DETAILED ACTION
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 .
Election/Restrictions
Applicant's election with traverse of (1) “metabolite synthesis process” from the species of biological synthesis processes, (2) the “biologic product concentration variant”, “biologic product addition variant”, and “biologic product elimination variant” for the species of sets of variants, (3) the “metabolite production rate bottleneck”, “protein expression level bottleneck”, and “product expression bottleneck” from the species of sets of growth rate bottlenecks, and (4) “evaluating variants according to a ranking order” of the species of evaluating the set of variants in the reply filed on 09 Jan. 2026 is acknowledged. The traversal is on the ground(s) that the species within each group are not independent or distinct, as they share a common inventive concept and require substantially overlapping search and examination such that examination together would not present undue burden, and there are not apparent differences between the species with respect to non-prior art issues. This is not found persuasive for the following reasons:
Independent claim 1 is directed to a method of optimizing a biologic synthesis process using a bottleneck for the synthesis process and variants of the synthesis process. The various species of biological synthesis processes encompass diverse biological processes that have unique bottlenecks and variants specific to a given synthesis process. For example, it is not persuasive that searching for a process of optimizing a fermentation process and bottlenecks specific to the fermentation process, such as oxygen transfer, would relate to or inform a process of optimizing DNA synthesis. Similarly, a variant of a synthesis process such as a biological product activity (claim 3) may relate to a plate growth process, but does not have a relationship to a DNA synthesis process. Each combination of a given synthesis process, set of variants, and bottleneck would clearly require separate text searches and separate classification searches. As explained in the election requirement mailed 20 Nov. 2025, the multiplicity of combinations of synthesis processes, variants, and bottlenecks encompassed by the claims covers nearly all of molecular biological and would impose undue burden upon the Examiner if not restricted.
The requirement is still deemed proper and is therefore made FINAL.
Claims 6-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 09 Jan. 2026.
Claims 1-5 and 11-20 are being initially examined with respect to the election of (1) “metabolite synthesis process” from the species of biological synthesis processes, (2) the “biologic product concentration variant”, “biologic product addition variant”, and “biologic product elimination variant” for the species of sets of variants, (3) the “metabolite production rate bottleneck”, “protein expression level bottleneck”, and “product expression bottleneck” for the species of bottlenecks. If the elected species or group of patentably indistinct species is not anticipated by or obvious over the prior art, the search and examination will be extended to a non-elected species or group of species that falls within the scope of a proper Markush grouping that includes the elected species. See MPEP 803.02 C.
Status of Claims
Claims 1-20 are pending.
Claims 6-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species there being no allowable generic or linking claim.
Claims 1-5 and 11-20 are rejected.
Claim 17 is objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application, PCT/US2025/031891 filed 02 June 2025, U.S. Provisional App. No. 63/655,575 filed 03 June 2024, and U.S. Provisional App. No. 63/803,471 filed 09 May 2025. under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Accordingly, the effective filing date of the claimed invention is 03 June 2024.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 13 Oct. 2025 and 27 Oct. 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Drawings
The replacement drawings filed 29 Sept. 2025 have been entered.
The drawings filed 29 Sept. 2025 are objected to because:
FIG. 39(Cont.), FIG. 41(Cont.), FIG. 43(Cont.), FIG. 46(Cont.), and FIG. 48(Cont.) fail to comply with 37 CFR 1.84(u)(1), which states partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. For example, FIG. 39 and FIG. 39(Cont.) should be relabeled FIG. 39A and FIG. 39B, accompanied by corresponding amendments to the specification referencing FIG. 39. Similar changes should be made for FIG. 41, 43, 46, and 48.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 17 is objected to because of the following informalities:
Claim 17 recites “includes a different variations of the feature” in the last two lines of the claim, which is grammatically incorrect and should recite “includes a different variation[[s]] of the feature”.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “evaluating a set of variants of the biological synthesis process”. Claim 14 recites “selecting, from the set of variants, a first set of candidate variants based on the ranking order”. Applicant’s specification at para. [2315] defines the term “set” to include a set with a single member, and further defines a “subset” to not require a proper subset such that a subset may be coextensive with a set. Therefore, a “set of variants” and similarly “a first set of candidate variants” are interpreted to encompass a set with a single variant. Furthermore, the first set of candidate variants selected from the set of variants encompasses selecting all variants from the set of variants.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 19 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 19 is indefinite for recitation of “The method of claim 18, wherein selecting the adjusted biologic synthesis process based on an evaluation of a set of variants of the biological synthesis process reduces at least one bottleneck of the biological synthesis process”. Examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are "wherein" clauses. See MPEP 2111.04. I. In the instant case, claims, 1, 14, and 18, from which claim 19 depend, do not recite a step of “selecting the adjusted biological synthesis process based on an evaluation of a set of variants…”. However, claim 1 does recite “selecting an adjusted biological synthesis process, wherein the adjusted biologic synthesis process includes at least one variant of the set of variants that reduces the at least one bottleneck of the biological synthesis process”. As a result, it is unclear if claim 19 intends to require that the selecting the adjusted biological synthesis process of claim 1 is based on an evaluation of the set of variants, or if claim 19 is referring to a different selecting step that is based on an evaluation of the set of variants. For purpose of examination, claim 19 is interpreted to mean that selecting the adjusted biological synthesis process is based on an evaluation of a set of variants of the biological synthesis process.
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 1-5 and 11-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
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 (claim 1 being representative) is directed to a method of optimizing a biological synthesis process. 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 mental processes grouping of abstract ideas:
identifying at least one bottleneck in the biological synthesis process;
evaluating a set of variants of the biological synthesis process; and
selecting an adjusted biological synthesis process, wherein the adjusted biological synthesis process includes at least one variant of the set of variants that reduces the at least one bottleneck of the biological synthesis process.
The identified claim limitations falls into the group of abstract ideas of mental processes for the following reasons. In this case, identifying a bottleneck of a biological synthesis process can be practically performed in the mind by analyzing a particular synthesis process, such as a metabolite synthesis process, and identifying a bottleneck of protein expression of the enzyme that creates the metabolite. Furthermore, evaluating a set of variants of the process encompasses merely analyzing synthesis process information, such as an amount of metabolite synthesized, for different variants of the synthesis process (e.g. processes having more product added). Last, selecting an adjusted process that reduces the bottleneck can be practically performed in the mind by identifying a best performing variant of the biological synthesis process. Therefore, these limitations recite a mental process. See MPEP 2106.04(a)(2) III.
Dependent claims 2-5 and 11-20 further recite an abstract idea and/or further limit the abstract idea of claim 1. Dependent claims 2-4 further limit the biological synthesis process, set of variants, and bottleneck of claim 1, and thus are part of the mental process of claim 1 discussed above. Dependent claim 5 further recites the mental process of performing data comparisons between a simulation or an experimental result. Dependent claim 11 further recites the mental process of evaluating variants according to a ranking order of the set of variants. Dependent claim 12 further recites the mental process of determining a score based on a comparison between the respective variant and the biological synthesis process and determining the ranking order based on the score. Dependent claim 13 further recites the mental process of comparing a distance between the respective variant and biological synthesis process, comparing two measurements of at least one objective, and comparing two measurements of a feature. Dependent claim 14 further recites the mental process of selecting a first set of variants based on the ranking order, evaluating the first set of variants based on at least one objective, and selecting a second set of variants based on the evaluation of the first set. Dependent claim 15 further recites the mental process of evaluating a simulation of variants or evaluating an experimental result. Dependent claim 16 further limits the variants of the set of second variants selected in claim 14, and thus are part of the mental process of claim 14. Dependent claim 17 further limits the variants of the first set of variants evaluated in claim 14, and thus are part of the mental process of claim 14. Dependent claim 18 further limits the variants of the first and second set of variants evaluated and selected, respectively, in claim 14, and thus are part of the mental process of claim 14. Claim 19 further limits the mental process of selecting the adjusted biologic synthesis process to be based on an evaluation of a set of variants, and thus is part of the mental process of claim 1. Claim 20 further recites the mental process of generating at least one explanation of an effect of at least one variant of the biological synthesis process on the at least one bottleneck. Therefore, claims 1-5 and 11-20 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 1-5 and 11-20 do not recite any elements in addition to the judicial exception. Therefore, the claims as a whole do no integrate the abstract idea into practical application, and claims 1-5 and 11-20 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 because claims 1-5 and 11-20 do not recite any elements in addition to the judicial exception.
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.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 and 11-20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Famili (2009).
Cited reference: Famili et al., US 2016/0364520 A1; Pub. Date: 2016, effectively filed: 2009 based on priority to U.S. Provisional App. No, 61/244,809 and 61/155,660.
Regarding claim 1, Famili discloses a method for developing cellular models of metabolism for producing small molecule chemicals or metabolites (i.e. a biological synthesis processes) ([0006]; [0088]; [0265]).
Famili discloses providing a constraint set specifying a particular set of environmental conditions on flux of mass through a reaction network (i.e. at least one bottleneck) for the biological synthesis process ([0153]; [0172]-[0173]). Famili also discloses an example of ATP energy as a constraint on product formation ([0016]; FIG. 9), and another example in which byproduct formation is a bottleneck for product yield ([0240]).
Famili discloses evaluating different in-silico media formulations or target reactions designed for increasing cell productivity, reducing growth rate, reducing media nutrients, and combinations thereof of the synthesis process (i.e. a set of variants of the biological synthesis process) and rank-ordering the scenarios ([0240]-[0241]; Table 7; [0346]; [0350]).
Famili discloses selecting the most promising cell engineering design based on a ranking of the in-silico variant evaluations ([0046]-[0047]; [0240], e.g. in silico media formulations rank ordered by performance). Famili discloses an example in which the selected engineering design is a design that lowers the energy requirement of the network to improve product formation when product formation is limited by energy (i.e. reducing the at least one bottleneck of ATP energy) ([0220]), and selecting a design with the highest productivity increases and byproduct reduction when byproduct formation limits product yield (i.e. reducing the at least one bottleneck) ([0240]).
Regarding claim 2¸ Famili discloses the biological synthesis process for the production of metabolites (i.e. a metabolite synthesis process) ([0265]; [0307]).
Regarding claim 3, Famili discloses the in-silico variants of the synthesis process include altering the media of the synthesis process by adding nutrients (biological addition variant) and removing nutrients (i.e. biological product elimination variant) ([0240]-[0241]), and a variants with different energy parameters such as ATP concentrations (i.e. biological production concentration variant) (FIG. 9; [0016]; [0220]). Famili also discloses the synthesis processes may include different target reactions (i.e. biological product transformation variant) (FIG. 22; [0029])
Regarding claim 4, Famili discloses the bottlenecks include ATP concentration (i.e. a product expression bottleneck) ([0016]; FIG. 9), amino acid uptake (i.e. a protein expression level bottleneck, given protein expression requires amino acids) ([0221]), and metabolic inefficiency of cells where they take up more nutrients then needed and create waste that limits product formation (i.e. a metabolite production rate bottleneck) ([0224]).
Regarding claim 5, Famili discloses comparing the in-silico simulations of the biological synthesis process, including the variants, with each other to identify a process with the highest productivity increases ([0240]; Table 7).
Regarding claim 11, Famili discloses evaluating variants of the synthesis process by rank-ordering the variants based on a productivity increases ([0240]).
Regarding claim 12¸ Famili discloses evaluating the variants comprises providing the “base case” of the synthesis process to benchmark improvements in productivity relative to the variants ([0232]) and calculating a percent increase in product titers for each of the variants over the base case (i.e. a score based on comparing a respective variant and the biological synthesis process) ([0236]-[0237]).
Famili further discloses rank-ordering the variants based on productivity increase (i.e. the score) ([0237]).
Regarding claim 13, Famili discloses the comparing comprises calculating a percent increase (i.e. a distance) in product titers for each of the variants over the base case e) ([0236]-[0237]). Alternatively, Famili also discloses comparing an objective of the variants to the base case (i.e. a measurement of at least one objective…)([0223], e.g. objective functions; [0233]-[0235], e.g. objective to minimize byproduct formation, maximize product production used).
Regarding claim 14, Famili discloses selecting one or more most promising synthesis processes (i.e. a first set of candidate variants) based on the rank-order of the set of variants ([0240]; [0346]; [0426]-[0429], e.g. computational results reviewed and the most promising designs determined for experimental validation).
Famili discloses testing the most promising process experimentally using mammalian cell culture in order to validate the in-silico synthesis process and demonstrate the technical feasibility of the superior synthesis process (i.e. evaluating based on an objective of respective variants of the first set) ([0046];[0240]; [0346], e.g. candidates rank-ordered and top candidate experimentally implemented).
Famili further discloses based on agreements between model predictions and experimental results, second generation modifications can be determined, except instead of comparisons of minimum byproduct forming phenotype(s) with a baseline synthesis process, it will be with the newly generated synthesis process, and second generation modifications will be suggested for all of the generated synthesis processes (i.e. a second set of variants selected based on experimental evaluation of the first set of variants) ([0435]-[0436]).
Regarding claim 15, Famili discloses evaluating the first set of candidate variants includes experimentally validating the first set of variants ([0240]; [0435]).
Regarding claim 16, Famili discloses the second set of variants applies a second generation modification to the first set of variants (i.e. at least one further variant of the first set of candidate variants) ([0435]-[0436]).
Regarding claim 17¸ Famili discloses the first set of variants include different cell-lines intended to have lower byproduct formation than the parent, with each cell-line having a different target gene knockout most likely to eliminate byproduct formation (i.e. at least two alternatives/variations of a gene/feature of the biological synthesis process) ([0426]-[0427]).
Regarding claim 18, Famili discloses the first set of variants include a single knockout gene (i.e. a single variation of a feature of the biological synthesis process) ([0426]-[0427], e.g. one gene knockout required). Famili further discloses making a second generation modification to the first set of variants ([0436]), thus producing a second set of variants with at least two different features of the biological synthesis process (e.g. the gene knockout of the first variant set + one other modification).
Regarding claim 19, Famili discloses the selected adjusted biological process is based on the best performing cell line in terms of increased protein productivity based on evaluating the variants ([0240]; [0434])
Regarding claim 20¸ Famili discloses explaining that byproduct formation was lowered in a variant compared with the “base case” values, even though the formulation was not designed specifically for reduced byproduct formation ([0237]).
Therefore, Famili anticipates the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5 and 11-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/340,736 (reference application) in view of Famili (2009).
Famili et al., US 2016/0364520 A1; Pub. Date: 2016, effectively filed: 2009 based on priority to U.S. Provisional App. No, 61/244,809 and 61/155,660.
Regarding instant claim 1, reference claim 3 discloses implementing a multi-objective optimization of a biological synthesis problem that evaluates multiple objectives of the biological synthesis process based on simulations of the process. Reference claim 7 discloses the machine learning for optimization is configured to increase expression without loss of activity (i.e. identify and reduce a bottleneck).
Regarding instant claim 2, reference claim 4 discloses the synthesis process is a metabolite synthesis process.
Regarding instant claim 3, reference claim 9 discloses determining genetic modification variants of proteins to exhibit features of other proteins (i.e. a product activity variant).
Regarding instant claim 4, reference claim 7 discloses the bottleneck is a product expression bottleneck.
The reference claims do not disclose the following limitations:
Regarding instant claim 1, the reference claims do not disclose selecting an adjusted biological synthesis process based on the evaluation, wherein the adjusted process includes at least one variant reducing the bottleneck.
Regarding instant claims 5 and 11-20, the reference claims further do not disclose this recited process of evaluating the variants of the biological synthesis process.
However, regarding instant claims 1, 5, and 11-20, Famili discloses a method for developing cellular models of metabolism for producing small molecule chemicals or metabolites (i.e. a biological synthesis processes) ([0006]; [0088]; [0265]).
Regarding instant claim 1, Famili discloses providing a constraint set specifying a particular set of environmental conditions on flux of mass through a reaction network (i.e. at least one bottleneck) for the biological synthesis process ([0153]; [0172]-[0173]), and evaluating different in-silico media formulations or target reactions designed for increasing cell productivity, reducing growth rate, reducing media nutrients, and combinations thereof of the synthesis process (i.e. a set of variants of the biological synthesis process) ([0240]-[0241]; Table 7; [0346]; [0350]). Famili then discloses selecting the most promising cell engineering design based on a ranking of the in-silico variant evaluations ([0046]-[0047]; [0240], e.g. in silico media formulations rank ordered by performance). Famili discloses an example in which the selected engineering design is a design that lowers the energy requirement of the network to improve product formation when product formation is limited by energy (i.e. reducing the at least one bottleneck of ATP energy) ([0220]), and selecting a design with the highest productivity increases and byproduct reduction when byproduct formation limits product yield (i.e. reducing the at least one bottleneck) ([0240]).
Regarding instant claim 5, Famili discloses comparing the in-silico simulations of the biological synthesis process, including the variants, with each other to identify a process with the highest productivity increases ([0240]; Table 7).
Regarding instant claim 11, Famili discloses evaluating variants of the synthesis process by rank-ordering the variants based on a productivity increases ([0240]).
Regarding instant claim 12¸ Famili discloses evaluating the variants comprises providing the “base case” of the synthesis process to benchmark improvements in productivity relative to the variants ([0232]) and calculating a percent increase in product titers for each of the variants over the base case (i.e. a score based on comparing a respective variant and the biological synthesis process) ([0236]-[0237]).
Famili further discloses rank-ordering the variants based on productivity increase (i.e. the score) ([0237]).
Regarding instant claim 13, Famili discloses the comparing comprises calculating a percent increase (i.e. a distance) in product titers for each of the variants over the base case e) ([0236]-[0237]). Alternatively, Famili also discloses comparing an objective of the variants to the base case (i.e. a measurement of at least one objective…)([0223], e.g. objective functions; [0233]-[0235], e.g. objective to minimize byproduct formation, maximize product production used).
Regarding instant claim 14, Famili discloses selecting one or more most promising synthesis es (i.e. a first set of candidate variants) based on the rank-order of the set of variants ([0240]; [0346]; [0426]-[0429], e.g. computational results reviewed and the most promising designs determined for experimental validation).
Famili discloses testing the most promising process experimentally using mammalian cell culture in order to validate the in-silico synthesis process and demonstrate the technical feasibility of the superior synthesis process (i.e. evaluating based on an objective of respective variants of the first set) ([0046];[0240]; [0346], e.g. candidates rank-ordered and top candidate experimentally implemented).
Famili further discloses based on agreements between model predictions and experimental results, second generation modifications can be determined, except instead of comparisons of minimum byproduct forming phenotype(s) with a baseline synthesis process, it will be with the newly generated synthesis process, and second generation modifications will be suggested for all of the generated synthesis processes (i.e. a second set of variants selected based on experimental evaluation of the first set of variants) ([0435]-[0436]).
Regarding instant claim 15, Famili discloses evaluating the first set of candidate variants includes experimentally validating the first set of variants ([0240]; [0435]).
Regarding instant claim 16, Famili discloses the second set of variants applies a second generation modification to the first set of variants (i.e. at least one further variant of the first set of candidate variants) ([0435]-[0436]).
Regarding instant claim 17¸ Famili discloses the first set of variants include different cell-lines intended to have lower byproduct formation than the parent, with each cell-line having a different target gene knockout most likely to eliminate byproduct formation (i.e. at least two alternatives/variations of a gene/feature of the biological synthesis process) ([0426]-[0427]).
Regarding instant claim 18, Famili discloses the first set of variants include a single knockout gene (i.e. a single variation of a feature of the biological synthesis process) ([0426]-[0427], e.g. one gene knockout required). Famili further discloses making a second generation modification to the first set of variants ([0436]), thus producing a second set of variants with at least two different features of the biological synthesis process (e.g. the gene knockout of the first variant set + one other modification).
Regarding instant claim 19, Famili discloses the selected adjusted biological process is based on the best performing cell line in terms of increased protein productivity based on evaluating the variants ([0240]; [0434])
Regarding instant claim 20¸ Famili discloses explaining that byproduct formation was lowered in a variant compared with the “base case” values, even though the formulation was not designed specifically for reduced byproduct formation ([0237]).
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 the reference claims to have selected an adjusted biological synthesis process and evaluated the variants of the synthesis process according to the methods of Famili, described above, thus arriving at the inventions of instant claims 1, 5, and 11-20. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Famili to identify a synthesis process design with highest productivity increases and byproduct reduction, as shown by Famili ([0240]). This modification would have had a reasonable expectation of success given both the reference claims and Famili optimize a biological synthesis process, and thus the methods of Famili are applicable to the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5 and 11-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/414,916 (reference application) in view of Famili (2009).
Famili et al., US 2016/0364520 A1; Pub. Date: 2016, effectively filed: 2009 based on priority to U.S. Provisional App. No, 61/244,809 and 61/155,660.
Regarding instant claim 1, reference claims 1 and 7 discloses a process for evaluating biological process scenarios, comprising generating simulated biological processes with each process having a different set of gene modifications (i.e. a set of variants), executing simulations of the process scenarios (i.e. evaluating the set of variants), and generating a set of recommendations for the process based on the simulation that enhance the production of the functional output by the strain performing the synthesis process (i.e. selected an adjusted process as claimed).
Regarding instant claim 2, reference claims 1 discloses the synthetic biological process is by a biological strain, reference claim 4 discloses the process data involves metabolic parameters, and reference claim 7 discloses the simulations of the process involve metabolite digital twins, demonstrating the synthesis process may be a metabolite synthesis.
Regarding instant claim 3, reference claim 7 discloses the variants may be gene modifications (i.e. a product activity variant).
The reference claims do not disclose the following limitations:
Regarding instant claim 1, the reference claims do not explicitly disclose identifying a bottleneck of the process and selecting the adjusted synthesis process that reduces the bottleneck.
Regarding instant claims 4-5 and 11-20, the reference claims do not disclose the particular bottleneck of claim 4, or the process of evaluating variants of claims 5 and 11-20.
However, regarding instant claims 1, 5, and 11-20, Famili discloses a method for developing cellular models of metabolism for producing small molecule chemicals or metabolites (i.e. a biological synthesis processes) ([0006]; [0088]; [0265]).
Regarding instant claims 1 and 4, Famili discloses providing a constraint set specifying a particular set of environmental conditions on flux of mass through a reaction network (i.e. at least one bottleneck) for the biological synthesis process ([0153]; [0172]-[0173]), and evaluating different in-silico media formulations or target reactions designed for increasing cell productivity, reducing growth rate, reducing media nutrients, and combinations thereof of the synthesis process (i.e. a set of variants of the biological synthesis process) ([0240]-[0241]; Table 7; [0346]; [0350]). Famili then discloses selecting the most promising cell engineering design based on a ranking of the in-silico variant evaluations ([0046]-[0047]; [0240], e.g. in silico media formulations rank ordered by performance). Famili discloses an example in which the selected engineering design is a design that lowers the energy requirement of the network to improve product formation when product formation is limited by energy (i.e. reducing the at least one bottleneck of ATP energy) ([0220]), and selecting a design with the highest productivity increases and byproduct reduction when byproduct formation limits product yield (i.e. reducing the at least one bottleneck) ([0240]).
Regarding instant claim 5, Famili discloses comparing the in-silico simulations of the biological synthesis process, including the variants, with each other to identify a process with the highest productivity increases ([0240]; Table 7).
Regarding instant claim 11, Famili discloses evaluating variants of the synthesis process by rank-ordering the variants based on a productivity increases ([0240]).
Regarding instant claim 12¸ Famili discloses evaluating the variants comprises providing the “base case” of the synthesis process to benchmark improvements in productivity relative to the variants ([0232]) and calculating a percent increase in product titers for each of the variants over the base case (i.e. a score based on comparing a respective variant and the biological synthesis process) ([0236]-[0237]).
Famili further discloses rank-ordering the variants based on productivity increase (i.e. the score) ([0237]).
Regarding instant claim 13, Famili discloses the comparing comprises calculating a percent increase (i.e. a distance) in product titers for each of the variants over the base case e) ([0236]-[0237]). Alternatively, Famili also discloses comparing an objective of the variants to the base case (i.e. a measurement of at least one objective…)([0223], e.g. objective functions; [0233]-[0235], e.g. objective to minimize byproduct formation, maximize product production used).
Regarding instant claim 14, Famili discloses selecting one or more most promising synthesis es (i.e. a first set of candidate variants) based on the rank-order of the set of variants ([0240]; [0346]; [0426]-[0429], e.g. computational results reviewed and the most promising designs determined for experimental validation).
Famili discloses testing the most promising process experimentally using mammalian cell culture in order to validate the in-silico synthesis process and demonstrate the technical feasibility of the superior synthesis process (i.e. evaluating based on an objective of respective variants of the first set) ([0046];[0240]; [0346], e.g. candidates rank-ordered and top candidate experimentally implemented).
Famili further discloses based on agreements between model predictions and experimental results, second generation modifications can be determined, except instead of comparisons of minimum byproduct forming phenotype(s) with a baseline synthesis process, it will be with the newly generated synthesis process, and second generation modifications will be suggested for all of the generated synthesis processes (i.e. a second set of variants selected based on experimental evaluation of the first set of variants) ([0435]-[0436]).
Regarding instant claim 15, Famili discloses evaluating the first set of candidate variants includes experimentally validating the first set of variants ([0240]; [0435]).
Regarding instant claim 16, Famili discloses the second set of variants applies a second generation modification to the first set of variants (i.e. at least one further variant of the first set of candidate variants) ([0435]-[0436]).
Regarding instant claim 17¸ Famili discloses the first set of variants include different cell-lines intended to have lower byproduct formation than the parent, with each cell-line having a different target gene knockout most likely to eliminate byproduct formation (i.e. at least two alternatives/variations of a gene/feature of the biological synthesis process) ([0426]-[0427]).
Regarding instant claim 18, Famili discloses the first set of variants include a single knockout gene (i.e. a single variation of a feature of the biological synthesis process) ([0426]-[0427], e.g. one gene knockout required). Famili further discloses making a second generation modification to the first set of variants ([0436]), thus producing a second set of variants with at least two different features of the biological synthesis process (e.g. the gene knockout of the first variant set + one other modification).
Regarding instant claim 19, Famili discloses the selected adjusted biological process is based on the best performing cell line in terms of increased protein productivity based on evaluating the variants ([0240]; [0434])
Regarding instant claim 20¸ Famili discloses explaining that byproduct formation was lowered in a variant compared with the “base case” values, even though the formulation was not designed specifically for reduced byproduct formation ([0237]).
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 the reference claims to have selected a particular bottleneck of the synthesis process, selected an adjusted biological synthesis process, and evaluated the variants of the synthesis process according to the methods of Famili, described above, thus arriving at the inventions of instant claims 1, 4-5, and 11-20. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Famili to identify a synthesis process design with highest productivity increases and byproduct reduction, as shown by Famili ([0240]). This modification would have had a reasonable expectation of success given both the reference claims and Famili optimize a biological synthesis process, and thus the methods of Famili are applicable to the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685