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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/25/2025 has been entered.
Claim Status
Claims 41, 45-51, 53-54, and 56-72 are currently pending and under examination herein.
Claims 1-40, 43-44, 52, and 55 were canceled.
Claim 42 is canceled.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/734,725, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Accordingly, claims 50, 51, 54, 59, 63, 65, 66, 67, 68, 70 are not entitled to the benefit of the prior application. The claim limitations not entitled to the benefit of the prior application are:
Claim 50, proteins are assayed using a “multiplex proximity extension assay (PEA)”.
Claim 51, the proteins comprise one or more members selected from the group consisting of: LAIR2, DLK1, GRN, and PA11.
Claim 54, performing a clinical assessment on the pregnant subject, wherein the clinical assessment is selected from the group consisting of: “a fetal monitoring, a chorionic villus sampling, an amniocentesis, an evaluation for preeclampsia, an evaluation for gestational hypertension, an evaluation for gestational diabetes, an evaluation for preterm labor, an evaluation for signs of preterm rupture of membranes, and a glucose screening”.
Claim 59, the pregnancy complication is selected from the group consisting of: early maladaptive pregnancy, gestational hypertension, gestational trophoblastic disease, hyperemesis gravidarum, post-term pregnancy, post-term labor”.
Claim 63, the plurality of different time points comprise a member selected from the group consisting of: “first missed menstruation, fertilization”.
Claim 65, the treatment is selected from the group consisting of: “a medication, an intravenous fluid, an antibiotic, a cervical cerclage, folic acid, iron, calcium, vitamin D, docosahexaenoic acid (DHA), iodine, a dietary supplement, estrogen, progestogen, progesterone, dydrogesterone, an induction of labor, a delivery of the fetus, a Caesarian delivery of the fetus, and a surgical procedure”.
Claim 66, the medication comprises a” tocolytic medication”.
Claim 67, the “tocolytic medication is selected from the group consisting of: indomethacin, magnesium sulfate, orciprenaline, ritodrine, terbutaline, salbutamol, nifedipine, fenoterol, nylidrin, isoxsuprine, hexoprenaline, and atosiban”.
Claim 68, the biological sample is selected from the group consisting of: “a stool sample, a urine sample, a saliva sample, and a biopsy sample”.
Claim 70, at least one protein is assayed using a “multiplex proximity extension assay (PEA)”.
Accordingly, the effective filing date of the above recited claims is 06/30/2021. The effective filing date of claims 41-45, 47-49, 52-53, 55-58, 60-62, 64, 69, and 71 is 09/21/2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/17/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Withdrawn Rejections/Objections
Rejections and/or objections not reiterated from previous office actions are hereby
withdrawn in view of the amendments filed 09/25/2025.
All rejections of claim 42 are hereby withdrawn; claim cancelation moot the
rejections.
The 35 U.S.C. 112(b) rejections to claims 41-42, 45-51, 53-54, and 56-71 in the office action filed 01/28/2025 has been withdrawn in view of amendments received 09/25/2025 specifically by reciting “… predicting, using a computational model, gestational progress …”.
The 35 U.S.C. 112(d) rejections to claims 42 in the office action filed 01/28/2025 has been withdrawn in view of amendments received 09/25/2025 specifically by canceling claim 42.
The 35 U.S.C. 101 rejections to claims 60, and 64-67 in the office action filed 01/28/2025 has been withdrawn in view of amendments received 09/25/2025 since they recite specific complications with their respective specific treatments that are particular, have more than insignificant relationship to the exception, and are not extra solution activities or field of use, therefore, integrate the recites abstract ideas into a practical application.
The following rejections and/or objections are either maintained or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS. - Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 47 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 47 recites " wherein the metabolites comprise THDOC, progesterone, estriol-16-glucuronide, and DHEA-S", which does not further limit claim 46 because claim 46 already requires the metabolites comprise THDOC, progesterone, estriol-16-glucuronide, or DHEA-S". 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.
Claims 41, 45-51, 53-54, 56-59, 61-63, and 68-72 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 is directed to a method of determining pregnancy complications. 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.
Claims 41, 45-51, 53-54, 56-59, 61-63, and 68-72 recite the following steps which fall under the mathematical concepts, mental processes, and/or certain methods of organizing human activity groupings of abstract ideas:
Claims 41 and 70 recite (c) predicting using a computational model gestational progress of the pregnant subject; and (d) administering one or more clinical assessments on the pregnant subject during one or more periodical medical checkups on the pregnant subject, wherein the one or more periodical medical checkups are to occur in accordance with the gestational progress of the pregnant subject as predicted in (c). The limitation predicting using a computational model is considered a mathematical calculation, as disclosed in specification [0006], “the computational model is one of: ridge regression, K-nearest neighbors, LASSO regression, elastic net, least angle regression (LAR), random forest, or principal components analysis.”. As such, said limitation falls into mathematical concepts groupings of abstract ideas. The limitation administering one or more clinical assessments can be particularly performed in human mind (mental process) because human mind is able to perform a clinical assessment (see Specification [0025] clinical assessment is medical checkups; also, claim 54: the assessment is evaluating for one or more diseases). In addition, the limitation administering one or more clinical assessments based on analyte measurements of a pregnant subject is considered a law of nature.
Claim 54 recites that the one or more clinical assessments are an evaluation for preeclampsia, an evaluation for gestational hypertension, an evaluation for gestational diabetes, an evaluation for preterm labor, an evaluation for signs of preterm rupture of membranes, and a glucose screening (mental process, see above).
Claim 59 recites that the one or more clinical assessments (mental processes) yield a result indicating the pregnant subject is at risk of having a pregnancy complication is selected from a group (mental process of indicate a risk based on the result of an analysis/assessment).
Claim 61 recites performing additional monitoring; the limitation performing monitoring can be practically performed in human mind, since human are capable of monitoring/tracking/observing a condition.
Claim 62 recites predicting, using the computational model, gestational progress of the pregnant subject; the limitation predicting is considered a mathematical calculation, and as such falls into mathematical concepts groupings of abstract ideas.
Claim 72 recites training a machine learning model to predict gestational progress; the limitation training a machine learning model/mathematical algorithm is considered mathematical calculations (specification [0114]), and as such, falls into mathematical concepts groupings of abstract ideas.
The dependent claims 45-48, 51-53, 55-58, and 68-69 further describe the sample selection, assay procedure and computer processing.
Additionally, claims 41, 45-51, 53-54, 56-59, 61-63, and 68-72 recite a correlation between analyte measurement of a pregnant subject and administering one or more clinical assessments, and as such, falls into judicial exception of Laws of nature and natural phenomena. See MPEP 2106(b) I.
The identified claims recite a law of nature, a natural phenomenon (product of nature) and/or fall into one of the groups of abstract ideas of mathematical concepts, mental processes, and/or certain methods of organizing human activity for the reasons set forth above. See MPEP 2106.04 (a)(2) III and MPEP 2106.04 (b) I. Therefore, claims are directed to a judicial exception and require further analysis in Prong Two. [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 41, 45-51, 53-54, 56-59, 61-63, and 68-72 recite the following additional elements:
Claims 41, 70, and 72 recite obtaining a biological sample, assaying the biological sample. Claim 72 further recites entering timepoints into the computational model.
Claims 49, 50, and 70 recite assaying using immunoassay, a multiplex proximity extension assay (PEA) or a microsphere-based multiplex assay.
The additional elements of obtaining a biological sample, assaying steps, and entering timepoints into the computational model amount to nothing more than gathering the data necessary to perform the abstract idea. Obtaining a biological sample is performed in order to gather data for the mental analysis step, and is a necessary precursor for the recited exception.
The assaying step does not pose meaningful limitations on the scope of the claims: they would be performed in exactly the same manner if the samples were analyzed using a different abstract idea, or not at all.
Therefore, these additional elements amount to insignificant extra-solution activity, which is not sufficient to integrate the recited judicial exception into a practical application. See MPEP 2106.05(g). Thus, claims 41, 45-51, 53-54, 56-59, 61-63, and 68-72 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.
Claims 41, 45-51, 53-54, 56-59, 61-63, and 68-72 recite the following additional elements:
Claims 41 and 70 recite obtaining a biological sample, assaying the biological sample.
Claims 49, 50, and 70 recite assaying using immunoassay, a multiplex proximity extension assay (PEA) or a microsphere-based multiplex assay.
Claim 54 recites performing a clinical assessment.
Claims 64, 65, 66, and 67 recite administrating a treatment/medication.
The additional elements of obtaining a biological sample, assaying the biological sample amount to conventional methods and systems for performing biomarker analysis.
Furthermore, the additional elements of obtaining a biological sample, assaying steps, and entering timepoints into the computational model amount to necessary data gathering and outputting, which does not amount to significantly more (see MPEP 2106.05(g)).
Furthermore, the additional elements of assaying using immunoassay, a multiplex proximity extension assay (PEA) or a microsphere-based multiplex assay, amount to conventional methods and systems for performing protein assay. This position is supported by Panezai et al. (Correlation of serum cytokines, chemokines, growth factors and enzymes with periodontal disease parameters, November 2017, PLOS | ONE, pg. 1-17). Panezai discloses assaying proteins using immunoassay (p. 4, Anti-CCP detection). Additionally, Panezai discloses analyzing cytokine (protein) measurements by using multiplex proximity extension assay (PEA) (p. 1, Materials and methods). Furthermore, regarding the additional element of microsphere-based immunoassays, Sabhachandani et al (Microsphere-based immunoassay integrated with a microfluidic network to perform logic operations, May 2015, Microchim Acta, 182:1835–1840) discloses that microsphere-based immunoassays are currently used for disease markers (p. 1836, col 1. Para. 2).
Therefore, the additional element is not sufficient to amount to significantly more than the judicial exception.
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea (and/or natural correlation) without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Claims 60, and 64-67 are eligible subject matter since they recite specific complications with their corresponding specific treatments that are particular, have more than insignificant relationship to the exception (the administration/ treatment steps lowers the risk of pre-term labor in claim 60, lower the risk of spontaneous abortion in claim 64, lowers the risk of complications for mother and fetus in claim 65, and lowers the risk of premature delivery in claim 66), and are not extra solution activities or field of use (the administering/treatment steps in claims 60, and 64-66 applies the exception by using the mental and mathematical information of predicting and administering assessments in claim 41 to lower the mentioned risks), therefore, integrate the recites abstract ideas into a practical application.
Response to Applicant’s Remarks
Applicant's arguments filed 09/25/2025 have been fully considered but they are not persuasive.
Applicant states
Claim 41 is subject matter eligible under Step 2A Prong 2 because the claim as a whole is directed to an improved practical application of prenatal monitoring. The method of claim 41 comprises a novel determination of gestational progress of a pregnant subject using her analyte measurements as features within a trained machine-learned computational model. The computational model predicts gestational progress which is used to determine when periodical medical checkups are to occur. The method provides that clinical assessments are performed during the periodical checkups.
The claimed method is an improvement over previous methods because it is personalized and can be used when standard methods of gestation dating are less accurate.
It is respectfully submitted that this is not persuasive. The Applicant remarks are directed to Step 2A Prong Two of 101 analysis, specifically whether the additional elements integrate the recited judicial exception into a practical application of the exception.
With regards to applicant stating “the claim as a whole is directed to an improved practical application of prenatal monitoring”, Examiner submits that taken as a whole the present invention is directed to judicial exception of prenatal monitoring (see above rejection). It is important to note, the judicial exception alone cannot provide the improvement (See MPEP 2106.04(d) III). The improvement must be provided by one or more additional elements. See the discussion of Diamond v. Diehr, 450 U.S. 175, 187 and 191-92, 209 USPQ 1, 10 (1981)). In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception. See MPEP § 2106.04(d) (discussing Finjan, Inc. v. Blue Coat Sys., Inc., 879 F.3d 1299, 1303-04, 125 USPQ2d 1282, 1285-87 (Fed. Cir. 2018)). A claim for a new abstract idea is still an abstract idea.
As stated above, the additional elements of obtaining a biological sample, assaying the biological sample, entering timepoints into the computational model amount to necessary data gathering and outputting, which does not integrate the judicial exception into a practical application and does not amount to significantly more (see MPEP 2106.05(g)). These additional elements are considered insignificant extra-solution activities. As explained by the Supreme Court, the addition of insignificant extra-solution activity does not amount to an inventive concept. See MPEP 2106.05(g)(3).
With regards to Applicant stating “The method of claim 41 comprises a novel determination of gestational progress”, Examiner submits that the "‘novelty’ of any element or steps in a process, or even of the process itself, is of no relevance in determining whether the subject matter of a claim falls within the § 101 categories of possibly patentable subject matter." Intellectual Ventures I v. Symantec Corp., 838 F.3d 1307, 1315, 120 USPQ2d 1353, 1358 (Fed. Cir. 2016) (quoting Diamond v. Diehr, 450 U.S. at 188–89, 209 USPQ at 9). See also Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1151, 120 USPQ2d 1473, 1483 (Fed. Cir. 2016) ("a claim for a new abstract idea is still an abstract idea. The search for a § 101 inventive concept is thus distinct from demonstrating § 102 novelty."). In addition, the search for an inventive concept is different from an obviousness analysis under 35 U.S.C. 103. See, e.g., BASCOM Global Internet v. AT&T Mobility LLC, 827 F.3d 1341, 1350, 119 USPQ2d 1236, 1242 (Fed. Cir. 2016). See MPEP 2106.05 I.
Applicant further states:
Claim 41 is subject matter eligible under Step 2B because it recites additional elements that are not well-understood, routine, or conventional. Claim 41, on the contrary, administers clinical assessments within periodical medical checkups in accordance with a predicted gestation progress that utilizes analyte measurements from a pregnant subject's biological sample as features within a computational prediction model. It is unconventional to collect a biological sample from a pregnant subject for the purpose of determining gestational progress. It is further unconventional to predict gestational progress via a computational prediction model utilizing analyte measurements from the pregnant individual. And it is also unconventional to administer clinical assessments within periodical medical checkups in accordance with the predicted gestation progress yielded from the computational prediction model.
It is respectfully submitted that these are not persuasive. The Applicant remarks are directed to Step 2B of 101 analyses, specifically evaluating additional elements to determine whether they amount to an inventive concept by considering the additional elements both individually and in combination to ensure that they amount to significantly more than the judicial exception itself.
In response to Applicant stating that “It is unconventional to collect a biological sample, to predict gestational progress via a computational prediction model , and to administer clinical assessments within periodical medical checkups in accordance with the predicted gestation progress yielded from the computational prediction model”, Examiner submits that respectfully submits that the question of whether a particular claimed invention is novel or obvious is "fully apart" from the question of whether it is eligible. Moreover, the mentioned predicting and administering clinical assessments steps are judicial exceptions not additional elements.
In step 2B analysis, when making a determination whether the additional elements in a claim amount to significantly more than a judicial exception, the examiner should evaluate whether the elements define only well-understood, routine, conventional activity.
The additional elements of obtaining a biological sample, assaying the biological sample, entering timepoints into the computational model amount to necessary data gathering and outputting, which does not amount to significantly more (see MPEP 2106.05(g)). These additional elements are considered insignificant extra-solution activities. As explained by the Supreme Court, the addition of insignificant extra-solution activity does not amount to an inventive concept. See MPEP 2106.05(g)(3).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims, 41, 45, 48-51, 53,-54, 56-64, and 68-72 are rejected under 35 U.S.C. 103 as being unpatentable over BONIFACE et al. (AU 2014228009 A1) in view of Boniface et al. (US20180143202A1), hereinafter Boniface 2017.
Regarding claims 41 and 70, Boniface discloses a method for prenatal monitoring of pregnant ([0002], methods for determining the probability for preeclampsia in a pregnant female [0002] and predicting a probability of preeclampsia, monitoring of progress of preeclampsia in a pregnant female (abstract)), comprising: (a) obtaining a biological sample of the pregnant subject ([0013], biological sample obtained from the pregnant female); (b) assaying the biological sample of the pregnant subject for analytes to yield biomarker data, wherein the analytes comprise ([0030], biomarkers can be detected through a variety of assays) for at least two members ([0031], one or more of the isolated biomarkers) selected from the group consisting of a protein biomarker, a metabolite biomarker, ([0051], biomarkers include protein and metabolite; [0077]: quantification of analytes in MRM assay), to yield biomarker data. Boniface further discloses c) predicting, using a computational model, gestational progress of the pregnant subject, wherein the computational model has been trained to predict gestational progress from analyte measurement features, wherein the analyte measurements generated in (b) are used as features within the computational model; ([0008], The present invention provides compositions and methods for predicting the probability of preeclampsia in a pregnant female; [0023], determining probability for preeclampsia in a pregnant female encompass analyzing the measurable feature of one or more isolated biomarkers using a predictive model; [0024], determining probability for preeclampsia in a pregnant female encompass using one or more analyses selected from a linear discriminant analysis model, a support vector machine classification algorithm, a recursive feature elimination model, a prediction analysis of microarray model, a logistic regression model, a CART algorithm, a flex tree algorithm, a LART algorithm, a random forest algorithm, a MART algorithm, a machine learning algorithm, a penalized regression method, and a combination thereof; [0029], the present disclosure includes methods for generating a result useful in determining probability for preeclampsia in a pregnant female by obtaining a dataset associated with a sample, where the dataset at least includes quantitative data about biomarkers and panels of biomarkers that have been identified as predictive of preeclampsia, and inputting the dataset into an analytic process that uses the dataset to generate a result useful in determining probability for preeclampsia in a pregnant female; [00117], predict Gestational Age of time to event (preeclampsia); [00148], univariate and multivariate Cox analyses were performed using transitions collected in Example 1 to predict Gestational Age at Birth, including Gestational age on the day of specimen collection as a covariate. [00139], for the purpose of the Cox analyses, preeclampsia subjects have the event on the day of birth).
Boniface further discloses (d) administering one or more clinical assessments on the pregnant subject during one or more periodical medical checkups on the pregnant subject, wherein the one or more periodical medical checkups are to occur in accordance with the gestational progress of the pregnant subject as predicted in (c)([0028], one major advantage of the present disclosure is that risk of developing preeclampsia can be assessed early during pregnancy so that management of the condition can be initiated in a timely fashion; [00105], the output of the predictive model can be communicated to a healthcare provider, where communication informs a subsequent treatment decision for said pregnant female (claims 13 and 14)).
Further regarding claim 70, BONIFACE et al. discloses that the proteins are assayed using a multiplex proximity extension assay (PEA) or a microsphere-based multiplex assay ([0095] detection of biomarkers in microsphere multiplex assays).
Further regarding claims 41 and 70, Boniface does not expressly disclose that the computational model predicts gestational progress, Boniface 2017 discloses a method of determining probability for preterm birth in a pregnant female, the method comprising measuring in a biological sample obtained from the pregnant female one or biomarkers. Boniface further discloses analyzing a measurable feature to determine the probability for preterm birth in a pregnant female encompasses one or more of a machine learning algorithm, a penalized regression method, or a combination thereof [0124]. Boniface 2017 further discloses that the predictive model is trained using a training set comprising quantification of biomarkers to generate an algorithm [0123]. Boniface 2017 further discloses inputting biomarker data into the predictive model which will classify the sample according to the state, where the resulting information can be communicated to a patient or health care provider [0130]. Boniface 2017 further discloses that the model can be used to identify robust and accurate classifiers and predict probability of preterm birth, predicting probability of term birth, predicting gestational age at birth (GAB), predicting time to birth and/or monitoring of progress of preventative therapy in a pregnant female [0046]. methods of determining probability for preterm birth in a pregnant female encompass communicating the probability to a health care provider health care providers can implement various clinical strategies [0080].
Regarding claim 45, BONIFACE et al. Discloses assaying metabolites of the biological sample ([0025], quantifying in a biological sample obtained from the pregnant female an amount of each of N biomarkers selected from the biomarkers).
Regarding claim 48, BNIFACE et al. discloses that assaying the biological sample of the pregnant subject comprises assaying proteins of the biological sample ([0051], biomarkers include proteins).
Regarding claim 49, BONIFACE et al. discloses that the proteins are assayed using an immunoassay ([0074] the assay is an enzyme (protein) immunoassay (EIA); [0079] using an immunoassay to determine levels of biomarkers).
Regarding claim 50, BONIFACE et al. discloses that the proteins are assayed using a multiplex proximity extension assay (PEA) or a microsphere-based multiplex assay ([0095] detection of biomarkers in microsphere multiplex assays).
Regarding claim 51, BONIFACE et al. discloses that the proteins comprise one or more members selected from the group consisting of: NTRK2, LAIR2, CD200R1, LXN, DRAXIN, ROB02, CD93, NTRK3, MDGA1, CRTAM, IL12B/IL12A, RGMA, IL2RA, ESM1, FcRL2, UPAR, MCP2, IL5Ralpha, CLM1, uPA, CCL28, PCSK9, PDGFRalpha, SMPD1, SKR3, DLK1, NRP2, MSR1, GMCSFRalpha, CTSC, RET, SMOC2, PRTG, PVRL4, ST2, NrCAM, SYND1, TNFRSF12A, DDR1, CD200, GRN, and PAI1 (p. 129-164, Tables 13, 14, 18, 21-22, IL12B).
Regarding claim 53, BONIFACE et al. discloses that the computational model comprises a regression model ([00138], regression analysis for depletion batch minimization; [00143] Lasso regression
models estimate regression coefficients; [00145] Multivariate analyses using regression models; p. 167, claim 19; [0032] identification of risk using learning algorithm, for example regression).
Regarding claim 54, BONIFACE et al. discloses that the clinical assessment is selected from the group consisting of: a medical imaging, a fetal monitoring, a chorionic villus sampling, an amniocentesis, an evaluation for preeclampsia, an evaluation for gestational hypertension, an evaluation for gestational diabetes, an evaluation for preterm labor, an evaluation for signs of preterm rupture of membranes, and a glucose screening ([0032] Additional markers).
Regarding claim 56, BONIFACE et al. discloses wherein the gestational progress is selected from the group consisting of: a gestational age of the fetus, a time to delivery, a labor onset, and any combination thereof ([00139-00142] various analysis performed based on gestational age; [0005] Management decisions depend on the gestational age. [0071] gestational age of a pregnant female at the time the biological sample is collected).
Regarding claims 57 and 58, BONIFACE et al. discloses the gestational progress comprises the gestational age of the fetus ([00139-00142] various analysis performed based on gestational age). Boniface 2017 discloses predicting probability of preterm birth, predicting probability of term birth, predicting gestational age at birth (GAB), predicting time to birth (TTB) and/or monitoring of progress of preventative therapy in a pregnant female [0034].
Regarding claim 59, BONIFACE et al. discloses that the pregnancy complication is selected from the group consisting of: early maladaptive pregnancy, spontaneous abortion, gestational diabetes, gestational hypertension, gestational trophoblastic disease, preeclampsia, hyperemesis gravidarum, pre-term labor, post-term pregnancy, post-term labor, and any combination thereof (Abstract; methods and kits for determining the probability for preeclampsia in a pregnant female).
Regarding claim 60, Boniface 2017 discloses a method of determining probability for preterm birth in a pregnant female where the pregnancy complication is preterm birth (abstract). the treatment plan can include, for example, higher or additional doses of progestogen, such as 17-OHPC, closer monitoring (high intensity care management), and earlier antenatal therapy, including steroids [0035].
Regarding claim 61, BONIFACE et al. discloses that the gestational complication comprises the preeclampsia (Abstract; methods and kits for determining the probability for preeclampsia in a pregnant female). Boniface further discloses that management of preeclampsia consists of two options: delivery or observation and that reliable early detection of preeclampsia would enable planning appropriate monitoring and clinical management, potentially providing the early identification of disease complications [0005-0006]. Boniface further discloses that the treatment decision comprises one or more selected from the group of consisting of more frequent assessment of blood pressure and urinary protein concentration, uterine artery doppler measurement, ultrasound assessment of fetal growth and prophylactic treatment with aspirin. [0023].
Regarding claim 62, BONIFACE et al. discloses applying the computational model to biomarker data generated from biological samples obtained or derived from the pregnant subject at a plurality of different time points ([00108]-[00170] computational model; [0071]); and comparing the biomarker data to each other ([0066] comparing the amount of one or more biomarkers in a biological sample obtained from a pregnant female to a standard or reference score)to determine that the pregnant subject has or is at risk (risk score) of having the pregnancy complication. Boniface further discloses that for discovery of biomarkers of preeclampsia, 20 samples collected between 17-28 weeks of gestation were analyzed. Samples included 9 cases, 9 term controls matched within one week of sample collection and 2 random term controls [00133]. Boniface 2017 discloses that in order to generate a predictive model for preterm birth, a robust data set, comprising known control samples and samples corresponding to the preterm birth classification of interest is used in a training set [0131]. Boniface 2017 further discloses that the methods of determining probability for preterm birth in a pregnant female further encompass detecting a measurable feature for one or more risk indicia associated with preterm birth, where the measurable feature is characteristic or aspect that can be determined and correlated with the probability for preterm birth in a subject and/or the presence, amount, or altered structure of the biomarker as a part of a profile of more than one biomarker [0075].
Regarding claim 63, BONIFACE et al. discloses that the plurality of different time points comprise a member selected from the group consisting of: first missed menstruation, fertilization, birth, first trimester, second trimester, third trimester, 4 weeks gestation, 6 weeks gestation, 8 weeks gestation, 10 weeks gestation, 12 weeks gestation, 16 weeks gestation, 24 weeks gestation, 28 weeks gestation, 32 weeks gestation, 36 weeks gestation, 40 weeks gestation, 1 week before delivery, 2 weeks before delivery, 3 weeks before delivery, 4 weeks before delivery, 6 weeks before delivery, and 8 weeks before delivery ([0071] the gestational age of a pregnant female at the time the biological sample is collected can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 weeks).
Regarding claim 68, BONIFACE et al. discloses that the biological sample is selected from the group consisting of: a blood sample, a plasma sample, a stool sample, a urine sample, a saliva sample, and a biopsy sample ([0030] the biological sample is selected from the group consisting of whole blood, plasma, and serum).
Regarding claim 69, BONIFACE et al. discloses that the biological sample is the plasma sample ([0030] the biological sample is selected from the group consisting of whole blood, plasma, and serum).
Regarding claim 71, BONIFACE et al. discloses that the proteins comprise one or more members selected from the group consisting of: NTRK2, LAIR2, CD200R1, LXN, DRAXIN, ROB02, CD93, NTRK3, MDGA1, CRTAM, IL12B/IL12A, RGMA, IL2RA, ESM1, FcRL2, UPAR, MCP2, IL5Ralpha, CLM1, uPA, CCL28, PCSK9, PDGFRalpha, SMPD1, SKR3, DLK1, NRP2, MSR1, GMCSFRalpha, CTSC, RET, SMOC2, PRTG, PVRL4, ST2, NrCAM, SYND1, TNFRSF12A, DDR1, CD200, GRN, and PAI1 (p. 129-164, Tables 13, 14, 18, 21-22, IL12B).
Regarding claim 72, Boniface 2017 discloses determining the probability for preterm birth in a pregnant female encompasses an initial step that includes formation of a probability/risk index by measuring the ratio of isolated biomarkers selected from the group in a cohort of preterm pregnancies and term pregnancies with known gestational age at birth. For an individual pregnancy, determining the probability of for preterm birth in a pregnant female encompasses measuring the ratio of the isolated biomarker using the same measurement method as used in the initial step of creating the probability/risk index, and comparing the measured ratio to the risk index to derive the personalized risk for the individual pregnancy [0082]. Boniface 2017 further discloses that the maternal blood of the cohort was collected 170/7-286/7 weeks gestation, serum was extracted and processed by a proteomic workflow, and proteins were evaluated in each sample by multiple reaction monitoring mass spectrometry. Proteomic biomarkers with p<0.05 were considered potential candidates and were further analyzed [0158-0159]. Boniface 2017 further discloses using the cohort analyte measurements to training the predictive model [0197]; Tables 12-18; FIGs 11-12.
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 predictive model of BONIFACE to have used the known gestational progress (for example, a gestational age of the fetus, a time to delivery, a labor onset, and any combination thereof, as claimed in claim 56), as discloses by Boniface 2017 to improve detection, monitoring, and management of pregnancy complications. One of ordinary skill in the art would have been motivated to combine the methods of BONIFACE, and Boniface 2017 based on a finding that the method of Boniface contained the base method upon which the method of Boniface can be seen as improvement. One ordinary skilled in the art could have applied the known gestational progress improvement of Boniface 2017 to the method of Boniface and the results would have been predictable (Boniface 2017 [0072], although described and exemplified with reference to methods of determining probability for preterm birth in a pregnant female, the present disclosure is similarly applicable to methods of predicting an abnormal glucola test, gestational diabetes, hypertension, preeclampsia, …).
Claims 46 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Boniface (AU 2014228009 A1) in view of Boniface et al. (US20180143202A1), hereinafter Boniface 2017, as applied to claims 41, 45, 48-51, 53-54, 56-64, and 68-72 above, in view of Biro et al. (Urinary steroid profile in early pregnancy after in vitro fertilization, February 2012, Acta Obstet Gynecol Scand. 2012;91:625–629), previously cited on the [07/30/2021] IDS form, and further in view of Andreolini et al. (Improved Determination of Estriol-16a-Glucuronide in Pregnancy Urine by Direct Liquid Chromatography with Fluorescence Detection, CLINICAL CHEMISTRY 31/1, 124-126 (1985)), previously cited on the [07/30/2021] IDS form.
Regarding claims 46 and 47, BONIFACE et al. discloses a method for determining that a pregnant subject has or is at risk of having a pregnancy complication ([0002], methods for determining the probability for preeclampsia in a pregnant female), comprising: (a) obtaining a biological sample of the pregnant subject ([0013], biological sample obtained from the pregnant female); (b) assaying the biological sample of the pregnant subject ([0030], biomarkers can be detected through a variety of assays) for at least two members ([0031], one or more of the isolated biomarkers) selected from the group consisting of a protein biomarker, a metabolite biomarker, ([0051], biomarkers include protein and metabolite ), to yield biomarker data;(c) computer processing the biomarker data generated in (b)( [0085], assays used to practice the invention can be automated or performed robotically); and (d) determining that the pregnant subject has or is at the elevated risk ([0065], feature of expressing the probability as a risk score), increased risk/risk score) of having the pregnancy complication (increased likelihood of preeclampsia), based at least in part on the computer processing in (c)([0023-0024], In further embodiments, the disclosed methods of determining probability for preeclampsia in a pregnant female encompass analyzing the measurable feature of one or more isolated biomarkers using a predictive model for example a regression model).
Further regarding claim 46 and 47, BONIFACE et al. Discloses the metabolites comprise a sugar, an amino acid, a nucleotide, an antioxidant (fatty acids), an organic acid, a polyol, or a vitamin ([0029], metabolite data includes amino acids, peptides, polypeptides, proteins, nucleotides, nucleic acids, nucleosides, sugars, fatty acids, steroids, metabolites, carbohydrates, lipids, hormones, antibodies, regions of interest that serve as surrogates for biological macromolecules and combinations thereof; [0031] list of protein biomarkers in tables 2, 3, 4, 5, and 7 through 22; table 9: phosphatidylinositol-glycan-specific phospholipase D (that for example is the biosynthesis pathway of inositol)). BONIFACE does not expressly disclose that the metabolites comprise THDOC, progesterone, estriol-16-glucuronide, or DHEA-S.
Biro compares the levels of urinary steroid metabolites such as dehydrocorticosterone (DEHA-S) pregnanediol (progesterone metabolite) and tetrahydro-corticosterone (THDOC) of patients with successful in vitro fertilization and patients who failed to achieve pregnancy. Brio further determined that levels of dehydrocorticosterone (DEHA-S), pregnanediol, and tetrahydro-corticosterone (THDOC) were significantly higher in women with successful pregnancy. Biro further discloses that the production of androgens, progesterone and corticoid steroid metabolites is altered in the early pregnancy period after in vitro fertilization (abstract).
Further regarding claims 46 and 47, Andreolini determines estriol-16a-glucuronide in pregnancy urine for the purpose of monitoring fetal well-being (pg. 124, para. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of BONIFACE to have used the known metabolites of Biro (Abstract) and Andreolini (pg. 124, para. 1-2) to improve detection of pregnancy complications. One of ordinary skill in the art would have been motivated to combine the methods of BONIFACE, Biro, and Andreolini based on a finding that at the time of the invention there had been a recognized problem of relation of DEHA-S, progesterone metabolites, THDOC, and estriol-16-glucuronide with fetal/pregnancy complications. One of ordinary skill in the art could have combined the metabolite list of BONIFACE to include DEHA-S, progesterone metabolites, THDOC, and estriol-16- glucuronide metabolite of Biro and Andreolini to detect fetal/pregnancy complication and the results of the combination would have been predictable because assaying DEHA-S, progesterone metabolites, THDOC, and estriol-16-glucuronide can be employed to detect gestational complications.
Claims 64 is rejected under 35 U.S.C. 103 as being unpatentable over Boniface (AU 2014228009 A1) in view of Boniface et al. (US20180143202A1), hereinafter Boniface 2017, as applied to claims 41, 45, 48-51, 53-54, 56-63, and 68-72 above, in view of Wahabi et al. (Progestogen for treating threatened miscarriage, published in Issue 9, 2018, Cochrane Database of Systematic Reviews).
Claim 64 depends on claim 59. Limitations of claim 59 has been taught in the above rejections.
Regarding claim 64, BONIFACE et al. discloses administering a treatment to the pregnant subject for the pregnancy complication based on the determining in (d) ([0064] [0098] treatment). Boniface 2017 discloses selecting additional markers including spontaneous abortions [0056] and that the treatment includes progesterone therapy [0049] [0197]. Boniface and Boniface 2017 do expressly disclose that the administering estrogen or progesterone for spontaneous abortion. Wahabi discloses that Progesterone's physiological role is to prepare the uterus for the implantation of the embryo, enhance uterine quiescence and suppress uterine contractions, hence, it may play a role in preventing rejection of the embryo. Inadequate secretion of progesterone in early pregnancy has been linked to the a etiology of miscarriage and progesterone supplementation has been used as a treatment for threatened miscarriage to prevent spontaneous pregnancy loss (Background).
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 used the progesterone treatment of Wahabi for spontaneous abortion of Boniface 2017. One of ordinary skill in the art could have used the progesterone of Wahabi and the result would have been predictable because progesterone supplementation has been used as a treatment for threatened miscarriage to prevent spontaneous pregnancy loss, as stated by Wahabi (abstract).
Claims 65 is rejected under 35 U.S.C. 103 as being unpatentable over Boniface (AU 2014228009 A1) in view of Boniface et al. (US20180143202A1), hereinafter Boniface 2017, as applied to claims 41, 45, 48-51, 53-54, 56-63, and 68-72 above, in view of Thangarajah et al. (Induction of Labour in Late and Postterm Pregnancies and its Impact on Maternal and Neonatal Outcome, Geburtshilfe Frauenheilkd. 2016 Jul;76(7):793–798).
Claim 65 depends on claim 41. Limitations of claim 41 has been taught in the above rejections.
Regarding claim 65, BONIFACE et al. discloses ([0005] management of preeclampsia consists of delivery or observation; [0022] prophylactic treatment with aspirin). Boniface 2017 discloses methods of predicting postterm pregnancy [0072]. Thangarajah discloses that women with uncomplicated pregnancies should usually be offered induction of labour (IOL) between 41 + 0 and 42 + 0 weeks to avoid the risks of prolonged pregnancy (pg. 794, col. 1, first para.; Introduction).
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 used the labor induction treatment of Thangarajah for post-term pregnancies of Boniface 2017. One of ordinary skill in the art could have used the labor induction of Thangarajah and the result would have been predictable because labor induction has been used as a treatment for prolong pregnancies, as stated by labor induction (abstract).
Claims 66 and 67 are rejected under 35 U.S.C. 103 as being unpatentable over Boniface (AU 2014228009 A1) in view of Boniface et al. (US20180143202A1), hereinafter Boniface 2017, as applied to claims 41, 45, 48-51, 53-54, 56-64, and 68-72 above, in view of T C et al. (Tocolytic treatment for the management of preterm labour: A systematic review, June 2006, Singapore Medical Journal 47(5):361-6).
Regarding claims 66 and 67, BONIFACE et al. discloses a method for determining that a pregnant subject has or is at risk of having a pregnancy complication ([0002], methods for determining the probability for preeclampsia in a pregnant female), comprising: (a) obtaining a biological sample of the pregnant subject ([0013], biological sample obtained from the pregnant female); (b) assaying the biological sample of the pregnant subject for analytes to yield biomarker data, wherein the analytes comprise ([0030], biomarkers can be detected through a variety of assays) for at least two members ([0031], one or more of the isolated biomarkers) selected from the group consisting of a protein biomarker, a metabolite biomarker, ([0051], biomarkers include protein and metabolite; [0077]: quantification of analytes in MRM assay), to yield biomarker data;(c) applying a computational model to the biomarker data generated in (b) ( [0085], assays used to practice the invention can be automated or performed robotically; [00108]-[00170] use of various computer software to process computational models/algorithms for processing biomarker data, such as K-means-like, random forest, Cox models, …) to predict gestational progress of the pregnant subject ([0005]: Management of preeclampsia consists of two options: delivery or observation. Management decisions depend on the gestational age (for example, gestational progress; [0071]: the gestational age of a pregnant female at the time the biological sample is collected) at which preeclampsia is diagnosed and the relative state of health of the fetus ; [00140]: the analysis was done according to center, gestational age (for example, gestational progress) and ethnicity); and (d) determining that the pregnant subject has or is at risk ([0065], feature of expressing the probability as a risk score), increased risk/risk score) of having the pregnancy complication (increased likelihood of preeclampsia), based at least in part on the predicting gestational progress in (c)([0023-0024], In further embodiments, the disclosed methods of determining probability for preeclampsia in a pregnant female encompass analyzing the measurable feature of one or more isolated biomarkers using a predictive model for example a regression model; [0071]: the gestational age of a pregnant female at the time the biological sample is collected) at which preeclampsia is diagnosed and the relative state of health of the fetus ; [00140]: the analysis was done according to center, gestational age (for example, gestational progress) and ethnicity).
Further regarding claims 66 and 67, BONIFACE et al. discloses that the treatment is selected from the group consisting of: a medication ([0005] management of preeclampsia (pregnancy complication) consists of delivery or observation; [0022] prophylactic treatment with aspirin (medication)).
Further regarding claim 66, BONIFACE et al. does not expressly disclose that wherein the pregnant subject is determined to be having premature contractions, the medication comprises a tocolytic medication. However, T C et al. reviews the effectiveness of tocolytics to stop uterine contractions (first-line therapy) and discloses use of tocolytic treatment for the management of preterm labor (abstract).
Further regarding claim 67, BONIFACE et al. does not expressly disclose that the tocolytic medication is selected from the group consisting of: indomethacin, magnesium sulfate, orciprenaline, ritodrine, terbutaline, salbutamol, nifedipine, fenoterol, nylidrin, isoxsuprine, hexoprenaline, and atosiban. However, T C et al. discloses use of tocolytic treatment such as indomethacin for the management of preterm labor (p. 362, col. 2, para. 1).
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 used the treatment of BONIFACE for a pregnancy complication with the tocolytic treatment of T C et al. for preterm labor/premature contractions. One of ordinary skill in the art could have used the tocolytic treatment of T C et al. and the result of the substitution would have been predictable because tocolytics are associated with significant decreases in the odds of delivery and therefore effective in complications such as preterm labor as stated by T C et al (abstract).
Response to Applicant’s Remarks
Applicant's arguments filed 09/25/2025 have been fully considered but they are not persuasive.
Applicant states
Claim 41 is novel and patentable because the cited references neither teach neither teach or make obvious: "(c) predicting, using a computational model, gestational progress of the pregnant subject; ... wherein thee analyte measurements generated in (b) are used as features within the computational model; and (d) administering one or more clinical assessments on the pregnant subject during one or more periodical medical checkups on the pregnant subject, wherein the one or more periodical medical checkups are to occur in accordance with the gestational progress of the pregnant subject as predicted in (c)."
In the rejection of claim 41, the Office Action relied upon the Boniface reference to allege the claim is anticipated, suggesting that the reference teaches that the reference teaches the use of biomarkers to teach an increased likelihood of preeclampsia. The Office reasserted that prediction of gestational progress is recited within the Boniface reference but failed to list any citations of computational prediction of gestational progress. This concept of computationally predicting gestational progress is not taught or made obvious by the Boniface reference. Further, none of the cited references make up for the deficiencies of the Boniface reference.
It is respectfully submitted that this is not persuasive. The amendments to the claims necessitated a new round of art rejections. As such, the new combination of art rejections teaches all limitations of claims.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ngo et al. (Noninvasive blood tests for fetal development predict gestational age and preterm delivery, American Association for the Advancement of Science, Published in June 8, 2018; Pages1133 - 1136). Ngo et al. developed two noninvasive blood tests that provide a window into the progression of individual pregnancies. The first blood test predicted fetal age and delivery date with an accuracy comparable to that of ultrasound using biomarker data. The second blood test, discriminated women at risk of preterm delivery from those who delivered at full term. Ngo further disclosed that noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care.
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/G.S./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686