DETAILED ACTION
Applicant’s response, filed 21 Oct. 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 Claims
Claims 1-11 are pending.
Claims 1-11 are rejected.
Claim 11 is objected to.
Claim Objections
The objection to claims 2 and 8-9 in the Office action mailed 21 July 2025 has been withdrawn in view of claim amendments received 21 Oct. 2025.
Claim 11 is objected to because of the following informalities. This objection is newly recited and necessitated by claim amendment.
Claim 11 recites “The method according to claims 2…”, which is a grammatical error and should recite “according to claim[[s]] 2…”.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “monitoring, in real-time either (i) the modeled fit shows an offset… or (ii) the modeled fit has a chi2 value…of more than 5, determining that the cultivation is affected by a problem if the monitoring provides at least one positive result from (i) or (ii)”. MPEP 2111.04 states the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. In the instant case, the claim does not require that there is a positive result from (i) or (ii), and therefore, under the broadest reasonable interpretation of the claim, the claim does not require determining that the modeled fit shows the offset of more than 10% or the chi2 value of more than 5, or require the step of adjusting cultivation parameters in response to determining the cultivation is affected by a problem. However, the claim is interpreted to require monitoring a modeled fit of an offset with respect to raw data or a chi2 value.
Claim 2 recites “determining that a cultivation of step a) is affected by a problem when the fit obtained for the clone in step b) for the process data for the clone’s cultivation obtained in step a) in said metabolic model (i) shows an offset with respect to the raw data of more than 10%, or (ii) the Pearson’s chi2 value determined by a Pearson’s chi-squared test for the fit is 5 or more”. For the same reasons discussed above for claim 1, under the broadest reasonable interpretation of the claim, the step of determining that the cultivation is affected by a problem is not required because the claims do not require that the conditions (i) and/or (ii) are met. In embodiments in which it is determined there is no problem, claim 2 then requires “selecting the clone…”.
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 1 recites “…fitting the process data, comprising at least a first number of on-line process parameters and a second number of off-line parameters, acquired in a time-dependent manner”. The limitations relating to how the process data was previously obtained (i.e. on-line or off-line and in a time-dependent manner” are interpreted as a product by process limitation, and thus a step of measuring the process data on-line or off-line in a time-dependent manner is not required by the claims.
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 rejection of claim 11 under 35 U.S.C. 112(a) in the Office action mailed 21 July 2025 has been withdrawn in view of claim amendments received 21 Oct. 2025, which now require claim 11 depends from claim 2 only.
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 and 3-10 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; the basis of this rejection remains the same.
Claim 1, and claims dependent therefrom, recite “…adjusting cultivation parameters in response to determining that the cultivation is affected by the problem”, and previously recites “determining that the cultivation is affected by a problem if the monitoring provides at least one positive result form (i) or (ii)”.
Applicant remarks filed 18 Feb. 2025 at pg. 5, para. 1 states the amendments are fully supported by the original application as filed, now published, at Figures 3A and 3B and paragraphs [0150], [0175], [0181], [0191], [0211], and [0216]. However, after reviewing the specification, including the paragraphs and Figures cited by Applicant, Applicant’s specification does not provide support for adjusting cultivation parameters in response to the recited determinations. Para. [0211] describes how good and bad data points are determined based on error bars.
Figures 3A-3B and para. [0216] describe different cultivation and model scenario combinations, and discloses different chi-squared values for the different fermentation batches tested and used for model development. Para. [0150] discloses determining If process data is affected by a problem based on the recited determinations (i) and (ii), but does not discuss adjusting cultivation parameters in response. Para. [0175], [0181], [0191] discusses various compartments and phases of the metabolic model and describes how the metabolic model was built. None of these paragraphs disclose the recited feature of “adjusting cultivation parameters in response to determining…”. While the specification discusses identifying a problem with a cultivation based on the recited determinations, the specification does not disclose adjusting cultivation parameters as claimed.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the limitation of adjusting cultivation parameters recited in claims 1 and 3-11 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 21 Oct. 2025 regarding 35 U.S.C. 112(a) have been fully considered but they are not persuasive.
Applicant remarks that claims 1 and 3-11 have been amended in a manner that is believed to obviate the pending rejection (Applicant’s remarks at pg. 5, para. 4).
This argument is not persuasive. Applicant does not explain why Applicant believes the amendments obviate the rejection. While claim 1 was slightly re-worded, claim 1 still requires the limitation of “adjusting cultivation parameters in response to determining that the cultivation is affected by the problem”, and requires that the problem is detected if (i.e. the adjusting is in response to) (i) the modeled fit shows the offset or (ii) the modeled fit has a chi2 value of more than 5, which is what was previously discussed as lacking written description. Therefore, the rejection is maintained for the reasons previously discussed and reiterated above.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 2-11 under 35 U.S.C. 112(b) in the Office action mailed 21 July 2025 has been withdrawn in view of claim amendments received 21 Oct. 2025.
Claim Rejections - 35 USC § 101
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 1-11 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:
fitting the process data, comprising at least a first number of on-line process parameters and at least a second number of off-line parameters, acquired in a time-dependent manner during the cultivation of the mammalian or bacterial cell expressing a recombinant, heterologous polypeptide using a metabolic model generated for the same mammalian or bacterial cell expressing the same recombinant, heterologous 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 cell line used;
monitoring, in real-time, either: (i) the modeled fit shows an offset with respect to the raw data of more than 10% or (ii) the modeled fit has a chi2 value determined by a Pearson’s chi-squared test of more than 5;
determining that the cultivation is affected by a problem if the monitoring provides at least one positive result from (i) or (ii).
Claim 2 recites the following steps which fall under the mathematical concepts, mental processes, and/or certain methods of organizing human activity groupings of abstract ideas:
b) fitting the process data acquired in a time-dependent manner in step a) of the clone individually using a metabolic model that has been generated for the same mammalian or bacterial cell line, and evaluating the fit using a Pearson’s chi2 test, wherein the process data comprises at least a first number of on-line process parameters and at least a second number of off-line parameters…wherein the metabolic model is a constraint-based model that comprises specific metabolic phases within compartments tailored to particular cell line used, and wherein the metabolic phases within compartments are defined based at least in part on the particular cell line used;
c) determining that a cultivation of step a) is affected by a problem when the fit obtained for the clone in step b) for the process data for the clone’s cultivation obtained in step a) in said metabolic model (i) shows an offset with respect to the raw data of more than 10%, or (ii) the Pearson’s chi2 value determined by a Pearson's chi-squared test for the fit is 5 or more; and
repeating steps a) to c) with the clones that had a problem in the cultivation as determined in step c) or if no clone had a problem in the cultivation as determined in step c) selecting the clone from the multitude of clones expressing a heterologous polypeptide that has (i) the highest titer, (ii) the highest level of product quality attribute(s), and/or (iii) a metabolic phenotype meeting predetermined criteria or highest rank in metabolic performance indicators.
The identified claim limitations falls into one of the groups of abstract ideas of mental processes for the following reasons. In this case, 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 and the recited 10% threshold or between a chi2 value and the threshold of 5. Claim 2 further requires repeating the fitting and determining steps if clones are identified to have a problem, which can be performed mentally as already discussed above. Last, the step of selecting the clone that has one of the recited characteristics simply requires comparing characteristics of each of the clones to make a selection, which is equivalent to human mental work. 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 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 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.
Dependent claims 4-11 further recite an abstract idea and/or further limit the abstract idea of claims 1-2 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 claims 1 and 2 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 1-11 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 3-11 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception. It is noted that dependent claims 3-11 are interpreted to depend from claim 1, and thus are not required to further limit the additional element of cultivating cell clones to record temporal process data in claim 2.
The additional element of claim 1 includes:
adjusting cultivation parameters in response to determining that the cultivation is affected by the problem.
The additional elements of claim 2 includes:
separately cultivating a multitude of mammalian or bacterial cell clones that produce the same heterologous peptide, whereby during the cultivating, temporal process data is recorded for clone; and
repeating step a)…with the clones that had a problem in the cultivation as determined in step c).
The additional element of cultivating cell clones only serves to collect data for use by the abstract idea of fitting the process data, determining if the cultivation is affected by a problem, and then selecting a clone from the multitude of clones. Similarly, the step of repeating the cultivating if clones had a problem only serves to collect additional data for use by the abstract idea of ultimately selecting a clone from the multitude of clones. Therefore, these limitations amount to insignificant extra-solution activity. See MPEP 2106.05(g).
In addition, regarding the additional elements of adjusting cultivation parameters and repeating the cultivating, these additional elements do not integrate the recited judicial exception into a practical application because they are not required under the broadest reasonable interpretation of the claims, as discussed in claim interpretation.
Further regarding the step of “adjusting cultivation parameters…”, even if this step was required by the claims, the step would amount to mere instructions to apply the exception because the claim merely recites the idea of a solution or outcome without reciting details as to how the solution to the problem is accomplished. Specifically, the claims broadly require adjusting cultivation parameters with no details regarding how the cultivation parameters are adjusted based on the recited determining steps. See MPEP 2106.05(f).
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 1-11 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 3-11 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception. It is noted that dependent claims 3-11 are interpreted to depend from claim 1, and thus are not required to further limit the additional element of cultivating cell clones to record temporal process data in claim 2.
The additional element of claim 1 includes:
adjusting cultivation parameters in response to determining that the cultivation is affected by the problem.
The additional elements of claim 2 includes:
separately cultivating a multitude of mammalian or bacterial cell clones that produce the same heterologous peptide, whereby during the cultivating, temporal process data is recorded for a clone; and
repeating step a)…with the clones that had a problem in the cultivation as determined in step d).
Cultivating separate mammalian cells that produce the same heterologous peptide is well-understood, routine, and conventional. 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).
With respect to the steps of adjusting cultivation parameters and d) repeating the cultivation in step a), this additional element is not required under the broadest reasonable interpretation of the claim, and thus cannot provide significantly more.
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 21 July 2025 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Step 2A, Prong 1:
Applicant remarks claim 1 does not recite a judicial exception because claim 1 does not recite a mathematical relationship and does not recite methods of organizing human activity (Applicant’s remarks at pg. 7, para. 1-2).
This argument is not persuasive. First, it was not alleged the claims recite a method of organizing human activity. Regarding mathematical concepts, Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out why claim 1 does not recite a mathematical concept. Claim 1 recites a mathematical concept for the reasons set forth above.
Applicant remarks the claims do not recite a judicial exception because the claimed subject matter is not a concept that can be performed in the human mind, and involves “fitting the process data…” and “adjusting cultivation parameters…”, which require the use of a “constraint-based model”, which cannot be feasibly performed in the human mind (Applicant’s remarks at pg. 7, para. 3 to pg. 8, para. 2).
This argument is not persuasive. First, Applicant has not provided any explanation why fitting data using a “constraint-based model” cannot be performed in the human mind. As discussed in Applicant’s specification at pg. 6, liens 8-10, a constraint-based metabolic model simply uses maximum and minimum allowed flux values for each reaction in the model. As discussed in the above rejection, 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, while simply setting constraints on certain values of the model. Furthermore, the step of adjusting a cultivation parameter is not considered a mental process, as discussed in the above rejection, and instead was considered an additional element of the claim.
Last, it is further noted that even of the fitting of data using a constraint-based model did not recite a mental process, the limitation still recites a mathematical concept, and thus would recite a judicial exception regardless.
Step 2A, Prong 2:
Applicant remarks that claim 1 is not directed to an abstract idea, but a specific practical application of a technology because the claim involves “fitting process data, comprising at least a first number of on-line process parameters…acquiring in a time-dependent manner during the cultivation…”, which specifies the use of a “constraint-based metabolic model comprising metabolic phases”, which is a concrete technological tool and not an abstract idea (Applicant’s remarks at pg. 9, para. 2-3).
This argument is not persuasive. Under Step 2A, Prong 2, whether the additional elements integrate a judicial exception into a practical application is evaluated. See MPEP 2106.04(d). Fitting process data with a metabolic model is part of the abstract idea as explained in the above rejection, and therefore cannot provide integration. While Applicant states a “metabolic model” is a concrete technological tool, Applicant’s specification discloses mathematical techniques as the only supported embodiments in performing the model fitting 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 in addition to a mental process and is part of the abstract idea.
Applicant remarks the use of “a constraint-based metabolic model” in combination with quantitative thresholds provides actionable insights into the cultivation process which comprise “adjusting the cultivation parameters”, and therefore, the claimed subject matter provides the consistency and quality of recombinant polypeptide production, which is a practical application that improves the functionality of the cultivation process (Applicant’s remarks at pg. 8, para. 4).
This argument is not persuasive. First, the step of “adjusting the cultivation parameters” cannot provide integration because they are not required under the broadest reasonable interpretation of the claims, as discussed in claim interpretation. Furthermore, even if this step was required by the claims, the step would amount to mere instructions to apply the exception because the claim merely recites the idea of a solution or outcome without reciting details as to how the solution to the problem is accomplished. Specifically, the claims broadly require adjusting cultivation parameters with no details regarding how the cultivation parameters are adjusted based on the recited determining steps. See MPEP 2106.05(f). For this reason, it is also not apparent that the adjustment of cultivation parameters improves the functionality of the cultivation process, as the claims encompass adjusting parameters in any way, which may result in a worse cultivation.
Applicant remarks the instant claims are analogous to claim 3 of example 47, which recites a method for detecting malicious network packets because claim 3 involves the practical application of detecting network packets by training an ANN and taking real-time actions of dropping malicious packets and blocking traffic, and similarly the instant claims also integrate data analysis with concrete actions using a metabolic model to analyze cultivation data and adjust parameters to improve the consistency and quality of peptide production (Applicant’s remarks at pg. 8, para. 5 to pg. 11, para. 2).
This argument is not persuasive for the same reasons already discussed above regarding the step of adjusting cultivation parameters.
Step 2B:
Applicant remarks that even if the claims involve an abstract idea, they incorporate significantly more because the method involves “fitting processing data…” and “adjusting cultivation parameters…”, and these operations use a constraint-based model tailored to a specific cultivation system which goes beyond the abstract idea and provides a concrete application and furthermore, the claimed method improves the operation of cultivation processes by enabling precise identifications of problems during cultivation, leading to actionable insights that enhance quality in polypeptide production, which is a practical improvement over conventional methods, addressing real-world challenges in biological manufacturing systems (Applicant’s remarks at pg. 11, para. 3 to pg. 12, para. 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.
The claims do not integrate the recited judicial exception into a practical application for the same reasons already discussed above under the response to the Step 2A, Prong 2 arguments. Furthermore, the additional elements recited in the claim are well-understood, routine, and conventional for the reasons set forth in the above rejection, and Applicant has not pointed out any supposed errors with the analysis of the conventional of the additional elements under Step 2B above. Whether the abstract idea in combination with the additional elements is conventional is not considered under Step 2B.
Applicant remarks that claim 2 has been amended to include similar elements as claim 1 and therefore is eligible under 35 U.S.C. 101 , and furthermore, claim 3 incorporates all the elements of claims 1 and 2 and further includes additional elements making it patent-eligible (Applicant’s remarks at pg. 12, para. 3).
This argument is not persuasive for the same reasons discussed above for claim 1. Further regarding claim 2, claim 2 does not recite any limitations relating to “adjusting cultivation parameters”, as recited in claim 1 and argued by Applicant; therefore any arguments relating to the adjusting of cultivation parameters are not applicable to claim 2. Regarding claim 3, the limitation of claim 3 is part of the abstract idea as explained in the above rejection, and is not an “additional element” that may provide a practical application or significantly more.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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). Any newly recited portion is 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; and
Famili et al., US 2016/0364520 A1; previously 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 computing Pearsons and Spearman correlations (i.e. fitting) of process data using a CHO metabolic network model (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 recombinant, heterologous polypeptide) (pg. 2006, col. 1, para. 4 to col. 2, para. 1; pg. 2006, col. 2, para. 5). Popp further discloses the CHO metabolic model 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,
Popp discloses computing a Spearman and Pearson correlation of metabolic data, process data (i.e. raw data), and intracellular flux distributions (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).
Regarding the steps of determining that the cultivation is affected by a problem if the monitoring provides at least one positive result from (i) or (ii), and adjusting process parameters in response to determining that the cultivation is affected by a problem, as discussed above in claim interpretation, because the claims do not require there is a positive result for either (i) the modeled fit shows an offset with respect to raw data of more than 10% or (ii) the modeled fit has a chi2 value determined by a Pearson’s chi-squared test of more than 5, under the broadest reasonable interpretation of the claims, the steps of determining that the cultivation is affected by a problem and adjusting cultivation parameters are not required.
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) computing Pearsons and Spearman correlations of the process data using a CHO metabolic network model (i.e. fitting and evaluating the fit using a chi2 test) (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 c), as discussed above in claim interpretation, the step of determining that a cultivation of step a) is affected by a problem is not required under the broadest reasonable interpretation of the claims because the claims do not require the fit (i) shows an offset with respect to raw data of more than 10% or (ii) the chi2 value determined by a Pearson’s chi-squared test for the fit is 5 or more.
Regarding d), given the embodiment in which no problem in the cultivation is determined in step c)-d), the claims do not require repeating steps a)-d).
Further regarding d), Popp discloses selecting a clone from the clones expressing the polypeptide based on having the highest score of 40 different indicators of metabolic performance (i.e. having the highest rank in metabolic performance indicators) (pg. 2009, col. 1, para. 2 to col. 2, para. 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 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 a first number of on-line parameters in addition to the off-line parameters 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 claim 1, Popp does not explicitly disclose monitoring, in real-time, whether the modeled fit shows an offset with respect to raw data of more than 10%.
However, 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 discloses that major differences between the simulated values and experimental values result from differences in essential amino acid requirements for cell growth and product formation due to experimental error or low sensitivity of analytical measurements for measuring metabolite concentrations ([0216]; [0225]). Famili 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).
Furthermore, 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 for monitoring and controlling product quality during cultivation (pg. 2018, col. 1, para. 2).
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 whether a modeled fit shows an offset with respect to raw data of more than 10%, as shown by Famili above, and to have further 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 error such as incorrect essential amino acid requirements, 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.
Regarding claim 3, claim 3 further limits the chi2 test in the condition of (ii) in the contingent step of adjusting cultivation parameters in claim 2. As discussed above, the step of adjusting cultivation parameters is not required under the broadest reasonable interpretation of the claim. Therefore, claim 3 is rejected for the same reasons discussed above for claim 2. Furthermore, it is noted that only monitoring (i) or (ii) is required in claim 1, and Popp in view of Famili disclose monitoring (i), such that monitoring (ii) is not required.
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 heterologous 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, the claim further limits the step of determining that a cultivation is affected by a problem in claim 2 to be a technical problem. As discussed above, the step of determining there is a problem with the cultivation is not required under the broadest reasonable interpretation of the claim. Therefore, claim 11 is rejected for the same reasons discussed above for claim 2.
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), as applied to claim 1 or 2 above, further in view of Charaniya (2010). This rejection is previously recited.
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 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 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, as applied to claims 1 and 2 above, do not disclose the following:
Regarding claim 7, Popp in view of Famili, 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, 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 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 21 Oct. 2025 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks that claim 1 is not obvious over Popp (2016) in view of Famili because Popp discloses a “genome-based CHO network model comprising five compartments”, but does not disclose or suggest 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 cell line used”, and further remarks that Famili does not cure the deficiency of Popp (Applicant’s remarks at pg. 12, para. 5 to pg. 13, para. 1). Applicant remarks that claim 2 has been amended to recite similar language to claim 1, and thus the rejection of claims 1 and 2 should be withdrawn (Applicant’s remarks at pg. 13, para. 2-3).
This argument is not persuasive. As discussed in the above rejection, Popp discloses dividing the model including compartments into physiologically distinct phases (pg. 2006, col. 2, para. 2; pg. 2008, col. 2, para. 3, e.g. flux distributions calculated using network model for each phase; Suppl. Table 3-4 and 9). Popp separately models the different phases in the compartment model (see Suppl. Tables S3-S4 and S9, for calculations specific to phases). 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 and fitted compartments are tailored to the particular cell-line) (pg. 2006, col. 2, para. 2, e.g. modeling 654 reactions to estimate production rate; Table 1; Figure 8). Popp explicitly discloses the biomass compositions of the model were chosen comparable to previous studies for CHO cells and furthermore, the model was fitted based on process data from CHO cells, and that the whole process of the model was mass balanced (e.g. based on the biomass specific to CHO cells) (pg. 2006, col. 1, para. 4 to col. 2, para. 2-4; pg. 2008, col. 2, para. 3). The claims do not require any details regarding how the phases are defined based on the cell line use that distinguish the metabolic model from the model in Popp. It is also noted that, Applicant’s specification at para. [0086] and [0103] similarly discloses fermentation data is divided into physiologically distinct process phases and employing metabolic phases in the metabolic model. The phases described in Applicant’s specification at para. [0103] are also the same phases as those described in Popp (see Suppl. Table S3). Therefore, the disclosure of Popp is considered to read on “phases within compartments” as claimed.
Applicant remarks claims 3-11 depend from and include all the elements of claims 1 and 2, and therefore, the rejection of the claims should be withdrawn (Applicant remarks at pg. 13, para. 3).
This argument is not persuasive for the same reasons discussed above for claims 1 and 2.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAITLYN L MINCHELLA whose telephone number is (571)272-6485. The examiner can normally be reached 7:00 - 4:00 M-Th.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached at (571) 272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
Prosecution Insights