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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12 December 2025 has been entered.
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 19, 21-24 and 26-30 are rejected under 35 U.S.C. 103 as being unpatentable over Thakkar (US 20210283606) in view of Kelso (US 20230051840) and Determan (WO 2022137061).
With respect to claim 19, Thakkar discloses a system in which a cell processing cartridge (Figure 102:10210) is provided. The cartridge includes a transduction system comprising a fluidic manifold (see paragraph [0407]), a flow cell for electroporation (Figure 102:10260), a bioreactor module (Figure 102:10230, 10232, 10234, 10236), and at least one tube configured to connect the flow cell to the bioreactor module. This is taught in paragraphs [0324]-[0366] and [0429]-[0460]. Paragraph [0409] teaches that processing in the flow cell and bioreactor may be repeated (“a module may be used more than once in a method of cell processing”), which suggests that the tube connecting the flow cell and bioreactor is configured as a bidirectional flow path. Regardless, the limitation “provides a bidirectional flow path” is an intended use recitation that is afforded reduced patentable weight in the context of an apparatus claim. 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. The tube shown by Thakkar is arranged as a transfer bus (Figure 102:10295) that links all modules, including the flow cell and bioreactor. Paragraphs [0407]-[0414] state that the tube (transfer bus) is in communication with multiple pumps capable of producing a change in fluid flow direction. Thakkar, however, does not expressly teach a surface area to volume ratio.
Kelso teaches a transduction system that includes a plurality of modules (e.g., electroporation flow cell, cell expansion bioreactor) connected by a plurality of tubes. See the annotated Fig. 1 of Kelso above. Kelso further teaches in paragraph [0056], [0057], [0060] and [0061] that the diameter of the tube can vary widely and generally may be within the range of 50 microns to 2 mm. The surface area of a basic cylinder is 2πrh, while the volume of a basic cylinder is πr2h. Given that there are 1,000 mm3 in a mL, the claimed surface area to volume ratio will be satisfied when the radius of the tube is approximately 0.5-1.0 mm, which falls well within the range taught by Kelso. Kelso expressly recognizes that the “dimensions of a specific fluid channel (width, depth, and/or length) may be tuned depending on its specific function”.
Similarly, Determan discloses transduction system that includes a plurality of modules connected to a plurality of tubes. See Fig. 1. Determan teaches that a lysis reagent is mixed with a viral vector to produce a transfection solution. The transfection solution is delivered through a coiled tube that performs a mixing and incubation function. The transfection solution is then delivered to a bioreactor. Determan teaches in paragraphs [00151], [00164], [00177] and [00179] that the size of the tube can vary widely. Determan expressly discloses configurations in which the surface area to volume ratio of the tube is between about 1,260 mm2/mL and about 5,080 mm2/mL.
Therefore those of ordinary skill would have been able to experiment within the disclosed range to modify fluid flow behavior in a predictable way and arrive at the claimed ratio when using and manufacturing the Thakkar system.
Kelso additionally teaches a transduction efficiency of at least 50% in paragraphs [0088] and [0158]. Before the effective filing date of the claimed invention, it would have been obvious to ensure that Thakkar achieves a transduction efficiency of at least 50%. Thakkar teaches that transduction (i.e., electroporation) efficiency may be affected by a variety of factors, including electric field properties, flow channel geometry, cell type and exposure time. As evidenced by Kelso, it is within the ability of one of ordinary skill to obtain a very high transduction efficiency approaching 100%. It would have been desirable to maximize transduction rate and efficiency during the Thakkar method to enhance the production of a cell therapy product.
As for the limitations “provides…flow…for about 60 minutes to 90 minutes” and “a constant flow rate range of about 5 mL/min to about 10 mL/min”, it is again noted 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. In the alternative, it would have been obvious to adjust the time period of transduction and the time period it takes to travel through the tube (e.g., by modifying the length of the tube, direction of flow, and flow rate through the tube) from the electroporation module to the bioreactor module in order to enhance transduction efficiency and allow sufficient time for membrane resealing. Those of ordinary skill would have understood that exposure time to a transduction treatment (e.g., electroporation) is one of many factors that contributes to the success of the transduction operation. Paragraph [0354] of Thakkar states that fluid flow through the electroporation module is discontinuous, which increases the time it takes to travel through the tube. It is additionally noted that Kelso teaches flow rates as low as 0.1 mm/sec in paragraph [0104]. Furthermore, Determan expressly teaches the claimed flow rate and incubation time in paragraphs [0079]-[0081] and [00176]-[00178].
With respect to claim 21, Thakkar, Kelso and Determan disclose the combination as described above. As previously discussed, Thakkar shows an electroporation flow cell and bioreactor module in Figs. 72 and 102 that are linked using the tube.
With respect to claim 22, Thakkar, Kelso and Determan disclose the combination as described above. Determan additionally teaches that a mixing chamber is provided at a T-junction prior to the coiled incubation tube. See Fig. 1 and paragraph [0011].
With respect to claim 23, Thakkar, Kelso and Determan disclose the combination as described above. Kelso gives a few examples in paragraph [0056], [0057], [0060] and [0061] in which the diameter of the tube is between about 1.57 mm and about 3.18 mm – for example, 2 mm and 3 mm. Determan does the same in paragraphs [00151], [00164], [00177] and [00179].
With respect to claim 24, Thakkar, Kelso and Determan disclose the combination as described above. Kelso states in paragraph [0104] that a cell solution is transported through the tube at a constant flow rate during the first time period using a pump.
With respect to claim 26, Thakkar, Kelso and Determan disclose the combination as described above. Thakkar additionally shows in Fig. 14 that the cartridge is received within a docking station. See paragraph [0347].
With respect to claims 27-30, Thakkar, Kelso and Determan disclose the combination as described above. Thakkar further teaches that the system includes a plurality of reagent vaults (Figure 1A:118) configured to store one or more reagents, including transduction reagents. Kelso describes in paragraphs [0010] and [0040] that cells are suspended in a solution comprising transduction reagents. Likewise, Determan shows a plurality of reagent vaults in Fig. 1. Thakkar further teaches in paragraph [0237] a sterile liquid transfer device (Figure 1A:142) interfaces with cartridge input and output ports in order to exchange reagents between a reagent vault and the cell processing cartridge.
Allowable Subject Matter
Claims 1-7, 9, 12-14 and 18 are allowed.
Thakkar, Kelso and Determan provide the individual teachings described above, but do not teach a corresponding method in which a viral vector is introduced into a cell solution within a bioreactor prior to flowing the modified cell solution through a flow cell and a tube disposed between the bioreactor and flow cell. Determan, instead, teaches that a viral vector and transfection agent are incubated in the tubing prior to be added to the bioreactor. Determan also fails to teach a flow cell, a bidirectional flow path, or a processing cartridge.
The Tapia (WO 2017190790) reference, like Determan, does not teach that a viral vector 4 is introduced into a cell solution within a bioreactor 2, but rather states that the viral vector is mixed with cell solution in a mixing unit 12 prior to introduction into a plug flow tube 1. Tapia does not clearly show a flow cell, a bidirectional flow path, or processing cartridge.
The De Mollerat Du Jeu (WO 2023064187) reference teaches cultivating viral production cells grown in a viral production medium and mixing with a transfection agent in an in-line static mixer, so that the product is delivered to a bioreactor. De Mollerat Du Jeu does not teach introducing the viral vector into a cell solution within a bioreactor and transferring the combined solution through a flow cell. De Mollerat Du Jeu does not describe a bidirectional flow path or a cell processing cartridge.
Response to Arguments
In response to Applicant’s amendment filed 12 December 2025, the previous rejections involving Thakkar and Kelso have been withdrawn. However, upon further consideration, a new ground of rejection is made in view of the combination of Thakkar with Kelso and Determan.
Conclusion
This is a non-final rejection.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The Holaday (US 6773669) reference teaches the state of the art regarding tubes configured to promote transfection of cells.
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/NATHAN A BOWERS/Primary Examiner, Art Unit 1799