DETAILED ACTION
The Applicant’s response, received 20 November 2025, 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 .
Status of the Claims
Claims 1, 3, 6-14, 16, 17, 19, and 20 are pending.
Claims 1, 3, 6-14, 16, 17, 19, and 20 are rejected.
Claim 12 is objected to.
Priority
The effective filing date of the claimed invention is 25 October 2019.
Claim Interpretationi1
Claim 1 recites the limitation “wherein the computer system is adapted…to control the pump…” in lines 26-28, and claim 13 recites the limitation “the computer system…is adapted to control the pump…” in lines 6-7. These limitations are interpreted to mean that the computer system includes an automated control unit (ACU; specification, page 13, lines 25-30 through page 15).
Claim Objections
The claim objection advisory regarding claims 11 and 15 in the Office action mailed 20 August 2025 is withdrawn in view of the amendment received 20 November 2025.
The amendment received 20 November 2025 has been fully considered, however after further consideration, new grounds of objection are raised in view of the amendment.
Claim 12 is objected to because of the following informalities: The word “a” in line two before the word “model” should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The rejection of claims 1, 3, and 16-20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 20 August 2025 is withdrawn in view of the amendment received 20 November 2025.
Claim Rejections - 35 USC § 101
The Applicant’s amendment received 20 November 2025 has been fully considered, however after further consideration, the rejection of claims 6-17, 19, and 20 under 35 U.S.C. 101 in the Office action mailed 20 August 2025 is maintained with modification in view of the amendment.
The rejection of claim 15 under 35 U.S.C. 101 in the Office action mailed 20 August 2025 is withdrawn in view of this claim having been cancelled in the amendment received 20 November 2025.
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 6-14, 16, 17, 19, and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite: (a) mathematical concepts, (e.g., mathematical relationships, formulas or equations, mathematical calculations); and (b) mental processes, i.e., concepts performed in the human mind, (e.g., observation, evaluation, judgement, opinion).
Subject matter eligibility evaluation in accordance with MPEP 2106.
Eligibility Step 1: Step 1 of the eligibility analysis asks: Is the claim to a process, machine, manufacture or composition of matter?
Claims 6-14, 16, 17, 19, and 20 are directed to a method (i.e., a process) of auto-inoculating a bioreactor by using a system for controlling a seed train process.
Therefore, these claims are encompassed by the categories of statutory subject matter, and thus, satisfy the subject matter eligibility requirements under Step 1.
[Step 1: YES]
Eligibility Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim.
Independent claim 6 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
a multivariate model that provides one or more process variable predictions based on Raman spectral data from process variable measurements (i.e., mental processes and mathematical concepts);
process the Raman spectral data to generate the multivariate model providing one or more process variable predictions i.e., mental processes and mathematical concepts);
compare one or more process variable predictions to one or more predefined process set points to determine if the one or more process variable predictions have satisfied a predefined trigger value (i.e., mental processes);
determining that the one or more process variable predictions in the Raman spectral data has satisfied the predefined trigger value (i.e., mental processes); and
when comparing process variable predictions from the multivariate model to the one or more predefined process set points, use the Raman spectral data based on the process variable measurements in wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1 (i.e., mental processes);
provide data to the multivariate model that predicts one or more process variables (i.e., mental processes);
comparing process variable predictions from the multivariate model with predefined process set points (i.e., mental processes); and
determining that one or more process variable predictions from the multivariate model satisfies a predefined trigger value (i.e., mental processes).
Dependent claims 7-14, 16, 17, and 20 further recite the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas, as noted below.
Dependent claim 7 further recites:
wherein the predefined trigger value is a viable cell density value (VCD) (i.e., mental processes).
Dependent claim 8 further recites:
wherein the viable cell density value is equal to or within a range of -10% of a predetermined target viable cell density (i.e., mental processes and mathematical concepts).
Dependent claim 9 further recites:
wherein the predefined trigger value is a lactate level value (i.e., mental processes).
Dependent claim 10 further recites:
wherein the lactate level value is equal to or within a range of +10% of a predetermined minimum lactate level (i.e., mental processes and mathematical concepts).
Dependent claim 11 further recites:
wherein the predefined trigger value is a model predicted VCD value (i.e., mental processes).
Dependent claim 12 further recites:
wherein the model predicted VCD value is equal to or within a range of -10% of a predetermined maximum cell growth rate (i.e., mental processes and mathematical concepts).
Dependent claim 13 further recites:
determine that a process variable prediction from the multivariate model satisfies either the first or second predefined trigger value (i.e., mental processes).
Dependent claim 14 further recites:
wherein the second predefined trigger value is a lactate level value (i.e., mental processes).
Dependent claim 16 further recites:
generates the multivariate model by processing the Raman spectral data (i.e., mental processes and mathematical concepts); and
obtains the process variable measurements from the multivariate model for comparison with the predefined trigger values (i.e., mental processes and mathematical concepts).
Dependent claim 17 further recites:
generates a partial least squares regression model (i.e., mental processes and mathematical concepts).
Dependent claim 20 further recites:
wherein the process variable measurements obtained from the local analyzer serves as a baseline reference for the Raman spectral data (i.e., mental processes).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to recite limitations that can practically be performed in the human mind with the aid of a pen and paper (e.g., generating a multivariate model; and comparing process variable predictions from the multivariate model with predefined process set points), and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas (e.g., predicting process variables using a partial least squares regression model) are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Therefore, claims 6-14, 16, 17, 19, and 20 recite an abstract idea.
[Step 2A Prong One: YES]
Eligibility Step 2A Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A Prong One are not integrated into a practical application because of the reasons noted below.
Dependent claims 7, 8, 9, 10, 11, 12, 14, and 20 do not recite any elements in addition to the judicial exception(s), and thus are part of the judicial exception.
The additional elements in independent claim 6 include:
an expansion chamber for receiving an initial cell stock for expansion into a viable cell culture;
a bioreactor in fluid communication with the expansion chamber for receiving a viable cell culture;
a pump for effecting transfer of a viable cell culture from the expansion chamber to the bioreactor through a fluid communication path between the expansion chamber and the bioreactor;
a Raman spectrometer having at least one probe for monitoring the cell expansion process within the expansion chamber using Raman spectrometry, the Raman spectrometer being adapted to generate Raman spectral data;
a computer system in signal communication with the Raman spectrometer for receiving Raman spectral data;
a computer system in signal communication with the pump for controlling operation of the pump for effecting transfer of a viable cell culture from the expansion chamber to the bioreactor; wherein the computer system is adapted to control the pump to execute an auto-transfer of a cell culture volume from the expansion chamber to the bioreactor;
expanding a cell stock in the expansion chamber;
generating Raman spectral data, using the Raman spectrometer;
a computer system controlling the pump to auto-inoculate the bioreactor with a viable cell culture from the expansion chamber; and
wherein a user selects the predefined trigger value.
The additional elements in dependent claims 13, 16, 17, and 19 include:
a computer system (claims 13, 16 and 17);
the computer system stores a first predefined trigger value based on a predetermined viable cell density, and stores a second predefined trigger value based on a predetermined processing variable other than viable cell density (claim 13);
the computer system is adapted to control the pump to auto-inoculate the bioreactor with a viable cell culture from the expansion chamber (claim 13);
receiving data from a Raman spectrometer (claim 16); and
obtaining a sample of the cell expansion in the expansion chamber and obtaining the process variable measurements by testing the one or more process variables of the cell expansion in the expansion chamber in a local analyzer (claim 19).
The additional element of a computer system (claims 6, 13, 16, and 17) invokes a computer merely as a tool for use in the claimed process, i.e., executing an abstract idea, and/or to perform the functions of receiving data and/or inputting data and/or outputting data and/or storing data and/or selecting data; and therefore is not an improvement to computer functionality itself, or an improvement to any other technology or technical field, and thus, does not integrate the judicial exceptions into a practical application (see MPEP 2106.04(d)(1)).
The additional elements of receiving data and/or inputting data and/or outputting data and/or storing data and/or a user selects the predefined trigger value (i.e., selecting data) and/or obtaining data (claims 6, 13, 16, and 19); are merely pre-solution activities of gathering data for use in the claimed process – nominal additions to the claims that do not meaningfully limit the claims, and therefore do not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The additional elements of an expansion chamber for receiving an initial cell stock for expansion into a viable cell culture (claim 6); a bioreactor in fluid communication with the expansion chamber for receiving a viable cell culture (claim 6); a pump for effecting transfer of a viable cell culture from the expansion chamber to the bioreactor through a fluid communication path between the expansion chamber and the bioreactor (claim 6); a computer system in signal communication with the Raman spectrometer for receiving Raman spectral data, and in signal communication with the pump for controlling operation of the pump for effecting transfer of a viable cell culture from the expansion chamber to the bioreactor (claim 6); expanding a cell stock in the expansion chamber (claim 6); and obtaining a sample of the cell expansion in the expansion chamber and obtaining the process variable measurements by testing the one or more process variables of the cell expansion in the expansion chamber in a local analyzer (claim 19); are not meaningful limitations because they do not sufficiently limit the use of the abstract ideas to a practical application of auto-inoculating a bioreactor due to the controlling step being contingent on the computer system determining that one or more process variable predictions from the multivariate model satisfies a predefined trigger value, which is a limitation that is not required by the claims, and therefore these additional elements do not integrate the recited judicial exceptions into a practical application (MPEP 2106.05(e)).
The additional element of a Raman spectrometer having at least one probe for monitoring the cell expansion process within the expansion chamber using Raman spectrometry, the Raman spectrometer being adapted to generate Raman spectral data (claim 6); and generating the Raman spectral data, using the Raman spectrometer (claim 6); are merely pre-solution activities for gathering data for use in the claimed process – nominal additions to the claims that do not meaningfully limit the claims, and therefore do not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
Thus, the additionally recited elements merely invoke a computer as a tool, and/or amount to insignificant extra-solution activities, and/or do not meaningfully limit the claims, and as such, when all limitations in claims 6-14, 16, 17, 19, and 20 have been considered as a whole, the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, and therefore claims 6-14, 16, 17, 19, and 20 are directed to an abstract idea (MPEP 2106.04(d)).
[Step 2A Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. Evaluating additional elements to determine whether they amount to an inventive concept requires considering them both individually and in combination to ensure that they amount to significantly more than the judicial exception itself (MPEP 2106.05(I)).
The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
Dependent claims 7, 8, 9, 10, 11, 12, 14, and 20 do not recite any elements in addition to the judicial exception(s).
The additional elements recited in independent claim 6 and dependent claims 13, 16, 17, and 19 are identified above, and carried over from Step 2A: Prong Two along with their conclusions for analysis at Step 2B. Any additional element or combination of elements that was considered to be insignificant extra-solution activity at Step 2A: Prong Two was re-evaluated at Step 2B, because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and all additional elements and combination of elements were evaluated to determine whether any additional elements 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).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s) because the additional elements of a computer system (claims 6, 13, 16, and 17); and performing functions of receiving data and/or inputting data and/or outputting data and/or storing data and/or selecting data and/or obtaining data (claims 6, 13, 16, and 19); are conventional (see MPEP at 2106.05(b) and 2106.05(d)(II) regarding conventionality of computer components and computer processes).
The additional elements of a pump for effecting transfer of a viable cell culture from the expansion chamber to the bioreactor through a fluid communication path between the expansion chamber and the bioreactor (claim 6); a computer system adapted to control a pump to execute an auto-transfer of a cell culture volume from the expansion chamber to the bioreactor (claims 6 and 13); and obtaining a sample of the cell expansion in the expansion chamber and obtaining the process variable measurements by testing the one or more process variables of the cell expansion in the expansion chamber in a local analyzer (claim 19); are conventional. Evidence for the conventionality is shown by Ozturk (Advances in Biochemical Engineering/Biotechnology, 2013, Volume 139, https://doi.org/10.1007/10_2013_259, pp. 69-92, as cited in the Office action mailed 18 June 2024). Ozturk reviews information on commonly used equipment in industrial mammalian cell culture, with an emphasis on bioreactors (Title; and Abstract). Ozturk further shows pumps can be used for the addition of cell suspension to the bioreactors, and that these pumps can be manually operated or remotely controlled by the automation software (page 83, para. 2). Ozturk further shows that bioreactor monitoring and control relies on offline data generated from the samples withdrawn from the bioreactor, and that cell density and viability determinations can be performed manually using a hemocytometer or automatically using particle counters such as a Nova Bioprofile Flex (Nova Biomedical; page 84, bottom).
The additional elements of an expansion chamber (claim 6); expanding a cell stock in the expansion chamber (claim 6); and a bioreactor in fluid communication with the expansion chamber for receiving a viable cell culture (claim 6); are conventional. Evidence for the conventionality is shown by Tapia et al. (Applied Microbiology and Biotechnology, 2016, Vol. 100, pp. 2121-2132, as cited in the Office action mailed 18 June 2024). Tapia et al. reviews bioreactors for high cell density and continuous multi-stage cultivations (Title; and Abstract), and shows the use of two-stage stirred-tank bioreactors (STR) for virus production, where the first reactor serves only for cell propagation and the subsequent bioreactor is for virus infection and continuous virus replication (page 2127, column 2, lines 11-15; and Figures 2A and 2B). Additional evidence for conventionality is shown by Frensing et al. (PLoS ONE, 2013, Vol. 8(9): e72288, doi: 10.1371/journal.pone.0072288, pp. 1-9, as cited in the Office action mailed 18 June 2024). Frensing et al. shows a two-stage bioreactor setup (page 3, Figure 1) with a first bioreactor where cells grew constantly (i.e., expansion) and were fed via tubing (i.e., fluid communication; color-coded purple in the drawing) into a second bioreactor for virus infection and propagation (i.e., production).
The additional elements of a Raman spectrometer with a probe (claim 6); and generating Raman spectral data (claim 6); are conventional. Evidence for the conventionality is shown by Jenzsch et al. (Advances in Biochemical Engineering/Biotechnology, Volume 165, https://doi.org/10.1007/10_2017_18, pp. 211-252, as cited in the Office action mailed 18 June 2024). Jenzsch et al. reviews trends in bioprocessing (Title; and Abstract) and shows that in-line sensors for bioreactor monitoring may use Raman spectroscopy (page 218, para. 2); and further shows that Raman probes for bioprocess monitoring are commercially available and reports of their application have been published recently, for example, for measuring product concentration in-line (page 219, Section 2.2.3).
Therefore, when taken alone, all additional elements in claims 6-14, 16, 17, 19, and 20 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as a combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 6-14, 16, 17, 19, and 20 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exception(s) (MPEP 2106.05(II)).
[Step 2B: NO]
Response to Arguments
The Applicant’s arguments/remarks received 20 November 2025 have been fully considered, but are not persuasive.
The Applicant summarizes the current guidance by the Patent Office for eligibility analysis on pages 12-13 of the Remarks, and summarizes the rejection under 35 U.S.C. 101 at Steps 2A Prong One and Prong Two in the Office action mailed 20 August 2025 (page 13). The Applicant states on page 14 that claim 6 has been amended to recites “wherein a user selects the predefined trigger value” and that the claimed methods require the user of the method to select a predefined trigger, which imposes a meaningful limit on the recited judicial exception(s), and integrates the judicial exception(s) into a practical application.
These arguments are not persuasive, because the phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole. The considerations described in MPEP § 2106.05(a)-(d) are meaningful limitations when they amount to significantly more than the judicial exception, or when they integrate a judicial exception into a practical application, however the limitation “wherein a user selects the predefined trigger value” does not amount to significantly more than the judicial exceptions when evaluated individually and in combination at Step 2B, and does not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception at Step 2A Prong Two, because the selection of a predefined trigger is a pre-solution activity used in the claimed process – a nominal addition to the claims that does not meaningfully limit the claims because the selection of the predefined trigger value does not apply, rely on or use the judicial exceptions, but rather, the judicial exceptions rely on the user having previously selected the predefined trigger value, and therefore the limitation “wherein a user selects the predefined trigger value” does not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The Applicant states on page 14 (para. 3) of the Remarks that the presently amended claims are patent eligible because they are directed to a judicial exception integrated into a practical application when viewed as a whole, and that in determining patent eligibility, examiners should consider whether the claim purport(s) to improve the functioning of the computer itself or any other technology or technical field. The Applicant further states (para. 4) that claim 6 is directed to a method of auto-inoculating a bioreactor using a system for controlling a seed train process including the limitations as in claim 1, therefore the limitations of the system also need to be considered when determining if claim 6, and the claims which depend therefrom, are directed to patentably eligible subject matter, and the Applicant further contends that the Raman spectral data based on the process variable measurements in wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1 puts a meaningful limit on the judicial exceptions of mathematical concept and/or mental process. The Applicant further states that the present claims are not directed to a mental process and/or mathematical concept, because the claimed methods are directed to using a system for controlling a seed train process including the limitations as in claim 1 with input from the user, specifically, selecting a predefined trigger value, and additionally, the system includes a computer system, a multivariate model, a Raman spectrometer connected to an expansion chamber, a bioreactor, and a pump and reflects an improvement in measuring a seed culture and inoculating a culture in a bioreactor by limiting Raman spectral data to the wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1, which successfully reduced errors.
These arguments are not persuasive, because first, the limitations of the system as recited by claim 1 were considered when determining the eligibility of claim 6, and the claims which depend therefrom, in the Office action mailed 20 August 2025. Second, consideration was given with regard to whether the claim(s) provided an improvement in the functioning of the computer itself or to any other technology or technical field in the Office action mailed 20 August 2025, and in the above rejection. Third, the Raman spectral data based on the process variable measurements in wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1 does not put a meaningful limit on the judicial exceptions of mathematical concept and/or mental process, because the Raman spectral data based on the process variable measurements in the wavelength regions comprise the judicial exception(s) themselves, and therefore cannot provide a meaningful limitation (i.e., the Raman spectral data is not an additional element). Fourth, the purported improvement in reducing errors in measuring a seed culture by limiting Raman spectral data to particular wavelengths is a purported improvement to an abstract idea, and not an improvement to the functioning of a computer itself or any other technology or technical field. Fifth, with regard the additional elements recited as components of the system, these additional elements do not apply, rely on or use the judicial exceptions in a meaningful way at Step 2A Prong Two, as discussed in the above rejection, and further do not amount to significantly more (i.e., do not provide an inventive concept) than the judicial exceptions at Step 2B, also as discussed in the above rejection.
The Applicant states on page 15 (para. 2) of the Remarks that the invention improves the seed train process when starting a large culture in a bioreactor of a cell line from an initial cryopreserved cell stock, and that complications in the field are outlined in the specification at pages 1 and 2, and that starting the final culture in the bioreactor requires the viable cell density (VCD), or other process variable, to be in a specific range depending on cell type to have increased concentration of final target protein and consistency between batches, and that the claimed subject matter aims to lessen the variability from batch to batch and increase throughput. The Applicant further states (para. 3) that the wavelength regions limited to a combination of four distinct ranges, as claimed in claim 6, are non-conventional and improve the existing technology, and any mathematical concepts/mental processes are merely utilized to create an improved laboratory technique. The Applicant further states that the specification provides examples of where the claimed system is improved compared to the traditional methods to determine when a cell culture is at the required VCD, or other process variables, to effectively inoculate a bioreactor. The Applicant further points to Figure 5 in the disclosure, and states that Figure 5 compares the measurements taken by the Raman spectrometer and offline Nova methods (process of taking samples from the cultures manually), and since the offline method requires samples to be taken manually, only four samples are taken in total, whereas the Raman measurements are much more frequent throughout the culture, resulting in a target VCD having been reached at 44 hours as determined by Raman measurements, whereas in contrast, the offline method showed a target reached at about 60 hours. The Applicant further states on page 16 (para. 1) that since the VCD is critical for the culture in the bioreactor to reach optimal output, in using the traditional method, the VCD would have been too high, which would produce lower cell growth because cells are exiting exponential growth, and therefore, based on the Raman measurements the bioreactor would be inoculated at an optimal VCD and produce greater cell growth. The Applicant further points to Figure 7 in the disclosure and states that it shows the Raman measurements retrieved by the presently claimed system displayed noticeably less sample-to-sample variability compared to the traditional offline method. The Applicant further states (para. 2) that as evidenced by the improved functions of the claimed system, and therefore the claimed method of using the system of claim 1, the system incorporates the use of a Raman spectrometer and multivariate models to predict process variables, such that the VCD, and other variables, can be accurately determined to ensure optimal concentration of viable cells for inoculation of a bioreactor. The Applicant further states that as shown by Figure 5, the manual process of measuring the growth of the seed culture and then determining the concentration to inoculate the bioreactor is significantly inaccurate and can lead to inconsistencies for each batch of cells grown, however, the present systems have improved the accuracy, based on the specific wavelength regions, for when the seed culture is at its optimal VCD, or other process variable, and ready to inoculate the bioreactor.
These arguments are not persuasive, because with regard to the Applicant’s argument that the wavelength regions being limited to a combination of four distinct ranges, as claimed in claim 6, are non-conventional and improve the existing technology, it is reiterated that the Raman spectral data based on the process variable measurements in the four wavelength regions comprise the judicial exception(s) themselves, and further reiterated that conventionality at Step 2B only takes into consideration the additional elements that have been carried over from Step 2A Prong Two. Furthermore, and as discussed in the foregoing responses to arguments, the purported improvement in measuring a seed culture by limiting Raman spectral data to particular wavelengths is a purported improvement to an abstract idea, and not an improvement to the functioning of a computer itself or any other technology or technical field.
The Applicant states on page 16 (para. 3) of the Remarks that even if a particular step of a claim could be performed in one’s head, the claims as a whole are directed to a method of using a system which can accurately determine VCD, or other process variable, of a seed culture and start a bioreactor at an optimal cell concentration of cells at an optimal part of the cell cycle. The Applicant further states (para. 4) that therefore, the presently claimed method provides improved function of the process of inoculating a bioreactor with an optimal VCD, or other process variable, and that the mental process and mathematical concept are integrated into a practical application when viewed as a whole, therefore the presently amended claim 1 and dependent claims are patent eligible.
These arguments are not persuasive, because as discussed in the foregoing responses to arguments, the claims do not recite any additional elements that apply, rely on or use the judicial exceptions in a meaningful way (also as discussed in the above rejection) when the claims are considered as a whole at Step 2A Prong Two, and when all additional elements are considered individually and in combination at Step 2B, the claims are deemed to not recite any additional elements that provide an inventive concept.
The Applicant states on page 17 (para. 2) of the Remarks that the presently claimed method, as a whole (including the system used by the method), amounts to significantly more than just the judicial exception, and further states that the present claims are not directed to a mental process and/or mathematical concepts, because the claimed methods are directed to using a system for controlling a seed train process including the limitations as in claim 1 with input from the user, specifically, selecting a predefined trigger value. The Applicant points to BASCOM Global Internet Servs. V. AT&T Mobility LLC (an inventive concept may be found in the non-conventional and non-generic arrangement of components that are individually well-known and convention) and further states (para. 3) that the combination of the computer system, the bioreactor and associated components comprise an inventive concept because of the non-conventional limitation of the wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1 for the Raman spectral data. The Applicant summarizes the references used at Step 2B (i.e., as evidence of the conventionality of additional elements that were carried over from Step 2A Prong Two) including the Ozturk reference (Remarks, page 17, para. 4) and stating that nothing in Ozturk suggests that the combination of the claimed methods of claim 6 where a user selects the predefined trigger values and uses the system for controlling a seed train process including the limitations as in claim 1 (Remarks, page 18, para. 1). The Applicant further states (para. 2) that the other references used to show evidence of conventionality at Step 2B (i.e., the references Tapia, Frensing, and Jenzsch) in addition to Ozturk do not disclose any specific wavelength regions for Raman spectral data or selecting a predefined trigger value. The Applicant further states (para. 3) that the claimed methods require a user to select a predefined trigger value including significantly more to the judicial exceptions, and the inventive concept may be found in the non-conventional elements, such as the combination of non-conventional wavelength ranges of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1 for the Raman spectral data. The Applicant further states that the present claimed systems show significant improvement in determining the VCD, or other process variable, for when to inoculate a bioreactor and increase cell growth and target protein production and reproducibility between batches, and therefore, the presently amended claims (para. 4) are directed to allowable subject matter, because 1) a user is required to select a predefined trigger value; 2) any mental processes and/or mathematical concepts are integrated into a practical application, because the use of the specific wavelengths for Raman spectral data greatly improve the technology, and 3) the specific wavelengths are an inventive concept of a system for controlling a seed train and including the limitations as in claim 1, which when claim 6 is viewed as a whole, include an inventive concept.
These arguments are not persuasive, because first, and as discussed in the foregoing responses to arguments, the Raman spectral data based on the process variable measurements in wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1 comprise the judicial exception(s) themselves, and therefore is not an additional element, and therefore is not evaluated at Step 2B (i.e., at Step 2B, the additional elements from 2A Prong Two are carried over and further evaluated to determine whether the additional elements contribute an “inventive concept”) and consequently, the references used to show evidence of conventionality are cited to show conventionality of the additional elements recited by the claimed process. Second, the limitation reciting “wherein a user selects the predefined trigger value” is at most an additional element of inputting data into a computer for use in the claimed process (i.e., a conventional computer-related function, as noted in the above rejection), however it is noted that the step of selecting a data value could also be interpreted to be a mental process, and potentially identified as a judicial exception at Step 2A Prong One. Third, when the claims are viewed as a whole at Step 2A Prong Two, the judicial exceptions identified at Step 2A Prong One are not integrated into a practical application because the additional elements do not sufficiently limit the use of the abstract ideas to a practical application of auto-inoculating a bioreactor due to the controlling step being contingent on the computer system determining that one or more process variable predictions from the multivariate model satisfies a predefined trigger value, which is a limitation that is not required by the claims, and therefore these additional elements do not integrate the recited judicial exceptions into a practical application (MPEP 2106.05(e)).
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3, and 6-20 under 35 U.S.C. 103 as being unpatentable over Murthy in view of Moretto et al. in the Office action mailed 20 August 2025 is maintained with modification in view of the amendment received 20 November 2025.
The rejection of claims 15 and 18 is withdrawn in view of these claims having been cancelled in the amendment received 20 November 2025.
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, 3, 6-14, 16, 17, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Murthy (WO 2018/005521, as cited in the Office action mailed 20 August 2025) in view of Moretto et al. (International Publication No.: WO 2016/196315, as cited in the Information Disclosure Statement (IDS) received 03 June 2022).
Independent claims 1 and 6 are broadly directed to a system and method of auto-inoculating a bioreactor by controlling a seed train process, wherein the system comprises an expansion chamber in fluid communication with a bioreactor; a pump for effecting transfer of a viable cell culture from the expansion chamber to the bioreactor; a Raman spectrometer having at least one probe for monitoring the cell expansion process and generating Raman spectral data; a multivariate model that provides one or more process variable predictions based on the Raman spectral data from process variable measurements; and a computer system in signal communication with the Raman spectrometer for receiving Raman spectral data; and the computer system in signal communication with a pump for controlling operation of the pump for effecting a transfer of a viable cell culture from the expansion chamber to the bioreactor; wherein the computer system is adapted, upon determining that one or more process variable predictions provided by the multivariate model has satisfied a predefined trigger value, to control the pump to execute an auto-transfer of a cell culture volume from the expansion chamber to the bioreactor, using Raman spectral data based on process variable measurements in wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1.
Dependent claims 3, 7-14, 16, 17, 19, and 20 further define the steps in the process, e.g., determining the multivariate model and the predefined trigger values.
Murthy shows cell culture chambers and methods of uses (Title) such as providing for an expansion and stimulation of T-cells (Abstract).
Moretto et al. shows cell culture methods and systems related to the field of process analytical technology with respect to biotherapeutic protein production processes and products (page 1); and methods and systems for controlling product yield and/or quality in a cell culture process and for improving cell culture performance, e.g., increasing the viable cell density (VCD; page 2, lines 1-5).
Regarding independent claims 1 and 6, Murthy shows cell culture chambers configured to fluidically connect to one another, such that cells can be automatically transferred between chambers to allow for further culturing and expansion of the cells in a new cell culture chamber (page 2, lines 27-30); a PLC logic controller for controlling the chambers in the system (page 3, lines 22-23); to assist with the flow of fluid through each chamber and between chambers, the cell culture chamber can comprise one or more pumps (page 4, lines 17-18); computational modeling for automated determination and monitoring of parameters within the cell culture chamber (page 21, lines 26-30); and process decision variables (page 24, lines 24-34).
Regarding independent claims 1 and 6, Murthy does not show a Raman spectrometer having at least one probe for monitoring the cell expansion process within the expansion chamber using Raman spectrometry, the Raman spectrometer being adapted to generate Raman spectral data (claim 1); a computer system in signal communication with the Raman spectrometer for receiving Raman spectral data, wherein the Raman spectrometer is adapted to generate the Raman spectral data, the computer system processes the Raman spectral data received from the Raman spectrometer to generate the multivariate model of the one or more process variables, and the computer system is adapted to compare the process variable measurements to one or more predefined process set points to determine if the one or more process variable measurements have satisfied a predefined trigger value, wherein the computer system is adapted, upon determining that the one or more process variable measurements in the Raman spectral data has satisfied a predefined trigger value, to control the pump to execute an auto-transfer of a cell culture volume from the expansion chamber to the bioreactor, and wherein the computer system is adapted, when comparing process variable predictions from the multivariate model to the one or more predefined process set points, to use the one or more process variable measurements based on Raman spectral data in the wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1 (claim 1); or generating the Raman spectral data, using the Raman spectrometer, to provide data to a multivariate model that predicts one or more process variables of the cell expansion in the expansion chamber (claim 6); or wherein a user selects the predefined trigger value (claim 6). Murthy further does not show the limitations of claims 3, 7-14, 16, 17, 19, and 20.
Regarding independent claims 1 and 6, Moretto et al. shows feedback control automation is achieved, at least in part, through the use of spectroscopic instrumentation, such as, for example, Raman spectroscopic instrumentation, which enables online process monitoring while minimizing physical interactions with the culture, and decreasing process risk from contaminations, and that by using Raman spectroscopy, a completely sealed system with an immersed optical probe is used that allows for the possibility of simultaneous monitoring of multiple cell culture components (page 6, lines 27-32 through page 7, lines 1-4); Raman spectral acquisition, automation, multivariate analysis, and software (page 66, lines 25-32 through page 67, lines 1-16); using Raman scans of cell culture components (e.g., a reading of lactate from a Raman measurement) and comparing the cell culture component to a threshold and/or a set-point level (page 8, lines 21-31); prediction models including a partial least squares model that relates predicted variables (e.g., culture parameters) and observable variables (e.g., Raman spectral data) (page 27, lines 26-32); a control scheme for maintaining parameters using set-point values and partial least squares (PLS) regression models for automated control of parameters such as lactate (page 6, lines 1-12) by increasing or decreasing transfer of glucose to the cell culture based on set-point values (page 8, lines 3-31); a continuously operating pump activated as part of a feedback loop for automatically adjusting parameters (page 35, lines 10-30); a computer with one or more input and output devices, and an example of an input device that can be used for a user interface include keyboards, and pointing devices, such as mice, touch pads, and digitizing tablets (page 42, lines 3-8); and that parameters may be manipulate via the computer interface (page 60, lines 11-15) with various user defined fields such as target concentration set-points (page 60, line 17, through page 61, line 31); prediction models (e.g., lactate or glucose prediction models) that are to be used in cell culture processes for real-time predictions are developed using a training data set based on one or more informative subsets or an entire Raman spectra across 500-1700 cm-1 (page 19, lines 24-29), and in other embodiments, the Raman signatures comprise at least 4 peaks in the 200 cm-1 to 3400 cm-1 wavenumber range, wherein individual ranges comprise 835-875 (page 25, line 11); 1262-1290 (page 24, line 23); and 2840-3020 (page 26, line 20).
Regarding dependent claims 3 and 17, Moretto et al. further shows an online probe, e.g., a Raman spectroscopy probe, used to monitor a fed-batch mammalian cell culture and predict lactate concentrations, e.g., via multivariate calibration using partial least squares (PLS) regression (page 5, lines 30-32 though page 6, lines 1-12).
Regarding dependent claims 7, 9, 13, and 14, Moretto et al. further shows that in some embodiments of the methods, the culture components are lactate and viable cell density (page 22, lines 20-25); methods of evaluating a culture component level in a culture medium further comprises evaluating an additional culture parameter, where an additional culture parameter is one or more of the following culture parameters: viable cell density (VCD), and level of lactate (page 33, lines 30-32 through page 34, line 1); a continuously operating pump activated as part of a feedback loop for automatically adjusting parameters (page 35, lines 10-30); and first and/or second thresholds are reached (page3, lines 29-32).
Regarding dependent claims 8, 10, and 12, Moretto et al. further shows using one or more set-points throughout the culture until a threshold level of a parameter is reached or exceeded or drops below the threshold (page 31, lines 2-32); and regulating parameters comprises maintaining the amount and/or frequency of the parameter supplied to the cell culture when steady state parameter levels are within ± 25% below the set-point (page 76, lines 1-5); monitoring when the level of lactate is above a threshold level (page 78, lines 10-15); first and second threshold levels (page 2, lines 25-32 through page 3, lines 1-10); and first and second set-point values (page 30, lines 24-33 through page 31, lines 1-19).
Regarding dependent claim 11, Moretto et al. further shows a culture component (e.g., lactate, or VCD) is measured using Raman, the raw data is collected by the Raman system and transmitted to a model application system, wherein the data treatments of the predictive partial least squares (PLS) model are applied to raw spectra and the peaks are analyzed giving a predicted culture component value (page 35, lines 29-32).
Regarding dependent claim 16, Moretto et al. further shows Raman spectral acquisition, automation, multivariate analysis, and software (page 66, lines 25-32 through page 67, lines 1-16); using Raman scans of cell culture components (e.g., a reading of lactate from a Raman measurement) and comparing the cell culture component to a threshold and/or a set-point level (page 8, lines 21-31); prediction models including a partial least squares model that relates predicted variables (e.g., culture parameters) and observable variables (e.g., Raman spectral data) (page 27, lines 26-32);
Regarding dependent claim 19, Moretto et al. further shows offline analytical methods used to measure cell culture components such as viable cell density (VCD), total cell density, and culture viability (page 52, lines 13-18).
Regarding dependent claim 20, Moretto et al. further shows partial least squares (PLS) modeling of cell culture data wherein a calibration dataset was created by correlating offline sampling with the Raman spectral data (page 56, line 5-11).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing data of the claimed invention to have modified Murthy by incorporating a methods for multivariate modeling of cell culture data generated from online Raman spectroscopy measurements as shown by Moretto et al., and discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Murthy and Moretto et al., because Moretto et al. shows using online Raman measurements with a multivariate model to automate a cell culture system. This modification would have had a reasonable expectation of success because both Murthy and Moretto et al. disclose automated control of cell culturing systems.
Response to Arguments
The Applicant’s arguments/remarks received 20 November 2025 have been fully considered, but are not persuasive.
The Applicant states on page 20 (middle) of the Remarks that the test for prima facie obviousness is consistent with the legal principles enunciated in KSR, and points the MPEP at 2143 and further states that for a reference to render a claim obvious, the reference must teach or suggest all of the claim limitations. The Applicant further states on page 21 (bottom) that claim 1 has been amended to recite, in part, “to use the Raman spectral data based on the process variable measurements in wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1.” The Applicant further states on page 22 (para. 2) that the Examiner has failed to establish a prima facie case of obviousness, since the references, alone or in combination, fail to teach or suggest each element of the claimed methods and fail to provide the necessary motivation and a reasonable expectation of success to one of ordinary skill in the art to achieve the claimed invention, and (para. 3) therefore, one skilled in the art at the time of filing would not have found the presently amended claims obvious in view of Murthy and/or Moretto, alone or in combination.
These arguments are not persuasive, because first, instant claims 1 and 6 recite “to use the Raman spectral data based on the process variable measurements in wavelength regions of 800-850 cm-1; 1260-1470 cm-1; 1650-1840 cm-1; and 2825-3080 cm-1” and Moretto et al. shows cell culture process spectral ranges that at least comprise wave numbers within the recited wavelength regions, as discussed in the rejection above, and furthermore, it is noted that in the record, the Information Disclosure Statement received 19 March 2025 shows the reference Abu-Absi et al. (2011) (“Real time monitoring of multiple parameters in mammalian cell culture bioreactors using an in-line Raman spectroscopy probe”) using Raman spectra between 250 and 1,800 cm-1, which at least suggests that one skilled in the art at the time of filing would not have found the claimed wavelength regions to be unknown or surprising. Second, one of ordinary skill in the art would have been motivated to combine the methods of Murthy and Moretto et al., because Moretto et al. shows using online Raman measurements with a multivariate model to automate a cell culture system, and furthermore, this modification would have had a reasonable expectation of success because both Murthy and Moretto et al. disclose automated control of cell culturing systems.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/S.W.B./Examiner, Art Unit 1687
/Joseph Woitach/Primary Examiner, Art Unit 1687