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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/06/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Applicant’s arguments with respect to claim 1 have been considered but are moot in view of a new grounds of rejection necessitated by the amendments to the claims.
The claim amendments have overcome the previous rejection under 35 U.S.C. 112(b).
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-4, and 6-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the final stage of harvesting a produced biomolecule" in lines 11-12. There is insufficient antecedent basis for this limitation in the claim.
Dependent claims are rejected for the same reason as the base claim(s) upon which they depend.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, and 6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jäger (High Density Perfusion Culture Of Animal Cells Using A Novel Continuous Flow Centrifuge).
Regarding claim 1, Jäger discloses a method for operating a bioprocessing system adapted for perfusion mode operation (Abstract), comprising the steps of:
producing a cell culture mixture in a fermentor (called bioreactor) (Abstract, p. 210 last para., p. 212 first para., p. 215 second para.);
conducting a flow of a cell culture mixture from the fermentor into an interior of a centrifugal separator (Abstract, p. 209 last para., p. 212 first para.) (Fig. 2, p. 211), the separator comprising a rotor which defines a separation space in which a surface enlarging insert (called disk stack; reads on a surface enlarging insert consistent with Applicant’s specification) is arranged (p. 209 last para.) (Fig. 1, p. 210), simultaneously with the step of producing the cell culture mixture (Abstract, p. 212 first para. ) (Figs. 2-4, pp. 211-214); and
returning continuously from the interior of the centrifugal separator a flow of liquid to the fermentor, simultaneously with the steps of producing the cell culture mixture and conducting the flow of cell culture mixture (Abstract, p. 212 first para. ) (Figs. 2-4, pp. 211-214),
wherein the method comprises, during a first time period that is not the final stage of harvesting a produced biomolecule (Jäger discloses that the following steps occur during fermentation rather than a final stage of harvest, see pp. 212-215; furthermore, Jäger discloses conducting the entire method for the purpose of culturing HeLa cells wherein no biomolecule production is disclosed, see entire document), the steps of:
separating the flow of cell culture mixture into a light phase and a heavy phase in the centrifugal separator (p. 209 last para., p. 212 first para.-p. 215 last para.), wherein the step of returning continuously from the interior of the centrifugal a flow of liquid to the fermentor comprises during the first time period:
returning the heavy phase separated in the centrifugal separator to the fermentor as the flow of liquid to the fermentor (Abstract, p. 212 first para.-p. 215 last para.),
wherein during the first time period, the heavy phase comprises a growth medium and whole cells and the light phase comprises the growth medium and debris from the cell culture mixture of a particle size smaller than whole cells and is free of whole cells (p. 209 last para., p. 212 first para.-p. 215 last para.).
Regarding claim 4, Jäger discloses, during the first time period, a step of conducting the light phase separated in the centrifugal separator to a receiving container (Fig. 2, p. 211).
Regarding claim 6, Jäger discloses wherein during the first time period, the flow of the cell culture mixture as conducted at a flowrate (reads on the claimed flowrate 1) (p. 212 first para.-p. 213 last para.) (Fig. 2, p. 211), wherein the centrifugal separator is operated such that at the flowrate, whole cells having a specified diameter (reads on the claimed diameter d) are separated from the cell culture mixture (Abstract, p. 212 first para.-p. 215 last para.). Thus, although Jäger does not expressly teach the Area Equivalent as claimed, it is understood that the prior art centrifugal separator is necessarily operated at an Area Equivalent such that whole cells are separated, as the prior art discloses that this function occurs at the flowrate.
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Jäger (High Density Perfusion Culture Of Animal Cells Using A Novel Continuous Flow Centrifuge) in view of Xu et al. (Gene modification of the acetate biosynthesis pathway in Escherichia coli and implementation of the cell recycling technology to increase L-tryptophan production) (already of record).
Regarding claim 3, Jäger discloses separating the cell culture mixture into a light phase and a heavy phase, as set forth above. Jäger is primarily directed towards returning the heavy phase to the fermentor (Abstract, p. 212 first para.-p. 215 last para.).
Jäger is silent as to wherein a flow of the separated light phase forms a maximum of 5% V/V of the flow of the cell culture mixture.
Xu et al. discloses a process of conducting a flow of a cell culture mixture from a fermentor into an interior of a centrifugal separator, separating the cell culture mixture into a light phase and a heavy phase therein, and returning the heavy phase to the fermentor (Abstract, Fig. 1, p. 5). Xu et al. discloses a ratio of 1:1 V/V for the heavy phase: light phase (p. 5 para. 1), and further discloses that increasing the ratio of the light phase necessitates a higher shear force during operation of the centrifugal separator which can negatively affect cell metabolism (p. 11 para. 2, p. 16 para. 5).
It has been held that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, when the particular parameter is recognized as a result-effective variable (MPEP §2144.05). In this case, Xu et al. discloses general conditions for the percentage of the separated light phase with respect to the total volume and further discloses that the particular parameter is a result-effective variable as cell metabolism is impacted, as discussed above. Therefore, it would have been obvious to one of ordinary skill in the art to discover an optimum or workable range by routine experimentation for a maximum volume percentage of the light phase with respect to the volume of the cell culture mixture.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Jäger (High Density Perfusion Culture Of Animal Cells Using A Novel Continuous Flow Centrifuge) in view of Leung (Centrifugal Separations in Biotechnology) (already of record).
Regarding claim 7, Jäger discloses wherein conducting a flow of the cell culture mixture into the centrifugal separator and separating the cell culture mixture during a first time period, as set forth above, wherein the centrifugal separator is a disc stack centrifuge (p. 209 last para.) (Fig. 1, p. 210). Jäger further discloses running purified water through the outer space of the centrifugal separator as a sealing liquid (p. 209 last para.).
Jäger is silent as to wherein preceding the first time period, the method comprises priming the centrifugal separator with a liquid other than cell culture mixture.
Leung discloses that it is important to avoid contact between cells and air during operation of a disk centrifuge to protect the cells from damage (p. 78 para. 1-4), and further discloses ensuring that the bowl of a centrifugal separator is “always filled”, e.g., by filling the bowl with buffer liquid before a feed to be separated is introduced (p. 70 para. 4-p. 71 para. 1).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method disclosed by Jäger to comprise priming the centrifugal separator with buffer prior to the first time period, based on the teachings of Leung, in order to ensure that the centrifugal separator remains constantly filled before operation to avoid damaging contact between cells and air.
Claims 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Jäger (High Density Perfusion Culture Of Animal Cells Using A Novel Continuous Flow Centrifuge) in view of Eppendorf (Braking Ramps) (already of record).
Regarding claim 8, Jäger discloses returning continuously from the interior of the centrifugal separator a flow of liquid to the fermentor, as set forth above. Jäger further discloses wherein the centrifugal separator comprises a rotor that rotates at an operating speed to separate the cell culture mixture (p. 209 last para.).
Jäger is silent as to the method comprising, during a second time period, returning the flow of cell culture mixture from the interior of the centrifugal separator unseparated to the fermentor as the flow of liquid to the fermentor.
Eppendorf discloses that cultured cells can be sensitive to sudden changes in centrifugal forces (p. 2 last para.) and that it was known in the art to gradually ramp up to and down from a final operating speed of a centrifuge configured to separate cells (see entire document).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method disclosed by Jäger such that during a second time period (e.g., before, after, or both before and after the first time period wherein the centrifugal separator is operating at a maximum desired speed for separation), the centrifugal separator rotor is operated at a lower speed or a speed of zero, and thus unseparated cell culture mixture is returned from the interior of the centrifugal separator to the fermentor as the flow of liquid, based on the teachings of Eppendorf, as the skilled artisan would have been motivated to provide one or more transitional time periods wherein centrifugal speed is lowered or zero in order to gradually ramp to or from a final operating speed in order to protect the cells from damage.
Regarding claim 9, Jäger in view of Eppendorf teaches wherein during the second time period, a rotor of the centrifugal separator is standing still (zero speed) or rotating at a lower rotational speed than during the first time period, as set forth in the rejection of claim 8, above.
Regarding claim 10, Jäger in view of Eppendorf teaches wherein the second time period occurs before, after, or both before and after the first time period, as set forth in the rejection of claim 8 above, thus fulfilling the limitation of wherein the first and second time periods are alternated.
Regarding claim 11, Jäger discloses a flow of the cell culture mixture into the interior of the centrifugal separator, and Jäger in view of Eppendorf et al. teaches the first and second time periods, as set forth in the rejection of claim 8, above. Jäger further discloses a flow rate (reads on the claimed flowrate q) of the cell culture mixture into the interior of the centrifugal separator (p. 212 first para.-p. 213 last para.) (Fig. 2, p. 211).
The prior art combination does not expressly teach wherein a flow of the cell culture mixture into the interior of the centrifugal separator is at substantially a same flowrate q during the first and second time periods.
Nonetheless, it would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method taught by the prior art combination such that a flowrate during each of the first and second time periods is the same flowrate disclosed by Jäger, as the skilled artisan would have been motivated to use a flowrate recognized in the art to be suitable for operation with a centrifugal separator for each of the operational time periods.
Regarding claim 12, Jäger discloses, during a third time period, stopping the step of returning continuously from the interior of the centrifugal separator a flow of liquid to the fermentor, conducting a flow of the cell culture mixture from the fermentor to the centrifugal separator, separating the flow of cell culture mixture in the separator into a light phase and a heavy phase, and conducting the heavy phase separated in the step of separating to a receiving vessel for the purpose of analyzing rotor speed on separation efficiency (p. 213).
Regarding claim 13, Jäger discloses during the third time period, conducting the light phase separated in the step of separating to a receiving container (Fig. 2, p. 211).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Jäger (High Density Perfusion Culture Of Animal Cells Using A Novel Continuous Flow Centrifuge) in view of Eppendorf (Braking Ramps) (already of record), as applied to claim 12, above, and in further view of Takashiki et al. (US Patent 5,250,432) (already of record).
Regarding claim 14, Jäger conducting a separated heavy phase to a receiving vessel during a third time period for the purpose of analyzing the effect of rotor speed on separation efficiency, as set forth in the rejection of claim 12, above.
Jäger is silent as to wherein during the third time period, a rotor of the centrifugal separator is rotating at a higher rotational speed than during the first period; however, Jäger discloses that the rotor is capable of rotating at a higher rotational speed (p. 209 last para.).
Takashiki et al. discloses a method of conducting a flow of cell culture mixture from a fermentor to a centrifugal separator and separating the cell culture mixture into a light phase and a heavy phase therein (Abstract). Takashiki et al. further discloses performing a series of experiments wherein the rotational speed of the rotor of the centrifugal separator is increased (col. 24-27). The rotational speed of the rotor must be high enough to achieve separation but low enough to prevent cell rupture (col. 8 lines 54-68).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the method taught by Jäger such that during the third time period, a rotor of the centrifugal separator is rotating at a higher rotational speed than during the first period, based on the teachings of Takashiki et al., as the skilled artisan would have been motivated to perform analysis during a time period in which the speed is increased in order to determine the effects of higher rotor speeds on separation efficiency and cell quality.
Allowable Subject Matter
Claims 15-17 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Conclusion
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 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 HOLLY KIPOUROS whose telephone number is (571)272-0658. The examiner can normally be reached M-F 8.30-5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Marcheschi can be reached at 5712721374. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HOLLY KIPOUROS/Primary Examiner, Art Unit 1799
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