DETAILED ACTION
Applicant’s response, filed 09 April 2026 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09 April 2026 has been entered.
Status of Claims
Claims 1-11 are pending.
Claims 1-11 are rejected.
Claims 1-2 are objected to.
Claim Objections
The objection to claim 11 in the Office action mailed 09 Jan. 2026 has been withdrawn in view of claim amendments received 09 April 2026.
Claims 1-2 are objected to because of the following informalities. This objection is newly recited and necessitated by claim amendment.
Claim 1 recites “in response to the cultivation is identified to be affected…”, which is grammatically incorrect and should recite “…in response to the cultivation being identified to be affected…”.
Claim 2 recites “in response to at least one cultivation is determined to be affected…” and “in response to no cultivation is determined to be…”, which are grammatically incorrect and should recite “…in response to at least one cultivation being determined to be affected…” and “in response to not cultivation being determined…”.
Claim 2 recites “c) determining a cultivation of step a) being affected by a problem comprising the fit…”, which is grammatically incorrect and should recite “…determining a cultivation of step a) is affected by a problem comprising…”.
Claim 2 recites “c) determining a cultivation of a) being affected by a problem comprising the fit…(i) showing an offset…or (ii) the chi2 value determined…being 5 or more…”, which is nonsensical. The claim should be amended to recite “…the fit…for the process data : (i) an offset…, or (ii) the chi2 value…being 5 or more”, or a similar amendment.
Claim 2 recites “d) in response to at least on cultivation is determined to be affected by the problem… or e) in response to no cultivation is determined to be affected by the problem”, but previously recites in step c) “determining a cultivation…[is] affected by a problem”, such that step e) is never required. To increase clarity and readability, step e) should be removed from the claims.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “obtaining process data during cultivation…, wherein the process data comprises measured values of at least one on-line process parameter and at least one off-line process parameter”. The process in which the obtained process data was previously measured is considered a product by process limitation, and the claims do not require a step of measuring the process data. See MPEP 2113 stating "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production.
Claims 1-2 recite “on-line process parameters” and “off-line process parameters”. The terms are understood by one of ordinary skill in the art to refer to parameters monitored in real-time during the cultivation process and parameters measured by sampling from the culture at specific time points, as described in Applicant’s specification at para. [0144].
Claims 1-2 recite “the metabolic model…comprises specific metabolic phases within compartments tailored to a particular cell line used”. Applicant’s specification at para. [0102]-[0103], [0236], and [0258], that estimates cellular uptake and production rates was performed by first subdividing the fermentation process into physiologically distinct phases”, that intracellular flux distributions for each process phase were calculated using the network model, and that metabolic flux analysis (i.e. including the compartments) is used to predict values for all of the metabolic phases. Therefore, in light of Applicant’s specification, the limitation is interpreted to mean that the compartments include parameters/inputs for different phases (i.e. phases within compartments), rather than the phases being sub-compartments within the compartment.
Claim 2 recites “ e) in response to no cultivation [being] determined to be affected by a problem, selecting…”. Claim 2 previously recites “c) determining a cultivation of step a) being affected by a problem…”, and thus requires that a cultivation is determined to be affected by a problem. As a result, the condition precedent for step e) is never met by claim 2 and thus is not required by claims. See MPEP 2111.04 II.
Claim 11 recites “…wherein the problem is a technical problem”. Applicant’s specification at pg. 4, lines 9-16 discloses the problem can be a technical problem or a biological problem, and that a technical problem is based on a failure in the hardware used for performing the cultivation and a biological problem is based on the cell (e.g. contamination). Therefore, in light of Applicant’s specification a “technical problem” is interpreted to refer to any problem affecting the cultivation that is a result of hardware/equipment rather than biological components of the cultivation.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-11 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains 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, at the time the application was filed, had possession of the claimed invention. Any newly recited portion is necessitated by claim amendment.
Claim 1, and claims dependent therefrom, recite “…in response to the cultivation is identified to be affected by the problem excluding the affected process data from further analysis or clone selection…initiating inspection or recalibration of a cultivation device performing the cultivation”.
The specification does not provide support for (1) “excluding the affected process data from further analysis” and (2) “initiating inspection or recalibration of a cultivation device performing the cultivation” (similar to “adjusting cultivation parameters in response to determining that the cultivation is affected by the problem” as previously recited).
Applicant remarks filed 09 April 2026 at pg. 6, para. 1 states the amendments are fully supported by the specification, and support for the amendments is provided in the original claims and paragraphs [0016], [0096], [0114], [0126]-[0128], [0132], and [0158] of the as-published specification. However, these paragraphs do not provide support for the claimed initiating inspection or recalibration step.
Applicant’s specification at para. [0016] discuses an aim of the invention is to determine cell cultures identified by a problem, such as a technical problem or a biological problem. Applicant’s specification at para. [0096] discloses that identification of technical problems during cultivation run include probe shut down, sensor drift, plugged pipes, in process-control analytic errors, culture media preparation issues, etc. and/or pre-processing/data consistency check in process control, which identifies problems with the cultivation device. This does not provide support for the above identified limitations.
Applicant’s specification at para. [0126]-[0128] provides an example of a poor fit between process data and predicted data due to incorrect input data, that the lack of fit is resolved by identifying the underlying reason, and that after resolving the inconsistency the chi-squared value was acceptable, which shows correcting input oxygen uptake rate (OUR) data in response to identifying the incorrect input data, which is an example of broadly “fixing the problem” as recited in claim 2. Applicant’s specification at para. [0129]-[0132] discussed that OUR is not directly measured, but is calculated using equations, and after reviewing the input data, it turned out the mathematical calculation used for the calculation contained an error, and after identification thereof, the data was reprocessed with the curated equation resulting in an improved chi2 value. However, there is no disclosure of excluding the affected process data from further analysis. To the contrary, the paragraphs cited by Applicant analyze the affected process data to identify the issue with the mathematical calculation used for the calculation (i.e. analyzing the affected process data). Furthermore, there is no discussion of inspecting a cultivation device or recalibrating the cultivation device (or initiating inspecting or recalibrating) as opposed to simply correcting the input values by correcting the equation used to calculate the data. Applicant has not point out exactly which of the above paragraphs are intended to correspond to each of the amended claim elements, and the specification does not appear to broadly disclose excluding affected process data from further analysis or any examples of inspecting or recalibrating a cultivation device.
Claim 2, and claims dependent therefrom, similarly recite “in response to at least one cultivation is determined to be affected by the problem, fixing the problem”.
MPEP 2163 II states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014)
In the instant case, claim 2 recites the genus of “fixing the problem”, thus encompassing fixing any problem with the cultivation. However, as discussed above with respect to claim 1, the specification only provides a single species of fixing a problem with input data derived via a mathematical equation from data collected from a cultivation, by correcting the mathematical equation to fix the input data. This is not representative of the large variety of potential problems discussed in the specification.
Applicant’s specification at para. [0016] and [0114] discloses the problem may be a technical problem or a biological problem such as bacterial contamination of the culture, and discloses a wide variety of technical problems that my be identified by the invention, including “no off-gas (CO2, O2), pH-sensor drift during cultivation, plugged pipes and no feed added despite pump working, no debris measured, unmeasured metabolites (e.g. organic acids and precursors thereof, polyamines and precursors thereof, sugars and precursors thereof, activated sugars and precursors thereof, nucleotides and precursors thereof, nucleosides and precursors thereof, redox equivalents and precursors thereof, redox active compounds and precursors thereof, lipids and precursors thereof, endogenous host proteins, etc.) no sample drawing, inaccurate measurements of biomass or metabolites, analytical errors resulting in wrong values, etc.”.
Fixing a mathematical model to correct an identified problem of input data is not representative of the genus as claimed, particularly due to the wide variation in the claimed genus (i.e. any problem with the culture), ranging from sensor drift, plugged pies, unmeasured metabolites, contamination, no sample drawing etc. The claimed problem is identified by simply analyzing offsets between model predicted data and measured process data (i.e. a general problem with the culture is identified), which does not inform one of ordinary skill in the art how to (1) identify the source of the problem from the large list of potential technical and biological problems in the specification, and (2) how to fix every potential issue with the cultivation and/or cultivation device.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the limitations above recited in claims 1-11 to demonstrate to one of ordinary skill in the art that the inventor possessed the invention at the time the application was filed. THS IS A NEW MATTER REJECTION. For more information regarding the written description requirement, see MPEP §2161.01- §2163.07(b).
Response to Arguments
Applicant's arguments filed 09 April 2026 regarding 35 U.S.C. 112(a) have been fully considered but they are not persuasive.
Applicant remarks that claim 1 has been amended to remove the limitation being rejected, and therefore, the rejection should be withdrawn, and furthermore that support for the amended claims can found in at least para. [0016], [0096], [0114], [0126]-[0128], [0132], and [0158] of the as-published specification (Applicant’s remarks at pg. 6, para. 5 to pg. 7, para. 2).
This argument is not persuasive. First, claim 1 previously recited “…adjusting cultivation parameters in response to determining that the cultivation is affected by the problem”. Claim 1 was amended to recite “initiating inspection or recalibration of a cultivation device”. Recalibrating a device involves adjusting parameters, and thus the same 112(a) issue remains. If Applicant intends for the addition of “initiating” to differentiate the claims, there is still no support for initiating recalibration (or adjusting parameters) of a cultivation device. Furthermore, the cited paragraphs do not provide support for the reasons provided in the above rejection.
If Applicant disagrees with the rejection, it is requested that Applicant explain how any cited paragraphs provide support for a given amendment, assuming the specification does not use identical language as in the claims.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2-11 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claim 2, and claims dependent therefrom, are indefinite for recitation of “…fitting the process data for each clone individually…and evaluating the fit using…”. Claim 2 also recites “the fit” in line 5 of step c). Given the claim recites fitting the process data for each clone individually, thus resulting in one fit per clone, it is not clear which fit, “the fit” is referring to in the evaluating step. Clarification is requested via claim amendment. For purpose of examination, the limitation is interpreted to mean “evaluating each fit”.
Dependent claims 3 also recite “the fit”, and therefore are indefinite for the same reasons discussed above for claim 2.
Claim 2, and claims dependent therefrom, are indefinite for recitation of “c)…in step b) for the process data (i) showing an offset between model predictions and the process data exceeding”. Claim 2 previously recites “a)…measuring process data for each clone”, such that there are multiple process data. As a result, it is not clear which process data “the process data” is referring to. For purpose of examination, the limitation is interpreted to mean “the process data for the corresponding clone”.
Dependent claims 6-8 also recites “the process data” and therefore is indefinite for the same reasons discussed above for claim 2.
Claim 2, and claims dependent therefrom, are indefinite for recitation of “d)…the clones that had the problem in the cultivation as determined in step c)”. There is insufficient antecedent basis for this limitation in the claim because claim 2 previously recites “c) determining a cultivation of step a) being affected by a problem comprising the fit obtained for the corresponding clone in step b)”, such that only a single clone is determined as being affected by a problem. However, the claim did not require multiple clones having the problem as determined in c). The limitation is interpreted to mean “the clone that had the problem..”
Claim Rejections - 35 USC § 101
The rejection of claim 2 under 35 U.S.C. 101 in the Office action mailed 09 Jan. 2026 has been withdrawn in view of claim amendments received 09 April 2026.
Claim 2 recites “in response to at least one cultivation is [being] determined to be affected by the problem, fixing the problem and repeating steps a) to c) with the clones that had the problem…”. Therefore, claim 2 integrates the recited judicial exception of identifying a problem with the cultivation device, by fixing the problem and ultimately the additional element of re-cultivating the mammalian or bacterial cell clones that had the problem after the problem is fixed, resulting in an improved cell culture. This additional element meaningfully integrates the judicial exception into a practical application, in view of Applicant’s specification at para. [0006]-[0007] and [0095] which discloses identifying problems in cultures and re-culturing cells results in improved quality control of high-throughput cultivation data. See MPEP 2106.05(e).
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 3-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. Any newly recited portion is necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1-2 being representative) is directed to a method. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 1 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
obtaining a metabolic model generated for the mammalian or bacterial cell expression the polypeptide…wherein the metabolic model is a constraint-based model comprising metabolic phases within compartments tailored to a particular cell line used, and wherein the metabolic phases within compartments are defined based at least in part on the particular cel line used;
fitting the process data to the metabolic model to generate model predictions corresponding to the at least one on-line process parameter and at least one off-line process parameter;
monitoring, in real-time, the model predictions to identify the cultivation being affected by a problem, wherein the cultivation being affected by the problem comprises either: (i) the modeled fit showing an offset between the model predictions and the process data exceeding 10% or (ii) the modeled fit having a chi2 value determined by a Pearson’s chi-squared test of more than 5; and
in response to the cultivation is identified to be affected by the problem, excluding the affected process data from further analysis or clone selection, and flagging the cultivation for review or initiating inspection or recalibration of a cultivation device performing the cultivation.
The identified claim limitations falls into one of the groups of abstract ideas of mental processes for the following reasons. In this case, the step of obtaining a metabolic model compasses collecting and/or reading information on a model to obtain the model, which is a mental process. The steps of fitting the process data using a metabolic model that is a constraint based model can be practically performed in the mind aided with pen and paper by inputting numerical values into linear equations representing metabolic reactions to determine and output, and then determining a difference between the calculated and expected values for the data (e.g. determining an offset or chi2 value) multiple times over time (i.e. monitoring). Furthermore, determining the cultivation is affected by a problem as claimed can be practically performed in the mind by performing data comparisons between an offset of the predicted data and process data and the recited 10% threshold or between a chi2 value and the threshold of 5. Excluding affected process data from further analysis or clone selection encompasses a mental selection to remove data from consideration, and flagging the cultivation for review encompasses making a mental determination to review the cultivation at a later time. Initiating inspection of a device encompasses beginning to analyze a cultivation device, which is a mere analysis of information that can be practically performed in the mind. Therefore, these limitations recite a mental process. See MPEP 2106.04(a)(2) III.
Furthermore, the step of fitting the process data using a constraint-based metabolic model and evaluating the fit using an offset between model predictions and process data or using a chi2 test further recite a mathematical concept. The claims amount to a textual equivalent of performing mathematical calculations, in light of Applicant’s specification which discloses mathematical techniques as the only supported embodiments in performing the model fitting, offset determination (i.e. subtraction), and chi-squared test (see Applicant’s specification at pg. 6, lines 1-10; pg. 8 lines 25 to 30; pg. 42 lines 1-14; pg. 50 lines 1-19; pg. 53 lines 6-17; see pg. 7, lines 26-30 for the chi-squared test). Therefore this limitation recites a mathematical concept. See MPEP 2106.04(a)(2) I.
The step of “initiating inspection or recalibration of a cultivation device performing the cultivation” further recites certain methods of organizing human activity because the limitation encompasses managing personal behavior or interactions between people. Specifically, the limitation encompasses a person instruction another person to inspect or recalibrate a device.
Dependent claims 3-11 further recite an abstract idea and/or further limit the abstract idea of claim 1 above. Dependent claim 3 further limits the mathematical concept and mental process of performing a chi-squared test to include evaluating a median chi2 value. Dependent claims 4-5 further limit the mental process and mathematical concept of fitting process data in claim 1 to include process data for a particular cell producing an antibody. Dependent claims 6-8 further limit the mental process and mathematical concept of fitting the process data in claim 1 to include fitting process data including various parameters. Dependent claims 9-10 further limit the mental process and mathematical concept of fitting the process data to use a particular metabolic model. Dependent claim 11 further limits the mental process of identifying a problem to be a technical problem. Therefore, claims 1 and 3-11 recite an abstract idea. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Claims 3 and 9-11 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional element of claim 1 includes:
obtaining process data during cultivation of a mammalian or bacterial cell expression a polypeptide, wherein the process data comprises measured values of at least one on-line process parameter and at least one off-line process parameter.
The additional element of claims 4-8 include:
wherein the cell is (i) a mammalian cell is a CHO cell, and/or (ii) a bacterial cel is E. coli (claim 4); and
wherein the polypeptide is an antibody (claim 5);
wherein the process data comprises temporal values of at least 15 process parameters (claim 6);
wherein the process data comprises temporal values of at least 12 on-line process parameters and at least 28 off-line process parameters (claim 7); and
wherein the process data comprises at least 6 temporal values for one or more process parameters (claim 8).
The additional element of obtaining process data during cultivation of a mammalian or bacterial cell only serves to collect information for use by the abstract idea. Dependent claims 3-8 only serve to further limit the process data obtained in step 1, and are part of the collection of data. Therefore, these limitations amount to insignificant extra-solution activity. See MPEP 2106.05(g).
Therefore, the additionally recited elements amount to insignificant extra-solution activity and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1 and 3-11 are directed to an abstract idea. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Claims 3 and 9-11 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional element of claim 1 includes:
obtaining process data during cultivation of a mammalian or bacterial cell expression a polypeptide, wherein the process data comprises measured values of at least one on-line process parameter and at least one off-line process parameter.
The additional element of claims 4-8 include:
wherein the cell is (i) a mammalian cell is a CHO cell, and/or (ii) a bacterial cel is E. coli (claim 4); and
wherein the polypeptide is an antibody (claim 5);
wherein the process data comprises temporal values of at least 15 process parameters (claim 6);
wherein the process data comprises temporal values of at least 12 on-line process parameters and at least 28 off-line process parameters (claim 7);
wherein the process data comprises at least 6 temporal values for one or more process parameters (claim 8).
The additional element of obtaining process data during cultivation of a mammalian or bacterial cell expressing a polypeptide encompasses real-time transmitting of measured process data during the cultivation over a network. Claims 4-8 only serve to further limit the information being obtained or transmitted, and the claims do not require any steps of cultivating the mammalian or bacterial cell and/or measuring the process parameters. The courts have found receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information); TLI Communications LLC v. AV Auto. LLC, 823 F.3d 607, 610, 118 USPQ2d 1744, 1745 (Fed. Cir. 2016) (using a telephone for image transmission); OIP Techs., Inc., v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015) (sending messages over a network); buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network); but see DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1258, 113 USPQ2d 1097, 1106 (Fed. Cir. 2014) ("Unlike the claims in Ultramercial, the claims at issue here specify how interactions with the Internet are manipulated to yield a desired result‐‐a result that overrides the routine and conventional sequence of events ordinarily triggered by the click of a hyperlink." (emphasis added)).
Furthermore, obtaining process parameters during cultivation of a mammalian cell that produce a heterologous peptide is well-understood, routine, and conventional, as demonstrated by Long et al. (The development and application of high throughput cultivation technology in bioprocess development, 2014, 192, pg. 323-338; previously recited). Long reviews the development and application of high-throughput cultivation technologies (Abstract), and discloses a plurality of commercially available high-throughput cultivation systems (Table 1), including platforms with multi-well plates and microfluidic systems for cultivating clones in parallel (Figures 2-3; pg. 334, col. 2, para. 2 to pg. 335, col. 1, para. 2; Fig. 5). Long further discloses current engineering technologies offer many options to construct strains for producing a protein in bacteria and mammalian expression systems (pg. 324, col. 2, para. 1; Table 1). Long further discloses typical processes for clone selection for expressing recombinant proteins (i.e. heterologous peptides) (pg. 328, col. 2, para. 3 to pg. 329, col. 1, para. 2; Figure 2, e.g. plasmid transformed into host cell and screened). Long further discloses various bioreactor platforms that monitor process parameters in real-time during cultivation (pg. 332, col. 1, para. 1-2; pg. 333, col. 2, para. 2; pg. 335, col. 2, para. 2 and 4).
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 09 April 2026 regarding 35 U.S.C. 101, as applicable to claims 1 and 3-11 above, have been fully considered but they are not persuasive.
Applicant remarks the independent claims have been amended to remove the conditional language and to mandate specific actions of “excluding the affected process data from further analysis…” (Applicant’s remarks at pg. 7, para. 4. Applicant remarks claim 1 recites specific concrete details of how the problem is resolved and improvement achieved by “…excluding the affected process data from further analysis or clone selection, and flagging the cultivation for review or initiating inspection or recalibration…”, thus providing a practical improvement to the consistency and reliability of the clone selection process (Applicant’s remarks at pg. 7, para. 5 to pg. 8, para. 1).
This argument is not persuasive. The conditional language has been removed. However, the step of “initiating inspection or recalibration…” is not required given its recited as an alternative. Furthermore, this limitation is part of the abstract idea for the reasons discussed in the above rejection, and therefore, does not provide integration or significantly more under Step 2A, Prong 2 and Step 2B.
Furthermore, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements. See the discussion of Diamond v. Diehr, 450 U.S. 175, 187 and 191-92, 209 USPQ 1, 10 (1981)) in subsection II, below. In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception. See MPEP § 2106.04(d). See MPEP 2106.05(a). Therefore, the improvement cannot be provided by the abstract idea of excluding data from further view, initiating inspection, etc.
Applicant remarks the amended claims align with the claims in Diamond v. Diehr, because here the alleged judicial exception are utilized as the specific trigger to execute physical and data-control interventions on the cultivation system, such as initiating recalibration of the cultivation device (Applicant’s remarks at pg. 8, para. 2).
This argument is not persuasive. In Diehr, the claim was directed to the use of the Arrhenius equation (an abstract idea or law of nature) in an automated process for operating a rubber-molding press. 450 U.S. at 177-78, 209 USPQ at 4. The Court evaluated additional elements such as the steps of installing rubber in a press, closing the mold, constantly measuring the temperature in the mold, and automatically opening the press at the proper time, and found them to be meaningful because they sufficiently limited the use of the mathematical equation to the practical application of molding rubber products. 450 U.S. at 184, 187, 209 USPQ at 7, 8.
In the instant case, the claims do not even require the “initiating recalibration of the cultivation device” and instead only require “excluding the affected process data from further analysis and clone selection, and flagging the cultivation for review…”, which, unlike the operation of a rubber molding process in Diehr, encompasses a mental process of determining to no longer consider the affected process data and making a mental determination to review the cultivation at later time. The abstract idea cannot integrate itself into a practical application, as discussed above.
Regardless, even if the claim did require the “initiating recalibration”, the claim does not require recalibrating the cultivation device, and instead encompasses simply “initiating” recalibration as discussed in the above rejection. Therefore, this limitation encompasses an abstract idea of organizing human activity, given it encompasses managing interactions between people (a person instructing another person to recalibrate a device). Therefore, the claim does not recite any additional element(s) that integrate the judicial exception into a practical application, unlike the claims in Diehr.
Applicant remarks the claims are similar to example 47 because the present claims integrate the use of the constraint based model by mandating concrete, real-world actions including excluding affected data, flagging the run for review, and initiating device recalibration (Applicant’s remarks at pg. 8, para. 3).
This argument is not persuasive for the same reasons already discussed above. First, the claim does not require all three of these steps, and these steps are part of the abstract idea.
Applicant remarks that even if the claims involve an abstract idea, they incorporate significantly more because while “cultivating cells” may be conventional, the ordered combination of using a constraint-based metabolic model and associated criteria to mandate physical device recalibration, data exclusion and repetition is not conventional (Applicant’s remarks at pg. 9, para. 1-3).
This argument is not persuasive. . In step 2B, examiners should: (1) carry over their identification of the additional element(s) in the claim from Step 2A Prong Two; (2) carry over their conclusions from Step 2A Prong Two on the considerations discussed in MPEP §§ 2106.05(a) - (c), (e) (f) and (h): and (3)-(4) evaluate whether any additional element or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP § 2106.05(d). See MPEP 2106.05 II.
Therefore, only the additional elements are evaluated for conventionality, alone and in combination. Therefore, the use of the constraint-based model, data exclusion, flagging for review, and initiating device recalibration are not evaluated under Step 2B. The additional elements in the claim are well-understood, routine, and conventional for the reasons discussed in the above rejection.
Claim Rejections - 35 USC § 103
The rejection of claims 1-6 and 8-11 under 35 U.S.C. 103 as being unpatentable over Popp (2016) in view of Famili (2016) in the Office action mailed 09 Jan. 2026 has been withdrawn in view of claim amendments received 09 April 2026.
The rejection of claim 7 under 35 U.S.C. 103 as being unpatentable over Popp (2016) in view of Famili (2016), as applied to claim 1 or 2 above, further in view of Charaniya (2010) in the Office action mailed 09 Jan. 2026 has been withdrawn in view of claim amendments received 09 April 2026.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6 and 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Popp (2016) in view of Famili (2016) and Invitrogen (2016). This rejection is newly recited and necessitated by claim amendment.
Cited references:
Popp et al., A Hybrid Approach Identifies Metabolic Signatures of High-Producers for Chinese Hamster Ovary Clone Selection and Process optimization, 2016, Biotechnology and Bioengineering, 113(9), pg. 2005-2019 and Suppl; previously cited;
Famili et al., US 2016/0364520 A1; previously cited; and
Invitrogen, Cell Culture Basics, 2016, pg. 1-54; newly cited.
Regarding claim 1, Popp discloses a method for clone selection in cultivations of Chinese Hamster Ovary (CHO) cells (i.e. mammalian cells) (Abstract) comprising the following:
Popp discloses performing cultivations for CHO cell clones (pg. 2006, col. 2, para. 5 to pg. 2007, col. 2, para. 1, e.g. cultivations of a given clone inoculated from same pre-culture; Figure 1, e.g. separate cultivation profiles for each clone), wherein the cell clones all express an identical monoclonal IgG4 antibody (i.e. a polypeptide) (pg. 2006, col. 2, para. 5) and wherein product titer data over time (i.e. obtaining process data) is recorded during the cultivating for clones (Figure 1, e.g. see product Titer amount over process time per clone). Popp further discloses the recorded process data includes parameters comprise at least product titer, viable cell density, lactate, alanine concentration, and metabolic profiling sampled daily (i.e. off-line parameters) (Figure 1; FIG. 9; pg. 2006, col. 2, para. 5)
Popp discloses obtaining a CHO metabolic model (pg. 2006, col. 2, para. 2) generated for CHO cells to determine production rates of the polypeptide (i.e. the model is tailored to a particular cell-line: the same mammalian cell expressing the polypeptide) (pg. 2006, col. 2, para. 2, e.g. modeling 654 reactions to estimate production rate; Table 1; Figure 8).
Popp discloses computing Pearsons and Spearman correlations (i.e. fitting) of process data using a CHO metabolic network model to generate model predictions from the process data (pg. 2006, col. 2, para. 2-4; pg. 2008, col. 2, para. 3; FIG. 8; Table 1), wherein the process data includes parameters comprise at least product titer, viable cell density, lactate, alanine concentration, and metabolic profiling sampled daily (i.e. off-line parameters acquired in a time-dependent manner) (Figure 1; FIG. 9; pg. 2006, col. 2, para. 5) and the process data was acquired from CHO-K1 clones expressing a recombinant human IgG4 monoclonal antibody (i.e. a polypeptide) (pg. 2006, col. 1, para. 4 to col. 2, para. 1; pg. 2006, col. 2, para. 5).
Popp discloses computing a Spearman and Pearson correlation of metabolic data, process data and intracellular flux distributions (monitoring model predictions) (pg. 2006, col. 2, para. 3; Table 1 and Figure 8, e.g. Pearson correlation of 0.37 between raw data “cell growth” and metabolic indicator, in addition to F, R2, t statistics), and confirming that the model correctly recapitulates expected interrelations between measured product titer and calculated cell viability (i.e. the modeled fit showing an offset with respect to raw data) (pg. 2011, col. 1, para. 3; Table 1).
Popp further discloses the metabolic model is a stochiometric flux-based analysis model (i.e. a constraint-based model), given a stoichiometric model is constrained by metabolite mass balance (Figure 5; pg. 2008, col. 2, para. 2,e.g. the network model is “stoichiometric” pg. 2008, col. 2, para. 3) and comprises compartments for a CHO network model (i.e. tailored to the CHO cell line) (pg. 2006, col. 2, para. 2), wherein the compartments are divided into physiologically distinct phases (i.e. phases within compartments) (pg. 2006, col. 2, para. 2; pg. 2008, col. 2, para. 3, e.g. flux distributions calculated using network model for each phase; Table S3-4; Table S9, e.g. separate model scores for each phase). Popp discloses the CHO metabolic model, including the phases within compartments, is generated for CHO cells to determine production rates of the polypeptide (i.e. the model is tailored to a particular cell-line: the same mammalian cell expressing the same polypeptide) (pg. 2006, col. 2, para. 2, e.g. modeling 654 reactions to estimate production rate; Table 1; Figure 8), including using specific biomass compositions for CHO cells and mass balancing of all compartments (pg. 2006, col. 2, para. 2-4; pg. 2008, col. 1, para. 3).
Regarding claim 2, Popp discloses a method for clone selection in cultivations of Chinese Hamster Ovary (CHO) cells (i.e. mammalian cells) (Abstract) comprising the following steps:
Popp discloses a) performing separate cultivations for CHO cell clones (pg. 2006, col. 2, para. 5 to pg. 2007, col. 2, para. 1, e.g. cultivations of a given clone inoculated from same pre-culture; Figure 1, e.g. separate cultivation profiles for each clone), wherein the cell clones all express an identical monoclonal IgG4 antibody (i.e. the same heterologous polypeptide) (pg. 2006, col. 2, para. 5) and wherein product titer data over time (i.e. temporal process data) is recorded during the cultivating for clones (Figure 1, e.g. see product Titer amount over process time per clone).
Popp discloses b) obtaining a CHO metabolic model (pg. 2006, col. 2, para. 2) generated for CHO cells to determine production rates of the polypeptide (i.e. the model is tailored to a particular cell-line: the same mammalian cell expressing the polypeptide) (pg. 2006, col. 2, para. 2, e.g. modeling 654 reactions to estimate production rate; Table 1; Figure 8).
Popp discloses computing Pearsons and Spearman correlations of the process data using a CHO metabolic network model (i.e. fitting and evaluating the fit) (pg. 2006, col. 2, para. 2-4; FIG. 8; Table 1), wherein the fitting is performed for a clone individually (Figure 8, e.g. see spearman correlation for each clone separately). Popp further discloses the CHO metabolic model is generated for CHO cells (i.e. the same mammalian cell) (pg. 2006, col. 2, para. 2). Popp further discloses the recorded process data includes parameters comprise at least product titer, viable cell density, lactate, alanine concentration, and metabolic profiling sampled daily (i.e. off-line parameters) (Figure 1; FIG. 9; pg. 2006, col. 2, para. 5).
Regarding step e), the limitation is not required under the broadest reasonable interpretation of the claims because the condition precedent has not been met, as discussed in claim interpretation above.
Popp further discloses the metabolic model is a stochiometric flux-based analysis model (i.e. a constraint-based model), given a stoichiometric model is constrained by metabolite mass balance (Figure 5; pg. 2008, col. 2, para. 2,e.g. the network model is “stoichiometric” pg. 2008, col. 2, para. 3) and comprises compartments for a CHO network model (i.e. tailored to the CHO cell line) (pg. 2006, col. 2, para. 2), wherein the compartments are divided into physiologically distinct phases with different inputs for different phases (i.e. phases within compartments) (pg. 2006, col. 2, para. 2; pg. 2008, col. 2, para. 3, e.g. flux distributions calculated using network model for each phase and mass balancing). Popp discloses the CHO metabolic model, including the phases within compartments, is generated for CHO cells to determine production rates of the polypeptide (i.e. the model is tailored to a particular cell-line: the same mammalian cell expressing the same polypeptide) (pg. 2006, col. 2, para. 2, e.g. modeling 654 reactions to estimate production rate; Table 1; Figure 8), including using specific biomass compositions for CHO cells and mass balancing of all compartments (pg. 2006, col. 2, para. 2-4; pg. 2008, col. 1, para. 3).
Regarding claims 1-2, Popp does not disclose the following limitations:
Regarding claims 1-2, Popp does not disclose the process data comprises at least one on-line parameter in addition to the off-line parameter discussed above.
However, Famili discloses a method for optimizing cell lines, including CHO cell cultivation (Abstract; [0030]), which comprises collecting on-line biochemical data using NOVA 400 gas analyzer at each sampling point ([0396]; [0203]), the biochemical data including, glucose, lactate, ammonium, pCO2, pO2, and other element concentrations ([0394]). Famili discloses these elements include carbon, nitrogen, sulfur, phosphate, hydrogen, and oxygen ([0180]; [0226]). Famili further discloses sampling each bioreactor periodically for viability cell density, offline pH, glucose, glutamine, glutamate, lactate ammonium, sodium, potassium, amino acids, IgG, and vitamin analysis (i.e. off-line parameters) ([0203]; [0396]; Figure 11), and fitting the off-line and on-line process data to a CHO metabolic network ([0294]). Famili further discloses once the computational representation of metabolism is complete, the reconstructed network can be used to interrogate network capabilities and design new strategies for media optimization or cell engineering ([0205]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Popp to have utilized on-line process parameters in addition to the off-line parameters in the process data for fitting a CHO metabolic network, as shown by Famili above. One of ordinary skill in the art would have been motivated to combine the methods of Popp and Famili in order to facilitate to the design of new strategies for media optimization and cell engineering for CHO cells, as shown by Famili ([0205]), given Popp discloses enriched process data allows for novel process control regimens (pg. 2005, col. 2, para. 2 to pg. 2006, col. 1, para. 2). This modification would have had a reasonable expectation of success given both Popp and Famili utilize process data for metabolic network modeling of CHO cells, such that the such that the parameters of Famili are applicable to Popp.
Further regarding claims 1-2, Popp does not explicitly disclose: monitoring, in real-time, the model predictions to identify the cultivation being affected by a problem wherein the cultivation being affected by the problem comprises (i) the modeled fit showing an offset with respect to raw data of more than 10%, and in response to the cultivation being identified as having a problem, excluding the affected process data from further analysis or clone selection, and flagging the cultivation for review, as recited in claim 1; or c) determining a cultivation of step a) is affected by a problem comprising the fit obtained for the corresponding clone in b) for the process data showing (i) an offset between model predictions and the process data exceeding 10%, and in response to the cultivation being determined to be affected by the problem, fixing the problem, and repeating steps a) to c) with the clones that had the problem, as recited in claim 2.
However, Popp does disclose that the uses of applying a mechanistic approach for CHO cell culture performance analysis can be manifold, and that with the increased availability of online analysis, such model-supported systems can be employed as early warning systems (i.e. identifying a problem) for monitoring and controlling product quality during cultivation (pg. 2018, col. 1, para. 2).
Furthermore, these limitations were known in the art before the effective filing date of the claimed invention, as shown by Famili and Invitrogen below.
Regarding claims 1-2, Famili discloses a method for optimizing cell lines, including CHO cell cultivation (Abstract; [0030]) comprising fitting the off-line and on-line process data to a CHO metabolic network ([0294]), as discussed above, and further discloses benchmarking simulation results of the model by comparing substrate uptake and byproduct secretion predicted by the model to experimental measurements (i.e. the raw data) to determine differences between the simulated values and experimental values (i.e. the modeled fit showing an offset with respect to raw data) ([0225]; [0293]-[0294]; Table 11). Famili further discloses determining if simulated results are outside of the experimental range, including those more than 10% ([0226]; Table 5, e.g. simulation result -0.007 identified as outside range compared to experimental value of -0.004), and then explains that these major differences between the simulated values and experimental values may result from differences in essential amino acid requirements for cell growth and product formation due to experimental error or errors in experimental measurements or low sensitivity in analytical measurements for measuring metabolite concentrations (i.e. identifying a culture problem in response to there being a major difference, >10%) ([0216]; [0225]). Famili further discloses that further investigation of media components, experimental measurements, and incompleteness of experimental protocol should be investigated to provide additional insights (i.e. flagging the cultivation for review ([0226]). Famili further discloses that the present invention provides methods for optimizing cell culture media, and can be used to develop nutritional modifications to media to improve growth and productivity of cultures ([0042]-[0044]), and that this approach is iterative, which demonstrates repeating cell cultures, taking measurements, and model fitting in order to further optimize a culture (i.e. repeating steps a)-c) ([0435]-[0436]).
Famili does not disclose or explicitly disclose, in response to the identified problem: excluding the affected process data from further analysis or clone selection, as recited in claim 1, or fixing the problem prior to repeating steps a)-c), as recited in claim 2. However, this is shown by Invitrogen.
Further regarding claims 1-2, Invitrogen overviews cell culture basics, and includes a troubleshooting guide listing potential problems with cell cultures (i.e. cultivations) and possible solutions that help you troubleshoot your cell culture experiments (pg. 43). Invitrogen discloses that if the culture is contaminated, the cells, media, and reagents should be discarded (i.e. excluding the affected process data from further analysis or clone selection), and perform the culture with new cells and fresh media and reagents (i.e. fixing the problem prior to repeating step a)) (pg. 43, see last row in table). Invitrogen further discloses other examples of potential culture problems, and instructs a user to fix the problem in a subsequent culture (pg. 43 see table, e.g. at least “cells were thawed incorrectly”, “cells have been passaged to many times”).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Popp to have determined there is a cultivation problem of an experimental error or measurements when a modeled fit shows an offset with respect to raw data of more than 10% , reviewed the cultivation in response, and furthermore, repeated steps a)-c) to optimize the culture, as shown by Famili above, and furthermore, to have monitored the offset over time, as suggested by Pop (pg. 2018, col. 1, para. 2). One of ordinary skill in the art would have been motivated to combine the methods of Popp and Famili in order to detect major differences in simulated and experimental values that are a result of experimental, as shown by Famili ([0216]; [0225]) and monitor such experimental errors during cultivation to provide any early warning system for product quality, as shown by Popp (pg. 2018, col. 1, para. 2). This modification would have had a reasonable expectation of success because both Popp and Famili utilize process data for metabolic network modeling of CHO cells, such that the such that detected differences in Famili could be monitored according to Popp.
It would have been further prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Popp in view of Famili, to have further, in response to identifying the problem, discarded the cell culture (i.e. exclude the affected process data from further analysis or clone selection) and to start a fresh cell culture of the cells, as shown by Invitrogen above. One of ordinary skill in the art would have been motivated to combine the methods of Popp in view of Famili with Invitrogen in order to carry out solutions for the most commonly encountered problems in cell culture, as shown by Invitrogen (pg. 43, para. 1). This modification would have had a reasonable expectation of success given Famili detects differences in model fit and measured data may be due to experimental error and measurements, and therefore, the culture troubleshooting guide of Invitrogen is applicable to Famili.
Regarding the dependent claims:
Regarding claim 3, claim 3 further limits the chi2 test in (ii). However, the chi2 test in (ii) is recited in the alternative form, and the alternate embodiment in which (i) the fit showing an offset exceeding 10% is disclosed by Popp in view of Famili and Invitrogen as applied above. Therefore, the limitation in claim 3 is not required in the claims, and claim 3 is rejected for the same reasons discussed above for claims 1-2.
Regarding claim 4, Popp further discloses the cell is a CHO cell (Abstract; pg. 2006, col. 2, para. 2).
Regarding claim 5, Popp further discloses the polypeptide is a monoclonal IgG4 antibody (pg. 2006, col. 2, para. 5).
Regarding claim 6, Popp further discloses the process data includes cell number, cell diameter, product titer, metabolite concentrations, and amino acid concentrations in fermentation broth, which is at least 15 process parameters (pg. 2006, col. 1, para. 1; Suppl. S7 Table; Suppl S8 Table, e.g. > 15 amino acids; Figure 1, e.g. alanine concentration, lactate concentration).
Regarding claim 8, Popp further discloses the process data includes at least 6 values across time for one or more process parameters (Figure 1).
Regarding claim 9, Popp discloses the metabolic model is a genome-based CHO network model (pg. 2006, col. 2, para. 2).
Regarding claim 10, Popp further discloses the metabolic model includes 654 reactions (i.e. at least 600 reactions), 583 metabolites (i.e. at least 500 metabolites), and 266 ORFs (i.e. at least 250 genes, given an open reading frame corresponds to a gene as discussed at pg. 38, line 25 of Applicant’s specification) (pg. 2006, col. 2, para. 2).
Regarding claim 11, Popp in view of Famili and Invitrogen make obvious determining the cultivation is identified as being affected by a problem, as applied to claims 1-2 above. Famili, as applied to claims 1-2 above, discloses the major differences in fit may be due to the low sensitivity in analytical measurements for measuring metabolite concentrations (i.e. a technical problem, given the problem is with measuring equipment/sensors) ([0216]; [0225]).
Therefore, the invention is prima facie obvious.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Popp (2016) in view of Famili (2016) and Invitrogen (2016), as applied to claim 1 or 2 above, further in view of Charaniya (2010). This rejection is newly recited and necessitated by claim amendment.
Cited references: Charaniya et al., Mining manufacturing data for discovery of high productivity process characteristics, 2010, Journal of biotechnology, 147, pg. 186-197 (previously cited).
Regarding claim 7, Popp in view of Famili and Invitrogen disclose the invention of claims 1 and 2, as applied above.
Further regarding claim 7, as applied to claims 1 and 2 above, Popp in view of Famili and Invitrogen make obvious the use of on-line parameters in addition to off-line parameters in process data for fitting a metabolic model. Famili discloses the on-line parameters include glucose, lactate, ammonium, pCO2, pO2, and other element concentrations ([0203]; [0394]; [0396]), and further discloses sampling each bioreactor periodically for viability cell density, offline pH, glucose, glutamine, glutamate, lactate ammonium, sodium, potassium, amino acids, IgG, and vitamin analysis (i.e. off-line parameters) ([0203]; [0396]; Figure 11), and fitting the off-line and on-line process data to a CHO metabolic network ([0294]). Given there are 20 amino acids, Popp in view of Famili disclose the use of 28 off-line parameters.
Popp in view of Famili and Invitrogen, as applied to claims 1 and 2 above, do not disclose the following:
Regarding claim 7, Popp in view of Famili and Invitrogen, as applied to claims 1 and 2 above, do not disclose the process data comprises at least 12 on-line parameters.
However, Charaniya discloses obtaining 23 additional off-line parameters relating to nutrient consumption and metabolite production by drawing samples from a bioreactor (pg. 188, col. 1, para. 3; Table 1) in addition to 130 online parameters from automated control and data logging systems (pg. 187, col. 2, para. 3; Table 1). Charaniya discloses these the process parameters are correlated to protein productivity in cell cultures (pg. 198, col. 1, para. 3).
It would have been further prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Popp in view of Famili and Invitrogen, to have further used additional on-line process parameters, as shown by Charaniya, thus arriving at the invention of claim 7. One of ordinary skill in the art would have been motivated to combine the methods of Popp in view of Famili and Invitrogen with Charaniya in order to include additional process parameters correlated with protein productivity in cell cultures, as shown by Charaniiya (pg. 198, col. 1, para. 3), given Popp discloses predicting protein productivity using the metabolic model (Table 1) and that the breadth of process data available allows for novel process control regimens (pg. 2005, col. 2, para. 2 to pg. 2006, col. 1, para. 2). This modification would have had a reasonable expectation of success given both Popp and Famili utilize process data for metabolic network modeling of CHO cells, such that the parameters of Charaniya are applicable to the model of Popp in view of Famili.
Therefore, the invention is prima facie obvious.
Response to Arguments
Applicant's arguments filed 09 April 2026 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks that the cited art of record, alone or in combination, does not teach the combination of features of “monitoring, in real-time…. and in response to the cultivation is identified to be affected by the problem, excluding…” in claim 1 and “c) determining a cultivation of step a) being affected by a problem….; d) in response to at least one cultivation being effected by the problem, fixing the problem and repeating…”, and that the Office has not pointed to any disclosure in Popp that teaches the now mandatory steps of excluding process data, flagging, initiating inspection or recalibration, or fixing the problem and repeating the cultivation steps (Applicant’s remarks at pg. 9, para. 5 to pg. 10, para. 3).
This argument is not persuasive because Popp is not relied upon to teach these features. Instead, in the new grounds of rejection above, the combination of Famili and Invitrogen (newly cited) are relied upon for these limitations.
Applicant remarks the Office has not pointed to any disclosure in Famili for teaching these differences such as “initiating inspection or recalibration of a cultivation device” or “excluding the affected process data” (Applicant’s remarks at pg. 10, para. 3).
This argument is not persuasive because it is not commensurate with the scope of the claims. Claim 1 only requires “excluding the affected process data…., and flagging the cultivation for review or initiating inspection or recalibration”. Therefore only one of (1) flagging and (2) initiating are required, but not both. As a result, the initiating inspection or recalibration is not required by the claims.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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