DETAILED ACTION
Notice of 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 .
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 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.
Withdrawal of Objections and Rejections
Applicant's response, filed 06/10/2026, has been fully considered.
In view of the amendment and remarks from 06/10/2026, the rejection of the following claims are withdrawn:
claim 9 under 35 USC § 101;
claim 9 under 35 U.S.C. § 103.
The following rejections and/or objections are either maintained or newly applied for claims 1-8 and 10-23. They constitute the complete set applied to the instant application. Herein, "the previous Office action" refers to the Final Rejection of 12/29/2025.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/10/2026 has been entered.
Status of the Claims
Claim 9 is canceled.
Claims 1-8 and 10-23 are pending.
Claims 1, 3-4, and 7 are objected to.
Claims 1-8 and 10-23 are rejected.
Priority
This application is a 371 of PCT/EP2019/061878 (05/08/2019), which claims no further priority herein as reflected in the filing receipt mailed on Apr. 01, 2022. The claims to the benefit of priority are acknowledged and the effective filing date of claims 1-8 and 10-23 is 05/08/2019.
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 1-8 and 10-23 are rejected under 35 USC § 101 because the claimed inventions are directed to one or more Judicial Exceptions (JEs) without significantly more. Regarding JEs, "Claims directed to nothing more than abstract ideas..., natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 §I). Abstract ideas include mathematical concepts and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). Any newly recited portions are necessitated by claim amendment.
101 background
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Analysis of instant claims
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The instant claims are directed to a method (claims 1-8), a system (claims 10-11, 14-15 and 20-23), and a CRM (claims 12-13 and 16-19); each of which falls within one of the categories of statutory subject matter. [Step 1: claims 1-8 and 10-23: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Background
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Analysis of instant claims
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mathematical concepts (in particular mathematical relationships and formulas) and mental processes (in particular procedures for observing, analyzing and organizing information) are as follows.
Mathematical concepts (in particular mathematical relationships and formulas) include:
• "reducing the number of and overlaying the elementary flux modes by a trainable matrix H to obtain a reduced matrix
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red of base flux modes" (independent claim 1, 12 and 14);
• "solving the resulting mass balances of substrates, products and biomass" (independent claim 1, 12 and 14);
• "training the H matrix and the neural network by the dynamic cultivation data" (independent claim 1, 12 and 14);
• "generating an optimized process specification for operation of the reactor system, the optimized process specification including at least one of feeding strategy, medium composition, osmolality, medium pH, pO2, or temperature" (independent claim 1, 12 and 14);
• "an intermediate state model, describing the changes in the cultivation volume and the state vector as a continuous function of time for a certain time step while ensuring correct mass balance; the neural network, computing the update of the base flux modes f(t) by training the neural network weights W along with their corresponding biases b, where the neurons of the next layer are activated by a sigmoidal activation function α:
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L denotes the index of the last hidden layer; a flux-based rate estimation obtaining the extracellular rates by:
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and an exponential growth model calculating the state vector for the next time step t + ∆t, wherein WL is a matrix of neural network weights between layer L and L+1 X(t) is an intermediate state vector between time point t and t+∆t, bL is the basis of a Lth layer of the neural network, µ(t) is the growth rate at time point T, and r(t) is extracellular rates" (claims 3, 16 and 20); and
• "transforming all metabolic fluxes to separate off reversible reactions to obtain all irreversible reactions; minimizing an objective function and deactivation of inactivate transformers are recurrently applied to obtain elementary flux modes, the objective function being: min(Numrxns,vnonzero) where Numrxns,vnonzero is the number of reactions with non- zero fluxes; and - collecting all elementary flux modes identified and stacking them into a mode matrix M" (claims 6, 19 and 23).
The claims identified above read on math. The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation and determined each element performed by mathematical operation. The step directed to “executing algorithmic operations for the construction of a Digital Twin for a cell cultivation process” requires mathematical techniques as the only supported embodiments because it describes the mathematical technique of adding numbers together in words (MPEP 2106.04(a)(2) pertains). Further support for the mathematical techniques used in the claims is provided in the specification at pg. 17 para. 1, which discloses optimization problem solved using an optimization algorithm i.e. stochastic gradient descent and raining steps performed until the objective function converges to a value that does not significantly change anymore over a certain number of iterations. Thus, the recited terms correspond to verbal equivalents of mathematical concepts because they constitute actions executed by a group of mathematical steps in a form of a mathematical algorithm; thus mathematical concepts (MPEP 2106.04(a)(2)). A mathematical concept need not be expressed in mathematical symbols, because "words used in a claim operating on data to solve a problem can serve the same purpose as a formula." In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989). MPEP 2106.04(a)(2) pertains.
Mental processes, defined as concepts or steps practically performed in the human mind such as steps of observations, evaluations, judgments, analysis, opinions or organizing information include:
• "providing a mode matrix M of elementary flux modes, extracted from metabolic fluxes of a real biological cell" (independent claims 1, 12 and 14);
• "assigning a neural network for describing the kinetics of the individual base flux modes
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red" (independent claims 1, 12 and 14);
• "connecting the base flux modes to extracellular reactions of the cell cultivation process" (independent claims 1, 12 and 14);
• "connecting the base flux modes to inflows and outflows to and from the reactor system of the cell cultivation process" (independent claims 1, 12 and 14);
• "evaluating the trained RNN by calculating Loss on the basis of a second subset of the cultivation data (evaluation set), the second subset being different from the first subset" (claims 5, 18 and 22);
• "adapting or generating the optimized process specification from the acquired cultivation data by applying a Digital Twin obtainable according to claim 1" (claims 7-8); and
• " adapt or generate process specifications of the reactor system from the acquired cultivation data" (claim 10).
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind (i.e. concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) or because the method only requires a user to manually determine action based on an added number. Under the BRI, the recited limitations are mental processes because a human mind is also sufficiently capable of organizing how the base flux modes are connected; deciding to use a particular neural network; writing down a matrix of numbers based on data from a cell; applying that matrix/ neural network to decide on a process based on cultivation data and evaluating data to generate a process.
Dependent claims 2, 4, 13, 15, 17 and 21 recite further steps that limit the judicial exceptions in independent claims 1, 12 and 14 and, as such, also are directed to those abstract ideas. For example, claims 2, 13 and 15 recite further details about the reduced stoichiometric matrix and claims 4, 17 and 21 recite further details about the training the model step.
[Step 2A Prong One: claims 1-8 and 10-23: Yes ]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Background
MPEP 2106.04(d).I lists the following example considerations for evaluating whether a judicial exception is integrated into a practical application:
An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
Analysis of instant claims
Instant claims 1, 11-14, 16, and 23-26 recite additional elements that are not abstract ideas:
• "providing dynamic cultivation data from a real cell cultivation process" (independent claims 1, 12 and 14);
• "controlling operation of the reactor system by applying the optimized process specification, wherein the optimized process specification adjusts at least one physical actuator of the reactor system to improve at least one of: a product titer, a productivity, a biomass concentration, or a product quality" (independent claims 1, 12 and 14);
• "acquiring cultivation data of the cell cultivation process" (claim 7);
• "acquiring/acquire cultivation data of the cell cultivation process" (claims 8 and 10);
• "cultivating the biological cells in the reactor system" (claim 8);
• "computing device including a processor, and a memory" (claim 10);
• "device and reactor" (claim 11); and
• "non-transitory computer-readable storage medium" (claims 12-13 and 16-19).
Considerations under Step 2A, Prong Two
The recited limitations in claims 1-8 and 10-23 are interpreted as requiring the use of a computer. Hence, the claims explicitly recite steps executed by computers and therefore can be described as computer functions or instructions to implement on a generic computer.
Further steps directed to additional non-abstract elements of a computing device/computer do not describe any specific computational steps by which the "computer parts" perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions.
The judicial exceptions in the claims are considered to perform the claimed abstract idea with a computer, which is not sufficient to integrate an abstract idea into a practical application (see MPEP 2106.05(f)); since steps that can be performed mentally and merely performing the mental process in a computer environment do not negate the fact that something that can be carried out in the human mind. See MPEP 2106.04(a)(2).III.C.
Claims directed to: "acquiring cultivation data of the cell cultivation process" (claim 7); "cultivating the biological cells in the reactor system" (claim 8); "acquire/acquiring cultivation data from the cell culture in the reactor system" (claims 8 and 10); "providing dynamic cultivation data from a real cell cultivation process" (claims 1, 12 and 14) and "device and reactor" (claim 11) read on data gathering activity; reciting steps performed to gather information that is used as input for the subsequent mathematical calculations, reading on receiving or transmitting data over a network, e.g., using the Internet to gather data, MPEP-cited case law Symantec, 838 F.3d at 1321. MPEP 2106.05(a) pertains
Regarding "controlling operation of the reactor system by applying the optimized process specification, wherein the optimized process specification adjusts at least one physical actuator of the reactor system to improve at least one of: a product titer, a productivity, a biomass concentration, or a product quality" (independent claims 1, 12 and 14); and "cultivating the biological cells in the reactor system" (claim 8); there are no additional limitations to indicate details of exactly how the judicial exception is being integrated by the recited additional elements. It is still not apparent what details about the optimized specification is being applied into a practical application and how that specification correlates to the judicial exceptions – hence, the described recitations read on just an apply it step. Additionally, there are no additional limitations to indicate that the claimed computer, processor, or computer readable medium require anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. MPEP 2106.05(b).
Hence, these are mere instructions to apply the abstract idea using a computer and insignificant extra-solution activity and therefore the claims do not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; 2106.05(f); and 2106.05(g)).
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs).
In this Step 2A, Prong Two immediately above claim steps and/or elements were identified as part of one or more additional elements. Additional elements are further discussed in Step 2B below.
Here in Step 2A, Prong Two, no additional step or element clearly demonstrates integration of the JE(s) into a practical application.
[Step 2A Prong Two: claims 1-8 and 10-23: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during examination that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
Claims 1-8 and 10-23 recite a computer or computer functions, interpreted as instructions to apply the abstract idea using a computer, where the computer does not impose meaningful limitations on the judicial exceptions; which can be performed without the use of a computer (MPEP 2106.04(d) § I; and MPEP 2106.05(f)).
As discussed above regarding acquiring data cannot integrate a judicial exception as mere data gathering activity; reading on performing a standard computer task, which the courts have identified as a conventional computer function in Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362; OIP Techs., Inc., v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015); and buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014). MPEP 2106.05(d) pertains.
With respect to the instant claims, the prior art review to Cuperlovic-Culf "Machine Learning Methods for Analysis of Metabolic Data and Metabolic Pathway Modeling" Metabolites 8:4 (2018) and Hemmerich "Microbioreactor Systems for Accelerated Bioprocess Development" Biotechnol. J. 13:1700141 (2018), cited on the 07/14/2025 PTO-892 Form) disclose that use of automated bioreactor systems to cultivate cells in a reactor while applying processes to the reactor ( pg. 2 Table 1 Cuperlovic-Culf) while using artificial neural network algorithms to improve metabolic data and metabolic pathway modeling (pg. 3 Table 1 Hemmerich) is routine, well-understood and conventional in the art.
When the claims are considered as a whole, they do not integrate the abstract idea into a practical application; they do not confine the use of the abstract idea to a particular technology; they do not solve a problem rooted in or arising from the use of a particular technology; they do not improve a technology by allowing the technology to perform a function that it previously was not capable of performing; and they do not provide any limitations beyond generally linking the use of the abstract idea to a broad technological environment. See MPEP 2106.05(a) and 2106.05(h).
The instant claims constitute insignificant extra solution activity, and when considered individually, are insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (see MPEP 2106.05(g)). Hence, these elements, when considered individually, are insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (see MPEP 2106.05(d)).
[Step 2B: claims 1-8 and 10-23: No]
Conclusion: Instant claims are directed to non-statutory subject matter
For the reasons above, the claims in this instant application, when the limitations are considered individually and as a whole, are directed to an abstract idea and lack an inventive concept not clearly anything significantly more.
Response to applicant's remarks in regard to Claim Rejection 35 U.S.C. ~ 101
The Remarks of 06/10/2026 have been fully considered but are not persuasive for the reasons below:
Applicant asserts starting in pg. 17 para. 2:
Without conceding the propriety of the rejections, independent claims 1, 12, and 14 are amended substantially in the manner discussed during the Interview and are believed to overcome the rejections under 35 U.S.C. § 101. Accordingly, Applicant respectfully submits that independent claims 1, 12, and 14 are patentable
It is respectfully submitted that this is not persuasive because, regarding the argued practical application at Step 2A, Prong 2, the amended claims do not provide a clear practical application related to applying the optimized specifications in real life. The analysis at Step 2A, Prong 2, considers the claims as a whole, i.e., the additional elements in combination with the judicial exceptions (see MPEP 2106.05(a)), although the integration or improvement provided in the claim must flow from the additional elements and not the judicial exceptions to be considered persuasive. In this case, the identified additional element reciting "controlling operation of the reactor system by applying the optimized process specification, wherein the optimized process specification adjusts at least one physical actuator of the reactor system to improve at least one of: a product titer, a productivity, a biomass concentration, or a product quality" (independent claims 1, 12 and 14); and "cultivating the biological cells in the reactor system" (claim 8); do not recite clear additional limitations to indicate details of exactly how the judicial exception is being integrated by the recited additional elements. It is still unclear what details about the optimized specification is being applied into a practical application and how that specification correlates to the judicial exceptions – hence, the described recitations read on just an apply it step. The remarks also do not make it clear why the claim must deliver these asserted real life application (i.e. as discussed in the noted interview) for all embodiments within the scope of the claim.
No prior art has been applied to the following claims
Claims 1-8 and 10-23 are free of the analogous art at least because close art, e.g. Gulik, Chan and Cuperlovic-Culf, as cited in the now withdrawn art rejections as well as art found on the IDSs and in the search histories, either individually or in obvious combination, does not teach the recited combination of “reducing the number of and overlaying the elementary flux modes by a trainable matrix H to obtain a reduced matrix
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red of base flux modes” and “assigning a neural network for describing the kinetics of the individual base flux modes.”
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCINI A FONSECA LOPEZ whose telephone number is (571)270-0899. The examiner can normally be reached Monday - Friday 8AM - 5PM ET.
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/F.F.L./Examiner, Art Unit 1685
/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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