DETAILED ACTION
Applicant’s response, filed 06 Nov. 2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-115, 117-118, 121-132, 141, 143-144, 151, 159, and 161 are cancelled.
Claims 162-169 are newly added.
Claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 are pending.
Claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 are rejected.
Priority
The effective filing date of the claimed invention is 31 Jan. 2018.
Claim Objections
The objection to claims 138-140, 142, and 154-156 in the Office action mailed 06 May 2025 has been withdrawn in view of claim amendments received 06 Nov. 2025.
Claim Interpretation
Claims 136-137 recite “…wherein the subject is between 10-12 weeks of gestation at the time the sample is obtained”. Claim 116, from which claims 136-137 depend, recites “…determining measurements associated with a panel of markers in microparticle-enriched fraction from a plasma or serum sample from the subject”. Because claim 116 only requires determining measurements from an already obtained microparticle-enriched fraction generated from a plasma or serum sample, claims 136-137 are interpreted to define the process in which the sample of the subject was previous obtained. See MPEP 2113.
Response to Arguments
Applicant's arguments filed 06 Nov. 2025 regarding claim interpretation have been fully considered but they do not clearly present any arguments.
Applicant remarks claims 136 and 137 have been amended to recite “wherein the subject is between 10-12 weeks gestation at the time the sample is obtained”, which clarifies the nature of the sample rather than incorporating any particular method step in the claim (Applicant’s remarks at pg. 6, para. 8-9).
The previous claim interpretation has not been changed. It is agreed that claims 136-137 merely clarify the nature of the sample, and do not incorporate a method step in the claim. In other words, claims 136-137 are defining the product (i.e. the sample) according to how it was previously obtained (the process), but the claims do not require a step of obtaining the sample between 10-12 weeks of gestation.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brohman (2017). Any newly recited portion is necessitated by claim amendment.
Cited reference: Brohman, WO 2017096405 A1; Pub. Date 08 June 2017; cited on IDS filed 17 Nov. 2020; previously cited.
Regarding claim 116, Brohman discloses a method of treating a subject at high risk of spontaneous preterm birth (Abstract), comprising the following steps:
Brohman discloses determining a subject as being at high risk of preterm birth ([0062]) by performing the following steps.
Brohman discloses determining a quantitative measure of a panel of microparticle-enriched fraction of a blood sample from a pregnant subject (Claim 1; [0008]), wherein the blood sample is a plasma or serum sample ([0008]).
Brohman discloses executing a classification rule based on the measurements ([0008]; [0014]).
Brohman discloses the classification rule has an ROC with an AUC of at least 0.7 ([0070]).
Brohman discloses the execution of the classification rule stratifies the subject as being at high risk, moderate risk, or low risk ([0019]; [0062]).
Brohman discloses the panel of markers includes FBLN1, IC1, LCAT, and ITIH2 ([0008]; [0017], e.g. one or more proteins selected from…). Brohman discloses the panel comprises at least three proteins selected from a group of only 21 proteins ([0008]), and thus one of ordinary skill in the art would at once envisage that no more than 8 proteins are selected and could include FBLN1, IC1, LCAT, and ITIH2. See MPEP 2131.02 III.
Brohman discloses administering to the subject determined to be at high risk, a cervical cerclage, vaginal progesterone, or parenteral 17-alpha-hydrozyprogesterone caproate ([0071]).
Regarding claim 119, Brohman discloses the classification rule has a sensitivity of at least 75% ([0019]).
Regarding claim 120, Brohman discloses the classification rule produces a correlation between preterm birth and term birth with a p value of less than at least 0.05 (claim 36).
Regarding claims 133-135, Brohman discloses controls were matched to subjects based on parity (i.e. nulliparous, primiparous, multiparous) ([0107]), and furthermore that the classification rule considers if a subject is primiparous ([0008]), as opposed to nulliparous or multiparous. Given Brohman takes into account whether a subject is primiparous, and subject is inherently nulliparous, primiparous, or multiparous, this is considered to read on the claims.
Regarding claims 136-137, Brohman discloses the subject is at 10-12 weeks gestation or 18-24 weeks gestation ([0014]; [0049]).
Regarding claims 138-140, and 142, Brohman discloses the panel can further IT1H4, F13A, and TRFE ([0049]; [0051]).
Regarding claim 145, Brohman discloses the panel includes at least 7 markers ([0008];[0051]).
Regarding claim 146-148, Brohman discloses the measurements are determined by an immunoassay ([0066]), mass spectrometry ([0008], or liquid chromatography-mass spectrometry ([0008]).
Regarding claim 149-150, Brohman discloses the classification rule is generated by a machine learning algorithm including binary decision trees, artificial neural networks, discriminant analyses, logistic classifiers, or support vector classifiers ([0008]).
Regarding claims 152-153, Brohman discloses the classification rule assigns a probability of the risk of preterm birth ([0062]), and this risk can be stratifies according to gestational age ([0063]).
Regarding claims 154-156, Brohman discloses the risk is of preterm birth at or before 34 weeks gestation, 33 weeks gestation or 23 weeks gestation ([0063]).
Regarding claims 157-158 and 160, Brohman discloses the treatment comprises cervical cerclage, vaginal progesterone, or 17-alpha-hydroxyprogesterone caproate ([0071]).
Regarding claims 162-165, Brohman discloses the panel further comprises TRFE, IT1H4, and HEMO ([0017]). The panel of Brohman includes a sufficiently limited list of proteins from which one or more proteins may be selected, which anticipates the panel of no more than 8 proteins. See MPEP 2131.02 III.
Regarding claims 166-169, Brohman discloses the subject has a hazard ratio of over 3.0 for preterm birth ([0064]).
Therefore, Brohman anticipates the claimed invention.
Response to Arguments
Applicant's arguments filed 06 Nov. 2025 regarding 35 U.S.C. 102(a)(1) have been fully considered but they are not persuasive.
Applicant remarks that claim 116 recites the classification rule stratifies a subject as being at high risk, moderate risk, or low risk of spontaneous preterm birth, and Broman refers to classifying a subject being at high risk of preterm birth, but Applicant does not see where the classification rule classifies subjects and to any of the other two categories, and thus the rejection should be withdrawn (Applicant’s remarks at pg. 6, para. 10 to pg. 7, para. 3).
This argument is not persuasive. Claim 116 broadly recites that execution of a “classification rule” stratifies the subject as being at high risk, moderate risk, or low risk of spontaneous preterm birth.
Brohman at para. [0062] states that “In some embodiments, assessing risk of spontaneous preterm birth involves assigning a probability on the risk of preterm birth. In some embodiments, assessing risk of spontaneous preterm birth involves stratifying a pregnant subject as being at high risk, moderate risk, or low risk of spontaneous preterm birth.”. Thus Brohman demonstrates the “classification rule” is able to stratify between high, moderate versus low risk of spontaneous preterm birth.
It is further noted that Brohman discloses an embodiment in which the classification rules classifies a subject as belonging to a preterm birth class (a high risk of spontaneous preterm birth) or a term birth class (i.e. a low risk of spontaneous preterm birth) ([0019]), which is also considered to read on the claim, given claim 116 only require execution of classification rule stratifies the subject as being at high risk, under the broadest reasonable interpretation of the claim.
Claim Rejections - 35 USC § 103
The rejection of claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 under 35 U.S.C. 103 as being unpatentable over Hickok (2016) in view of Cantonwine (2020) in the Office action mailed 06 May 2025 has been withdrawn in view of claim amendments received 06 Nov. 2025.
Applicant’s arguments at pg. 9, para. 5 to pg. 10, para. 4 are persuasive. In particular, Hickok in view of Cantonwine do not make obvious a panel of markers comprising specifically FBLN1, IC1, LCAT, and ITIH2 that does not comprise more than eight proteins.
Double Patenting
The provisional rejection of claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. US 10,928,402 B2 in view of Hickok (2016) in the Office action mailed 06 May 2025 has been withdrawn in view of claim amendments filed 06 Nov. 2025. However, a new grounds of rejection is set forth below in view of the amendment.
The provisional rejection of claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/494,607 (reference application) in view of Hickok (2016) and Cantonwine (2020) in the Office action mailed 06 May 2025 has been withdrawn in view of claim amendments filed 06 Nov. 2025. However, a new grounds of rejection is set forth below in view of the amendment.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 116, 119-120, 133-140, 142, 145-150, 152-168, 160, and 162-169 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. US 10,877,046 B2 in view of Hickok (2016). This rejection is previously recited.
Cited reference:
Hickok et al., US 2017/0146548 A1; Pub. Date 25 May 2017; Filed 5 Oct. 2016; previously cited.
Regarding instant claim 116, reference claim 1 discloses a method for treating a pregnant human comprising the following:
Reference claim 1 discloses characterizing a panel having micro-particle-associated proteins, wherein the panel comprises IC1, LCAT, FBLN1, F13A, and ITIH2, from a blood sample from the pregnant subject and that the measured panel indicates an increased risk of spontaneous preterm birth.
Reference claim 1 further discloses administering a cervical cerclage, a hormone, or a corticosteroid to the subject at the increased risk of preterm birth.
Regarding instant claim 133, reference claim 3 discloses the subject is primigravida (i.e. nulliparous).
Regarding instant claims 136-137¸ reference claim 4 discloses the sample is taken during the first trimester (i.e. 0-12 weeks), which encompasses the claimed range of 10-12 weeks, or that the sample is taken during the second trimester (i.e. 14-27 weeks), which encompasses the claimed range of 18-24 weeks of gestation. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Regarding instant claim 138¸ reference claim 1 discloses the panel comprises (i) at least plasma protease C1 inhibitor (IC1), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and lecithin-cholesterol acyltransferase (LCAT).
Regarding instant claim 139, reference claim 1 discloses the panel comprises, IC1, LCAT, fibulin 1 (FBLN1), coagulation factor XIII A chain (F13A) and inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).
Regarding instant claim 140¸ reference claim 1 discloses the panel includes ICI, LCAT, TRFE, and FBLN1.
Regarding instant claim 142, reference claim 1 discloses the panel comprises F13A, FBLN1, IC1, and LCAT.
Regarding claims 145, reference claim 1 discloses biomarkers of the panel can include IC1, ITIH4, LCAT, TRFE, FBLN1, ITIH2, F13A.
Regarding instant claim 147-148, reference claim 12 discloses the quantitative measure is determined by liquid chromatography/mass spectrometry.
Regarding instant claims 154-156, the reference claims disclose the sample from the subject can be analyzed during the first trimester (i.e. between 0-12 weeks gestation), which demonstrates the subject is determined to be at risk of preterm birth before 34, 33, or 32 weeks of gestation, respectively.
Regarding instant claim 157, reference claim 1 discloses the treatment is cervical cerclage.
Regarding instant claim 158, reference claim 1 discloses the treatment is a hormone or corticosteroid.
Regarding instant claim 160, reference claim 2 discloses the treatment is vaginal progesterone or 17-alpha-hydroxyprogesterone caproate.
Regarding instant claims 162-163, reference claim 1 discloses the panel includes ITIH4 and TRFE.
The reference claims do not disclose the following limitations:
Further regarding instant claim 116, the reference claims do not disclose the subject is determined to be at an increased risk by execution of a classification rule with an ROC-AUC of at least 0.7 that determines a risk of spontaneous preterm birth, or that the classification rule stratifies the subject into low, moderate, or high risk.
Regarding instant claim 119-120, the reference claims do not disclose the classification rule has a sensitivity of at least 75% and produces a correlation between preterm birth and a term birth with a p-value of less than at least 0.05, respectively.
Regarding instant claims 134-135, the reference claims do not disclose the sample is primiparous, or multiparous.
Regarding instant claim 146, the reference claims do not disclose the measurements are determined by immunoassay.
Regarding instant claims 149-150, the reference claims do not disclose the classification rule is a machine learning algorithm, including a support vector machine.
Regarding instant claims 152 the reference claims do not disclose the classification rule stratifies the subject as being high risk, moderate risk, or low risk, as recited in claim 151, and that the classification rule further assigns a probability of spontaneous preterm birth, as recited in instant claims 152 and 161.
Regarding instant claim 153, the reference claims do not disclose determining a probability of spontaneous preterm birth as a function of gestational age.
Regarding instant claims 164-165, the reference claims do not disclose the panel includes HEMO.
Regarding instant claims 167-169, the reference claims do not disclose the subject has a hazard ratio of over 3.0 for preterm birth.
However, these limitations were known in the prior art, before the effective filing date of the claimed invention, as shown by Hickok.
Regarding instant claims 116, 119-120, 134-135, 146, 149-153, and 164-169, Hickock discloses a method for predicting a probability of pre-term birth in a female (Abstract; claim 1), which includes determining the pregnant female is at risk for preterm birth ([0007]) by quantifying a panel of biomarkers from proteins attached to enriched microparticles using an immunoassay, from a plasma sample of the pregnant female ([0037], e.g. panel of biomarkers used to predict preterm birth; [0085], e.g. sample is plasma; [0091]; [0096], e.g. immunoassay; [0103], e.g. quantification of biomarkers; [0108]; [0111]-[0112]).
Hickok discloses using a predictive model (i.e. classification rule) to analyze the measured biomarkers ([0117]-[0118]) to determine a probability for spontaneous preterm birth ([0086], e.g. methods directed to determine the probability of spontaneous preterm birth; [0117], e.g. model determines the probability; [0120]). Hickok discloses the biomarkers include HEMO (Table 8). Hickok further discloses the predictive model has an area under the curve of the ROC curve of at least 0.75 ([0121]), has a sensitivity of at least 0.8 ([0122]), and that the predictive model uses proteins with p-values less than 0.5 showing differences between cases (i.e. pre-term birth) and controls (term birth) ([00162]; [0169]; [0174]; [00233]; Tables 1, 7, 54, and 55). Hickok discloses the predictive model classifies the subject at being at a high risk of preterm birth when the probability is at least 80% or higher ([0120]), which shows the subject has a hazard ratio of over 3.0 (i.e. a probability of at least 75%) for preterm birth. Hickok further discloses using the past pregnancy history of the subject, including whether the female had a previous preterm birth (i.e. the subject is primiparous) or that the subject had multiple gestations (i.e. the subject is multiparous) ([0042]) Hickok further discloses the predictive model is a support vector machine classification algorithm ([0030]; [0117]), and that the predictive model classifies the sample as belonging to a particular class based on a cutoff ([0120]), and the cutoffs delineate between term birth (i.e. low risk), pre-term birth, moderate preterm birth (i.e. moderate risk), very preterm birth (i.e. high risk) ([0086]). Hickok further discloses the predictive model predicts the probability of preterm birth based on a predicted gestational age ([0132]; [0188]-[0190]). Hickok further discloses the above method is able to classify a sample at a risk of preterm with an accuracy of at least 0.95, as shown by Hickock ([01210]).
It would have been prima facie obvious, to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims with the method of Hickok, to have determined the biomarker measurements using an immunoassay in a subject that is primiparous or multiparous, utilizing a support vector machine to provide a probability of and/or stratify the subject as being a high risk of spontaneous pre-term abortion as recited in the instant claims, and shown by Hickok above. One of ordinary skill in the art would have been motivated combine the methods of the reference claims with Hickok to classify a sample at a risk of preterm with an accuracy of at least 0.95, as shown by Hickok ([01210]). This modification would have had a reasonable expectation of success given both the reference claims and Hickok analyze biomarkers determined from microparticles from plasma to predict preterm birth, such that the method of Hickok is applicable to determine to administer a treatment as in the reference claims.
Regarding claim 142 and 144-145 the reference claims do not disclose the panel specifically includes TRFE, with ICI, ITIH4, and LCAT, or that the panel of markers comprise at least six or seven markers, as recited in instant claim 145. However, as discussed above, reference claim 1 discloses biomarkers of the panel can include IC1, ITIH4, LCAT, TRFE, FBLN1, ITIH2, F13A (i.e. at least 7 biomarkers are associated with predicting preterm birth).
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 reference claim 1, to have combined the biomarkers of the various panels in (i)-(iv). One of ordinary skill in the art would have been motivated to combine the biomarkers in the reference claims 1based on combining the different known panels of reference claim 1, given reference claim 1 discloses the biomarkers indicate a risk of preterm birth, as discussed above. Furthermore, the combination of biomarkers would have predictably resulted in a set of biomarkers capable indicating a risk of preterm birth, given each of the biomarkers is associated with preterm birth.
Claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. US 10,928,402 B2 in view of Brohman (2017). This rejection is newly recited and necessitated by claim amendment.
Cited reference: Brohman, WO 2017096405 A1; Pub. Date 08 June 2017; cited on IDS filed 17 Nov. 2020; previously cited.
Regarding instant claim 116, reference claim 1 discloses a method for treating a subject at risk of preterm birth, comprising the following:
Reference claim 1 discloses detecting levels of ITIH4, TF, (TRFE) and IC1 (e.g. SERPING1) in microparticles from blood of a pregnant subject.
Reference claim 1 discloses determining the pregnant subject is at risk of preterm birth when the levels of the biomarkers are above a threshold level.
Reference claim 1 further discloses administering cervical cerclage or progesterone to the subject.
Regarding instant claims 134-135, reference claim 1 discloses the subject is multigravida or primigravida.
Regarding instant claim 136, reference claim 4 discloses the subject is at 10, 11, or 12 weeks gestation.
Regarding instant claim 137, reference claim 3 discloses the sample was taken from the subject in the second trimester (i.e. 14-27 weeks), which encompasses the claimed range of 18-24 weeks of gestation. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Regarding instant claims 147-148, reference claim 8 discloses the measurements are determined using liquid chromatography/mass spectrometry.
Regarding instant claims 154-156, reference claim 1 discloses the subject is at 8 to 20 weeks gestation (i.e. before 32-43 weeks gestation).
Regarding instant claim 157 reference claim 1 discloses administering cervical cerclage or progesterone to the subject.
Regarding instant claims 162-163 reference claims 1-2 disclose the markers include TF (TRFE), and ITIH4.
Further regarding instant claim 116, the reference claims do not disclose the biomarkers include FBLN1, LCAT, or ITIH2, that the subject is determined to be at an increased risk by execution of a classification rule with an ROC-AUC of at least 0.7 that determines a risk of spontaneous preterm birth and stratifies the subject into low, medium or high risk groups.
Regarding instant claim 119-120, the reference claims do not disclose the classification rule has a sensitivity of at least 75% and produces a correlation between preterm birth and a term birth with a p-value of less than at least 0.05, respectively.
Regarding instant claims 133, the reference claims do not disclose the sample is nulliparous
Regarding instant claim 145 and the reference claims do not disclose the panel of markers includes at least 7 markers from the recited group.
Regarding instant claim 146, the reference claims do not disclose the measurements are determined by immunoassay.
Regarding instant claims 149-150, the reference claims do not disclose the classification rule is a machine learning algorithm, including a support vector machine.
Regarding instant claims 152 the reference claims do not disclose t the classification rule further assigns a probability of spontaneous preterm birth, as recited in instant claims 152.
Regarding instant claim 153, the reference claims do not disclose determining a probability of spontaneous preterm birth as a function of gestational age.
Regarding instant claims 158 and 160 the reference claims do not disclose the treatment is a hormone, including vaginal progesterone or 17-alpha-hydroxyprogesterone caproate.
Regarding instant claims 164-165, the reference claims do not disclose the markers include HEMO.
Regarding instant claims 166-169, the reference claims do not disclose the subject has a hazard ratio of over 3.0 for preterm birth.
However, these limitations were known in the prior art, before the effective filing date of the claimed invention, as shown by Brohman.
Regarding instant claims 116, 119-120, 133, 145, 146, 149-150, 152-153, 158, 160, and 166-169, Brohman discloses a method of treating a subject at high risk of spontaneous preterm birth (Abstract), comprising the following steps: Brohman discloses determining a subject as being at high risk of preterm birth ([0062]) by performing the following steps. Brohman discloses determining a quantitative measure of a panel of microparticle-enriched fraction of a blood sample from a pregnant subject (Claim 1; [0008]), wherein the blood sample is a plasma or serum sample ([0008]). Brohman discloses executing a classification rule based on the measurements ([0008]; [0014]). Brohman discloses the classification rule has an ROC with an AUC of at least 0.7 ([0070]).
Brohman discloses the execution of the classification rule stratifies the subject as being at high risk, moderate risk, or low risk ([0019]; [0062]). Brohman discloses the panel of markers includes FBLN1, IC1, LCAT, and ITIH2 ([0008]; [0017], e.g. one or more proteins selected from…). Brohman discloses the panel comprises at least three proteins selected from a group of only 21 proteins ([0008]). Brohman discloses the classification rule has a sensitivity of at least 75% ([0019]). Brohman discloses the classification rule produces a correlation between preterm birth and term birth with a p value of less than at least 0.05 (claim 36). Brohman discloses controls were matched to subjects based on parity (i.e. nulliparous, primiparous, multiparous) ([0107]), and furthermore that the classification rule considers if a subject is primiparous ([0008]), as opposed to nulliparous or multiparous. Given Brohman takes into account whether a subject is primiparous, and subject is inherently nulliparous, primiparous, or multiparous, this is considered to read on the claims. Brohman discloses the panel includes at least 7 markers ([0008];[0051]).Brohman discloses the measurements are determined by an immunoassay ([0066]), mass spectrometry ([0008], or liquid chromatography-mass spectrometry ([0008]). Brohman discloses the classification rule is generated by a machine learning algorithm including binary decision trees, artificial neural networks, discriminant analyses, logistic classifiers, or support vector classifiers ([0008]). Brohman discloses the classification rule assigns a probability of the risk of preterm birth ([0062]), and this risk can be stratifies according to gestational age ([0063]). Brohman discloses the treatment comprises cervical cerclage, vaginal progesterone, or 17-alpha-hydroxyprogesterone caproate ([0071]). Brohman discloses the subject has a hazard ratio of over 3.0 for preterm birth ([0064]).
It would have been prima facie obvious, to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims with the method of Brohman, to have determined the biomarker measurements for at least seven biomarkers from the recited group, using an immunoassay in a subject that is nulliparous, utilized a support vector machine to provide a probability of and/or stratify the subject as being a high risk of spontaneous pre-term abortion as recited in the instant claims, and treat the subject with vaginal progesterone, as shown by Hickok above. One of ordinary skill in the art would have been motivated combine the methods of the reference claims with Brohman to classify a sample at a risk of preterm with an AUC of at least 0.95 and inform treatment decisions of the subject, as shown by Brohman ([0008]; [0070]). This modification would have had a reasonable expectation of success given both the reference claims and Brohman analyze biomarkers determined from microparticles from plasma to predict preterm birth, such that the method of Brohman is applicable to determine to administer a treatment as in the reference claims.
Claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/494,607 (reference application) in view of Brohman (2017). This rejection is newly recited and necessitated by claim amendment.
Cited reference: Brohman, WO 2017096405 A1; Pub. Date 08 June 2017; cited on IDS filed 17 Nov. 2020; previously cited.
Regarding instant claim 116, reference claim 1 discloses a method for assessing the risk of preterm birth in a pregnant subject comprising:
Reference claims 1 and 20 discloses determining measurements of a panel of proteins in a micro-particle enriched fraction from a pregnant subject, wherein the proteins include, SERPING (i.e. IC1), TF (i.e. TRFE), ITIH1, ITIH2, and FBLN1 (i.e. less than eight proteins).
Reference claims 1 and 20 discloses determining the subject is at an increased risk of preterm birth based on the measurements of the protein being below a threshold.
Reference claim 20 further discloses administering a hormone or steroid to the subject to decrease the risk of preterm birth.
Regarding instant claims 134-135, reference claims 8-9 disclose the pregnant subject is primigravida or multigravida (i.e. primiparous or multiparous), respectively.
Regarding instant claim 136, reference claim 11 discloses the sample is taken from the subject within 15 weeks of gestation, which encompasses the range of 10-12 weeks. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Regarding instant claim 137, reference claim 11 discloses the sample is taken during the second trimester, (i.e. 14-27 weeks), which encompasses the claimed range of 18-24 weeks of gestation. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Regarding instant claim 145, reference claims 1 and 20 discloses the proteins include, SERPING (i.e. IC1), TF (i.e. TRFE), ITIH1, ITIH2, KNG1, CD5L, and APOL1 (i.e. at least seven markers from the group).
Regarding instant claim 146, reference claims 17-18 discloses the measuring involves antibody binding to each protein or an enzyme-linked immunosorbent assay (i.e. an immunoassay).
Regarding instant claims 147-148, reference claim 19 discloses the measuring uses liquid chromatography/mass spectrometry.
Regarding instant claims 154-156, reference claim 11 discloses the sample of the pregnant subject is taken within 15 weeks of gestation, such that the subject is determined to be at risk of preterm birth before 32-34 weeks of gestation.
Regarding instant claim 161, reference claims 1 and 20 discloses the proteins include, SERPING (i.e. IC1), TF (i.e. TRFE), ITIH1, ITIH2, KNG1, CD5L, and APOL1 (i.e. at least seven markers from the group).
Regarding instant claim 162, reference claims 1 and 20 discloses determining measurements of a panel of proteins in a micro-particle enriched fraction from a pregnant subject, wherein the proteins include, TF (i.e. TRFE).
Further regarding instant claim 116, the reference claims do not disclose the biomarkers include LCAT or determining the subject is at risk of preterm birth by executing a classification rule based on the measurements to determine the risk of preterm birth, wherein the classification rule has an ROC-AUC value of at least 0.7, or stratifying the subject as claimed.
Regarding instant claims 119-120, the reference claims do not disclose the classification rule has a sensitivity of at least 75% and produces a correlation between preterm birth and a term birth with a p-value of less than at least 0.05, respectively.
Regarding instant claims 133, the reference claims do not disclose the sample is nulliparous.
Regarding instant claims 149-150, the reference claims do not disclose the classification rule is a machine learning algorithm, including a support vector machine.
Regarding instant claims 152, the reference claims do not disclose that the classification rule further assigns a probability of spontaneous preterm birth, as recited in instant claims 152 and 161.
Regarding instant claim 153, the reference claims do not disclose determining a probability of spontaneous preterm birth as a function of gestational age.
Regarding instant claim 157, the reference claims do not disclose the treatment is cervical cerclage.
Regarding instant claim 158 or 160, the reference claims do not disclose the progesterone treatment is vaginal or is 17-alpha-hydrozyporgesterone caproate.
Regarding instant claims 163-165, the reference claims do not disclose the biomarkers include ITIH4 and HEMO.
Regarding instant claims 166-169, the reference claims do not disclose the subject has a hazard ratio of over 3.0 for preterm birth.
However, these limitations were known in the prior art, before the effective filing date of the claimed invention, as shown by Brohman.
Regarding instant claims 116, 119-120, 133, 149-150, 152-153, 157, and 160, Brohman discloses a method of treating a subject at high risk of spontaneous preterm birth (Abstract), comprising the following steps: Brohman discloses determining a subject as being at high risk of preterm birth ([0062]) by performing the following steps. Brohman discloses determining a quantitative measure of a panel of microparticle-enriched fraction of a blood sample from a pregnant subject (Claim 1; [0008]), wherein the blood sample is a plasma or serum sample ([0008]). Brohman discloses executing a classification rule based on the measurements ([0008]; [0014]). Brohman discloses the classification rule has an ROC with an AUC of at least 0.7 ([0070]).
Brohman discloses the execution of the classification rule stratifies the subject as being at high risk, moderate risk, or low risk ([0019]; [0062]). Brohman discloses the panel of markers includes FBLN1, IC1, LCAT, ITIH2, ITIH4, and HEMO ([0008]; [0017], e.g. one or more proteins selected from…). Brohman discloses the panel comprises at least three proteins selected from a group of only 21 proteins or one or more protein selected from a limited list of proteins ([0008];[0017). Brohman discloses the classification rule has a sensitivity of at least 75% ([0019]). Brohman discloses the classification rule produces a correlation between preterm birth and term birth with a p value of less than at least 0.05 (claim 36). Brohman discloses controls were matched to subjects based on parity (i.e. nulliparous, primiparous, multiparous) ([0107]), and furthermore that the classification rule considers if a subject is primiparous ([0008]), as opposed to nulliparous or multiparous. Given Brohman takes into account whether a subject is primiparous, and subject is inherently nulliparous, primiparous, or multiparous, this is considered to read on the claims. Brohman discloses the panel includes at least 7 markers ([0008];[0051]).Brohman discloses the measurements are determined by an immunoassay ([0066]), mass spectrometry ([0008], or liquid chromatography-mass spectrometry ([0008]). Brohman discloses the classification rule is generated by a machine learning algorithm including binary decision trees, artificial neural networks, discriminant analyses, logistic classifiers, or support vector classifiers ([0008]). Brohman discloses the classification rule assigns a probability of the risk of preterm birth ([0062]), and this risk can be stratifies according to gestational age ([0063]). Brohman discloses the treatment comprises cervical cerclage, vaginal progesterone, or 17-alpha-hydroxyprogesterone caproate ([0071]). Brohman discloses the subject has a hazard ratio of over 3.0 for preterm birth ([0064]).
It would have been prima facie obvious, to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims with the method of Brohman, to have determined the biomarker measurements for at least seven biomarkers from the recited group, using an immunoassay in a subject that is nulliparous, utilized a support vector machine to provide a probability of and/or stratify the subject as being a high risk of spontaneous pre-term abortion as recited in the instant claims, and treat the subject with vaginal progesterone, as shown by Brohman above. One of ordinary skill in the art would have been motivated combine the methods of the reference claims with Brohman to classify a sample at a risk of preterm with an AUC of at least 0.95 and inform treatment decisions of the subject, as shown by Brohman ([0008]; [0070]). This modification would have had a reasonable expectation of success given both the reference claims and Brohman analyze biomarkers determined from microparticles from plasma to predict preterm birth, such that the method of Brohman is applicable to determine to administer a treatment as in the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 06 Nov. 2025 regarding the double patenting rejection have been fully considered but they are not persuasive.
Applicant remarks the claims of the reference patents do not recite stratifying subjects into three different risk categories, and Hickok provides no motivation to do so, and it was not obvious to use the combination of markers claimed as here among the myriad combinations possible in view of Hickok (Applicant’s remarks at pg. 10, para. 6 to pg. 11, para. 2).
This argument is not persuasive. First, Hickok is only relied upon for the double patenting rejection over U.S. Patent 10,877,046 B2, above. This reference patent does disclose the recited panel of biomarkers, and Hickok is not relied upon to disclose the biomarker panel of less than 8 proteins as recited. Furthermore, the arguments do not take into account Brohman, newly relied upon in the provisional double patenting rejections in view of Applicant’s claim amendments, which discloses the claimed biomarker panel.
Regarding the arguments relating to stratification, as explained in the above rejection, Hickok discloses the predictive model classifies the subject at being at a high risk of preterm birth when the probability is at least 80% or higher ([0120]), which shows the subject has a hazard ratio of over 3.0 (i.e. a probability of at least 75%) for preterm birth. The instant claims only require “wherein the execution of the classification rule stratifies the subject as being at high risk, moderate risk or low risk…”, which provides a list of alternatives in which the classification rule may stratify the subject. Therefore, a classification rule stratifying the subject as being at high risk reads on the claim. These arguments are similarly not persuasive for Brohman for the same reasons discussed above in the 102 rejection.
Conclusion
No claims are allowed.
Claims 116, 119-120, 133-140, 142, 145-150, 152-158, 160, and 162-169 are patent eligible for the reasons discussed in the Office action mailed 06 May 2025.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685