DETAILED ACTION
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 1-6 and 9-17 are rejected under 35 U.S.C. 103 as being unpatentable over De (US 20190048305) in view of Claes (US 20100015696).
With respect to claim 1, De discloses a bioreactor comprising a cultivation vessel (Figure 2:200) that has a working volume between 20 ml to 350 ml and a total volume of less than 500 mL (“The perfusion bioreactor can be any size such as 0.1 liter to about 1000 liters or more. The perfusion bioreactor can be miniaturized to small scale like 15 ml volumes which could enable high throughput continuous culture assays”, paragraph [0042]). The vessel has a stirrer shaft (Figure 4:234), at least one impeller (Figure 4:232), a sparging tube (Figure 3:236) connected to a sparger, and at least one feed line (Figure 3:208). Each of these elements pass through a reactor head plate (Figure 3:204) that includes a fitting for connected a drive axis of a motor to the stirrer shaft. A sparger gas inlet, a gas outlet, and at least one inlet for liquids of the feed line are additionally provided through the head plate and arranged at a supply port area. Each liquid inlet is in communication with a corresponding feed line. An in-situ sensor port (Figure 3:240) is provided for accepting a pH sensor and/or a glucose sensor (Figure 3:254) (“ sensor port 240 is connected to a sensor 254 that has an end 256 located in the inner compartment 218 (as shown) or the outer compartment 220 (not shown). For example, the sensor 254 can be a: dissolved oxygen (DO.sub.2) sensor, a carbon dioxide (CO.sub.2) sensor, a pH sensor, a cell density sensor, a glucose sensor, or a flow or shear stress and temperature sensor, or any other sensor”, paragraph [0035]). Paragraph [0031] further states that the cultivation vessel and the reactor head plate may be made from glass, ceramic or plastic. De, however, does not appear to show that the sparging tube and the feed line(s) are arranged within a common feed pipe, or that the glucose sensor is fixed to the feed pipe.
Claes discloses a bioreactor comprising a cultivation vessel comprising a head plate (Figure 2A:104) having a fitting (Figure 2A:105) for accepting a stirrer shaft (Figure 2A:130). A sleeve is configured as a feed pipe (Figure 19:1640), such that the feed pipe comprises a sparging tube (Figure 19:1665) and at least one feed line (Figure 19:1691). A sparger (Figure 19:1675) is connected to the sparging tube via the feed pipe, and liquids pass through the feed pipe and feed line as they are delivered to the interior of the cultivation vessel. Multiple sensors (Figure 18:1681-1683) are connected to the feed pipe 1640. This is taught in paragraph [0138].
Before the effective filing date of the claimed invention, it would have been obvious to deliver gas and liquid to the De cultivation reactor using a common feed pipe having both a sparging tube and a feed line. Claes teaches that uniform environmental conditions within the reactor may be readily achieved when gases and liquids are simultaneously transported to the same area. Those of ordinary skill would have additionally recognized that the provision of a common feed pipe would decrease the number of connections required to be formed through the head plate, and would have thereby simplified construction and decreased interference with the culture fluid and other reactor elements (e.g., impeller) caused by multiple delivery tubes.
Before the effective filing date of the claimed invention, it would have been obvious to also ensure that the De glucose sensor is fixed to the feed pipe. Claes teaches that this is beneficial because the feed pipe extends into the middle of the bioreactor volume and allows the sensor to directly contact cell culture at different internal locations when the sensor is attached to the feed pipe. Those of ordinary skill would have recognized that this would produce a more accurate representation of bioreactor conditions than a glucose sensor attached to a sidewall or head plate of the reactor.
De, however, still differs from Applicant’s claimed invention because De does not expressly teach multiple baffles.
Claes discloses the bioreactor as described above. Claes additionally states that the cultivation vessel includes two or more baffles (Figure 4A:202A-B) extending from a wall of the cultivation vessel perpendicular in direction to the center of the cultivation vessel. This is taught in paragraphs [0112] and [0113] and shown in Figs. 4A-7C.
Before the effective filing date of the claimed invention, it would have been obvious to provide the De cultivation with a plurality of baffles. Claes expressly states that baffles substantially improve mixing within a bioreactor (“With the addition of the baffles 212A, 212B to the tank 211, the motion of the mixing paddle 110 at a nonzero angle relative to the substantially central vertical axis 240 of the tank 211 yields substantially better mixing over a broader range of conditions than the tank 101 illustrated in FIG. 3B. This is particularly advantageous in bioprocessing applications where it is desired to achieve rapid oxygen saturation in a liquid such as water, and/or to maintain relatively high levels of oxygen saturation despite the presence of oxygen-consuming biological moieties”).
With respect to claims 2-6, De and Claes disclose the combination as described above. The De reactor is fully capable of being sterilized prior to use. Apparatus claims cover what a device is, not what a device does. A claim containing a recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus if the prior art apparatus teaches all the structural limitations of the claim. See MPEP 2114. Sterilization removes contaminants, but does not impart any additional structure. Furthermore, many sterilization techniques are well known in the art. See paragraph [0041] of De (“The assembled perfusion bioreactor can be gamma irradiated, e-beam sterilized, ultra-violet (UV) sterilized, ethanol sterilized or gas sterilized”).
With respect to claims 9 and 10, De and Claes disclose the combination as described above. Claes further teaches in paragraph [0140] that the sensors determine changes in a measured analyte over time and send data to a controller via a wireless transmitter.
With respect to claim 11, De and Claes disclose the combination as described above. Claes further shows various feed ports (Figure 2A:180,185) and sampling ports (Figure 2A:160).
With respect to claim 12, De and Claes disclose the combination as described above. De shows in Fig. 3 that the sensor port passes through the head plate in approximately in the same location (i.e., supply port area) as the feed line and sparging tube.
With respect to claims 13 and 14, De and Claes disclose the combination as described above. De and Claes both teach corresponding methods of using the disclosed bioreactors. De and Claes each describe how sensors are used to measure and report environmental conditions during cell culture. See, for example, paragraphs [0035] and [0036] of De.
With respect to claim 15, De and Claes disclose the combination as described above. De further shows in Fig. 2 an embodiment in which the fill height is roughly equal to the bioreactor inner diameter. Furthermore, De teaches that the cultivation vessel may be configured to have a wide variety of volumes, thereby producing vessels characterized by a wide variety of diameters that at least some of which would read on the claimed ratio. Alternatively, “filling height” is not a structural feature of the bioreactor, but rather represents how the reactor is being used during a given culture operation. It is well established that apparatus claims cover what a device is, not what a device does. A claim containing a recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus if the prior art apparatus teaches all the structural limitations of the claim. See MPEP 2114.
With respect to claim 16, De and Claes disclose the combination as described above. De further shows in at least Figs. 2-4 that the conveying element diameter is 0.2 to 0.8 as long as the inner diameter of the cultivation vessel. Alternatively, De teaches that the cultivation vessel may be configured to have a wide variety of volumes, thereby producing vessels characterized by a wide variety of diameters that at least some of which would read on the claimed ratio.
With respect to claim 17, De and Claes disclose the combination as described above. De teaches in paragraph [0042] that the volume of the reactor may vary significantly. Accordingly, De contemplates embodiments in which the stirrer shaft has a height of 20mm to 500mm.
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over De (US 20190048305) in view of Claes (US 20100015696) as applied to claim 1, and further in view of Stine (US 20220041973).
De and Claes disclose the combination as described above. Although De describes the use of glucose sensors, De does not specifically teach sensors that include screen-printed electrodes coated with an immobilized enzyme.
Stine discloses a bioreactor comprising a cultivation vessel comprising a head plate and a sparging tube connected to a sparger. See Fig. 6. Paragraph [0147] teaches that glucose sensors are used to continuously measure glucose concentration in the reactor, and that the sensors include screen-printed electrodes coated with an immobilized enzyme.
Before the effective filing date of the claimed invention, it would have been obvious to use essentially any commercially available glucose sensor to measure nutrient conditions with the De reactor. As evidenced by Stine, glucose sensors comprising screen-printed electrodes coated with an immobilized enzyme are available for purchase from known vendors, and that these particular sensors are precise and accurate and may be used to wirelessly transmit updated glucose concentration values to a controller in real time.
Response to Arguments
In response to Applicant’s remarks and amendment to the Figures, the previous rejection under 35 U.S.C. 112 has been withdrawn.
Applicant's arguments filed 21 August 2026 have been fully considered but they are not persuasive.
It is agreed that De discloses a small-volume bioreactor that includes a sensor, wherein the sensor may be a glucose sensor or a pH sensor (“the sensor 254 can be…a glucose sensor; “ the sensor 254 can be…a pH sensor”). See paragraphs [0035], [0036] and [0056].
De further suggests that multiple sensors may be used in the same bioreactor. See paragraph [0034] (“a wide range of sensors (e.g., temperature, DO.sub.2, CO.sub.2, pH, cell density) can be added to one or both the inner compartment and the outer compartment for continuous multivariate QbD and process analytical technology (PAT) design and operation”). Similarly, Claes shows how multiple sensors may be arranged in a common bioreactor to simultaneously detect and evaluate different variables. Accordingly, those of ordinary skill would not have been limited to using only a single sensor when using the De reactor, but rather would have found it obvious to use multiple sensors to detect multiple parameters.
When doing this, Claes indicates that a sensor may be positioned on a feed pipe. This would have been beneficial because the feed pipes of Claes and De each extend toward the center of the reactor, thereby enabling detection of glucose in the mixed culture fluid when a sensor is attached to that feed pipe. Those of ordinary skill would have recognized that this would have been beneficial because it would allow for detection at areas other than along the reactor sidewalls, which may not provide an accurate representation of the condition of the bulk fluid across the entire reactor volume. Furthermore, it is well established that a mere rearrangement of parts (here, locating the glucose sensor of De on the feed pipe) that produces a predictable and/or minimal change in operation is prima facie obvious. See MPEP 2144.04.
Applicant argues that the sleeve 1640 of Claes is not analogous to the claimed feed pipe. However, the sleeve and the rod 1610 of Claes are hollow (“Each sealed sleeve 940A, 940B contains a mixing paddle 910A, 910B joined to a hollow shaft 930A, 930B”), extend into the reactor volume, and carry tubes for the delivery of culture fluid and gases. Accordingly, Claes teaches a feed pipe structure that is similar in both design and function when compared to the claimed feed pipe.
Lastly, Applicant states that the feed pipe of Claes is configured as a paddle that is rotated to provide motion and mixing action, and that this is incompatible with the stationary feed pipe of De. In response, it is noted that the proposed combination of references is not premised on altering the De feed pipe so that it rotates and functions as a mixing element. Rather, the combination of references would lead one to experiment with different locations for positioning the De glucose sensor, including configurations where the sensor is disposed on the feed pipe.
Conclusion
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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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