DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 March 2026 has been entered.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2 and 6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Novak (CA 2838737).
With respect to claim 1, Novak discloses a method for controlling fluid flow in a bioreactor system. The bioreactor system includes a bioreactor volume (Figure 1:30), a filtration part (Figure 1:42) and a recirculation line (Figure 1:48) between the bioreactor volume and the filtration part. Novak discloses the use of a recirculation pump (Figure 2:54) and a plurality of sensors configured to monitor pressure parameters Pin, Pout, Pp and flow rate parameters Finf, Fb, Fs, Fa, Fp in the recirculation line. The signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump. This is taught in paragraphs [0014]-[0027] and Table 1. Novak indicates that a recirculation flow rate sensor Fs, Fa and a recirculation pressure sensor Pin, Pout are provided, and that fluid flow rate at the recirculation pump 54 is controlled in response to the plurality of signals from the sensors indicative of fluid flow rate and pressure (“In one of the more conventional embodiments of the present control system, the flow rates into and out of the MBR are measured together with the permeate flow rate and input to a microprocessor based controller which employs a control strategy to change the pump flow rates and settings for any backpressure valves to maintain the MBR flow rates within the desired or prescribed ranges” and “In other conventional embodiment of the present control system the pressures of the sludge flow in and out of the membrane and the pressure of the permeate flow out of the membrane are measured”).
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With respect to claim 2, Novak discloses the method described above. Novak further shows that a plurality of valves are used to control the flow of process fluid (“The flows within the illustrated systems in Figs 1 and 2 are monitored and controlled via the illustrated pumps as well as a plurality of control valves (not shown) disposed in the various conduits operatively coupled to a microprocessor based controller. The control valves are controlled by opening and closing, as needed, to maintain the appropriate flows and pressures of the streams and proper operating conditions within the MBR system in response to the measured and calculated parameters”).
With respect to claim 6, Novak discloses the method as described above. Novak indicates that membrane modules 42 each comprising a plurality of membranes are provided along the recirculation line.
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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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4, 6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Serway (US 20140093952) in view of Novak (CA 2838737).
With respect to claim 1, Serway discloses a method and control system for controlling fluid flow in a bioreactor system. The bioreactor system includes a bioreactor volume (Figure 1:11), a filtration part (Figure 1:14) and a recirculation line (Figure 1:12,16) between the bioreactor volume and the filtration part. The recirculation line includes a recirculation pump (Figure 3A:26) and a plurality of sensors (Figure 3A:44,46). The sensors are used to monitor pressure parameters in the recirculation line, and signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump (“the pump 26 and tangential flow filter waste pump 22 are controlled by software to maintain the desired flow through the hollow fiber tangential flow filter 30”). This is taught in paragraphs [0018]-[0028]. Serway, however, does not appear to teach that flow rate, in addition to pressure, is also detected along the recirculation line and used to control the operation of the recirculation pump.
Novak discloses a method and control system for controlling fluid flow in a bioreactor system. The bioreactor system includes a bioreactor volume (Figure 1:30), a filtration part (Figure 1:42) and a recirculation line (Figure 1:48) between the bioreactor volume and the filtration part. Novak discloses the use of a recirculation pump (Figure 2:54) and a plurality of sensors configured to monitor pressure parameters Pin, Pout, Pp and flow rate parameters Finf, Fb, Fs, Fa, Fp in the recirculation line. The signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump. This is taught in paragraphs [0014]-[0027] and Table 1.
Before the effective filing date of the claimed invention, it would have been obvious to ensure that both flow rate and flow pressure information is obtained in the recirculation line of Serway. Novak shows that it is important to measure flow rate and pressure, and that this is accomplished using flow meters and pressure transducers that are known and commonly available. Novak teaches that this allows for greater control over the recirculation process and will promote a more effective separation operation at the filtration part (“Specifically, the flow rate of the sludge into the MBR is compared to the desired or prescribed range of acceptable flow rates. If the measured flow rate of sludge into the MBR is too high, the energy use and associated costs of energy will increase and the MBR system performance will suffer due to erosion and membrane fouling. If the measured flow rate of sludge into the MBR is too low, the MBR system performance will also suffer due to decreased membrane efficiency”).
With respect to claims 4 and 6, Serway and Novak disclose the combination as described above. Serway further states a single recirculation pump 26 is used to exchange process fluid from the bioreactor through hollow fiber filters 30 and back to the bioreactor. Paragraph [0023] specifically references the KrosFlo Fitler Module manufactured by Spectrum Labs, which is a filter module comprising a plurality of hollow fiber membrane filters.
With respect to claim 8, Serway and Novak disclose the combination as described above. Serway further shows that the bioreactor is connected to the recirculation line via a bottom inlet 11a.
Claims 1-6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Schick (US 20060027500) in view of Novak (CA 2838737).
With respect to claim 1, Schick discloses a method and control system for controlling fluid flow in a bioreactor system. A bioreactor volume (Figure 2:22) is provided in communication with a filtration part (Figure 2:24) and a recirculation line (Figure 2:23) disposed between the bioreactor volume and filtration part. The recirculation line includes a recirculation pump (Figure 2:25) and a plurality of sensors (Figure 2:P1,P2). The sensors are used to monitor pressure parameters in the recirculation line, and signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump. This is taught in paragraphs [0067]-[0070]. Schick, however, does not appear to teach that flow rate, in addition to pressure, is also detected along the recirculation line and used to control the operation of the recirculation pump.
Novak discloses a method and control system for controlling fluid flow in a bioreactor system. The bioreactor system includes a bioreactor volume (Figure 1:30), a filtration part (Figure 1:42) and a recirculation line (Figure 1:48) between the bioreactor volume and the filtration part. Novak discloses the use of a recirculation pump (Figure 2:54) and a plurality of sensors configured to monitor pressure parameters Pin, Pout, Pp and flow rate parameters Finf, Fb, Fs, Fa, Fp in the recirculation line. The signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump. This is taught in paragraphs [0014]-[0027] and Table 1.
Before the effective filing date of the claimed invention, it would have been obvious to ensure that both flow rate and flow pressure information is obtained in the recirculation line of Schick. Novak shows that it is important to measure flow rate and pressure, and that this is accomplished using flow meters and pressure transducers that are known and commonly available. Novak teaches that this allows for greater control over the recirculation process and will promote a more effective separation operation at the filtration part (“Specifically, the flow rate of the sludge into the MBR is compared to the desired or prescribed range of acceptable flow rates. If the measured flow rate of sludge into the MBR is too high, the energy use and associated costs of energy will increase and the MBR system performance will suffer due to erosion and membrane fouling. If the measured flow rate of sludge into the MBR is too low, the MBR system performance will also suffer due to decreased membrane efficiency”).
With respect to claim 2, Schick and Novak disclose the combination as described above. Schick further states in paragraphs [0009] and [0052] that a plurality of valves are used to control flow of process fluid based on process conditions, such as fluid pressure and clogging in filters.
With respect to claim 3, Schick and Novak disclose the combination as described above. Schick further states that net flow from the bioreactor is controlled and adjusted based on the weight of the bioreactor measured by load cell (Figure 2:37) and the motor speed of the recirculation pump. See, for example, paragraph [0061].
With respect to claims 4 and 6, Schick and Novak disclose the combination as described above. Schick shows in Fig. 2 that a single recirculation pump 25 is used to exchange process fluid from the bioreactor through hollow fiber filters 24 and back to the bioreactor. Schick further states in paragraph [0048] that a filtration unit comprising a plurality of porous hollow fibers is utilized.
With respect to claim 5, Schick and Novak disclose the combination as described above. Schick states in paragraph [0066] that the sensors are single use and disposable. Schick further calculates and monitors transmembrane pressure and a pressure difference based on output from the sensors. See Fig. 11, for example.
With respect to claim 8, Schick and Novak disclose the combination as described above. Schick further shows that the bioreactor is connected to the recirculation line via a tube that extends to the bottom of the bioreactor.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over either Serway (US 20140093952) or Schick (US 20060027500) each in view of Novak (CA 2838737) as applied to claim 1, and further in view of Grant (US 20200181554).
Serway and Schick each in combination with Novak disclose the method set forth as described above, however neither expressly teaches a bleed line.
Grant discloses a method and system for controlling fluid flow from a bioreactor volume (Figure 2:130) to a filtration part (Figure 2:140). A recirculation pump (Figure 2:110) is used to deliver fluid from the bioreactor to the filter, and a bleed line (Figure 2:180) in communication with a bleed tank is disposed downstream from the pump. This is taught in paragraphs [0021]-[0026].
Before the effective filing date of the claimed invention, it would have been obvious to provide both the Serway and Schick methods with a cell bleed step in which culture fluid is controllably removed from the recirculation line in order to maintain steady state perfusion. Grant states that bleeds are sometimes required to adjust critical culture parameters (e.g., stabilize cell density) and that it is useful to direct a portion of the fluid out of the system rather than continuing to circulate it through the recirculation line.
Claims 9 and 11-14 is rejected under 35 U.S.C. 103 as being unpatentable over Schick (US 20060027500) in view of Novak (CA 2838737) and Luttmann (US 20060014239).
With respect to claim 9, Schick discloses control system for controlling fluid flow to and from a bioreactor. A bioreactor (Figure 2:22) is provided in communication with a filter (Figure 2:24) and a recirculation line (Figure 2:23) disposed between the bioreactor volume and filter. The recirculation line includes a recirculation pump (Figure 2:25) and a plurality of sensors (Figure 2:P1,P2). The sensors are used to monitor pressure parameters in the recirculation line, and signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump. This is taught in paragraphs [0067]-[0070]. Schick, however, does not appear to teach that flow rate, in addition to pressure, is measured along the recirculation line and used to control the operation of the recirculation pump.
Novak discloses a method and control system for controlling fluid flow in a bioreactor system. The bioreactor system includes a bioreactor volume (Figure 1:30), a filtration part (Figure 1:42) and a recirculation line (Figure 1:48) between the bioreactor volume and the filtration part. Novak discloses the use of a recirculation pump (Figure 2:54) and a plurality of sensors configured to monitor pressure parameters Pin, Pout, Pp and flow rate parameters Finf, Fb, Fs, Fa, Fp in the recirculation line. The signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump. This is taught in paragraphs [0014]-[0027] and Table 1.
Before the effective filing date of the claimed invention, it would have been obvious to ensure that both flow rate and flow pressure information is obtained in the recirculation line of Schick. Novak shows that it is important to measure flow rate and pressure, and that this is accomplished using flow meters and pressure transducers that are known and commonly available. Novak teaches that this allows for greater control over the recirculation process and will promote a more effective separation operation at the filtration part (“Specifically, the flow rate of the sludge into the MBR is compared to the desired or prescribed range of acceptable flow rates. If the measured flow rate of sludge into the MBR is too high, the energy use and associated costs of energy will increase and the MBR system performance will suffer due to erosion and membrane fouling. If the measured flow rate of sludge into the MBR is too low, the MBR system performance will also suffer due to decreased membrane efficiency”).
Schick, however, still differs from the claimed invention because Schick does not appear to show that the bioreactor is in communication with a plurality of media containers.
Luttmann discloses a control system comprising a bioreactor (Figure 1:1) in communication with a plurality of media containers (Figure 1:35,36,37), a pump (Figure 1:14) and a filter (Figure 1:5). This is taught in paragraphs [0037]-[0041].
Before the effective filing date of the claimed invention, it would have been obvious to ensure that the Schick bioreactor is connected to multiple media containers. Luttmann teaches that different containers may hold different media, and that cell behavior may be modified and controlled by charging different combinations of media into the bioreactor at determined times. For example, Luttmann states that different media analytes are delivered to the bioreactor to cycle cells between growth, product formation and harvesting phases.
With respect to claim 11, Schick, Novak and Luttmann disclose the combination as described above. Schick further states in paragraphs [0009] and [0052] that a plurality of valves are used to control flow of process fluid based on process conditions, such as fluid pressure and clogging in filters.
With respect to claim 12, Schick, Novak and Luttmann disclose the combination as described above. Schick shows in Fig. 2 that a single recirculation pump 25 is used to exchange process fluid from the bioreactor through hollow fiber filters 24 and back to the bioreactor. Schick further states in paragraph [0048] that a filtration unit comprising a plurality of porous hollow fibers is utilized.
With respect to claim 13, Schick, Novak and Luttmann disclose the combination as described above. Schick states in paragraph [0066] that the sensors are single use and disposable. Schick further calculates and monitors transmembrane pressure and a pressure difference based on output from the sensors. See Fig. 11, for example.
With respect to claim 14, Schick, Novak and Luttmann disclose the combination as described above. Schick further shows that the bioreactor is connected to the recirculation line via a tube that extends to the bottom of the bioreactor.
Claims 9 and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Serway (US 20140093952) in view of Novak (CA 2838737) and Luttmann (US 20060014239).
With respect to claim 9, Serway discloses a control system for controlling fluid flow between a bioreactor (Figure 1:11) and a filtration part (Figure 1:14) using a recirculation line (Figure 1:12,16). The recirculation line includes a recirculation pump (Figure 3A:26) and a plurality of sensos (Figure 3A:44,46). The sensors are used to monitor pressure parameters in the recirculation line, and signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump (“the pump 26 and tangential flow filter waste pump 22 are controlled by software to maintain the desired flow through the hollow fiber tangential flow filter 30”). This is taught in paragraphs [0018]-[0028]. Serway, however, does not appear to teach that flow rate, in addition to pressure, is detected along the recirculation line and used to control the operation of the recirculation pump.
Novak discloses a method and control system for controlling fluid flow in a bioreactor system. The bioreactor system includes a bioreactor volume (Figure 1:30), a filtration part (Figure 1:42) and a recirculation line (Figure 1:48) between the bioreactor volume and the filtration part. Novak discloses the use of a recirculation pump (Figure 2:54) and a plurality of sensors configured to monitor pressure parameters Pin, Pout, Pp and flow rate parameters Finf, Fb, Fs, Fa, Fp in the recirculation line. The signals are sent from the sensors to one or more controllers in order to regulate fluid flow produced by the recirculation pump. This is taught in paragraphs [0014]-[0027] and Table 1.
Before the effective filing date of the claimed invention, it would have been obvious to ensure that both flow rate and flow pressure information is obtained in the recirculation line of Serway. Novak shows that it is important to measure flow rate and pressure, and that this is accomplished using flow meters and pressure transducers that are known and commonly available. Novak teaches that this allows for greater control over the recirculation process and will promote a more effective separation operation at the filtration part (“Specifically, the flow rate of the sludge into the MBR is compared to the desired or prescribed range of acceptable flow rates. If the measured flow rate of sludge into the MBR is too high, the energy use and associated costs of energy will increase and the MBR system performance will suffer due to erosion and membrane fouling. If the measured flow rate of sludge into the MBR is too low, the MBR system performance will also suffer due to decreased membrane efficiency”).
Serway, however, still differs from the claimed invention because Serway does not appear to show that the bioreactor is in communication with a plurality of media containers.
Luttmann discloses a control system comprising a bioreactor (Figure 1:1) in communication with a plurality of media containers (Figure 1:35,36,37), a pump (Figure 1:14) and a filter (Figure 1:5). This is taught in paragraphs [0037]-[0041].
Before the effective filing date of the claimed invention, it would have been obvious to ensure that the Serway bioreactor is connected to multiple media containers. Luttmann teaches that different containers may hold different media, and that cell behavior may be modified and controlled by charging different combinations of media into the bioreactor at determined times. For example, Luttmann states that different media analytes are delivered to the bioreactor to cycle cells between growth, product formation and harvesting phases.
With respect to claims 12 and 13, Serway, Novak and Luttmann disclose the combination as described above. Serway further states a single recirculation pump 26 is used to exchange process fluid from the bioreactor through hollow fiber filters 30 and back to the bioreactor. Paragraph [0023] specifically references the KrosFlo Fitler Module manufactured by Spectrum Labs, which is a filter module comprising a plurality of hollow fiber membrane filters.
With respect to claim 14, Serway, Novak and Luttmann disclose the combination as described above. Serway further shows that the bioreactor is connected to the recirculation line via a bottom inlet 11a.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over either Serway (US 20140093952) or Schick (US 20060027500) each in view of Novak (CA 2838737) and Luttmann (US 20060014239), and further in view of Grant (US 20200181554).
Serway and Schick each in view of Novak and Luttmann disclose the combinations set forth as described above, however Serway and Schick do not expressly teach a bleed line.
Grant discloses a method and system for controlling fluid flow from a bioreactor volume (Figure 2:130) to a filtration part (Figure 2:140). A recirculation pump (Figure 2:110) is used to deliver fluid from the bioreactor to the filter, and a bleed line (Figure 2:180) in communication with a bleed tank is disposed downstream from the pump. This is taught in paragraphs [0021]-[0026].
Before the effective filing date of the claimed invention, it would have been obvious to provide both the Serway and Schick systems with a cell bleed step in which culture fluid is controllably removed from the recirculation line in order to maintain steady state perfusion. Grant states that bleeds are sometimes required to adjust critical culture parameters (e.g., stabilize cell density) and that it is useful to direct a portion of the fluid out of the system rather than continuing to circulate it through the recirculation line.
Response to Arguments
In response to the amendment filed 009 March 2026, the previous rejections under 35 U.S.C. 112 have been withdrawn.
Applicant's arguments filed 09 March 2026 with respect to the prior art rejections have been fully considered but they are not persuasive.
Applicant argues that Novak does not state that several sensors are placed on the recirculation line. However, Figs. 1 and 2 of Novak clearly show that multiple flow rate and pressure sensors are located along the recirculation line in order to obtain information that is used to regulate the operation of the pump.
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Novak expressly states that flow rate information is used by the controller to make adjustments to system operation. See pages 7-13 (“Specifically, the flow rate of the sludge into the MBR is compared to the desired or prescribed range of acceptable flow rates. If the measured flow rate of sludge into the MBR is too high, the energy use and associated costs of energy will increase and the MBR system performance will suffer due to erosion and membrane fouling. If the measured flow rate of sludge into the MBR is too low, the MBR system performance will also suffer due to decreased membrane efficiency” and “the pressures of the sludge flow in and out of the membrane and the pressure of the permeate flow out of the membrane are measured and the Trans Membrane Pressure (TMP) and Cross Flow Pressure Drop (CFP) are calculated…The Trans Membrane Pressure (TMP) is then compared against a prescribed setpoint or range. If the calculated TMP value is above a higher limit setpoint or prescribed range, a control system alarm is produced indicating the MBR system may be clogged. Also, if the calculated TMP value is below a lower limit setpoint or prescribed range, another control system alarm is produced indicating the MBR system may be experiencing physical or control problems. Excessively high or low values of the calculated TMP may also be indicative of possible existence of extra cellular substances which may cause the system operator or the present control system to initiate other system control actions”).
The teachings set forth in the Paul reference are believed to be similar in scope to those of Serway, Schick and Novak, and therefore the prior art rejections based on Paul have been provisionally withdrawn in accordance with MPEP 2120 (“Merely cumulative rejections, i.e., those which would clearly fall if the primary rejection were not sustained, should be avoided”).
Conclusion
This is a non-final rejection.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATHAN ANDREW BOWERS whose telephone number is (571)272-8613. The examiner can normally be reached M-F 7am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Marcheschi can be reached at (571) 272-1374. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NATHAN A BOWERS/ Primary Examiner, Art Unit 1799
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