter selected from pH, and automatically introducing a volume of at least one additive selected from a pH control agent into the perfusion chamber, the volume effective of the at least one additive determined and introduced by a controller operatively connected to the at least one sensor.
Welch does not teach determining in response to the measurement of the at least one parameter, a cell state associated with at least one of metabolic activity of the cells, average size of the cells, and density of the cells in the media, nor does Welch teach the volume effective of the at least one additive determined in response to cell state.
In regards to determining, in response to the measurement of the at least one parameter, i.e., pH, a cell state associated with, for example, the metabolic activity of the cells, Examiner notes, and as a POSITA will appreciate, that it is well known that pH is a direct reflection of the metabolic activity of cells and thus a POSITA would be motivated to add a volume effective of at least one additive, i.e., a pH control agent, in response to a determined cell state, i.e., metabolic activity, to treat cells for cell therapy. Further, Examiner offers the teachings of Naciri.
Naciri teaches the pH measurement of a cell culture is a direct reflection of metabolic activity. Naciri teaches of monitoring pH and dissolved oxygen in mammalian cell cultures via sensors (Abstract). Naciri teaches a monitoring strategy based on direct measurements of the two major operational parameters, dissolved oxygen and pH, which provide information on both cell growth and cellular metabolism, may circumvent the problem with low throughput monitoring (Introduction, 3rd paragraph).
Naciri teaches dissolved oxygen and pH are good indicators of cell growth. Naciri notes lactic acid is given off as a by-product of cell metabolism, thus lowering the pH of the media. For cells in the growth phase of culture, we might expect a steady but rapid lowering of pH and oxygen levels reflecting the increase in total biomass and cellular metabolism (Introduction, 4th paragraph).
Thus, Naciri provides motivation to add a volume effective of at least one additive, i.e., a pH control agent, in response to a determined cell state, i.e., metabolic activity, to treat cells for cell therapy.
Thus, in regards to instant claims 1 and 16, it would have been obvious to a POSITA, before the effective filing date of the claimed invention to combine the teachings of Roy, Welch, and Naciri in order to have a small volume, high density perfusion method for treating cells (as taught by Roy and Welch), with an automated sensor to detect pH (as taught by Welch), connected to a controller automatically adding a pH control agent to maintain a desired pH (as taught by Welch) in response to the metabolic activity of the cells as based on pH (as taught by Naciri). A POSITA would have been motivated to combine the teachings of Roy and Welch due to both teaching of small volume (i.e., microarray/microfluidic/lab-on-a-chip) high density based perfusion and further due to Roy teaching of future steps involving the automation of the microarray based perfusion system in regards to cell culture conditions such as pH and dissolved oxygen and additionally due to Welch teaching the microfluidic system with engineering feedback principles to control pH, does so with a high degree of precision and additionally noting the system is an improvement over any other microfluidic feedback system to control pH because of the fast response time, easy integration into microfluidics, and the ability to adjust the setpoint of the device in real time. A POSITA would have been motivated to combine the teachings of Roy and Welch with the teachings of Naciri due to Welch teaching of real-time feedback control of pH and Naciri teaching of the pH measurement of a cell culture being a direct reflection of metabolic activity.
In regards to claim 16, Examiner notes claim 16 differs from claim 1 in that claim 16 states “introducing a media comprising at least about 0.5x10^6 cells/mL”. As discussed supra, Roy teaches a cell culture media with a cell density of 2.5x10^6 cells/mL (p29, lines 5-8).
Thus, the claims are obvious and are properly rejected.
In regards to claim 2, Roy teaches a cell culture media with a cell density of 2.5x10^6 cells/mL (p29, lines 5-8). Examiner notes the sole difference between the cell density of Roy and the instant application comprises only the routine optimization of cell density. Said optimization would have been obvious and well-within the purview of the ordinarily skilled artisan at the time of filing. Additionally, Examiner notes Roy teaches microcarriers allow for high density cell culture; typically, about two orders of magnitude higher cell densities (up to 2x 108 cells/mL, compared to 2-3x 106/mL cells without microcarrier) (p12, lines 10-22).
As a POSITA will appreciate, cell density is a result effective variable based on multiple parameters such as volume size, time spent in culture, the type of cells used, etc. Absent any teaching of criticality or unexpected results by the Applicant, it would be obvious that one of ordinary skill in the art would recognize that cell density is a result effective variable and Examiner notes that the optimization of cell density/concentration would have been prima facie obvious to one of ordinary skill in the art at the time of filing. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[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) (see MPEP 2144.05).
Thus, the claim is obvious and is properly rejected.
In regards to claim 3, Roy teaches in some embodiments of the present disclosure, stirred-tank type ambrTM micro-bioreactor systems (TAP Biosystems) that allows bioprocess optimization at microscale (10- 15 ml) are used, mimicking the core characteristics of classical bioreactors, but with reduced use of media and growth factors. Other embodiments can use the CartiGen perfusion bioreactor system (model C9-x, Instron), optionally without employing the compression feature due to the unknown effects of the associated mechanical stimuli. In either embodiment, fresh media can be perfused using a common flow loop in a varying flow rate, closely mimicking the physiological interstitial flow rate, ranging from 0.1-2.0 μm/s 25 (p13, lines 22-31 – p14, lines 1-4).
Thus, the claim is obvious and is properly rejected.
In regards to claim 12, Roy teaches a high viability. As is shown in Fig 8B, the cells of Roy have at least about 75% viability or higher. I.e., the harvested, treated cells have a viability of at least about 75% or higher.
Thus, the claim is obvious and is properly rejected.
In regards to claim 18, Roy teaches a final media volume of 2 mL (p33, lines 10-12) indicating that the perfusion chamber may accommodate a volume of 2.5 mL or less.
Thus, the claim is obvious and is properly rejected.
In regards to claim 23, Roy teaches of assessing cell culture fold change (i.e., changes in cell density) and phenotype via flow cytometry (i.e., measuring light scattering) and chemotaxis assay. Fold change (i.e., cell density) was quantified using a Countess automatic cell counter (measures light scattering). Roy teaches media was added after day 3, every 1-2 days based on media color (i.e., light scattering affecting media color) (p33, lines 13-17). Thus, Roy teaches of determining the density of the cells in the media via the measurement of light scattering.
Thus, the claim is obvious and is properly rejected.
Claims 5-6 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Roy in view of Welch and Naciri and further in view of Janas.
In regards to claims 5 and 19, Welch teaches wherein the additive comprises the pH control agent. Welch does not teach controlling pH of the media within the perfusion chamber to a pH value of between 6.8 and 7.4.
Janas teaches of perfusion’s role in the maintenance of high-density T-cell cultures. Janas teaches T-cell therapy is a rapidly growing field (p1, last paragraph-p2 1st paragraph). Janas teaches generating enough cells for anticancer T-cell therapy can present logistical and technical difficulties (p2, 2nd paragraph). Janas teaches, as such, cell therapy manufacturers have adopted many principles of the bioprocess industry, including the use of bioreactors for cell cultivation. Janas teaches the combination of rocking agitation and perfusion media exchange allows high cell concentrations to be reached and that using such bioreactors, a therapeutic dose of T-cells can be generated by a single 1L culture for either TILs or CAR-T cells (p2, 2nd paragraph).
Janas further teaches the culture conditions in bioreactors must be optimized for primary T cells to be infused into patients, as for example, at the end of T-cell therapy cultures, cell populations must be viable (p2, 3rd paragraph). Janas teaches of studying the impact of media perfusion on high density T-cell cultures and further teaches of analyzing the impact of perfusion on cell growth and viability, as well as its role in controlling key metabolites and growth factors (p2, 5th paragraph).
Janas teaches of initiating perfusion once cell density is greater than 2x10^6 cells/mL (Table 1). Janas teaches of recording the number of total viable cells and cell viability every day (Figure 1). Janas teaches with perfusion, cells continued to expand throughout the entire bioreactor period, ultimately reaching densities of 20x10^6 viable cells/mL. These results demonstrate an absolute requirement for media perfusion to expand healthy T-cell cultures to the large cell numbers required for therapy (p4, Results, 1st and 2nd paragraph).
Janas teaches of a pH control function. Janas teaches of bags containing an embedded pH optical sensor. A reservoir of 0.1 M NaOH was connected to such bags through an additional pump unit (p3, 3rd paragraph). Janas teaches of measuring pH from culture supernatants using either a BioProfile 400 bioanalyzer or a YSI 7100MBS bioanalyzer (p4, 1st paragraph). Janas teaches of measuring pH in the T-cell cultures (Fig 2) and teaches of determining in response to the pH measurement, the lactate and ammonia concentrations (i.e., metabolic activity) of the T-Cells (Fig 2). Janas further teaches of studying lactic acid concentrations in correlation with pH. Janas teaches at 20mM of lactic acid (pH 6.6), growth was inhibited, and at 30 mM of lactic acid (pH less than 6.6) both growth inhibition and a loss of cell viability occurred (Fig 3). Janas summarized that perfusion strategies should be set to ensure that lactate levels remain below that concentration (and therefore pH levels remain above 6.6) (p5, last paragraph).
Thus, Janas teaches of measuring pH, determining in response to the pH measurement a cell state associated with a metabolic activity and introducing a volume effective to treat the cells for cell therapy of a pH control agent, the volume effective selected responsive to the cell state (i.e., the pH needs to remain above 6.6).
Further, Janas teaches of using CO2 and a 0.1 M NaOH reservoir attached to the bioreactor to maintain pH at 7.1-7.2, which Janas teaches is considered optimal for proliferation of primary T cells (p6, 2nd paragraph).
Thus, both Janas and Roy teach of high-cell density perfusion of T cells for cell therapy, with Janas teaching a specific pH range to maintain for optimal proliferation of primary T cells and Roy teaching a method of perfusion with improved potency and efficacy. Therefore, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Janas and the above discussed references. A POSITA would have been so motivated in order to have the most effective high-cell density perfusion with improved potency and efficacy (as taught by the above discussed references) with optimal pH levels for primary T cell proliferation (as taught by Janas). A POSITA would have had a reasonable expectation of success in combining said teachings due to both the above discussed references and Janas studying perfusion in regards to high-cell density T cell cultures for cell therapy.
Thus, the claims are obvious and are properly rejected.
In regards to claim 6, Janas teaches a perfusion rate of 500 mL/day for cell densities of 2-10 x 10^6 cells/mL (Table 2). Janas further teaches for experiments with a pH-control function, a bag, i.e., a perfusion bag, containing an embedded pH optical sensor was used. Janas further teaches a reservoir of 0.1 M NaOH was connected to the perfusion bags (p3, Cell Expansion Culture System). Janas does not teach a flow rate in terms of VVD nor does Janas per se teach a flow rate for the introduction of the at least one additive, i.e., the pH control agent. However, as Janas teaches a set perfusion rate and teaches the pH control agent was added to the bag with the set perfusion rate, it is inherent that the pH control agent was added at a rate of 500 mL/day. To determine the VVD for 500mL/day, the daily flow rate is divided by the working volume of the bioreactor. Janas teaches a 1000mL bioreactor (Table 2). Thus, Janas teaches 0.5 VVD (i.e., 500/1000). Therefore, Janas teaches wherein the at least one additive is introduced at a flow rate of 5 VVD or less.
Thus, the claim is obvious and is properly rejected.
In regards to claim 20, the above cited references teach the method of claim 19. Further, Janas teaches using CO2 and a 0.1 M NaOH reservoir attached to the bioreactor, we maintained the pH at 7.1–7.2, which is considered optimal for proliferation of primary T cells (p6, 2nd paragraph). This reads on the limitations of claim 20.
Thus, the claim is obvious and is properly rejected.
Claims 24, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Roy in view of Welch and Groeber (Groeber, et al., Biotechnol (2013) 8: 308-316; PTO 892).
In regards to claims 24, 27 and 28, Examiner notes Roy teaches a method of treating cells for cell therapy comprising introducing a media comprising at least about 0.5x10^6 cells/ml into a perfusion chamber having a volume of 50mL or less. Please see the rejection of claims 1 and 16 above for more details.
Further, Welch teaches perfusing cells by introducing a first volume of at least one additive, i.e., a pH control agent, into the perfusion chamber and further teaches introducing a second volume of the at least one additive, i.e., a pH control agent. Please see the rejection of claims 1 and 16 above for more details.
In regards to “a first predetermine period of time” and “a second predetermined period of time”, Welch teaches feedback-controlled steps in pH (Fig 7). Welch teaches 16 “steps” and notes each step represents a 0.14 change in pH. Welch teaches said steps show controlled variations in pH over more than a 1.12 pH in both the ascending and descending directions. As seen in Fig 7, the feedback-controlled steps of Welch take measurements of the pH, at the minimum, every 200 seconds. Further, Welch teaches feedback control via using a weak acid (KH2PO4) and a strong base (NaOH) (Fig 5). Welch teaches the pH range achievable with the system is demonstrated by methodically stepping through the range of mixing ratios of the two fluids through the adjustment of the feedback setpoint (p1195, 1st paragraph).
Thus, the system of Welch reads on introducing a first volume of at least one additive (i.e., KH2PO4 and NaOH, i.e., pH control agents); after a first predetermined period of time (i.e., 200 seconds), introducing a second volume of the at least one additive (i.e., pH control agent). Further, the system of Welch teaches “wherein the first volume of the at least one additive, the second volume of the at least one additive, the first predetermined period of time are selected to approximate continuous perfusion of the perfusion chamber”. As can be seen in Fig 7, the system of Welch “pulses” continuously pH control agents, at least every 200 seconds (claim 27 and 28) to approximate continuous perfusion.
Welch, Fig 7
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In regard to a “second predetermined period of time” and withdrawing cell waste and byproducts from the perfusion chamber, Examiner notes Roy teaches cell waste withdrawal (see claim 1 and 16 rejections) but does not specify a precise time period for said withdrawal. Examiner notes Roy references the teachings of Groeber in regards to perfusion rates (p13, lines 26-27).
Groeber teaches of a pulsatile continuously controlled medium flow between 80 and 120mmHg in regards to bioreactor systems (Introduction, last paragraph). As a POSITA will appreciate, waste removal in a pulsatile perfusion chamber occurs continuously in real-time. Thus, as Roy references the teachings of Groeber in regards to perfusion rates, Roy thus teaches a pulsatile, continuously controlled medium flow. Additionally, Roy teaches fresh media can be perfused using a common flow loop in a varying flow rate, closely mimicking the physiological interstitial flow rate, ranging from 0.1-2.0 microm/s (p14, 1st paragraph). Thus, Roy teaches of an “approximate continuous perfusion”.
In regards to combining the teachings of Roy and Groeber, Examiner notes it would have been obvious to a POSITA, and a POSITA would have been so motivated, before the effective filing date of the claimed invention, to combine the teachings of Roy and Groeber due to Roy referencing the teachings of Groeber. A POSITA would have had a reasonable expectation of success in combining said teachings due to Roy and Groeber both teaching of perfusion.
Examiner notes that a set, predetermined period of time in regards to waste removal in a pulsatile, continuously controlled medium flow is a result effective variable dependent at least upon the cell being cultured, the internal volume of the perfusion chamber, and the amount of medium being perfused. Absent any teaching of criticality by the Applicant concerning the “second predetermined period of time”, it would be obvious that one of ordinary skill in the art would recognize said predetermined period of time is a result effective variable (claim 27). “[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) (see MPEP 2144.05).
In regards to harvesting the treated cells, Roy teaches said limitation. Please see the rejection of claims 1 and 16 above. In regards to obviousness and motivation to combine Roy and Welch, please see claims 1 and 16.
Thus, the claim is obvious and is properly rejected.
In regards to claims 27 and 28, the above discussed rejection of claim 24 teaches the limitations of said claims. As such, said claims are properly rejected.
In regards to claim 26, the limitations of said claim (cell density and perfusion chamber volume) have been discussed supra and noted as being taught by Roy. As such, the claim is properly rejected.
Response to Remarks/Amendment
RE: Rejections under 103
In response to Applicant’s remarks regarding the rejections under 103, Examiner notes the previously filed 103 rejections have been withdrawn and all remarks by Applicant related to issues in the previously filed rejections have been removed from the updated 103 rejections.
Conclusion
No claims are allowable. No claims are free of the prior art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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