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. Status of the Claims The c laim set(s) received 2 7 February 2023 have been entered into the application. Claims 1, 6- 8, 10 a nd 16-17 are objected to. Claim 1- 20 are pending. Priority This Application is a 371 of PCT/EP2021/073802 filed 20 August 2021 which claims foreign benefit to EP20193231.6 filed 27 August 2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP20193231.6 filed 27 August 2020. Election/Restrictions Claims 11-12, 14-15, and 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 13 November 2025. The Applicant traverses the restriction between Groups I and II with respect to claim 16. Claim 16 is rejoined with Group II. Claims 1-10, 13, and 16-17 are currently under examination . Information Disclosure Statement The information disclosure statement (IDS) submitted on 27 February 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Drawings The drawings were received on 27 February 2023 . These drawings are accepted . Specification The s pecification received 27 February 2023 has been entered into the application. The substitute specification received 27 February 2023 has been entered into the application. Claim Objections Claims 1, 7-8, 10, 16 are objected to because of the following informalities: The claims contains bullets “•”. The MPEP 608.01(m) states : "Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck , 36 USPQ2d 1211 (D.D.C. 1995). “ Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation… ”. Thus, it is recommended to amend the claims to address the bullets “•”. Claim 1 is objected to because of the following informalities: Claim 1 determining step (a) recites “… of at least two…”. It is recommended to amend the claim to recite “… of at least two…” to address the grammatical correctness and language consistency of the claim. Claim 1 is objected to because of the following informalities: Claim 1 assessing step recites “…said medicament to said subject comprising assessing the optimal time of administration of said medicament…”. The claim should be amended to recite “…said medicament to said subject comprises assessing the optimal time of administration of said medicament…” to address the grammatical correctness of the claim. Claim 6 is objected to because of the following informalities: Claim 6 recites “processing the determined gene expression levels to derive characteristic data for each of said genes, said processing comprising determining the mean expression level of expression of a gene and normalizing the gene expression levels using the mean expression level.” Claim 6 should be amended to recite “processing the determined gene expression levels to derive characteristic data for each of said genes, wherein said processing comprising determining the mean expression level of expression of a gene and normalizing the gene expression levels using the mean expression level.” to address the grammatical correctness of the claim. Claim 7 is objected to because of the following informalities: Claim 7 recites “… and/or and/or…”. The claim should be amended to recite “… and/or and/or…” t o address the grammatical correctness of the claim . Claim 10 is objected to because of the following informalities: Claim 10 recites “the medicament is bevacizumab and the target gene is Fcgr2b, Vegfa , Fcgr3 ; and the indication is Colorectal cancer and Non-small cell lung cancer “. The claim should be amended to recite “the medicament is bevacizumab and the target gene is Fcgr2b, Vegfa , Fcgr3 ; and the indication is Colorectal cancer and Non-small cell lung cancer.“ to address the grammatical correctness of the claim. New c laim 16 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 8. Here, although claim 8 was amended to recite “…expression level for at least one further gene included…” while claim 16 recites “…expression level for a plurality of further genes included…”. As such, even though claim 8 was amended to recite different language the language covers the same thing “at least one gene”/ “a plurality of genes”. Additionally, claim 8 and 16 are both dependent on claim 6. Therefore, when two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim Rejections - 35 USC § 112 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. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the appl icant regards as his invention. Claims 1-10 and 16-17 are rejec ted under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 recites “preferably” . The term renders the claim vague and indefinite because the claim does not recite any conditions or criteria which one of ordinary skill in the art could choose 3 samples versus 4 samples . Similarly, it is further not clear under what conditions or circumstances require 4 samples instead of 3 samples. Thus, it is not clear if the claim requires 3 samples or if the claim requires 4 samples. Claims 2-10 and 16-17 are rejected because they fail to provide limitations to overcome the deficiencies of the base claim(s). Claim 8 recites “…model, particularly optimize in terms of the representation of the periodic time course of the expression level for the at least one further gene.” The limitation renders the claim indefinite because it is not clear what the limitation is describing and/or not clear how the limitation limits the training of the machine learning model. Here, the phrase appears to be a sentence fragment. It is recommended to amend the claim to clarify what is particularly optimized, for example. Claim 10 recites “the medicament is bevacizumab and the target gene is Fcgr2b, Vegfa , Fcgr3; and the indication is Colorectal cancer and Non-small cell lung cancer”. The claimed step renders the claim indefinite because it is not clear how the target is Fcgr2b, Vegfa , Fcgr3. Here, “the target gene” implies that the target gene is to consist of “one” gene. Thus, it is not clear how the target gene can be more than more gene. It is noted the previous step “the medicant is Rituximab and the target gene is selected from the group comprising…”. It is not clear if the applicant intends to have the target gene selected similar to the previous steps . Therefore, the claimed steps with respect to bullets 3-11 contain similar issues which renders claim 10 is indefinite. There are numerous grammatical errors in this claim that need to be amended for grammatical correctness and clarity of the record . It is recommended to amend and revise the claim language of the claims to provide clarity of the claimed invention as the current claim language contains run-ons, sentence fragments, and punctuation errors that render s the claims confusing and unclear. 35 USC § 112(d) Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 13 was amended to recite a method comprising using the kit of claim 11 for collecting saliva samples for assessing circadian rhythm and timing of medication administration. Additionally, the elected group (i.e., rejoined Groups I and II) encompass claims 1-10, 13, and 16-17. It is noted that claim 13 is dependent on claim 11 which is not part of the elected group. As such, claim 13 should be amended to reflect the appropriate claim dependency. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. 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. Claim s 1- 10 and 16- 17 rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. Step 1 - Process, Machine, Manufacture or Composition Claims 1- 10 and 16- 17 are drawn to a method, so a process. Step 2A Prong I - Identification of an Abstract Idea Claim 1 recites: Determining gene expression of the following genes: at least two core-clock member genes from the group of step (a), at least one gene involved in the metabolism of a medicant to be administered including Ces2 (b), and at least one drug target gene that is the target of the administered medicant (c) . This step can be performed in the human mind by organizing information (i.e., gene expression data) of genes (i.e., at least two core-clock member genes, genes involved in medication metabolism, drug target gene) to determine gene expression and is therefore an abstract idea. assessing and predicting by means of a computational step based on said expression levels of said genes over the day the circadian rhythm of said subject and/or assessing a timing of administration of said medicament to said subject, comprising assessing the optimal time of administration of said medicament to said subject and/or assessing the non-optimal time of administration of said medicament to said subject. This step can be performed in the human mind by observing, judging, and evaluating genetic data (i.e., gene expression levels ) for assessing and predicting the circadian rhythm of a subject and is therefore an abstract idea. This step can further be performed in the human mind by observing, judging, and evaluating information (i.e., timing of administration of medications) for assessing optimal and non-optimal time of administration and therefore reads on abstract ideas. This step encompasses performing mathematical computations on gene expression data which reads on abstract ideas. Claims 4-10 and 16-17 are further drawn to limitations that describe the abstract ideas of claim 1 and are therefore also abstract ideas. Step 2A Prong Two: Consideration of Practical Application Claim 1 does not contain any additional elements that integrate the recited judicial exception into a practical application. Here, in the instant case, the claims merely set forth a method data analysis for assessing and predicting and assessing the timing of medication administration. As such, practicing the claims merely results in the assessing and predicting of information and assessing optimal and non-optimal timing of medication administration. Such a result only produces information a nd does not provide for a practical application in the physical-realm of physical things and acts, i.e., the claims do not utilize the data generated by the judicial exception to affect any type of change. See MPEP 2106.04(a)(2)(A)(iv) . Therefore, the claims do not utilize the obtained saliva samples, determined gene expression levels, and the assessed and predicted data, and the abstract ideas to construct a practical application such as treating a subject, transformation of matter, or improving upon an existing technology. Claim 10 recites using medications ( i.e , Filgrastim, Rituximab, R astuzumab ). However, the medication s of claim 10 do not integrate the recited judicial exception into a practical application because the medication s are used as data gathering elements for analyzing gene expression levels with respect to assessing/predicting timin gs of medication administration, not for treating a disease. Therefore, the medications of claim 10 are considered a n extra-solution activit y . See MPEP 2106.04(d)(2). Claims 8 and 16 recite “training a machine learning algorithm…” while claims 9 and 17 recite “…wherein the prediction computational model is based on machine learning…”. It is noted that the claims do not recite any computer limitations for performing the machine learning processes/computational steps. Here, even though the claimed steps utilize a “machine learning algorithm/model based on machine learning ”, the machine learning model s /algorithm s are broadly and generically recited and read on mere instructions to implement an abstract idea on a generic computer and read on mathematical/statistical computations (i.e., k-nearest neighbors , support vector machine). See 2024 Subject Matter Eligibility Update (AI) [Example 47 Claim 2] and MPEP 2106.04(a)(2)(III)(C) (1-3) and 2106.05(f). Furthermore , and for sake of compact prosecution, even if the machine learning algorithm/ model is also considered an additional element, the machine learning model s /algorithm s (MLM /A ) are used to generally apply the abstract idea without limiting how the trained (MLM /a ) functions. The MLM /A is described at a high level such that it amounts to using a computer with a generic MLM /A to apply the abstract idea. These limitations only recite the outcomes for “ training a machine learning algorithm…to form the network computation model (claim s 8 and 16 ) ” without any details about how to form a network computation model by training machine algorithm using derived characteristic data and recites the outcome s for “fitting a prediction computational model…wherein the computational model is based on machine learning…(claims 9 and 17) ” without any details about how the prediction computational models (i.e., machine learning: clustering and classification models) are fitted using data obtained from fitted periodic functions and/or said network computational model which does not integrate the judicial exception into a practical application or provide significantly more because this type of recitation is equivalent to the words "apply it". See 2024 Subject Matter Eligibility Update (AI) [Example 47 Claim 2] and MPEP 2106.05(f). This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria: An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field; an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition; an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim; an additional element effects a transformation or reduction of a particular article to a different state or thing; and an additional element applies or uses 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. Step 2B - Consideration of Additional Elements and Significantly More The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea. The additional element of providing samples (i.e., saliva) of claim 1 does not add significantly more than the recited judicial exception because using sample to provide a source of nucleic acids that is subsequently processed and analyzed by the abstract ideas is well-known and conventional. See MPEP 21406.05(d)(II)( i -iii, v, vii) and 2106.05(g). To provide evidence of conventionality of using saliva samples, Gozu et al. ( Gozu ) discloses measuring gene expression levels in sputum/saliva over time and measuring the circadian rhythm based on the gene expression levels [ Gozu , claims 1-2]. (Int. Patent Pub.: WO 2011114732, Patent Pub Date: 22 September 2011). The additional element of using clinical/laboratory methods ( Nanostring , RT-PCR, sequencing and microarray) of claims 2-3 does not add significantly more than the recited judicial exception because using techniques ( Nanostring , RT-PCR, sequencing and microarray) to obtain nucleic data from samples that is subsequently analyzed by the abstract ideas is well-known and conventional extra-solution activity . See MPEP 21406.05(d)(II)( i -iii, v, vii) and 2106.05(g). To provide evidence of conventionality of using the NanoString method for determining gene expression levels, Braun et al. (Braun) discloses using NanoString for measuring biomarkers [Braun, disclosure, page 6 right col para 0047]. (U.S Patent Pub: US 2018/0357360 : Patent Pub Date: 13 December 2018). The additional element of using/ administering medication (i.e., Filgrastim , bevacizumab , Everolimus ) of claim 10 does not add significantly more than the recited judicial exception because using medications for evaluating gene expression levels that are subsequently analyzed by the abstract ideas is well-known and conventional. See MPEP 21406.05(d)(II)( i -iii, v, vii) and 2106.05(g). To provide evidence of conventionality of using medication for analyzing gene expression Dallmann et al. ( Dallmann ) teaches using Erlotinib, Sunitinib, and Irinotecan [page 433 table 1] ( Trends in molecular medicine, 2016-05, Vol.22 (5), p.430-445 ). Viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter. 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. Claim (s) 1-5 , and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Ballesta et al. ( PLoS computational biology, 2011-09, Vol.7 (9), p.e1002143) (Cited in the IDS received 27 February 2023: NPL Citation No.: 4) in view of Wittenbrink et al. ( The Journal of clinical investigation, 2018-09, Vol.128 (9), p.3826-3839 ). Claim 1 recites providing at least three samples of saliva, more preferably four samples of saliva, from said subject, wherein said samples have been taken at different time points over the day. Claim 1 recites determining gene expression of the following genes in each of said samples a) of at least two members of the core-clock network in each of said samples, in particular of at least two members of the following genes, of the groups comprising ARNTL ( BMALl ), ARNTL2, CLOCK, PERl , PER2, PER3, NPAS2, CRYl , CRY2, NR1D1, NR1D2, RORA, RORB, RORC, in particular ARNTL ( BMALl ) and PER2, and b) at least one gene involved in the metabolism of a medicament to be administered to said subject having cancer, including Ces2, and c) at least one drug target gene that is a target of the medicament to be administered. Claim 1 recites assessing and predicting by means of a computational step based on said expression levels of said genes over the day the circadian rhythm of said subject and/or assessing a timing of administration of said medicament to said subject comprising assessing the optimal time of administration of said medicament to said subject and/or assessing the non-optimal time of administration of said medicament to said subject. Ballesta et al. ( Ballesta ) teaches observing the mRNA expression of clock genes PER2 and BMAL1 [abstract], as in claim 1 determining gene expression of the following genes in each of said samples a) of at least two members of the core-clock network in each of said samples, in particular of at least two members of the following genes, of the groups comprising ARNTL ( BMALl ), ARNTL2, CLOCK, PERl , PER2, PER3, NPAS2, CRYl , CRY2, NR1D1, NR1D2, RORA, RORB, RORC, in particular ARNTL ( BMALl ) and PER2. Ballesta teaches mRNA expression of genes (i.e., the activation enzyme carboxylesterase 2 (CES2), the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1) (i.e., metabolic pathway) , and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2) [abstract], as in claim 1 b) at least one gene involved in the metabolism of a medicament to be administered to said subject having cancer, including Ces2. Ballesta teaches mRNA expression of the drug target topoisomerase 1 (TOP1) and effect on the CPT11 (i.e., Irinotecan) [abstract], as in claim 1 c) at least one drug target gene that is a target of the medicament to be administered. Ballesta teaches using a mathematical model that predicted CTP11 bioactivation through the C es that was the main determinant of CPT 11 pharmacodynamics (PD) circadian rhythm [page 10 left col] . Ballesta teaches the experimental timing for 24 hours [page 2 left col author summary]. Ballesta teaches estimating PK-PD model by fitting experimental data [page7 table 2], as in claim 1 assessing and predicting by means of a computational step based on said expression levels of said genes over the day the circadian rhythm of said subject. Ballesta teaches computed optimal cumulative doses of CPT11 (i.e., Irinotecan) ranged from 241 to 1321µM.h and increased with tolerability threshold. Ballesta teaches an optimal scheme consisted administering CPT11 over 3h40 to 7h10 starting between CT2h10 and CT2h30 which corresponds to the lowest point or minimum level of expression (i.e., nadir) of CES [page 9 left col]. Ballesta teaches CPT11 should optimally be administered over a duration of 3h25 to 7h10 starting before the nadir of CPT11 bioactivation 1h30 to 1h50 [page 9 left col discussion]. Ballesta teaches the whole-body mathematical model could be fitted to the patient molecular profile and provide tailored chrono modulated administration scheme [page 10 bottom left to top right col], as in claim 1 assessing a timing of administration of said medicament to said subject comprising assessing the optimal time of administration of said medicament to said subject. Ballesta teaches the most toxic scheme (i.e., non-optimal ) was achieved when CPT11 was administered at CT21 over the exposure duration which also induced the largest DNA damage in cancer cells (4 h for the dose of 500mM.h) [page 7 right col minimizing toxicity without efficiency constraint], as in claim 1 assessing the non-optimal time of administration of said medicament to said subject. Dependent claims: 2 , 4- 5 , 7 Ballesta teaches using qRT -PCR [page10 right col RNA quantification], as in claim 2. Ballesta teaches using the analyzing the genes UGT1A1 and ABCB1 [abstract], as in claim 4. Ballesta teache s for each genes, ϕ is set to the phase estimated from the corresponding mRNA measurement [page 6 top of right col]. Ballesta teaches a table exemplifying circadian mRNA expression [page 5 table 1], as in claim 5. Ballesta teaches amplitude of Ces circadian was greater than UGT, ABC_CPT, and ABC_SN [page 6 right col]. as in claim 7 amplitude of change step. Bellesta teaches using means of parameter values of mRNA expression [page 5 table 1], as in claim 7 mean expression level step. Bellesta does not teach claim 1 providing at least three samples of saliva, more preferably four samples of saliva, from said subject, wherein said samples have been taken at different time points over the day. Ballesta does not teach claim 3. Wittenbrink et al. ( Wittenbrink ) teaches saliva samples were taken with blood draws every 3 hours over a period of 40 hours [page 3828 figure 1]. Wittenbrink teaches hourly salivary samples w ere taken for determination of melatonin secretion [page 3828 left col], as in claim 1 providing at least three samples of saliva, more preferably four samples of saliva, from said subject, wherein said samples have been taken at different time points over the day. Dependent claims: 3 Wittenbrink teaches using Nanostring data [page 3828 fig 1 and page 3830 table 1], as in claim 3. It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify Ballesta in view of Wittenbrink because Wittenbrink teaches an assay (i.e., BodyTime ) for analyzing RNA data (i.e., NanoString and RNA-seq) from blood samples and saliva samples (i.e., samples obtained at different timepoints) for assessing molecular circadian rhythm gene profiles (i.e., Per1/Per2 [page 3833 left col]). One of ordinary skill in the art would recognize that Ballesta and Wittenbrink are in similar fields of endeavor that process similar data for determining relationships between body fluids, genes, and circadian rhythm. One of ordinary would be motivated to combine Ballesta in view of Wittenbrink because Wittenbrink teaches using NanoString data of saliva and blood samples for estimating internal circadian time in a human(s). Here, as noted by Wittenbrink [page 3835 left col], the assay can be used as a tool for drug development to assess whether effectiveness and side effects of a drug are influenced by an administrations schedule which can be used investigate internal circadian phases in response to environmental changes and interventions (i.e., medication) [page 3835 left col]. Thus, one of ordinary skill in the art would have a reasonable expectation of success using the analysis steps of Ballesta to processes the saliva and blood samples (i.e., RNA-seq, NanoString ) of Wittenbrink to construct a predictable method for assessing a molecular circadian rhythm genetic profile of a subject with cancer and assessing and predicting medication administration timing (i.e., scheduling). Therefore, one of ordinary skill in the art would be motivated to use combination of Ballesta and Wittenbrink to develop a low cost, accurate gold standard equivalent method for assessing a molecular profile of circadian rhythm genes and medication administration. The rejection of claim(s) 6 , 8 , and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Ballesta in view of Gozu , as applied to claims 1-5 and 7 , and in further view of Hughey et al. (Nucleic acids research, 2016-05, Vol.44 (8), p.e80-e80) Ballesta in view of Wittenbrink teaches claims 1-5 and 7 . Ballesta in view of Wittenbrink teach of method of assessing circadian rhythm and assessing optimal medication administration timing using circadian rhythm genetic profile (i.e., core clock genes, genes involved with metabolism of medication, drug target gene) and circadian modulating substances using blood and saliva samples . Ballesta in view of Wittenbrink do not explicitly teach 6 , 8 , and 16 . Hughey et al. (Hughey) teaches a new matrix is constructed using the time dependent mean of each feature and discretizing the feature into a number of time-points and scaled by that feature’s standard deviation about the mean curve [page 3 figure 1], as in claim 6. Obvious claims: 8 and 16 Claim 8 and 16 Ballesta teaches the values for table 1 were estimated fitting the experimental gene expression data of figure 3 to equation 12 for finding parameter values of circadian mRNA expression [page 5 table 1], as in claim s 8 and 16 fitting step. Wittenbrink teaches a training and evaluating Zeit-Zeiger predictors based on RNA-seq and NanoString data for identifying optimal parameters by internal cross-validation and using the calcTimeDiff function for periodic variables provided by the Zeit-Zeiger R package [page 3837 right col first para], as in claim s 8 and 16 training step. It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify Ballesta in view of Wittenbrink in further view of Hughey because Hughey teaches using a Zeit-Zeiger supervised machine learning model for high-dimensional data from oscillatory system for analyzing gene expression data with respect to evaluating and predicting circadian time (internal time of day) [abstract]. One of ordinary skill in the in art would recognize that Ballesta , Wittenbrink , and Hughey are in similar fields of endeavo r of evaluating biomarkers in body fluids for evaluating gene expression level s with respect to assessing circadian molecular profile and cellular perturbations (i.e., CPT11 administration, Ballesta ) . Here, even though Hughey does not us e saliva similar to Wittenbrink , it is noted , gene expression analysis can be applied to any cell(s) and/or nucleic acid product. As such, one of ordinary skill in the art would be motivated to combine the gene expression level and medication analysis of Ballesta , the saliva samples and analysis of Wittenbrink , and normalization methods of Hughey to construct a method step for processing gene expression level using characteristic data (i.e., amplitude, peak expression levels) for normalization circadian rhythm biomarkers because Hughey teaches creating a multi-organ predictor of circadian time using gene expression data and mathematical models for determining means, peaks, and differences in gene expression levels . Therefore, one or ordinary skill in the art would expect a reasonable success combining the methods of Ballesta , Wittenbrink , and Hughey to construct a predictable method step using gene expression level data for normalizing gene expression level s . Conclusion Claims 1-10, 13, and 16-17 are rejected. No claims are allowed. Finality This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action. Inquiries Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT JOSEPH C PULLIAM whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-8696 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT 0730-1700 M-F . 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, FILLIN "SPE Name?" \* MERGEFORMAT Karlheinz Skowronek can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT (571) 272-9047 . 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. /J.C.P./ Examiner, Art Unit 1687 /Anna Skibinsky/ Primary Examiner, AU 1635