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 .
Status of the Claims
Claims 1-5, 7, 10, 15, 19, 21-24, and 27-30 are pending (claim set as filed on 06/10/2026).
Priority
This application is a 371 of PCT/US2021/054915 filed on 10/14/2021, which has a provisional application no. 63/092,327 filed on 10/15/2020.
Withdrawal of Rejections
The response and amendments filed on 06/10/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated herein for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s response to arguments section.
Briefly, the previous anticipation rejection by Bransby has been withdrawn necessitated by Applicant’s amendments to include an ATF filter and a cell bleed stream. However, a new ground of obviousness rejection is set forth below with a new secondary reference by Lin which teaches the new amended features.
Briefly, the previous obviousness rejection over Zhou in view of Nakai has been withdrawn necessitated by Applicant’s amendments to include the feature of a cell bleed stream. The Zhou reference is directed to continuous harvest without cell bleeding.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Grounds of Rejection Necessitated by Amendment
Claim Rejections - 35 USC §103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-5, 7, 10, 15, 19, 21-24, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Bransby (US 2019/0337979 A1 - cited by the ISA and in the IDS filed on 07/17/2023) in view of Lin (US 2020/0332251 A1 – newly cited).
Bransby’s general disclosure relates to methods, devices and systems for filtration of biological fluids, including filtration of bioreactor fluids; separating such cell debris from products of interest, including expressed target proteins, such as monoclonal antibodies, among others (see abstract & ¶ [0001], [0006]). The process is a continuous process (see ¶ [0010]).
Bransby teaches “filtration methods that comprise: (a) passing a first fluid that comprises cells, cell debris and a targeted product produced by the cells through a first filter such that the first fluid is separated by the first filter into a first retentate comprising the cells and a first permeate comprising the targeted product and a first portion of the cell debris that passes through the first filter; (b) combining resin beads having affinity for the targeted product with the first permeate such that a second fluid is formed that comprises the resin beads with bound target product and the first portion of the cell debris; and (c) passing the second fluid through a second filter such that the second fluid is separated by the second filter into a second retentate comprising the resin beads with the bound target product and second permeate comprising a second portion of the cell debris that passes through the second filter” (see ¶ [0007], [0030], [0054]-[0056], & Figure 6). Bransby teaches “the use of 1.0 μm up to 5.0 μm thick wall hollow fiber tangential flow filters employed in systems of this type have been shown to consistently pass nearly 100% of monoclonal-antibody-sized proteins for harvest from cell culture. However, a certain amount of cell debris also passes through such filters along with the protein. Therefore, a polishing filter is typically used to further separate the cell debris from the protein” (see ¶ [0002]-[0005]).
Regarding claims 3-5 pertaining to the filters, Bransby teaches the first filter has a mean pore size ranging from 1 μm to 8 μm, typically ranging from 1-2 μm (see ¶ [0015]-[0020], [0038]-[0039], & Figures 1-5 for the filters).
Regarding claim 10 pertaining to the filtration flow, Bransby teaches the second filter is a second tangential flow filter (see ¶ [0018], [0039]).
Regarding claims 27-28 pertaining to the biomolecule, Bransby teaches the targeted product is a protein, a monoclonal antibody or a polyclonal antibody (see ¶ [0013]).
However, Bransby does not teach: wherein the first filter is an Alternating Tangential Flow (ATF) filter and the cell culture vessel is in fluid connection with a cell bleed stream suitable for removing cell biomass to maintain a stable cell density culture (independent claims 1 and 29-30’s last limitations as amended).
Lin’s general disclosure relates to “improved cell culture media and methods that achieve greater cell specific productivity and better sustained and/or maintained viability relative to state of the art methods” (see ¶ [0002]). Cell culture includes a cell population that is maintained in a medium under conditions suitable to allow survival and/or growth of mammalian cell population (see ¶ [0114]).
Lin discloses “Another problem facing continuous perfusion cell culture systems is the challenge of maintaining a constant viable cell density, and by consequence, a healthier and more
productive cell culture. This has typically been addressed by allowing for ‘cell bleed.’ During cell bleeding, cells are removed and discarded as waste at a rate sufficient to allow for a steady state perfusion cell culture. In turn, this keeps viable cell density constant … The cell bleed rate is determined by rate of cell growth. A faster doubling time also necessitates a higher cell bleed to maintain constant cell density” (see ¶ [0010]).
Lin teaches “A perfusion culture may also be referred to as continuous culture. This provides a steady source of fresh nutrients and constant removal of cell waste products. Perfusion is commonly used to attain much higher cell density and thus a higher volumetric productivity than conventional bioreactor batch or fed batch conditions. Secreted protein products can be continuously harvested while retaining the cells in the reactor, e.g., by filtration, alternating tangential flow (ATF), cell sedimentation, ultrasonic separation, hydrocyclones, or
any other method known to the person skilled in the art” (see ¶ [0108]). Lin further discloses “Currently there are three systems that can be used at industrial scale, alternating tangential filters (ATF), gravitational (particularly inclined settlers) and centrifuges” and pore sizes can range from several hundred kDa (see ¶ [0171] & Examples).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ or substitute a first filter of an alternating tangential flow (ATF) such as taught by Lin the method of Bransby. The ordinary artisan would have been motivated to do so because Bransby is directed to a process that is a continuous process (see Bransby ¶ [0010]) and Lin discloses ATF filter for use in continuous process. Moreover, Lin discloses that ATF is one of the three systems that can be used at industrial scale (i.e., ATF systems are routine and commonly known in the art). Furthermore, it would have been secondly obvious to employ or use a cell bleed stream to allow for a steady state perfusion cell culture which in turn, this keeps viable cell density constant such as taught by Lin (see Lin at ¶ [0010]). The MPEP 2141(III) provides examples of rationales that may support a conclusion of obviousness include: (a) combining prior art elements according to known methods to yield predictable results; and/or (b) simple substitution of one known element for another to obtain predictable results. Thus, the claimed invention would have been readily apparent to one of ordinary skill in the art as the use of ATF either as a first and/or second filter and cell bleeding are routine and commonly used in the continuous perfusion process.
Furthermore, if not expressly taught by the references, based upon the overall objectives provided by Bransby and Lin with respect maximizing efficiency or productivity of the cell culture processes that can lead to greater product yield, the adjustments of particular conventional working conditions (e.g., the bioreactor vessel conditions such as pH/temperature/agitation/rotary/gas levels, cell culture or harvest duration, filtration characteristics such as flow rates) are deemed a matter of judicious selection and routine optimization which is within the purview of the skill artisan. Therefore, the cited prior art disclosure(s) establishes the conditions of variable parameters such that one of ordinary skill in the art would recognize that these condition as result effective variables dependent upon the cell type employed and biomolecule of interest. For example, Lin teaches “Physical parameters such as pH, dissolved oxygen and temperature in a perfusion bioreactor should be monitored on-line and controlled in real time. Determination of cell density, viability, metabolite, and product concentrations may be performed using off-line or on-line sampling. When the perfusion operation starts with continuous harvest and feeding the perfusion rate typically refers to the harvest flow rate, which may be manually set to a desired value. For example, a weight control for the bioreactor may activate the feed pump so that a constant volume in the bioreactor can be maintained. Alternatively, a level control can be achieved by pumping out culture volume above a predetermined level. The perfusion rate in the bioreactor must be adjusted to deliver sufficient nutrients to the cells. As the cell density increases in the bioreactor, the perfusion rate must be increased” (see Lin at ¶ [0172]-[0173]). This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning these conditions, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variable which can be met as a matter of routine optimization (MPEP 2144.05 II).
Conclusion
No claims were allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGHI V NGUYEN whose telephone number is (571)270-3055. The examiner can normally be reached Mon-Fri: 9 - 3 pm (EST).
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653
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