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 .
Response to Amendment
The amendment filed 6/08/2026, amending claims 1, 3, 5, 6, 8, 16, and 23 is acknowledged. Applicant’s amendments to the claims have overcome each and every 112(a) and 112(b) rejection previously set forth in the Non-Final Office Action mailed 1/06/2026.
Claims 1-8, 10-17, 20, and 23 are pending and under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The claims of the instant case are entitled to the priority date of EP19166531.4, filed 04/01/2019.
Claim Interpretation
Claim 1 recites “computing a soft sensor parameter by executing a software algorithm that processes at least one such system parameter and/or product parameter together to obtain an integrated output value”. As discussed in the 112(b) rejection below, the claim language does not require the integration of both a system parameter and a product parameter when computing a soft sensor parameter.
Additionally, the recitation “wherein the soft sensor is used as a basis for the adaptation in step d)” does not require the integration of the soft sensor into the method, nor does it state how the soft sensor is used (i.e., does not further limit the structure of the claimed invention).
Claim Rejections - 35 USC § 112(b) – New, necessitated by amendment
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 1 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.
Claim 1 recites in step c “computing a soft sensor parameter by executing a software algorithm that processes at least one such system parameter and/or product parameter together to obtain an integrated output value”. It is unclear whether step c only requires one parameter for computation or not. The recitation “at least one such system and/or product parameter” would read on only one parameter being required. However, the recitation of “together” implies at least two must be present. It would be remedial to rewrite the claim language to clearly state if only one parameter is required, at least one of each parameter (e.g., system and product), or if two parameters are required, but they may both be system parameters, for example. For examination purposes, the claim language is interpreted to only require one parameter to be computed.
Claim Rejections - 35 USC § 102- Maintained
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8, 10-17, 20, and 23 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Huacells (US 20190352589 A1, filed 12/21/2018).
Regarding claim 1, Huacells discloses
A method for a cell cultivation system, wherein the cultivation system comprises two or more cultivation vessels (e.g., hollow tube cartridges) (e.g., [0089]) for the production of at least one biologic agent and/or cell, wherein the cultivation vessels comprise cells in a suitable cultivation medium (e.g., Abstract), the method comprising the steps of
taking two or more liquid samples (e.g.., cells, cell media, etc.) from two or more cultivation vessels during an ongoing cultivation and transferring the two or more liquid samples from the two or more cultivation vessels to a sample-processing and/or analysis arrangement separate from the two or more cultivation vessels, (e.g., - “The cell culture media pumped from the reservoir 202 passes through gas exchange tubing 408 prior to arriving at the culture vessel 200. The gas exchange tubing 408 can be made of a material sufficient to satisfy metabolic gas exchange parameters of the cultured cells. For instance, the gas exchange tubing 408 can be platinum cured silicone. One or more sensors can be disposed along the length of the tubing 404 between the reservoir 202 and the culture vessel 200, such as the colorimetric pH sensor 214 or sensors 410 including one or more of other pH sensors, a dissolved oxygen sensor, a glucose sensor, a lactate sensor, or other types of sensors.” – [0098]- the tubing between the reservoir and culture vessel (and therefore, a separate arrangement from the culture vessel) can process/analyze samples)
analyzing at least one of the two or more liquid samples to acquire data relating to at least
one system parameter indicative for at least one of nutrient status and/or medium quality of the cultivation medium, or cell density, or cell viability and/or
one product parameter indicative for biologic agent quality and/or cell quality, (i.e., glucose and lactate levels) (e.g., [0151-0152])
c) computing a soft sensor parameter by executing a software algorithm that processes at least one such system parameter and/or product parameter (e.g., glucose uptake and lactate secretion) together to obtain an integrated output value, wherein the soft sensor is used as a basis for the adaptation in step d) (e.g., [0082] – “the computing system of the automated cell culture system for monitoring glucose consumption and lactate production in the cell culture media, e.g., as an indication of cell growth.”; [0087] – “one or more of the detected parameters can be used by the computing system to determine a phase of the cell culturing, e.g., an initial, slow growth phase, in a rapid (e.g., exponential) growth phase, or in a plateau in which cell proliferation is reduced or ceases. For instance, the glucose or lactate levels in the cell culture media, the dissolved oxygen concentration in the cell culture media, the rate at which the amount of nutrients in the cell culture media in the fluidic circuit decreases, or other parameters can be indicative of the phase of the cell culturing”; [0012], [0016], [0073], [0134]), and
e) in response to the outcome of step d), automatically adjusting in real-time during the ongoing cultivation, at least one process parameter and/or at least one feeding input in at least one cultivation vessel of the present cultivation system, or of a subsequent cultivation system (e.g., “The conditions of the cell culture environment in the automated cell culture system can be dynamically and automatically adjusted responsive to real time sensor monitoring to maintain steady state conditions in the cell culture media, e.g., to maintain parameters” - [0065]; “For instance, components of the automated cell culture system can be controlled in real time responsive to changes in parameters of the cell culturing environment, e.g., without waiting for a user to manually operate the system or manually input control instructions. The real time control of the system responsive to real time monitoring enables target parameters to be consistently maintained” - [0069]; [0070], [0076], [0102]).
Regarding claim 2, Huacells discloses the cell cultivation system being a bioreactor system suitable for culturing cells, wherein the bioreactor system comprises two or more bioreactors (i.e., hollow fiber cartridges of cell culture reactors) (e.g., [0151; 0155]).
Regarding claim 3, Huacells discloses the method of claim 1, wherein the sample-processing and/or analysis arrangement is an array of reaction vessels, wherein the array of reaction vessels comprises at least one of a microtitre plate with two or more wells, a series of sample cups or sample vials, or an array of microreaction tubes (e.g., [0090-0091] (e.g., tubes, also known as capillaries, of the hollow tube cartridge; cell culturing reagents can pass from the intra-capillary space to the extra-capillary space); [0098, 0099]; Fig. 4).
Regarding claim 4, Huacells discloses the method of claim 1, wherein the biologic agent is selected from the group consisting of a biomolecule, a cell-based product (i.e., a cell), and a vaccine (e.g., Jurkat cells, human T lymphocytes) (e.g., [0151; 0155, 0157]).
Regarding claim 5, Huacells discloses the method of claim 1, wherein the process parameter that is adjusted in step d) is at least one of the process parameters selected from the group consisting of: a cultivation temperature set point, stirring speed, stirrer blade tip speed, pH set-point, DO set-point, viable cell density set-point, conductivity, osmolality, specific power input, and bubble size [0065; 0069-0070].
Regarding claim 6, Huacells discloses the method of claim 1, wherein the at least one feeding input that is adjusted in step d) is at least one feeding input selected from the group consisting of: gassing rate, compressed air gassing rate, CO2 gassing rate, N2 gassing rate, input of feed solution, composition of feed solution, addition or omission of individual ingredients in feed solution, input of pH buffer, and addition of components related to increased productivity or prevention of cell death (e.g., [0065; 0069-0070]).
Regarding claim 7, Huacells discloses the method of claim 1, wherein at least one further system parameter is measured on-line in at least one of the cultivation vessels (i.e., temperature of culture vessel measured) (e.g., [0118]).
Regarding claim 8, Huacells discloses the method of claim 7, wherein said further system parameter measured on-line is at least one system parameter selected from the group consisting of pH, trypan blue staining, optical density, osmolarity, radio-frequency (RF) impedance, cultivation time, exhaust gas composition, O2 consumption, temperature, stirrer speed, and metabolite levels (e.g., [0118]).
Regarding claim 10, Huacells discloses the method of claim 1, wherein the two or more liquid samples are taken with at least one of a robotic liquid handler and/or a multi-valve sample system (e.g., [0090-0091]) (e.g., tubes, also known as capillaries, of the hollow tube cartridge; cell culturing reagents can pass from the intra-capillary space to the extra-capillary space) (e.g., [0075; 0099; 0101]) (e.g., valves to pump cell culture media).
Regarding claims 11 and 12, Huacells discloses the method of claim 10, wherein taking of two or more liquid samples is triggered by a given system parameter (claim 11) (e.g., [0110; 0124-0125]) or is triggered by a timer (claim 12) (e.g., [0106; 0110]).
Regarding claim 13, Huacells discloses the method of claim 1, wherein at least one of the two or more liquid samples comprises supernatant from one of the cultivation vessels (e.g., supernatant is used to measure the lactate secretion of cells) (e.g., [0154]).
Regarding claims 14 and 15, Huacells discloses method of claim 1, wherein the system parameter indicative for cell density (claim 14) and/or cell viability (claim 15) is at least one system parameter selected from the group consisting of: optical density (e.g., [0134]), cell permittivity, radio-frequency (RF) impedance, transmission spectrum, light scattering, and trvpan blue staining (Huacells used the Countess FL II cell counter to measure cell density and viability, which uses brightfield and two optional fluorescent channels with optics and image analysis, along with standard trypan blue) – see www.thermofisher.com/us/en/home/references/newsletters-and-journals/bioprobes-journal-of-cell-biology-applications/bioprobes-70/countess-ii-fl-automated-cell-counter.html.)
Regarding claim 16, Huacells discloses method of claim 1, wherein the system parameter indicative for nutrient status and/or medium quality of the cultivation medium is at least one system parameter selected from the group consisting of glucose concentration, concentration of at least one trace element, vitamin, organic acid or amino acid, osmolality, osmolarity, ammonia concentration, and pH value (e.g., [0087; 0151-0154]).
Regarding claim 17, Huacells discloses method of claim 4, wherein the biomolecule is an antibody or fragment or derivative thereof, an antibody mimetic, a growth factor, a hormone or a cytokine (e.g., [0065]).
Regarding claim 20, Huacells discloses method of claim 1, wherein the product parameter indicative for quality of the cell-based product is at least one selected from the group consisting of presence of one or more given surface markers and cell viability (e.g., antibodies targeting CD3, CD4, and CD9 for T lymphocytes) (e.g., [0158; 0160-0161]).
Regarding claim 23, Huacells discloses method of claim 1, wherein the purification step comprises at least one step selected from the group consisting of protein A based purification, protein G based purification, affinity tag based purification, lectin based purification, ion chromatography, affinity chromatography, and size exclusion chromatography (e.g., Dynabeads CD3/CD28, which are magnetic beads coated with antibodies against CD3 and CD28, are a form of affinity chromatography and can also activated T cells) (e.g., [0158; 0160]).
Response to Arguments
Applicant’s arguments, see pg. 3-4 of Remarks, filed 06/08/2026, with respect to the 112(b) rejection of claim 6 for reciting a “a cell-based product” and “biomolecule” have been fully considered and are persuasive. The 112(b) rejection of claim 4 has been withdrawn.
Applicant's arguments Huacells filed 06/08/2026 have been fully considered but they are not persuasive.
The Applicant argues “Huacells does not disclose withdrawing two or more liquid samples from two or more cultivation vessels during ongoing cultivation and transferring those samples to a sample-processing and/or analysis arrangement separate from the cultivation vessels. Huacells' hollow-fiber capillaries can not satisfy the claim 1 as amended herein.
Huacells describes the capillaries as structural components within the hollow fiber cartridge itself. The capillaries are disposed inside the cartridge casing, and the extra-capillary space within the cartridge is where cell culturing occurs. The capillaries provide nutrient and waste exchange as part of the culture vessel/fluidic circuit. They are not a separate sample processing and/or analysis arrangement to which liquid samples are transferred from the cultivation vessels.”
The examiner agrees that the hollow-fiber capillaries do not explicitly read on the amended claim language, as Huacells describes the hollow tube cartridge (e.g., Fig 3- 300) as an example cell culture vessel, and further specifices that the extra-capillary space (314) is where cell culturing occurs.
However, Fig. 4 and corresponding [0094-0098] of Huacells does read upon the amended claim language of withdrawing two or more liquid samples from two or more cultivation vessels during ongoing cultivation and transferring those samples to a sample-processing and/or analysis arrangement separate from the cultivation vessels. Huacells differentiates the culture vessel (200) from the reservoir (202), and teaches various tubing (e.g., 404, 408) connecting the two that can have one or more sensors.
Further, the method of taking two or more liquid samples taught by Huacells, such as in Fig. 4, aligns with the teachings of the instant specification, which recites:
“According to further embodiments of the invention, the liquid samples are taken with at least one of a robotic liquid handler, and/or a multi valve sample system…As used herein, the term "multi valve sample system" relates to systems in which samples are taken from the cultivation vessels by means of fixed valve/tube connections, i.e., without a pipetting robot. Such systems are for example provided by Eppendorf (DASGIP).” (pg. 13-14).
Additionally, the Applicant argues “amended claim 1 also requires that the soft sensor parameter is computed by executing a software algorithm that processes parameter data to obtain an integrated output value, and that the computed soft sensor parameter is used as the basis for the automatic real- time adaptation. Huacells' cited disclosures concern real-time sensor feedback, culture-phase determination, or control of reactor conditions. Huacells does not disclose the claimed arrangement in which liquid samples are first transferred from the cultivation vessels to a separate sample-processing and/or analysis arrangement, analysis data are obtained from those liquid samples, and a computed soft sensor parameter based on such analysis is then used as a basis for automatic real-time adaptation.” This argument is not persuasive because Huacells does teach using computing a soft sensor parameter by executing a software algorithm that processes parameter data to obtain an integrated output value, then adjusting automatically. For example, see [0094-0098] and [0102]. The Applicant fails to provide further evidence that the teachings of Huacells do not read upon the amended claim language.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “Huacells' examples report experimental characterization data demonstrating cell expansion and viability… Huacells does not disclose that such measurements are part of a control method in which liquid samples are transferred during ongoing cultivation to a separate sample-processing and/or analysis arrangement, a soft sensor parameter is computed from the resulting analysis data, and the computed soft sensor parameter is used as a basis for automatic real-time adjustment during the ongoing cultivation. At most, Huacells' examples report experimental characterization data demonstrating cell expansion and viability. Huacells does not disclose the claimed control loop.”) are not recited in the rejected claim(s). For example, the claim language does not require cell number, cell viability, or marker expression to be used in the claimed method. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
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 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 ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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