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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 05 December 2025.
PRIORITY
EP19215115.7, filed on 11 December 2019, is acknowledged.
CLAIMS UNDER EXAMINATION
Claims 1-15 and 17-21 are pending and have been examined on their merits.
WITHDRAWN CLAIM OBECTIONS
The objection to claims 4-18 has been withdrawn due to claim amendment.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
NEW GROUNDS OF REJECTION
New grounds of rejection have been necessitated by claim amendment.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 19 recite there is “no liquid flow” after transferring the fraction of the suspension into the container. “No liquid flow” would exclude liquid flowing in any other steps, including the return of cells from the container to the suspension culture, as required by the base claim. The specification provides support for the cells being held under static conditions in a pipette tip (step ii) “for a defined period of time” (3 or 5 minutes, [0032] of PG Pub). While the specification provides support for “static” conditions in the container, the specification does not provide support for no liquid flow in any other steps, or indefinite static conditions. This is new matter.
An amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). Applicant is required to cancel the new matter in the reply to this Office Action.
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 6 and 13-14 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.
Regarding claim 6, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Appropriate correction is required.
Claim 13 recites “the period” in which the cells are allowed to settle. There is a lack of antecedent basis for “the period”. Appropriate correction is required.
Claim 14 recites cells are dispensed “(-back-)” into the suspension culture. It is unclear what “(-back-)” means. The metes and bounds of the claim are unclear. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-15 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Kompala et al. (Particle settling devices. US11148076 with benefit of 15/586902, filed on May 4, 2017) as evidenced by Dill et al. (Adherent and suspension baby hamster kidney cells have a different cytoskeleton and surface receptor repertoire. PLoS One. 2021 Jun 4;16(6):e0246610) and Debem (What are peristaltic pumps and how do they work?, 2021, pages 1-11).
Kompala et al. teach a settling device for separating particles from a bulk fluid (Abstract). Figure 15 discloses Pichia pastoris cells were grown in a perfusion bioreactor (218) containing growth media. Yeast cell culture from the bioreactor is delivered to a cell settler (i.e., a container) (208). The settler has an opening (217) at the bottom (see arrow at bottom of settler). Larger live cells are recycled from the bottom of the cell settler back to the bioreactor. Effluent (hence, waste) from the settler, which contained smaller dead cells, was evacuated by effluent line (210). Evacuation of effluent containing dead cells is interpreted to read on discarding.
Kompala also teaches the following (see column 22, lines 15-31):
In each of the embodiments of this disclosure, liquid may be directed into, or drawn out of, any of the ports or openings in the conical settling device by one or more pumps (for example a peristaltic pump) in liquid communication with the port or opening. Such pumps, or other means causing the liquid to flow into or out of the settler devices, may operate continuously or intermittently. If operated intermittently, during the period when the pump is off, settling of particles or cells occurs while the surrounding fluid is still. This allows those particles or cells that have already settled to slide down the inclined conical surfaces unhindered by the upward flow of liquid. Intermittent operation has the advantage that it can improve the speed at which the cells slide downwardly, thereby improving cell viability and productivity. In a specific embodiment, a pump is used to direct a liquid suspension of cells from a bioreactor or fermentation media into the settler devices of the present disclosure.
The art also the settling device may or may not comprise a plug. The art teaches a plug prevents the flow of liquid (column 5, line 64-65). A plug may be provided at the opening (column 18, lines 47-49). The presence of the plug is therefore interpreted to stop the flow of liquid.
It would have been obvious to operate the settling device intermittently. One would have been motivated to do so since Kompala teaches intermittent operation allows cells that have already settled to slide down the inclined conical surfaces unhindered by the upward flow of liquid. One would do so to improve the speed at which the cells slide downwardly, thereby improving cell viability and productivity, as taught by Kompala. One would have had a reasonable expectation of success since Kompala teaches intermittent operation can be used to provide still (static) conditions. Therefore claim 1 is rendered obvious.
Kompala teaches a bioreactor (supra). Therefore claim 2 is included in this rejection.
In Figure 15, Kompala illustrates the bioreactor comprises an impeller (hence a stirred reactor). Therefore the cells are interpreted to be essentially homogenously distributed in the medium. Claim 3 is included in this rejection
The settler has a conical bottom (see Figure 15). Therefore claim 4 is included in this rejection.
Regarding claim 5: To aspirate means to draw by suction (Merriam Webster Dictionary).
Kompala teaches liquid may be directed into, or drawn out of, any of the ports or openings in the settling device by one or more peristaltic pumps in liquid communication with the port or opening. See (column 34, lines 48-52). As evidenced by Debem, “Peristaltic pumps are a type of volumetric pump used for pumping a large variety of fluids. The fluid is transported inside a flexible tube using an effective pumping principle, called peristalsis. This operating system is based on a compression action by means of rollers alternating with a relaxation action of the tube that allows the content suction by removing the fluid from the pump” (see first paragraph of section titled “How does a peristalic pump work” on page 1). Therefore Kompala is interpreted to teach aspiration. Claim 5 is included in this rejection.
The art teaches yeast cells that are P. pastoris (supra). Therefore claim 6 is included in this rejection.
Kompala teaches BHK cells. As evidenced by Dill et al., BHK cells are adherent cells that can be grown in suspension (page 1, first paragraph). Therefore the art teaches adherent cells that are cultured in suspension. Claim 7 is rejected.
The art teaches cardiomyocytes can be used (column 1, line 52). Therefore the art teaches cells obtained from an organ (heart). Claim 8 is included in this rejection.
The art teaches CHO cells (column 3, line 28a0. Therefore claim 9 is included in this rejection.
The art teaches human stem cells (column 10, line 64). Therefore claim 10 is included in this rejection.
The art teaches cell aggregates (column 43, line 33). Therefor claim 11 is included in this rejection.
Regarding claim 12: Kompala teaches fresh nutrient media is continuously supplied to the live and productive cells inside the high cell density bioreactors and the secreted proteins or enzymes are continuously harvested in the clarified outlet from the top port, while the concentrated live and productive cells are returned back to the bioreactor (see column 35, lines 50-57). Kompala teaches media levels in the bioreactor are controlled (column 36, lines 29-30). The skilled artisan would replace nutrient media with the same volume that is removed since Kompala teaches adding fresh media to the system continuously in a controlled manner to provide nutrients to the live, productive cells in the bioreactor. Therefor claim 12 is rendered obvious.
Regarding claim 13: Kompala teaches intermittent flow of liquid into or out of the settling device allows settling of cells while the surrounding fluid is still (supra). Kompala teaches this allows cells that have already settled to slide down the inclined conical surfaces unhindered by the upward flow of liquid. Intermittent operation has the advantage that it can improve the speed at which the cells slide downwardly, thereby improving cell viability and productivity (supra). Kompala teaches transferring cells from the bioreactor to a 12-liter cell settler slowly for 100 hours (column 36, lines 9-12). The optimize the time for settling under intermittent conditions to achieve the desired number of settled cells. Therefore claim 13 is included in this rejection.
Kompala teaches concentrated live and productive cells are returned back to the bioreactor, and dead cells are continuously removed (see column 35, lines 51-60). Kompala teaches very dead cells are evacuated as effluent (column 36, lines 25-26). The art teaches the effluent contains “very little cells” (column 36, lines 45-46). Therefore essentially all of the cells are interpreted to be returned to the suspension culture. Claim 14 is included in this rejection.
The art teaches a suspension of microcarrier beads with mammalian cells growing attached on the beads (column 10, lines 59-60). Therefore claim 15 is included in this rejection.
Kompala teaches liquid may be directed into, or drawn out of, any of the ports or openings in the settling device (column 34, lines 48-52). Therefore directing the suspension through the bottom opening and into the container is rendered obvious. Claim 17 is included in this rejection.
Kompala teaches live cells are recycled from the bottom of the cell settler back to the bioreactor (supra). Therefore claim 18 is included in this rejection.
The art teaches the absence of the plug allows fluid flow to prevent fluid flow. The art teaches intermittent pump operation to provide still conditions in the cell settler.
Therefore fluid flow is prevented. Claim 19 is included in this rejection.
The art teaches a stirred tank bioreactor (see impeller blades in Figure 15). Therefore claim 20 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Kompala in view of Amit et al. (Stem Cell Rev and Rep (2010) 6:248–259).
Claim 1 is rejected on the grounds stated above. The teachings of Kompala are reiterated. Kompala teaches a suspension culture. The art teaches stem cells can be cultured in the disclosed system. The art does not explicitly each culturing induced pluripotent stem cells.
Amit teaches induced pluripotent stem cells are cultured in suspension (Abstract; page 253, left column, second paragraph).
It would have been obvious to try culturing iPSCs in the system taught by Kompala. One would have been motivated to do since Kompala teaches a system for culturing stem cells in suspension culture and Amit teaches iPSCs are cultured in suspension. One would have had a reasonable expectation of success since Kompala teaches stem cells can be cultured in the disclosed system. One would have expected similar results since both references are directed to suspension culture. Therefore claim 21 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 05 December 2025 are acknowledged.
Argument 1: The Applicant acknowledges Kompala teaches intermittent operation, but states intermittent only refers to a temporary interruption. The arguments state Kompala teaches “If operated intermittently, during the period when the pump is off, settling of particles or cells occurs while the surrounding fluid is still. This allows those particles or cells that have already settled to slide down the inclined conical surfaces unhindered by the upward flow of liquid” (column 32, lines 54-58). The Applicant argues this means there is still a flow during intermittent operation.
Response to Argument 1: The arguments are not persuasive. Kompala teaches pumps control flow of fluid into and out of the cell settler. The art teaches the pumps can be operated intermittently (see column 22, lines 15-31). No fluid flows into the cell settler when the pumps are off. Kompala teaches “If operated intermittently, during the period when the pump is off, settling of particles or cells occurs while the surrounding fluid is still” (column 22, lines 21-24). This reads on the static conditions recited in claim 1. While the Applicant argues this is only a temporary disruption, the claims do not require permanent static conditions. Examiner notes the Applicant’s specification states the static conditions are for “a defined period of time” including “3 minutes” or “5 minutes” (see PG Pub [0032] [0107]). The base claim requires flow into the suspension culture.
The interpretation of Kompala provided by the Applicant is not persuasive. The “upward flow” in the section cited by the Applicant occurs when the pumps are on. The section cited states when the pump is off, cell settling is not hindered by the upward flow of liquid (hence, when the pumps are on). Kompala teaches when the pumps are off, “the surrounding fluid is still” (hence, static with no flow of liquid via the pumps).
CONCLUSION
No Claims Are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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