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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 14 January 2026 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-17 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Independent claim 1 requires “a feed pipe comprising i) a sparging tube connected to a sparger at its end, and ii) at least one feed line with an opening at its end… [and] at least one inlet for liquids, individual inlets of the at least one inlet for liquids being connected to a feed line of the at least one feed line”.
Accordingly, independent claim 1 contemplates a feed pipe comprising ii) a sparging tube for delivering gases to the bioreactor and ii) a feed line for delivering liquids to the bioreactor. However, this structure is not clearly disclosed in the specification and Figures in a way that definitely identifies the physical features of the claimed invention.
Page 11 of the amended specification filed 30 September 2025 describes that up to four liquid feed lines 118-121 and a sparging tube 141 are disposed on the headplate. Page 6 includes language further indicating that the feed pipe 107 includes a sparging tube 141 and at least one feed line 118. Accordingly, written description requirement of 112(a) appears to be met. The problem is that the Figures show a different configuration between the feed pipe 107, feed lines 118-121 and sparging tube 141, and, more specifically, do not clearly depict an embodiment in which the feed pipe comprises i) a sparging tube and ii) a feed line for liquids.
The 30 September 2025 amended Figure 3 is below.
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This is said to show and clearly depict a feed pipe 107 comprising both i) sparging tube 141 and ii) feed lines 118-121. However, it is unclear how the “feed pipe 107” can be understood as a “pipe” when it is shown as a rectangular area of the headplate. Instead, it is represented as a dashed line to define a generalized location similar to the supply port area 133. Because of this, it is unclear what structures read on a “feed pipe”.
The 30 September 2025 amended Figures 1 and 4 depict the feed pipe 107 as looking like a common “pipe”, but fail to illustrate how feed pipe 107 further comprises feed lines 118-121. The feed pipe 107 of Fig. 3 looks nothing like the feed pipe 107 of Figs. 1 and 4. There are no feed lines connected to the feed pipe.
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The Figures and specification do not clearly show how the individual feed lines 118-121 are a subunit of the feed line 107. Rather, the Figures and written description appear to present conflicting information regarding how this feature is structurally defined. When interpreting the claims in view of and consistent with the specification, it is therefore unclear what structure is contemplated by the limitation “a feed pipe comprising i) a sparging tube connected to a sparger at its end, and ii) at least one feed line with an opening at its end… [and] at least one inlet for liquids, individual inlets of the at least one inlet for liquids being connected to a feed line of the at least one feed line”.
With respect to claim 15, it is unclear if the limitation “a ratio of filling height to filling diameter of 1.0 to 2.5” is intended to recite a specific ratio (i.e., 1:2.5) or a ratio range (i.e., 1:1 to 1:2.5). A strict reading of the claim suggests that a singular ratio 1:2.5 is required. However, the paragraph [0172] of the printed publication appears to indicate that the limitation instead refers to a range of ratios (“the ratio H/D of filling height of the cultivation vessel (H) to cultivation vessel diameter (D) is of from 1.0 to 2.5, in a further embodiment of from 1.1 to 2.0, and in a further embodiment of from 1.4 to 1.8”).
With respect to claim 15, it is believed that the claim should read “a ratio of filling height to inner diameter”. It is unclear to what the term “filling diameter” refers.
With respect to claim 16, it is unclear if the limitation “the ratio of the conveying element diameter to the cultivation inner diameter is 0.2 to 0.8” is intended to recite a specific ratio (i.e., 0.2:0.8) or a ratio range (i.e., 1:0.2 to 1:0.8). A strict reading of the claim suggests that a singular ratio 0.2:0.8 is required. However, the paragraph [0172] of the printed publication appears to indicate that the limitation instead refers to a range of ratios (“The ratio d/D of stirrer diameter (d) to cultivation vessel diameter (D) is in one embodiment of from 0.2 to 0.8, in another embodiment of from 0.3 to 0.6, and in a further embodiment of from 0.33 to 0.5”).
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 and then immediately mixed and agitated through the action of an impeller. 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 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 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 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
Applicant's arguments filed 15 December 2025 have been fully considered but they are not persuasive.
Applicant argues that the claimed invention is directed to a small-volume bioreactor, and that Claes discusses only large liquid volumes and very large volume tanks. Applicant cites articles which discuss how scaling up or down bioreactors is not a simple or predictable task.
However, the primary reference to De already teaches a bioreactor that has a total volume of 500 mL or less and a working volume from 20 mL to 350 mL. See paragraph [0042] (“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. Currently the traditional AMBR bioreactor system is used to test fed batch cultures at the 15 ml volume level but is not currently capable of doing continuous cell culture scouting screens yet. With the new perfusion bioreactor this would be possible”).
De states that such a small-volume bioreactor may include a glucose sensor (“the sensor 254 can…a glucose sensor”). De states that the small-volume bioreactor may include a pH sensor (“ the sensor 254 can be…a pH sensor”). See paragraph [0035].
Accordingly, there is no issue with scaling down. De expressly teaches a small-volume bioreactor having a glucose sensor. De expressly teaches a small-volume bioreactor having a pH sensor. The rejection of record is not premised on scaling down Claes. Rather, the rejection of record is based on using both the De glucose sensor and the De pH sensor within the same reactor, such that the glucose sensor is fixed to the feed pipe. The De glucose sensor is already known to function predictably and successfully in the De reactor because De says that this is so.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The Mairesse (US 20210155892) and Ryan (US 20080131957) references teach the state of the art regarding small volume reactors.
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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/NATHAN A BOWERS/Primary Examiner, Art Unit 1799