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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Remarks
The amendments and remarks filed on 09/29/2025 have been entered and considered. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. The rejections and/or objections presented herein are the only rejections and/or objections currently outstanding. Any previously presented objections or rejections that are not presented in this Office Action are withdrawn.
Claims 2, 4-7, 10, 13-17, 29-36, and 38-49 are pending.
Claims 10 and 49 are amended.
Claims 1, 3, 8-9, 11-12, 18-28, and 37 are canceled.
Claim 30 is withdrawn.
Claims 2, 4-7, 10, 13-17, 29, 31-36, and 38-49 have been examined on the merits.
Priority
This application, U.S. Application number 17/006172, is filed on 08/28/2020 and claims for domestic priority under 35 U.S.C. 119(e) to provisional applications No. 62/892702 filed on 08/28/2019.
Rejections - Withdrawn
The rejection of the claim 37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn due to the cancellation of the claim filed on 09/29/2025.
Claim Rejections - 35 USC § 103
Claims 2, 6-7, 10, 13-16, 29, 31-36, 38-40, 43-44, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Grant (WO 2018/015405, 2018, cited in IDS) in view of Olesberg et al. (US 2015/0247210, 2015, of record) and Hideo et al. (JPH09266785, 1997, English translated version is cited in IDS).
Regarding Claim 10, Grant teaches a device and a method of using the device for monitoring microbial proliferation and maintaining a desired cell density in a bioreactor, wherein the device is specifically illustrated in Fig 3, which comprises a bioreactor “130”, a sample tube “150” connected to the bioreactor, a sample cell “120” connected to the sample tube, a sensor “190” for monitoring the sample cell, and a pump “110” having a plunger “112”; and the method comprises steps: operating the pump by alternatively moving its plunger in two opposite directions to alternate movement direction of a liquid culture medium in the sample cell, specifically: moving the plunger away from the sample cell to generate a negative pressure in the sample cell, thus drawing a liquid medium from the bioreactor through the sample tube into the sample cell (Note: these steps of operating a pump and collecting a sample are comparable to steps (a) and (b) of claim 10), and then moving the plunger of the pump towards the sample cell to generate a positive pressure in the sample cell, thus releasing the collected liquid medium into the bioreactor through the sample tube (Note: this step reads on the step (e) of claim 10), wherein the liquid medium is moved between the bioreactor and the sample cell without circulating through the pump (Fig. 3, page 3/lines 1-3, page 7/line 24 – page 8/line 10, page 12/line 30 – page 14/line 4, page 13/line 32 – page 14/line 4). Grant further teaches incorporating a sensor configured to sense cell density and cell viability into the device of Fig. 3 for monitoring microbial growth in the bioreactor; and when sensed data indicate cell density is rising above a predetermined threshold, a control system reduces cell density to a desired level by bleeding cells from the bioreactor as determined by the sensor (page 12/line 32 – page 13/line 11, and page 13/lines 7-10), which inherently comprises a step of monitoring a response of a sensor/detector and resolving sensed data (encompassing absorption spectrum data) of a liquid medium sample in the sample cell, so as to control the cell density at a desired level. It is noted that the measuring and analyzing cell density/viability of the sample in the sample cell by sensors as well as monitoring a response of sensors in the method of Grant are comparable to the steps (c) and (d) in Claim 10.
Grant does not teach transmitting light from a tunable laser to the sample cell and detecting with a sensor/detector the light transmitted through the sample cell, and monitoring a response of the detector as a function of wavelength of light from the tunable laser; wherein the sample cell is inserted into an access structure, and the sensor and detector are mounted in or located within the tether head, as recited in the steps a), c) and d) of the instant claim 10.
Hideo et al. teach a highly similar method of online monitoring a microbial proliferation process in a bioreactor by using a monitor device (paras 0001-2, abstract), wherein the monitor device comprises a sample tube (connected to a bioreactor “20”), a pump “30”, a filter “28”, and a tether head comprising: a sensor part “26” which comprises a light source “40”, a flow cell or measurement cell “32” (reading on the “sample cell” recited in the claim 10) mounted to the tether head, and a detector “42” (abstract, Figs 1 and 2, paras 0023-24); the method comprising steps: (i) operating a pump “30”, such that a culture medium in the bioreactor is sucked by the pump and drawn through the sample tube into the sample cell (this process comparable to steps (a) and (b) in the claim 10 since sucking of the pump generates a negative pressure in the sample cell); (ii) measuring and analyzing the culture medium; and after collecting data the culture medium in the sample cell is released and returned to the bioreactor without circulation through pump, i.e. through the sample tube by operating the pump to generate a positive pressure (comparable to step (e) in the claim) (paras 0006, 0023-24 and 0042, Figs. 1 and 2); wherein all the steps are repeated every one or several minutes for conducting the online measurement (para 0024: page 6/last line – page 7/line 3); wherein the pump is a perista pump (i.e. peristaltic pump) (Examples, para 0018); and wherein the culture sample is analyzed for measuring and monitoring a microbial concentration/cell density (paras 0006 and 0040, Claim 6-8).
Olesberg et al. teach a method of measuring a quantity parameter of a bioprocess within a vessel or sample cell and monitoring/controlling the bioprocess by near-infrared spectrometry, wherein the bioprocess is selected from a bacterial culture process, a yeast fermentation, and an insect or mammalian cell culture process; the method comprising steps: generating a beam (i.e. light) of near-infrared electromagnetic radiation, wherein the beam/light is generated by a near-infrared radiation emitter comprising a tunable laser diode (reading on the “tunable laser” in the claim 10); directing and transmitting the beam/light through a fluid sample, and measuring by a sensor/detector an intensity of the light (electromagnetic radiation) having interacted with and transmitted through the fluid sample, the measured intensity as a function of an instantaneous wavelength (of light of the tunable laser) forms a transmission optical spectrum of the fluid sample (i.e. an absorption spectrum of the sample), and monitoring and using the transmission optical spectrum/absorption spectrum of the sample (i.e. a response of the sensor/detector as the function of the instantaneous wavelength to resolve the transmission optical spectrum/absorption spectrum of the sample), to determine a quantity parameter of the fluid sample from the bioprocess within a sample cell; wherein the quantity parameter is one or more of cell density, cell viability, and turbidity; wherein the fluid sample of bioprocess is measured continuously or measured at different growth stages; and wherein a measurement frequency for the bioprocess is greater than 1 per minute (abstract, Claims 1, 2, 5, 13-15, 17, 21-22, 28, 31, 33, and 37, paras 0045/lines 1-13, 0049/lines , page 5/left col/para. 0048, Fig. 2). Olesberg et al. further teach that the measuring of the quantity parameters and monitoring the bioprocess are carried out by using the optical instrument “110”, where a fluid sample drawn from the bioreactor is optically monitored for providing quantified values of the fluid sample (in the sample cell) (para 0044, lines 4-8, Figs. 1-2), wherein the optical instrument “110” comprises: (i) an optical emitter “170” for emitting near-infrared radiation, which comprises a near-infrared radiation emitter “180”, and may also comprise a lens “190” for collimating/spectrally manipulating near-infrared radiation, and a wavelength selector “210”, such that the light source is tunable (paras 0045/lines 1-12, 0048/col 1/last 7 lines, Fig. 2) (Note: the optical emitter “170” having the components “180”, “190”, and “210” reads on the claimed “tunable laser”); (ii) a sensor/detector “230” connected to a controller “270” (reading on the detector and controller in claim 10 and 34, respectively) (para 0049/lines 1-6, Fig. 2), ; and (iii) a fluid sampling means “240” (reading on the claimed “sample cell”) that holds the fluid sample and is placed between the tunable laser and detector (para 0049/lines 7 and 9-10, page 4/col 2/lines 8-10, Fig. 2). Regarding the term “a tether head” recited in the claim 10, this term is not defined in the specification. The optical instrument “110” of Olesberg et al. comprises the sample cell and the detector (the required structural limitations of the claimed tether head), thus it can be considered as a tether head. Regarding the limitation “a sample cell is inserted into an access structure” recited in step (a) of claim 10, Olesberg et al. teach one or more sample cells/fluid conduits “330” are inserted/housed into the cartridge “340”, through the tubing assemblies “360” which further comprises a fluid delivery tubing assembly “130” and a fluid return tubing assembly “140” used for delivering/removing a fluid sample into/from the sample cells/fluid conduits “330” (para 0052/line 1-3, first half of para 0051, para 0053/lines 1-6, page 7/left col/lines 25-31; Figs. 4-6) (Note: the cartridge reads on the limitation “access structure” recited in step (a) of claim 10). Regarding the further limitation “a sample cell … mounted in a tether head” recited in step (a) of claim 10, Olesberg et al. teach mounting/securing the cartridge containing a sample cell/fluid conduit “330” to the optical interface by using a locking pin (para 0053: lines 11-19, Fig. 6). As such, the tether head of Olesberg et al. comprises a sample cell inserted into an access structure/cartridge and mounted to the tether head, as required by the claimed tether head.
It would have been obvious to one of ordinary skill in the art to modify the method taught by Grant by using a sensor/detector coupled with a tunable laser for measuring and monitoring the cell culture sample, so as to control the cell density at a desired level, as taught by Olesberg et al., wherein the modified method comprises steps of transmitting a light of near-infrared electromagnetic radiation generated from the tunable laser to the liquid culture medium (fluid sample) of the sample cell and detecting the light transmitted through the liquid medium with the detector, and monitoring a response of the detector as a function of an instantaneous wavelength to resolve an absorption spectrum of the liquid culture medium in the sample cell to determine a cell density of culture medium (a quantity parameter of a fluid sample), as taught by Olesberg et al. One of ordinary skill in the art would have been motivated to incorporate the teachings of Olesberg et al. into the method of Grant for measuring, monitoring, and controlling the cell density of liquid cultural medium in the bioreactor, because Grant expressively teaches incorporating a detector configured to sense cell density into the device in his method for monitoring and controlling microbial growth in the bioreactor, and the sensor/detector coupled with a tunable laser in a near-infrared spectrometry taught by Olesberg et al. is effective and efficient for sensing microbial growth and detecting cell density and allows effectively monitoring/controlling cell density at a desired level. One of ordinary skill in the art has a reasonable expectation of success at applying teachings of Olesberg et al. for modifying the method of Grant, because the sensor/near-infrared spectrometry and method of Olesberg et al. are established specifically for measuring cell density and monitoring microbial growth in a bioprocess, which is readily applicable to the method of Grant for monitoring controlling cell density of the liquid culture in the bioreactor.
Regarding the limitations that require that the sample cell is inserted into an access structure and that the sample cell and detector are respectively mounted in and located within the tether head in the claim 10, it is an obvious design choice to arrange a sample cell together with a detector in a tether head in method of Grant for monitoring cell culture in a bioreactor, because the detector is specifically applied for detecting light transmitted from the sample cell in method of Grant. Furthermore, it is well known in the art to apply a tether head comprising a detector and a sample cell, wherein the sample cell is inserted into an access structure and mounted in the tether head, for measuring and monitoring a cell culture, as supported by Olesberg et al. and Hideo et al. As such, it would have been obvious to one of ordinary skill in the art to include the detector and the sample cell in a tether head in the method suggested by Grant, Olesberg et al. and Hideo et al. for measuring and monitoring a cell culture in a bioreactor, wherein the sample cell is inserted into an access structure and mounted in the tether head. With regard to the limitation “within a main body of the tether head” newly added to the step c) of claim 10, both Olesberg et al. and Hideo et al. teach the detector is within a main body of the tether head (see the detector “42” in the tether head “26” on the top of bioreactor in Figs. 1 and 2 of Hideo et al., and the detector (“230” linked to “280” and “270”) in the tether head in Fig. 2 of Olesberg et al.). Given the detector is a device essential for measuring and monitoring cell density, it would have been obvious to place the detector in a main body of the tether head in the method suggested by Grant, Olesberg et al. and Hideo et al. for measuring and monitoring a cell culture in a bioreactor. Thus, the combined teachings of cited prior art render the claim 10 to be obvious.
Regarding Claim 2, Grant teaches that all the components/Labware including the sample cell, which are in direct contact with cell culture, are single-use disposable items (page 13/lines 23-25, page 14/lines 2-4).
Regarding Claim 6, Grant teaches the sample cell includes a straight fluid path (Fig. 3).
Regarding Claims 7 and 31, Grant does not teach the pump is a peristaltic pump. However, it would have been obvious to apply a peristaltic pump for pumping the cultural medium between the sample cell and the bioreactor in the method suggested by Grant, Hideo et al., and Olesberg et al., because the peristaltic pump had been well established in the art for manipulating and controlling fluid transition for monitoring bioreactor process, as supported by Hideo et al., who teach a method highly similar to that of Grant, which applies a peristaltic pump manipulating and controlling fluid transition, as indicated above. Regarding the further limitation in Claim 31, it would have been obvious to further include a sterile filter between the peristaltic pump and the sample cell in the device used in the method suggested by Grant, Hideo et al., and Olesberg et al. for preventing contamination of the sample cell caused by exposing to the pump. This is because Grant expressively teach the requirement of contacting the cell culture (in the sample cell) with clean and filtered air (page 14/lines 2-4); and teaches integrating sterile filters at locations where the pump is connected when the pump is not cleaned and un-sterilized (page 13/lines 29-32). Furthermore, Hideo et al. teach a filter “28” that is placed before the pumper “30”, where the pump is connected to the sample cell, for protecting the sample cell line (Figs 1 and 2, para 0042).
Regarding Claim 13, the steps in the method of Grant are repeated since the controlling cell density in the bioreactor, based on sensed data from the sample cell, is a continuous process (page 13/line 11). Olesberg et al. also teach that their method allows the sample to be measured continuously and at different growth stages (Claims 15, 17, 22, and 28); and Hideo et al. also teach all the steps are repeated every one or several minutes for conducting the online measurement.
Regarding Claim 14, Grant teaches the collected liquid medium is not circulated through the pump, as indicated above.
Regarding Claim 15, Fig. 3 of Grant does not display a sterile filter between the pump and the sample cell. However, it would have been obvious to include a sterile filter between the pump and the sample cell in the device used in the method suggested by Grant, Hideo et al. and Olesberg et al. for preventing contamination of the sample cell caused by exposing to the pump. This is because Grant expressively teach contacting the cell culture (in the sample cell) with clean and filtered air (page 14/lines 2-4); and teaches integrating sterile filters at locations where the pump is connected when the pump is not cleaned and un-sterilized (page 13/lines 29-32).
Regarding Claim 16, Grant teaches an assembled system comprising the sample tube, the sample cell, the pump, and sensors/detectors for monitoring the culture sample (Fig. 3, page 12/line 32 – page 13/line 1). Thus, the method of Grant inherently comprises a step of assembling all these components together for analyzing the culture sample. Hideo et al. (Figs. 1 and 2, as indicated above); and Olesberg et al. (Figs. 1-2, page 4/col. 1/last para, as indicated above) also teach an assembled system comprising a pump and a tether head comprising sample cell and detectors, and sample tube for monitoring culture samples, indicating their methods inherently comprise a step of assembling the pump, sample tube, and tether head (sample cell and detector). Furthermore, Olesberg et al. expressively teach assembling/installing and disassembling/removing the components in the tether head, which include: cartridge comprising a fluid conduit (i.e. sample cell), tubing assemblies (i.e. sample tubes), input optical assembly (i.e. tunable laser), and output optical assembly (i.e. detector) (Figs. 2 and 4-6, paras 0051 and 0053/lines 1-16, as indicated above). Thus, the claim would have been obvious over the cited prior art.
Regarding Claim 32, the method of Grant comprises loading the bioreactor with a cell culture before analyzing the sample, because the sample used for measurement and analysis was drawn from the cell culture in the bioreactor.
Regarding Claim 33, Olesberg et al. further teach controlling/operating a tunable laser and rapid scanning across all wavelengths of interest, and
scanning the entire wavelength of interest in less than 100 ms, thus enabling substantial scan to be performed within a standard data collection period (para 0048: page 5/left col./lines 8-15, and last 7 lines). Given that Olesberg et al. require a specific time range for performing the entire scan of a spectral band (i.e. sweep through a spectral scan band), the scan process of Olesberg et al. is controlled at a specific scan rate, thus meeting the limitation of the claim. As such, the claim would have been obvious over the cited prior art.
Regarding Claim 34, Olesberg et al. teach their monitoring the response of the detector to resolve the absorption spectrum of the sample is controlled by a controller connected to the detector, as indicated above. Thus, the claim would have been obvious over the cited prior art.
Regarding Claims 29 and 35, the wavelength range of 780 nm to 2500 nm recited in the claims is a near-infrared wavelength range, as evidenced by the para 0045 of the specification. Olesberg et al. teach the tunable laser generates a light in a near-infrared range. Olesberg et al. further teach utilizing the near-infrared (NIR) spectral range, roughly from 700 nm to 3000 nm, for industrial and laboratory applications (para. 0008/lines 1-6), which encompasses the claimed range of 780 nm to 2500 nm. Thus, it would have been obvious for the tunable laser used in the method suggested by Grant, Hideo et al., and Olesberg et al. to generate light in the range of 780 nm to 2500 nm. Thus, the claims would have been obvious over the cited prior art.
Regarding Claim 36, Grant teaches that only components that directly contact cell culture need to be sterile or provided as single-use disposable/sterile items (the para spanning pages 13-14). Olesberg et al. also teach that only components (including tubing and cartridge/sample cell) in contact with fluid samples should be made of materials such that they can withstand sterilization by techniques such as autoclaves, or be provided as a single-use, disposable, sterile component (paras 0051/page 6/col 2/lines 1-6, 0052/lines 6-15, 0018/lines 7-8). In view of the fact that optical components in the tether head are not in direct contact with cell culture, it would have been obvious not to sterilize the optical components in the method suggested by Grant, Hideo, and Olesberg et al. Thus, the claim would have been obvious over the cited prior art.
Regarding Claim 38, Fig. 2 of Olesberg et al. shows that light in a first optical path (in direction indicated by arrowed line A) is transmitted from a tunable laser (comprising components 180, 190, 200, and 210), through the sample cell/sample (component “240”) and then to the detector “230”. The component 220 in Fig. 2 is an optional component, which is only used for a second optical path (indicated in arrowed line B), not for the first optical path (para 0049, lines 16-18); and the component “250” in the first optical path is also an optional component, because Olesberg et al. teach this component is not essential, but may be further comprised in the first optical path (para 0049, lines 10-12). Thus, it would have been obvious for the light to be transmitted directly through the sample and then into the detector without using an optic fiber patch cable in the method suggested by the cited prior art for monitoring cell culture.
Regarding Claim 39, this claim recites a broad limitation “an instrument that includes the tunable laser”. Olesberg et al. teaches that the sensor/detector (e.g. “230”) generates signals, which are indirectly delivered to the wavelength selector 210 through the controller 270, wherein the controller 270 accepts input signals from the detector and delivers them as output signals for controlling the wavelength selector 210 (para 0050, lines 5-9). It is noted that the wavelength selector “210” is a part of the tunable laser, as indicated above. As such, it would have been obvious to return/deliver signals from the detector (“230”) to an instrument including the tunable laser in the method suggested by the cited prior art for controlling the wavelength selector 210/tunable laser, as taught by Olesberg et al.
Regarding Claims 40 and 43, Olesberg et al. teach an optical path defined by optical elements housed in the tether head intersects the sample cell (fluid sampling means “240”), and the light transmitted from the tunable laser “170” intersects the sample cell at a scan area (see Fig. 2: an optical path in the direction indicated by arrowed line A, the sample cell “240”, and light (in the direction “A”) transmitted from the tunable laser “170” intersected with a scan area of the “240”; para 0049/lines 1-2). Thus, the claims would have been obvious over the cited prior art.
Regarding Claim 44, Grant teaches immersing or maintaining the sample tube in the bioreactor (see Figs. 1A and 3, where the sample tube/liquid line “150” is immersed in the bioreactor). Thus, the claim would have been obvious over the cited prior art.
Regarding the claim 47, Grant does not teach a tether head at the top of the bioreactor. However, it is an obvious design choice to place the tether head at the top of the bioreactor in the method suggested by Grant, Olesberg et al. and Hideo et al. Furthermore, it is well known in the art that the top of the bioreactor is a place desirable for placing a tether head, as supported by Hideo et al. (see Figs. 1 and 2). Thus, the claim would be obvious over the cited prior art.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 17 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Grant (WO 2018/015405, 2018, cited in IDS) in view of Olesberg et al. (US 2015/0247210, 2015, of record) and Hideo et al. (JPH09266785, 1997, English translated version is cited in IDS), as applied to Claims 2, 6-7, 10, 13-16, 29, 31-36, 38-40, 43-44, and 47, further in view of Breaker (WO 2013/142184, 2013, of record).
The teachings of Grant modified with Olesberg et al. and Hideo et al. are described above.
Regarding Claims 17 and 48, the teachings of Grant modified with Olesberg et al. and Hideo et al.do not teach autoclaving the single-use disposable sample cell.
It would have been obvious to autoclave the single-use disposable sample cell, after the monitoring microbial cell culture and before disposal, in the method suggested by Grant and Olesberg et al. for preventing biohazard, because it is routine practice in the art to autoclave all the disposable materials used for cell culture before disposal due to biosafety concern of their hazard to human or the environment. In support, Breaker teaches a process of culturing yeast cells with disposable materials, and expressively provides precautions to emphasize that all the disposable materials, such as tubes, cuvettes (reading sample cells), should be contained in a biohazard bag and materials should be autoclaved before disposal (page 31, lines 1-20). This provides motivation in and of itself, along with a reasonable expectation of success, because protecting human and environment from biohazard provides the motivation; and autoclaving is a technique well established in the art, which provides a reasonable expectation of success for modifying the method of the cited prior art.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention
Claims 4 is rejected under 35 U.S.C. 103 as being unpatentable over Grant (WO 2018/015405, 2018, cited in IDS) in view of Olesberg et al. (US 2015/0247210, 2015, of record) and Hideo et al. (JPH09266785, 1997, English translated version is cited in IDS), as applied to Claims 2, 6-7, 10, 13-16, 29, 31-36, 38-40, 43-44, and 47, further in view of Hulme et al. (US 2009/0219527, 2009, of record).
The teachings of Grant modified with Olesberg et al. and Hideo et al. are described above.
Regarding Claim 4, the teachings of Grant modified with Olesberg et al. and Hideo et al. do not expressively teach that the sample cell is round cuvette.
It would have been obvious to one of ordinary skill in the art to apply a round cuvette as a sample cell in the method suggested by Grant, Hideo and Olesberg et al. for collecting and analyzing culture samples from the bioreactor, because it had been well known in the art that a round cuvette is well suited for collecting and analyzing samples, as supported by Hulme et al., who teach that cuvettes are referred as spectrophotometer cells or cells, and a cuvette is a kind of labware, usually a small tube of circular or square cross section (reading on round cuvette) made of plastic, glass, or quartz, and designated to hold samples for spectroscopic analysis, and plastic cuvettes are disposable (first half of para 0029); and that conventional cuvettes are round or square, and may look similar to test tubes (page 3, para 0029, lines 7-8 from bottom).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Grant (WO 2018/015405, 2018, cited in IDS) in view of Olesberg et al. (US 2015/0247210, 2015, of record) and Hideo et al. (JPH09266785, 1997, English translated version is cited in IDS), as applied to Claims 2, 6-7, 10, 13-16, 29, 31-36, 38-40, 43-44, and 47, further in view of Yoneyama et al. (Patent No. 5182617, 1993, cited in IDS).
The teachings of Grant modified with Olesberg et al. and Hideo et al. are described above.
Regarding Claim 5, Grant teaches the sample cell includes a straight fluid path, but not a tortuous fluid path. However, it is an obvious design choice to include a tortuous fluid path, instead of a straight fluid path, in the sample cell in the method suggested by Grant, Hideo and Olesberg et al., as needed, for conducting cultural analysis that requires collecting a larger volume of culture samples in the sample cell, because it had been known in the art that a tortuous fluid path in a sample cell/unit can effectively provide a substantially large storage capacity in a small volume/area. In support, Yoneyama et al. teach a fluid system controlled by a syringe (i.e. a syringe pump), which performs extruding and aspirating operation of a liquid, and the syringe pump is connected to a first and a second sample storage units, wherein the sample storage units “3” and “4” provide a substantially sufficient storage capacity in spite of their small volume because they have spiral-shaped flow units (i.e. having a tortuous fluid path) (Fig. 1, col. 2/line 50 – col 3/line 9).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 41 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Grant (WO 2018/015405, 2018, cited in IDS) in view of Olesberg et al. (US 2015/0247210, 2015, of record) and Hideo et al. (JPH09266785, 1997, English translated version is cited in IDS), as applied to Claims 2, 6-7, 10, 13-16, 29, 31-36, 38-40, 43-44, and 47, further in view of Abu-Shumays (Patent No. 4180739, 1979, cited in IDS).
The teachings of Grant modified with Olesberg et al. and Hideo et al. are described above.
Regarding Claims 41 and 42, the teachings of Grant modified with Olesberg et al. and Hideo et al. do not teach assembling plates to enclose the sample cell and do not teach the sample cell including cuvette and tubing is fabricated/assembled in two sandwiched plates.
It would have been obvious to one of ordinary skill in the art to assemble plates to enclose/define the sample cell including interrogation cuvette and tubing in the method suggested by Grant and other cited prior art for facilitating the measuring and monitoring process, because it had been well known in the art that the assembled plates provide rapid thermal equilibration and precise temperature control for the enclosed cuvette and tubing. In support, Abu-Shumays teaches a thermostable flow cell for optical measurement of a liquid sample, which provides rapid thermal equilibration and precise temperature control (abstract, claim 1), wherein the flow cell 10 is fabricated from metallic blocks/plates 20, and it comprises an internal cylindrical configuration (flow channel) suitable for liquid flow, defined by a window 30 and a cylindrical groove 23 of a cylindrical bore 22, and also comprises an inter tubing 41 and an outlet tubing 42 (col 3/lines 1-15, 40-44 and 61-68, col 4/lines 1-3, Fig. 2); and wherein the tubing 41 and 42 as well as the internal cylindrical configuration (flow channel) are enclosed/defined by the metallic block/plate 20, which provides heat transfer for heating or colling the flow channel to maintain a fluid therethrough at a constant desired temperature (Fig. 2, the para spanning cols 3 and 4, col 4/lines 20-28) (Note: the internal cylindrical configuration/flow channel is equivalent to an interrogation cuvette that holds a liquid solution to be measured optically).
Regarding the limitation “… cuvette and tubing fabricated in two sandwiched plates” recited in Claim 41, the Fig. 2 of Abu-Shumays shows that the tubing (41 and 42) and the cuvette/flow channel (23 and 20) are flanked/enclosed by the metallic block/plate 20 at both left and right sides. It would be an obvious design choice to assemble cuvette and tubing between two plates around in a sandwiched form for facilitating temperature control. Furthermore, an arrangement of metallic block/plate can be readily modified through routine optimization for achieving a desired heat transfer efficiency. It is well settled that routine optimization is not patentable, even though it results in significant improvement over the prior art (see MPEP 2144.05).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Grant (WO 2018/015405, 2018, cited in IDS) in view of Olesberg et al. (US 2015/0247210, 2015, of record) and Hideo et al. (JPH09266785, 1997, English translated version is cited in IDS), as applied to Claims 2, 6-7, 10, 13-16, 29, 31-36, 38-40, 43-44, and 47, further in view of Kacira et al. (US 20180187234 A1, 2018, of record).
The teachings of Grant, Olesberg et al. and Hideo et al. are described above.
Regarding the claim 49, the teachings of Grant modified by Olesberg et al. and Hideo et al. do not teach that the detector/sensor is sealed within a main body of the tether head.
It would have been obvious to one of ordinary skill in the art to seal the detector/sensor (and other relevant components in the tether head) within a main body of the tether head in the method suggested by Grant, Olesberg et al. and Hideo et al. for monitoring the microbial culture in a bioreactor, because it had been well known in the art that the sealing protects the detector/sensor from being influenced by external environments, and also avoids components in the system to be affected with each other. In support, Kacira et al. teach a multi-wavelength laser-based optical sensor system for monitoring a microorganism culture in a bioreactor, comprising: a laser light source “120”, a flow chamber/sample cell “110”, an inlet “112” and an outlet “114” of the flow chamber, an optical detector “130” (i.e. an optical density sensor unit) for measuring optical density of the culture, and other components, which are hold in a housing, wherein the microorganism culture is pumped from a microorganism production chamber into the flow chamber with the inlet “112” (pumped out with the outlet “114”), and light from the light source is transmitted through the flow chamber, then detected by the optical detector/sensor unit (abstract, Claim 1, paras 0010-11 and 0027, Figs 1-2); and Kacira et al. further teach that the components including the sensor unit are housed in an enclosure to withstand external environmental conditions, and the entire sensor unit is mounted/sealed within a water proof enclosure to prevent water damage in case of leak (paras 0042/lines 5-9, and 0037/lines 1-5 and last 4 lines).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 45 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Grant (WO 2018/015405, 2018, cited in IDS) in view of Olesberg et al. (US 2015/0247210, 2015, of record) and Hideo et al. (JPH09266785, 1997, English translated version is cited in IDS), as applied to Claims 2, 6-7, 10, 13-16, 29, 31-36, 38-40, 43-44, and 47, further in view of Bergin et al. (GB 2541351 A, 2017, of record).
The teachings of Grant, Olesberg et al. and Hideo et al. are described above.
Regarding the claims 45 and 46, Grant modified with Olesberg et al. and Hideo et al. does not teach that the tunable laser is external and brought to the tether head through an optical cable.
It would have been obvious to one of ordinary skill in the art to replace the light source of tunable laser in the tunable laser with an external light source of tunable laser in the method suggested by Grant, Olesberg et al. and Hideo et al. for monitoring the microbial culture, where light is brought from external tunable laser to the tether head through an optical cable, because it is well known in the art that the optical fiber/cable is capable of effectively delivering light from an external light source to a desired location, and the light brought from external tunable laser through an optical cable to the tunable laser is an art-recognized equivalent for the same purpose. In support, Bergin et al. teach that optical absorption sensors are used in the measurement of concentrations of analytes in samples such as gas, liquid, and solid samples (page 1/lines 4-.5). Bergin et al. further teach that a light source (used for detection) can be: a laser, LED, or the end of an optical fiber (i.e. optical cable), via which light has been directed and delivered from a remotely located light source (external light source) (page 19, lines 576 – 577). It is noted that the “laser” taught by Bergin et al. includes the tunable laser, as supported by the disclosure of Bergin et al. in page 20/lines 606-607 and 619-620. As such, in view of Bergin et al., one of ordinary skill in the art would have recognized that either light from tunable laser in the tether head or light delivered to the tether head by an optical fiber cable from an external tunable laser is suitable for detecting cell densities in the method suggested by the cited prior art.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicant's arguments about the rejection of claim 37 under 35 U.S.C. 112(b) in the response filed on 09/29/2025 (page 1) have been fully considered but they are moot because the rejection has been withdrawn, as indicated above.
Applicant's arguments about the rejections of claims 2, 4-7, 10, 13-17, 29, and/or 31-49 under 35 U.S.C. 103 over Grant in view of other cited prior art in the 09/29/2025 response (pages 3-4) have been fully considered, but they are not persuasive. This is because Applicant’s amendment to the claim 10 by adding a structural limitation “sample cell is inserted into an access structure” is not sufficient to overcome the 103 rejections of record. This newly added limitation appears to be a structural feature well known in the art, as supported by Olesberg et al., who expressively teach a sample cell//fluid conduit inserted into an access structure/cartridge (see detailed description in pages 7-10 of this office action). Thus, the amended claims 2, 4-7, 10, 13-17, 29, 31-36, and 38-49 would still have been obvious over the combined teachings of Grant, Olesberg et al., Hideo et al. and/or other prior art of record for all the reasons indicated in the 103 rejections above.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656