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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04 November 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 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Frank (US 20170349873) in view of Furuhashi (JP 2009297340) and Akechi (US 20090233351).
With respect to claim 1, Frank discloses a priming method for discharging a gas contained within hollow fibers. Liquid is introduced into a treatment unit comprising hollow fibers (Figure 1B:117) having a coating formed on inner circumferential surfaces that promotes cell adhesion and growth within inner cavities (Figure 1B:116). This is taught in paragraphs [0054]-[0064]. The hollow fibers are disposed in a container (Figure 1B:104) having an internal space. Paragraphs [0080]-[0083] and [0104]-[0105] teach that priming fluid is passed through an internal route where liquid is allowed to flow in the inner cavities (“To prime the bioreactor 501, 601, a bag (e.g., 546) may be attached (for example, to connection point 646) to the system 500, 600…PBS can then be directed into the first fluid circulation path 502, 602 by the IC inlet pump 554, 654 set to pump the PBS into the first fluid circulation path 502, 602”). Frank further states that priming fluid is also passed through an external route through which priming liquid is allowed to flow in the internal space on an outer side of the hollow fibers (“a bag (e.g., 568) may be attached (for example, to connection point 668) to the system 500, 600…media, e.g., PBS, can then be directed into the second fluid circulation path 504, 604 by the EC inlet pump 578, 678 set to pump the media into the second fluid circulation path 504, 604. Valve 582, 692 may be closed while the media enters the bioreactor 501, 601 through the inlet 501C, 601C and out the outlet 501D, 601D of the EC loop”). Frank identifies that the priming fluid may be a cleaning fluid, such as PBS. Frank specifically states in paragraphs [0050] and [0142] that PBS performs a “wash” (i.e., “cleaning”) function. Figure 10 shows that first and second cleaning fluids may be delivered to the IC and EC spaces at different rates. Paragraphs [0057], [0081] and [0095] indicate that the cleaning liquid is passed through the internal and external routes in opposite flow directions (“Fluid in first fluid circulation path 12 may flow in either a co-current or counter-current direction with respect to the flow of fluid in second fluid circulation path 14”). Frank, however, does not expressly state that a differential pressure is generated between liquid flowing through the inner cavities and liquid flowing through the internal space.
Furuhashi discloses a method in which a blood purification membrane (i.e., hollow fiber membrane) is treated with priming fluid. A transmembrane differential pressure is measured as gases are removed. Paragraphs [0036]-[0043] state that an ultrafiltration rate of the membrane is obtained based on the pressure differential.
Akechi discloses a degassing method in which a transmembrane pressure differential is generated between two liquid streams (Figure 1B:1 and Figure 1B:2) separated by a membrane (Figure 1B:5). The pressure differential is controlled in order to optimize the removal of gases from one stream. See, for example, paragraphs [0029] and [0042]-[0053] (“by providing a difference in liquid sending pressure between the two flow channels provided with the gas exchange unit being interposed therebetween, it is possible to control the transfer of bubbles between the two flow channels. This makes it possible to eliminate the influence of bubbles”). See also provisional claim 3 (“the transfer of bubbles is controlled by making a pressure in the second flow channel higher than a pressure in the first flow channel to remove bubbles from the second fluid by allowing the bubbles to transfer into the first fluid”).
Before the effective filing date of the claimed invention, it would have been obvious to create and control the transmembrane differential pressure when priming the Frank bioreactor. Furuhashi and Akechi teach that gases and bubbles may be forced into the priming fluid when they are required to move from a relatively high-pressure stream to a relatively low-pressure stream. One of ordinary skill would have recognized that this would allow one to confidently purge all gases by collecting them all into either the priming liquid passing through the internal route or the priming fluid passing through the external route.
With respect to claims 2, 6 and 7, Frank, Furuhashi and Akechi disclose the combination as described above. Frank further shows that an internal circulation circuit (Figure 6:602) is in communication with an internal supply (Figure 6:646) and an internal supply circuit. Frank likewise shows that an external circulation circuit (Figure 6:604) is in communication with an external supply (Figure 6:668) and an external supply circuit. Fluid is passed through both the internal and external circulation circuits to establish a differential pressure therebetween. Priming fluid with collected waste gases is disposed of in waste liquid reservoirs (Figure 6:699,686).
With respect to claims 3 and 5, Frank, Furuhashi and Akechi disclose the combination as described above. As previously discussed, Furuhashi and Akechi disclose methods for increasing or decreasing the differential pressure in order to influence gas and/or bubble transfer into a desired priming fluid path. Those of ordinary skill would have recognized that pressure and flow rate are directly related, and that changes in flow rate produce a predictable effect on pressure and the pressure differential. Accordingly, it would have been within the ability of one of ordinary skill to increase, decrease or stop the flow of priming fluid through either of the internal or external circulation circuits to create a desired transmembrane pressure differential and optimize the purging of gas from the system.
With respect to claim 4, Frank, Furuhashi and Akechi disclose the combination as described above. Frank further teaches that cleaning liquid and gas is discharged into a waste liquid bag (Figure 6:686). This is accomplished by opening a clamp (i.e., valve) (Figure 692) within a waste liquid route, and stopping flow through a first pump (Figure 6:612) in the IC route and/or stopping flow through a second pump (Figure 6:628) in the EC route. Third and/or fourth pumps (Figure 6:654,678) are then activated to force cleaning fluid and gas into the waste liquid route. Frank further teaches in paragraphs [0067], [0265] and [0294] that the bioreactor container is rotated to a vertical position to facilitate discharge liquids, such as the cleaning liquid, when it is necessary (“bioreactor 100 may also be rotated around rotational axis 144 and positioned in a horizontal or vertical orientation relative to gravity”).
With respect to claims 8 and 9, Frank, Furuhashi and Akechi disclose the combination as described above. Furuhashi and Akechi both teach that gases are forced across and out of a membrane in response to an elevated transmembrane pressure. Akechi expressly states how gases move into a first fluid when the pressure in a second fluid is increased. Those of ordinary skill would have understood how to apply this principle when practicing the Frank method by either increasing the internal pressure of the internal route above that of the external route or by increasing the internal pressure of the external route about that of the internal route (based on whether the gases are desired to be collected in the priming fluid passing through the internal or external route).
With respect to claim 10, Frank, Furuhashi and Akechi disclose the combination as described above. Frank teaches that the priming operation is conducted before a cell culture operation, wherein the cell culture operation includes causing cells to become adhered to the inner surfaces of the hollow fibers and contacting the cells with a supplied culture medium. This is discussed in at least paragraphs [0047]-[0054].
Response to Arguments
Applicant's arguments filed 04 November 2025 have been fully considered but they are not persuasive.
Applicant primarily argues that Akechi does not teach flowing the same cleaning fluid through both the internal and external routes. Although it is true that Akechi teaches a first flow channel containing carbon dioxide and a second flow channel containing deionized water, Akechi is not relied upon for teaching this limitation. Rather, Frank – the primary reference – already expressly teaches passing the same cleaning fluid through each of the internal and external flow routes. Paragraphs [0080]-[0083] and [0104]-[0105] state that a PBS cleaning fluid is delivered through all of the IC and EC channels to successfully prime the bioreactor.
Applicant additionally argues that Akechi teaches a co-current flow through the internal and external routes. It is agreed that Akechi shows a co-current configuration in Fig. 2B. However, Frank expressly teaches that flow many be co-current or counter-current, and that is well within the ability of one of ordinary skill to choose either strategy (especially give that these are the only two options available). See, for example, paragraphs [0057], [0081] and [0095] (“Fluid in first fluid circulation path 12 may flow in either a co-current or counter-current direction with respect to the flow of fluid in second fluid circulation path 14”).
Conclusion
This is a non-final rejection.
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/NATHAN A BOWERS/Primary Examiner, Art Unit 1799