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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-17, in the reply filed on 03/13/2026 is acknowledged. The traversal is on the ground(s) that a same or corresponding technical feature is present. This is not found persuasive because Applicant has not pointed to any specific errors in the Examiner’s reasoning that the technical feature of the invention Groups does not make a contribution over the prior art, as set forth in the Office Action dated 02/12/2026.
The requirement is still deemed proper and is therefore made FINAL.
Claims 24-25 and 46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02/12/2026.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/26/2023, 09/16/2024, and 12/15/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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.
Claim 5 is 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.
The term “substantially” in claim 5 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, the specification does not provide a standard for ascertaining what concentrations would and would not be considered to be “substantially free” of whole cells.
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 1-2 and 4-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Clark et al. (US Patent Application Publication 2014/0322777) (already of record).
Regarding claim 1, Clark et al. discloses a method for operating a bioprocessing system (Abstract, para. 175, 183), comprising the steps of:
producing a cell mixture in a fermentor (Abstract);
conducting a flow of a cell culture mixture from the fermentor into an interior of a centrifugal separator (para. 50) (Fig. 1, sheet 1 of 16) comprising a surface enlarging insert (the discs of disc stack 240 read on a surface enlarging insert as they effectively enlarge a surface area within the separator, see para. 53-54 and Fig. 2, sheet 2 of 16) simultaneously with the step of producing the cell culture mixture (para. 50, 56, 172, 174); and
returning continuously from the interior of the centrifugal separator a flow of liquid to the fermentor (para. 50, 56, 61) (Fig. 1, sheet 1 of 16), simultaneously with the steps of producing the cell culture mixture and conducting the flow of the cell culture mixture (para. 50, 56, 172, 174).
Regarding claim 2, Clark et al. discloses wherein the method comprises during a first time period a step of:
separating the flow of the cell culture mixture into a light phase and a heavy phase in the centrifugal separator (para. 53-56), and wherein the step of returning continuously from the interior of the centrifugal separator 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 (para. 50, 56) (Fig. 1, sheet 1 of 16).
Regarding claim 4, Clark et al. discloses wherein the method comprises, during the first time period a step of conducting the light phase separated in the centrifugal separator to a receiving container for further processing (para. 50, 184-185) (Fig. 1, sheet 1 of 16).
Regarding claim 5, Clark et al. discloses wherein during the first time period, the heavy phase comprises a growth medium and whole cells (para. 61, 183) and the light phase comprises the growth medium and debris from the cell culture mixture of a particle size smaller than whole cells (para. 50, 59-61, 133, 135) and is substantially free of whole cells (para. 52).
Regarding claim 6, Clark et al. discloses wherein during the first time period, the flow of the cell culture mixture is conducted at a flowrate (reads on the claimed flowrate q) (para. 183), 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 (para. 60, 183). Thus, although Clark et al. 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 Clark et al. (US Patent Application Publication 2014/0322777) (already of record) 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, Clark et al. discloses separating the cell culture mixture into a light phase and a heavy phase, as set forth above.
Clark et al. 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 Clark et al. (US Patent Application Publication 2014/0322777) (already of record) in view of Leung (Centrifugal Separations in Biotechnology).
Regarding claim 7, Clark et al. 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 (para. 52).
Clark et al. 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 Clark et al. 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 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Clark et al. (US Patent Application Publication 2014/0322777) (already of record) in view of Eppendorf (Braking Ramps).
Regarding claim 8, Clark et al. discloses returning continuously from the interior of the centrifugal separator a flow of liquid to the fermentor, as set forth above. Clark et al. further discloses wherein the centrifugal separator comprises a rotor that rotates at an operating speed to separate the cell culture mixture (para. 52-54).
Clark et al. 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 Clark et al. 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, Clark et al. 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, Clark et al. 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, Clark et al. discloses a flow of the cell culture mixture into the interior of the centrifugal separator, and Clark et al. in view of Eppendorf et al. teaches the first and second time periods, as set forth in the rejection of claim 8, above. Clark et al. further discloses a flow rate (reads on the claimed flowrate q) of the cell culture mixture into the interior of the centrifugal separator (para. 183).
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 Clark et al., 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.
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Clark et al. (US Patent Application Publication 2014/0322777) (already of record).
Regarding claim 12, Clark et al. discloses the method comprising conducting a flow of the cell culture mixture from the fermentor to the centrifugal separator, separating the cell culture mixture into a light phase and a heavy phase therein, and recycling the separated heavy phase back to the fermentor, as set forth above.
Clark et al. is silent as to the method comprising, 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 centrifugal separator into a light phase and a heavy phase, and conducting the heavy phase separated in the step of separating to a receiving vessel.
However, Clark et al. discloses that throughout the method samples are drawn to assess quality wherein each sample is conducted to a further unit operation for analysis (para. 186, 189, 193).
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 Clark et al. to comprise, during a third time period, stopping return to the fermentor, separating the cell culture mixture in the centrifugal separator, and conducting a separated heavy phase to a receiving vessel for sampling, based on the teachings of Clark et al., in order to receive a sample of the heavy phase for quality testing thereof.
Regarding claim 13, Clark et al. discloses the method comprising conducting a flow of the cell culture mixture from the fermentor to the centrifugal separator and separating the cell culture mixture into a light phase and a heavy phase therein, as set forth above; furthermore, Clark et al. teaches conducting separation during a third time period, as set forth in the rejection of claim 12, above. Clark et al. also discloses conducting the light phase separated in the step of separating to a receiving container (para. 50, 184-185) (Fig. 1, sheet 1 of 16). Therefore, Clark et al. arrives at the claimed subject matter.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Clark et al. (US Patent Application Publication 2014/0322777) (already of record) in view of Takashiki et al. (US Patent 5,250,432).
Regarding claim 14, Clark et al. teaches conducting a separated heavy phase to a receiving vessel during a third time period for sampling purposes, as set forth in the rejection of claim 12, above. Clark et al. also discloses wherein the centrifugal separator comprises a rotor that rotates at an operating speed to separate the cell culture mixture, as set forth above.
Clark et al. 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.
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 Clark et al. 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 sampling during a time period in which the speed is increased in order to determine an optimum or workable speed for obtaining a heavy phase with a desired cell quality.
Allowable Subject Matter
Claims 15-17 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Smith et al. (US Patent Application Publication 2023/0405611) is directed to a method of conducting a flow of cell culture mixture from a bioprocessing vessel to a centrifugal separator and recycling a separated component back to the bioprocessing vessel, wherein the recycling may be delayed until a confirmed steady state is reached.
Wase et al. (US Patent 2012/0040443) is directed to a centrifugal separator comprising “surface-enlarging inserts” for separating a cell culture mixture.
Conclusion
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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/HOLLY KIPOUROS/Primary Examiner, Art Unit 1799