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 .
Claims 1-30, 33-39, 41-70, 73, 75, 77-91, 96-116, 118-122, and 124-139 are cancelled.
Claims 31-32, 40, 71-72, 74, 76, 92-95, 117, 123, and 140-141 are pending.
Applicant’s election without traverse of Group I, claims 31-32, 40, 71-72, 74, 76, 92-95, and 140-141 in the reply filed on 05/04/2026 is acknowledged.
Upon further consideration of the claims presented in the 05/04/2026 claim amendments, the species election requirement is withdrawn in its entirety.
Claims 117 and 123 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/04/2026.
Claims 31-32, 40, 71-72, 74, 76, 92-95, and 140-141 are under examination on the merits.
Priority
This application is a 371 of PCT/US2021/062483, filed 12/08/2021, which claims benefit of US Provisional Application No. 63/123,467, filed 12/09/2020.
IDS
The information disclosure statements (IDS’) filed 04/12/2024 and 05/22/2024 have been considered.
Claim Interpretation
Recitations of classifying a GA are being interpreted to be consistent with what is disclosed in the specification. The specification does not define classification or classifying, but instead appears to use ‘classifying’ to be synonymous with determining the GA by performing the recited method steps.
Recitations of “between or between” are being interpreted to read “between”.
Specification
The specification is objected to for the following informalities: the specification is replete with instances of “between or between” “see for example, paragraphs 0066, 0091, 0105, 0142, etc.” which is grammatically incorrect. Appropriate correction of each and every instance is required.
Claim Objections
Claims 31-32 and 40 and their dependent claims 71-72 and 94-95 are objected to for the following informalities: recitations of “between or between” are grammatically incorrect and introduce unnecessary confusion regarding the claim scope.
Appropriate correction is required.
35 U.S.C. 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 31-32, 40, 71, 74, 76, 92-95, and 140-141 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extra solution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to mathematical concepts.
Claim 31 is directed to a method for classifying the gestational age (GA) of a pregnancy, comprising: (a) determining the concentration of PAPP-A in a biological sample obtained from a pregnant female subject; using an immunoassay, wherein: the biological sample is a whole blood, serum, or plasma sample and wherein the biological sample has a volume between or between about 0.5 µL and 10 µL, inclusive: and the immunoassay comprises detecting one or more PAPP-A proteoforms in a test sample derived from the biological sample, said one or more PAPP-A proteoforms comprising homodimeric PAPP-A or a heterotetrameric PAPP-A/proMBP complex, said detecting comprising: (i) diluting the volume of the biological sample in a sample diluent between or between about 2-fold and 100-fold, inclusive, thereby preparing the test sample: (ii) contacting the test sample with a capture antibody and a detection antibody, wherein the capture antibody and the detection antibody are independently capable of specifically binding to (1) homodimeric PAPP-A and (2) a heterotetrameric PAPP-A/proMBP complex, and wherein the contacting is carried out under conditions to form a complex comprising the capture antibody, the one or more PAPP-A proteoforms, and the detection antibody, wherein the detection antibody is conjugated to a detectable label that is capable of producing a detectable signal; (iii) assessing the degree of the detectable signal produced by the detectable label; and (iv) determining the concentration of PAPP-A in the obtained biological sample by comparison of the degree of the detectable signal to a standard curve; (b) comparing the concentration of PAPP-A in the biological sample to a predetermined concentration of PAPP-A, wherein the predetermined concentration is associated with a predetermined GA cutpoint using the immunoassay; and (c) classifying: the GA of the pregnancy as less than a predetermined GA cutpoint if the concentration of PAPP-A in the obtained biological sample is lower than the predetermined concentration; or the GA of the pregnancy as greater than or equal to the predetermined GA cutpoint if the concentration of PAPP-A in the obtained biological sample is higher than or equal to the predetermine concentration.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
YES-Claim 31 is directed to a method which is a process.
Step 2A – Prong I: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
YES- Claim 31 includes measuring a concentration of PAPP-A as part of a method for comparatively classifying the GA of a pregnancy (see lines 1-2, line 1 of part (a) and line 1 of part (b) as exemplary of the judicial exception which is a natural correlation between a PAPP-A concentration in a sample and the GA of that sample).
Step 2A – Prong II: Does the claim integrate the judicial exception into a practical application?
NO- Here, the instant claim 31 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B- Does the claim recite additional elements that amount to significantly more than the judicial exception?
NO-The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
The generic recitation of measuring a PAPP-A concentration from a sample, comparing the level to a predetermined concentration of PAPP-A which is associated with a predetermined GA cutpoint (comparison being a mental step, which is a judicial exception; see art b of claim 31), and classifying the GA according to part (c) of claim 31 “a further mental step, which is a judicial exception” amounts to no more than mere data gathering steps and the recitation of mental steps and does not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in lines exemplary lines 1-2, line 1 of part (a) and line 1 of part (b) of claim 31.
Claims 32, 40, 71, and 94-95 incorporate, via dependency, the judicial exceptions recited in claim 31 and are therefore included in this rejection.
Claim 32 recites the method of claim 31, wherein the predetermined GA cutpoint is a timepoint between or between about 5 weeks and 40 weeks, inclusive. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps are added by claim 32 so as to add significantly more.
Claim 40 recites the method of claim 31, wherein the predetermined concentration is between or between about 1 ng/mL and 70 ng/mL, inclusive. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps are added by claim 40 so as to add significantly more.
Claim 71 recites a method for screening a pregnant subject for a prenatal care or prenatal clinical treatment, comprising: (a) classifying the gestational age (GA) of a pregnancy according to the method of claim 31; and (b) based on the classifying, (i) selecting the pregnant female subject as eligible for a prenatal care or prenatal clinical treatment if the GA of the pregnancy is classified as less than the predetermined GA cutpoint; or (ii) selecting the pregnant female subject as not eligible for the prenatal care or prenatal clinical treatment or as a candidate for further assessment for the prenatal care or prenatal clinical treatment if the GA of the pregnancy is classified as greater than or equal to the predetermined GA cutpoint. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. The selection steps of parts (a) and (b) are mere mental steps (no treatment is administered). No active steps beyond mental steps of selection (which are judicial exceptions as drafted) are added by claim 71 so as to add significantly more.
Claims 94-95 incorporate, via dependency, the judicial exceptions recited in claim 71 and are therefore included in this rejection.
Claim 94 recites the method of claim 71, wherein the prenatal care or prenatal clinical treatment is a medical abortion or early aspiration; a decision about a medical abortion regimen; a decision about the risk of embryotoxicity; a clinical examination; a vaccination; a risk assessment; a fetal assessment; a blood assay; a urine assay; vitamin supplementation; a test for disease; education; counseling; or any combination of any of the foregoing. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps beyond the mental step of selecting are added by claim 94 so as to add significantly more.
Claim 95 recites the method of claim 71, wherein the prenatal care or prenatal clinical treatment is a medical abortion or early aspiration. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps beyond the mental step of selecting are added by claim 95 so as to add significantly more.
Claim 74 is directed to a method for determining the gestational age (GA) of a pregnancy, comprising: (a) detecting PAPP-A in a biological sample obtained from a pregnant female subject using an immunoassay, wherein: the biological sample is a whole blood, serum, or plasma sample; and the immunoassay comprises detecting one or more PAPP-A proteoforms in a test sample derived from the biological sample, said one or more PAPP-A proteoforms comprising homodimeric PAPP-A or a heterotetrameric PAPP-A/proMBP complex, said detecting comprising: (i) contacting the test sample with a capture antibody and a detection antibody, wherein the capture antibody and the detection antibody are independently capable of specifically binding to (1) homodimeric PAPP-A and (2) a heterotetrameric PAPP-A/proMBP complex, and wherein the contacting is carried out under conditions to form a complex comprising the capture antibody, the one or more PAPP-A proteoforms, and the detection antibody, wherein the detection antibody is conjugated to a detectable label that is capable of producing a detectable signal; and (ii) measuring the degree of the detectable signal produced by the detectable label; and (b) determining the GA of the pregnancy based on the degree of the detectable signal assessed from the test sample, wherein the determining comprises providing the degree of the detectable signal assessed from the test sample as input to a process that uses the degree of the detectable signal assessed from the test sample to predict GA.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
YES-Claim 74 is directed to a method which is a process.
Step 2A – Prong I: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
YES- Claim 74 includes detecting PAPP-A in a biological sample obtained from a pregnant female subject using an immunoassay (see lines 1-2, lines 1-2 of part (a) and lines 1-2 of part (b) as exemplary of the judicial exception which is a natural correlation between a PAPP-A concentration in a sample and the GA of that sample).
Step 2A – Prong II: Does the claim integrate the judicial exception into a practical application?
NO- Here, the instant claim 74 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B- Does the claim recite additional elements that amount to significantly more than the judicial exception?
NO-The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
The generic recitation of determining PAPP-A in a sample and determining the GA based on the degree of detectable signal assessed from the sample as input into a process amounts to no more than mere data gathering steps and does not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in lines exemplary lines 1-2, lines 1-2 of part (a) and lines 1-2 of part (b) of claim 74.
Claim 92 incorporates, via dependency, the judicial exceptions recited in claim 74 and are therefore included in this rejection.
Claim 92 recites a method of selecting a prenatal care or prenatal clinical treatment for a pregnant subject, comprising: (a) determining the gestational age (GA) of a pregnancy according to the method of claim 74; and (b) selecting a prenatal care or prenatal clinical treatment for the pregnant female subject based on the GA of the pregnancy. Note that the selection step of part (b) is merely a mental step which is a further judicial exception. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps beyond the mental step of selecting are added by claim 92 so as to add significantly more.
Claim 76 is directed to method for determining the gestational age (GA) of a pregnancy, comprising: (a) determining the concentration of PAPP-A in a biological sample obtained from a pregnant female subject using an immunoassay, wherein: the biological sample is a whole blood, serum, or plasma sample; and the immunoassay comprises detecting one or more PAPP-A proteoforms in a test sample derived from the biological sample, said one or more PAPP-A proteoforms comprising homodimeric PAPP-A or a heterotetrameric PAPP-A/proMBP complex, said detecting comprising: (i) contacting the test sample with a capture antibody and a detection antibody, wherein the capture antibody and the detection antibody are independently capable of specifically binding to (1) homodimeric PAPP-A and (2) a heterotetrameric PAPP-A/proMBP complex, and wherein the contacting is carried out under conditions to form a complex comprising the capture antibody, the one or more PAPP-A proteoforms, and the detection antibody, wherein the detection antibody is conjugated to a detectable label that is capable of producing a detectable signal; and (ii) assessing the degree of the detectable signal produced by the detectable label; and (iii) determining the concentration of PAPP-A in the obtained biological sample by comparison of the degree of the detectable signal to a standard curve; and(b) determining the GA of the pregnancy based on the concentration of PAPP-A in the obtained biological sample, wherein the determining comprises providing the concentration of PAPP-A in the obtained biological sample as input to a process that uses PAPP-A concentration as a continuous predictor of GAs.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
YES-Claim 76 is directed to a method which is a process.
Step 2A – Prong I: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
YES- Claim 76 includes determining GA comprising determining the concentration of PAPP-A in a sample and determining the GA based on the concentration of PAPP-A in the sample “see lines 1-2, line 1 of part (a) and line 1-2 of part (b) as exemplary of the judicial exception which is a natural correlation between a PAPP-A concentration in a sample and the GA of that sample”.
Step 2A – Prong II: Does the claim integrate the judicial exception into a practical application?
NO- Here, the instant claim 76 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B- Does the claim recite additional elements that amount to significantly more than the judicial exception?
NO-The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
The generic recitation of determining PAPP-A in a sample and determining the GA based on the PAPP-A concentration from the sample as input into a process/comparing to a standard curve amounts to no more than mere data gathering steps and does not add ‘significantly more,’ “see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289”. The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in lines exemplary lines 1-2, line 1 of part (a) and lines 1-2 of part (b) of claim 76.
Claims 140-141 incorporate, via dependency, the judicial exceptions recited in claim 76 and are therefore included in this rejection.
Claim 140 recites a method of selecting a prenatal care or prenatal clinical treatment for a pregnant subject, comprising: (a) determining the gestational age (GA) of a pregnancy according to the method of claim 76; and (b) selecting a prenatal care or prenatal clinical treatment for the pregnant female subject based on the GA of the pregnancy. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps beyond the mental step of selecting are added by claim 140 so as to add significantly more
Claim 141 recites a method for performing a prenatal care or prenatal clinical treatment on a pregnant subject, comprising performing a prenatal care or prenatal clinical treatment on a pregnant female subject, wherein the prenatal care or prenatal clinical treatment is selected according to the method of claim 140. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps beyond the mental step of selecting are added by claim 141 so as to add significantly more.
Therefore, claims 31-32, 40, 71, 74, 76, 92, 94-95, and 140-141 are rejected under 35 USC §101 as being directed towards patent ineligible natural phenomena and abstract ideas, failing to integrate or add substantially more so as to transform the metes and bounds of the claims into subject matter eligible for patentability.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 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 31-32, 74, and 76 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al (CLINICAL CHEMISTRY, vol. 48, no. 3, 1 March 2002 (2002-03-01), pages 473-483, XP055364489, US ISSN: 0009-9147; citation 27 under Non-Patent Literature on the IDS dated 04/12/2024) in view of Folkersen et al (Am J Obstet Gynecol. 1981 Apr 15;139(8):910-4. doi: 10.1016/0002-9378(81)90957-1) and Hytest (obtained from: https://web.archive.org/web/20190719141727/https://shop.hytest.fi/product/papp-human-antibody (available as of 07/19/2019 as evidenced by WayBack Machine); obtained from: https://web.archive.org/web/20190824100226/https://shop.hytest.fi/product/human-dimeric-form-papp-dpapp-dimer-antibody (available as of 08/24/2019 as evidenced by WayBack Machine)).
Regarding claim 31, Qin et al teach that PAPP-A concentrations in maternal serum increase with gestational age until term and describe a rapid point-of-care, time resolved immunofluorometric assay for PAPP-A (see for example, page 474). One-hundred first trimester serum samples were collected (the sample volume is undisclosed). Twelve whole blood samples (5 mL/sample) were obtained from healthy volunteers with heparin as the anticoagulant in the blood collection tubes. Each of these 12 whole blood samples was divided into two aliquots. To each aliquot Qin et al added a different concentration of PAPP-A, generating a total of 24 whole blood samples containing different amounts of PAPP-A (see for example, column 1 of page 473 at the abstract and column 2 of page 475 under the Sample Materials heading). 10µl of sample was mixed with 20µl of assay solution (reading upon a sample diluent to provide a 3-fold dilution” thereby providing the test sample added to the AIO dry-reagent well coated in anti-PAPP-A antibodies (see for example, column 2 of page 475). The circulating form of PAPP-A is a heterotetrameric complex composed of two 200- to 250-kDa PAPP-A subunits disulfide-bridged to two 50- to 90-kDa molecules of the proform of eosinophil major basic protein (proMBP). However, pregnancy serum or plasma is also reported to contain traces (<1%) of uncomplexed PAPP-A (see for example, column 2 of page 473). PAPP-A, either in free or complexed form, was detected by the antibodies used (see for example, column 1 of page 473 at the abstract). Qin et al teach that the assay procedure required 20 min and used 10 µL of sample. The calibration curve was linear from 5 to 10,000 mIU/L. The detection limit was 0.5 mIU/L (see for example the results subsection of the abstract at column 1 of page 473). Parallelism was examined by diluting three samples in different matrices with the 6% BSA-TSA buffer. These diluted samples were measured again as the new samples. Agreement between the expected values and the measured values was good, as shown in Figure 2 which shows a two-fold dilution (1/2 dilution as noted on the X axis of figure 2; see for example, column 2 of page 476- column 1 of page 477). Qin et al teach contacting the sample with antibodies binding one or more proteoforms of PAPP-A by teaching that sample is added to AIO dry-reagent wells with biotinylated antibodies immobilized in the wells (see for example, page 475). The instant specification does not explain how the capture antibody and detection antibody are independently capable of binding to PAPP-A. From the discussions of a sandwich ELISA throughout the specification, the Examiner is interpreting such recitations as consistent with a reciting that a capture and detection antibody bind PAPP-A in the conventional sandwich ELISA format. Qin et al teach that fourteen antibodies against PAPP-A were tested in pairs with each used as a capture or a detection antibody. A one-step sandwich assay format was used together with a 5000 mIU/L PAPP-A calibrator and a blank solution (see column 1 of page 475 for example). This is deemed to read upon the instant steps (ai) and (aii) of claim 31. The detection antibodies of Qin et al were labeled with a fluorescent Eu3+ chelate whose fluorescence was detected after the incubation, washing, and drying assay steps (see for example, 475) (reading on step (aiii) of claim 31).
Qin et al do not explicitly teach a gestational-age dependent reference curve/value for comparing to the measured PAPP-A level in order to classify/determine the gestational age of the pregnancy for which the sample was taken.
However, Folkersen et al teaches that the development of specific and sensitive
electroimmunoassays molecular weight alpha-2 mobile pregnancy-specific for pregnancy associated plasma protein A (also called PAPP-A or SP4) have permitted the detection of circulating levels of PAPP-A (10 μg/L) as early as the fifth week of pregnancy. In all 18 subjects
studied, the levels of PAPP-A rose from first detection in the first trimester until delivery at term.
The development of these assays now permit the evaluation of PAPP-A measurement as a diagnostic test of early pregnancy and as an index of fetal well-being throughout gestation (see
for example, the abstract at page 910). Folkersen et al establish a reference curve of reference PAPP-A values taken serially from 18 subjects at timepoints ranging from 6-42 weeks of gestation (see for example, figures 4a-b and their caption at page 912).
Qin et al and Folkersen et al do not explicitly teach antibodies that are explicitly taught to bind heterotetrameric PAPP-A/proMBP and/or homodimeric (dimeric) PAPP-A.
However, Hytest teaches antibodies that bind heterotetrametic PAPP-A and dimeric (synonymous with homodimeric) PAPP-A (see the two appended screen captures of Hytest where specificity is discussed).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to measure PAPP-A according to art known means and would have found it obvious to correlate a measured PAPP-A
level from a serum sample to a reference value, such as the reference curve/value of PAPP-A
taken at a known point in gestation, such as the curve/values taught by Folkersen et al in order to
determine/classify the gestational age of the pregnancy from which the PAPP-A serum sample was taken. Note that, the MPEP provides that,
“A person of ordinary skill in the art is also a person of ordinary creativity, not an
automaton.”KSR, 550 U.S. at 421, 82 USPQ2d at 1397. “[I]n many cases a person of
ordinary skill will be able to fit the teachings of multiple patents together like pieces of a
puzzle.”Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account “the
inferences and creative steps that a person of ordinary skill in the art would
employ.”Id. at 418, 82 USPQ2d at 1396,”
(see MPEP § 2141 II (c)). The artisan would have found it obvious to use art-known antibodies binding one or more of the heterotetrameric or homodimeric proteoforms of PAPP-A (such as the antibodies of Hytest) using a standard/calibration curve of known PAPP-A concentration (such as the curve at Figure 1 of page 476 of Qin et al) and/or a reference curve such as that of Folkersen et al (reading on step (aiv) of claim 31) to classify/determine the GA. Note that the recited cutpoints are only described throughout the specification as being weeks of gestation where a cutpoint of 5-42 weeks is made obvious by Folkersen et al teaching detection of PAPP-A at 5-42 weeks of gestation (see for example, figures 2-3 and their captions at page 911, figures 4a-b and their captions at page 912, and column to of page 913) (reading on step b of claim 31). It would have been obvious to the person having ordinary skill in the art to classify a GA as less than a comparative GA “cutpoint” where the measured PAPP-A is less than the reference/cutpoint associated PAPP-A concentration. It would have been obvious to the person having ordinary skill in the art to classify a GA as higher/older than a comparative GA “cutpoint” where the measured PAPP-A is higher than the reference/cutpoint associated PAPP-A concentration. It would have been obvious to the person having ordinary skill in the art to classify a GA as equal to a comparative GA “cutpoint” where the measured PAPP-A is equal to the reference/cutpoint associated PAPP-A concentration. This reads upon step c of claim 31. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 32, as noted above the recited cutpoints are only described throughout the specification as being weeks of gestation where a cutpoint of 5-42 weeks is made obvious by Folkersen et al teaching detection of PAPP-A at 5-42 weeks of gestation (see for example, figures 2-3 and their captions at page 911, figures 4a-b and their captions at page 912, and column to of page 913) (reading on step b of claim 31).
Regarding claim 74, as discussed above, the combined references make obvious a method of determining the gestational age (GA) of a pregnancy by detecting PAPP-A in a biological sample from a pregnant subject using an immune assay according to the steps recited in part (a) of claim 74 (see for example, the rejection of claims 31-32 above). The key distinction of claim 74 from claims 31-32 is the addition in step (b) of claim 74, that the determining comprises providing the degree of the detectable signal assessed from the test sample as input to a process that uses the degree of the detectable signal assessed from the test sample to predict GA. However, Qin et al make obvious the use of a process where the detectable signal assessed from the test sample (time-resolved fluorescence data) is input into a process (an autoanalyzer; the Victor analyzer) or where the assay is entirely conducted in an all-in-one (AIO) immunoanalyzer) (see for example, column 2 of page 474 at the Instrumentation section, column 2 of page 476 at the Assay Procedure section). Where there is no closed and preclusive definition throughout the instant disclosure, the process of Qin et al is deemed to be a process as instantly recited.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use a process such as that in Qin et al where Qin et al teach a process where PAPP-A detectable signal is the input, it would have been obvious to the artisan to modify the process to arrive at GA as the output where Qin et al teach that GA and PAPP-A concentration (and logically detectable signal related thereto) are positively correlated. This process would have been an obvious matter of choice yielding no more than predictable results. The artisan would have had a reasonable expectation of success prior to the effective filing date in light of the combined references.
Regarding claim 76, the key distinction between claim 74 and 76 is that the concentration of PAPP-A measured in the sample is input into a process that uses PAPP-A concentration as a continuous predictor of GAs. The process of Qin et al yields a PAPPA concertation concordance result as a continuous variable resulting from a regression analysis, where detected PAPP-A concentration was the input (see for example, the citations from the rejections of claims 31 and 74 above as well as column 2 of page 478 and Figure 7 and its caption at page 479).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use a process such as that in Qin et al where Qin et al teach a process where PAPP-A concentration is the input, it would have been obvious to the artisan to modify the process to arrive at GA as the output where Qin et al teach that GA and PAPP-A concentration are positively correlated. The regression process of Qin et al, taking PAPP-A concentration input clearly yields a continuous output. Where the output is GA, which is positively correlated with PAPP-A concentration, such an output would be a continuous predictor of GA as instantly recited. This process would have been an obvious matter of choice yielding no more than predictable results. The artisan would have had a reasonable expectation of success prior to the effective filing date in light of the combined references.
Claim 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al, Folkersen et al, and Hytest as applied to claims 31-32, 74, and 76 above, in further view of Bischof et al (BJOG: An International Journal of Obstetrics & Gynaecology, 89: 358-363. https://doi.org/10.1111/j.1471-0528.1982.tb05078.x “(1982)).
Regarding claim 40, Qin et al, Folkersen et al, and Hytest teach the method of instant claim 31.
The combined references do not teach the use of 1-70 ng.ml as the pre-determined PAPP-A concentration.
It is noted that measurement of PAPP-A concentration using different units (such as U/mL in Folkersen et al) is known in the art. The choice of units employed by the artisan would appear to be a routine matter of choice, whereby use of measured concentrations associated with samples from a known timepoint in gestation (gestational age) such as the curves taught in Qin et al and/or Folkersen et al would have been obvious to the artisan. Therefore, while the Examiner believes arriving at one or more pre-determined PAPP-A concentrations as predetermined for use as a reference value would have been a mere matter of optimizing a method of gestational aging yielding no more than predictable results, this rationale is not relied upon at this time.
Bischof et al teach that 0.07+/- 0.01 µg/ml of PAPP-A coincides with PAPP-A concentration corresponding to 8 weeks of gestation (see for example Table 2 at page 360). The artisan would understand that 0.07 µg/ml is 70ng/ml. Bischof et al make obvious a predetermined concentration of 69-70ng/mL which is included/overlaps with the claimed range of 1-70ng/mL (see MPEP §2144.05 which states that “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 reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use this pre-determined PAPP-A concentration (70ng/ml) as indicative of 8 weeks of gestation as taught by Bischoff et al in view of Qin et al, Folkersen et al, and Hytest. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claims 71-72, 92-95, and 140-141 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al, Folkersen et al, and Hytest as applied to claims 31-32, 74, and 76 above, in further view of American College of Obstetrics and Gynecology (ACOG) (Medication Abortion Up to 70 Days of Gestation “number 225-Practice Bulletin) Pub. October 2020; obtained from: https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2020/10/medication-abortion-up-to-70-days-of-gestation).
Regarding claim 71, as discussed above, Qin et al, Folkersen et al, and Hytest teach and make obvious the method of instant claim 31.
The combined references do not teach a method for screening a pregnant subject for prenatal care or prenatal clinical treatment. The instant specification supports that the recited ‘prenatal care or prenatal clinical treatment’ includes medical abortions (see for example, paragraph 0243 at page 74 of the specification).
American College of Obstetrics and Gynecology (ACOG) teach that medication abortion, also referred to as medical abortion, is a safe and effective method of providing abortion. Medication abortion involves the use of medicines rather than uterine aspiration to induce an abortion. The U.S. Food and Drug Administration (FDA)-approved medication abortion regimen includes mifepristone and misoprostol (see for example, the abstract at page 2/43). Most patients at 70 days of gestation or less who desire abortion are eligible for a medication abortion (see for example, page 4/43). 70 days is a valuable point for assessing eligibility for medical abortion because medication abortion failure (defined as the need for uterine aspiration because of ongoing pregnancy or retained tissue) increases with advancing gestational age through 70 days of gestation, although failure rates remain low even at this point. Clinicians should counsel patients that medication abortion failure rates, especially continuing pregnancy rates, increase as gestational age approaches 10 weeks (see for example, page 10/43).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use the method made obvious by Qin et al, Folkersen et al, and Hytest to classify determine if the sample gestational age was less than, equal to, or greater than 10 weeks (70 days) by comparison to a standard/reference PAPP-A predetermined concentration corresponding to the 10 week (70 day) time period in order to determine eligibility for a medical abortion “with eligibility being favored where the sample gestational age is classified/determined to be less than the 70 day/10 week cutpoint and disfavored where the sample gestational age is classified/determined to be equal to or greater than the 70 day/10 week cutpoint” as taught by ACOG. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 72, the only addition over claim 71 is that the prenatal care or clinical treatment is performed. Where the combined references make obvious eligibility for medical abortion of a pregnant person at a gestational age below 10 weeks, it would have been obvious to perform a medical abortion on said consenting person where ACOG further teaches methods for performing medical abortion (see for example, table 1 at page 9/43).
Regarding claim 92, as discussed above, Qin et al, Folkersen et al, and Hytest, teach and make obvious the method of instant claim 74. As discussed above (in the rejection of instant claim 71 under 35 USC §103, for example), the artisan would have been motivated to use the method made obvious by Qin et al, Folkersen et al, and Hytest to classify determine if the sample gestational age was less than, equal to, or greater than 10 weeks (70 days) by comparison to a standard/reference PAPP-A predetermined concentration corresponding to the 10 week (70 days) time period in order to determine eligibility for a medical abortion (with eligibility being favored where the sample gestational age is classified/determined to be less than the 70 day/10 week cutpoint and disfavored where the sample gestational age is classified/determined to be equal to or greater than the 70 day/10 week cutpoint) as taught and motivated by ACOG, thus selecting a prenatal treatment or prenatal clinical treatment (medical abortion) for the consenting subject with a GA of less than 70 days (10 weeks). The artisan would have further found it obvious to input the measured data into a process, such as a regression model and/or autoanalyzer process, as taught by Qin et al as an obvious matter of choice yielding no more than predictable results, to arrive at an optimized process for determining/predicting GA (as discussed above in the rejection of instant claim 74 above under 35 USC §103). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 93, where the combined references make obvious the method of claim 92, as discussed above, the addition of claim 92 is performing the medical abortion, the method for which is taught by ACOG, as discussed above.
Regarding claims 94-95, as discussed above, Qin et al, Folkersen et al, Hytest, and ACOG teach and make obvious claim 71, wherein the prenatal care or prenatal clinical treatment is a medical abortion.
Regarding claim 140, the only added limitation over claim 76 is selection of a prenatal care or prenatal clinical treatment for the pregnant subject based on the GA of the pregnancy. As discussed above, Qin et al, Folkersen et al, and Hytest teach and make obvious the method of instant claim 76. As discussed above, the artisan would have been motivated to use the method made obvious by Qin et al, Folkersen et al, and Hytest to classify/determine if the sample gestational age was less than, equal to, or greater than 10 weeks (70 days) by comparison to a standard/reference PAPP-A predetermined concentration corresponding to the 10 week (70 days) time period in order to determine eligibility for a medical abortion (with eligibility being favored where the sample gestational age is classified/determined to be less than the 70 day/10 week cutpoint and disfavored where the sample gestational age is classified/determined to be equal to or greater than the 70 day/10 week cutpoint) as taught and motivated by ACOG, thus selecting a prenatal treatment or prenatal clinical treatment (medical abortion) for the consenting subject with a GA of less than 70 days (10 weeks). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references and would have been motivated to provide medical abortion to consenting, care-seeking pregnant subjects with a GA or 70 days/10 weeks or less as this groups is taught by ACOG to be eligible with a lower risk of complications/failure.
Regarding claim 141, as discussed above, where the combined references make obvious the method of claim 140, as discussed above, the addition of claim 141 is performing the medical abortion, the method for which is taught by ACOG, as discussed above .
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy “a policy reflected in the statute” so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321”d” may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting “NSDP” rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 31-32, 71-72, 74, 76, 92-95, and 140-141 are rejected over reference A and provisionally rejected over copending Application No. ‘636 on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-8 of U.S. Patent No. 12066432 (reference A); and/or
claims 5-6, 13, 48, 52, 77-78, 80-83, and 86 of copending Application No. 18/767,636 (‘636);
in view Qin et al (CLINICAL CHEMISTRY, vol. 48, no. 3, 1 March 2002 (2002-03-01), pages 473-483, XP055364489, US ISSN: 0009-9147; citation 27 under Non-Patent Literature on the IDS dated 04/12/2024), Folkersen et al )Am J Obstet Gynecol. 1981 Apr 15;139(8):910-4. doi: 10.1016/0002-9378(81)90957-1), and Hytest (obtained from: https://web.archive.org/web/20190719141727/https://shop.hytest.fi/product/papp-human-antibody (available as of 07/19/2019 as evidenced by WayBack Machine); obtained from: https://web.archive.org/web/20190824100226/https://shop.hytest.fi/product/human-dimeric-form-papp-dpapp-dimer-antibody (available as of 08/24/2019 as evidenced by WayBack Machine)).
Regarding claims 31-32, the above enumerated claims of reference A are directed to a method for performing a prenatal care or prenatal clinical treatment on a pregnant subject, wherein the prenatal care or prenatal clinical treatment is a medical abortion or early aspiration, the method comprising:
(a) measuring the concentration of PAPP-A from a sample from a pregnant subject seeking the medical abortion or early aspiration, wherein:
the concentration of PAPP-A is measured by an immunoassay; and
the sample is a whole blood or serum sample;
(b) determining the gestational age (GA) of the pregnancy as less than 70 days, wherein
the subject is determined to have a GA of less than 70 days if the measured concentration of PAPP-A is lower than a predetermined threshold level for PAPP-A; and
the pregnant subject with GA classified as less than 70 days is eligible for a medical abortion or early aspiration; and
(c) performing the medical abortion or early aspiration on the pregnant subject (see for example, claim 1 of reference A), wherein the predetermined threshold level of PAPP-A is a value between at or about 3 ng/mL and at or about 10 ng/mL, inclusive (see for example, claim 2 of reference A), wherein the sample may be a serum sample (see for example, claim 8 of reference A).
The above enumerated claims of ‘636 are directed to a method for performing a prenatal care or prenatal clinical treatment on a pregnant subject, wherein the prenatal care or prenatal clinical treatment is a medical abortion or early aspiration, the method comprising (a) measuring the concentration of ADAM-12 from a sample from the pregnant subject seeking the medical abortion or early aspiration; (b) determining the gestational age (GA) of the pregnancy as less than at or about 70 days, wherein the subject is determined to have a GA of less than at or about 70 days if the measured concentration of ADAM-12 is lower than a predetermined threshold level for ADAM-12; and the pregnant subject with the GA determined as less than 70 days is eligible for a medical abortion or early aspiration; and (c) performing the medical abortion or early aspiration on the pregnant subject selected as determined to be eligible for the medical abortion or early aspiration, wherein: the measuring in (a) further comprises measuring the concentration of is-PAPP-A; and the determining in (b) further comprises determining if the measured concentration of PAPP-A is lower than a predetermined threshold level for PAPP-A (see exemplary claims 5 and 13 of ‘636).
The above enumerated claims of reference A and/or ‘636 do not explicitly claim that one or both heterotetrameric PAPP-A/ProMBP or homodimeric PAPP-A are measured/detected in a diluted sample using a capture and detection antibody each able to bind the PAPP-A “in a sandwich assay format” for determining the GA.
However, this is obvious in view of, Qin et al, Folkersen et al, and Hytest, as discussed below.
Regarding claim 31, Qin et al teach that PAPP-A concentrations in maternal serum increase with gestational age until term and describe a rapid point-of-care, time resolved immunofluorometric assay for PAPP-A (see for example, page 474). One-hundred first trimester serum samples were collected (the sample volume is undisclosed). Twelve whole blood samples (5 mL/sample) were obtained from healthy volunteers with heparin as the anticoagulant in the blood collection tubes. Each of these 12 whole blood samples was divided into two aliquots. To each aliquot Qin et al added a different concentration of PAPP-A, generating a total of 24 whole blood samples containing different amounts of PAPP-A (see for example, column 1 of page 473 at the abstract and column 2 of page 475 under the Sample Materials heading). 10µl of sample was mixed with 20µl of assay solution (reading upon a sample diluent to provide a 3-fold dilution) thereby providing the test sample added to the AIO dry-reagent well coated in anti-PAPP-A antibodies (see for example, column 2 of page 475). The circulating form of PAPP-A is a heterotetrameric complex composed of two 200- to 250-kDa PAPP-A subunits disulfide-bridged to two 50- to 90-kDa molecules of the proform of eosinophil major basic protein (proMBP). However, pregnancy serum or plasma is also reported to contain traces (<1%) of uncomplexed PAPP-A (see for example, column 2 of page 473). PAPP-A, either in free or complexed form, was detected by the antibodies used (see for example, column 1 of page 473 at the abstract). Qin et al teach that the assay procedure required 20 min and used 10 µL of sample. The calibration curve was linear from 5 to 10 000 mIU/L. The detection limit was 0.5 mIU/L (see for example the results subsection of the abstract at column 1 of page 473). Parallelism was examined by diluting three samples in different matrices with the 6% BSA-TSA buffer. These diluted samples were measured again as the new samples. Agreement between the expected values and the measured values was good, as shown in Figure 2 which shows a two-fold dilution (1/2 dilution on x-axis of Figure 2; see for example, column 2 of page 476- column 1 of page 477). Qin et al teach contacting the sample with antibodies binding one or more proteoforms of PAPP-A by teaching that sample is added to AIO dry-reagent wells with biotinylated antibodies immobilized in the wells (see for example, page 475). The instant specification does not explain how the capture antibody and detection antibody are independently capable of binding to PAPP-A. From the discussions of a sandwich ELISA throughout the specification, it is presumed that Applicant intends to recite that a capture and detection antibody bind PAPP-A in the convention sandwich ELISA format. Qin et al teach that Fourteen antibodies against PAPP-A were tested in pairs with each used as a capture or a detection antibody. A one-step sandwich assay format was used together with a 5000 mIU/L PAPP-A calibrator and a blank solution (see column 1 of page 475 for example). This is deemed to read upon the instant steps (ai) and (aii) of claim 31. The detection antibodies of Qin et al were labeled with a fluorescent Eu3+ chelate whose fluorescence was detected after the incubation, washing, and drying assay steps (see for example, 475) “reading on step (aiii) of claim 31).
Qin et al do not specifically, explicitly teach a gestational-age dependent reference curve/value for comparing to the measured PAPP-A level in order to classify/determine the gestational age of the pregnancy for which the sample was taken.
However, Folkersen et al teaches that the development of specific and sensitive
electroimmunoassays molecular weight alpha-2 mobile pregnancy-specific for pregnancy associated plasma protein A (also called PAPP-A or SP4) have permitted the detection of circulating levels of PAPP-A (10 μg/L) as early as the fifth week of pregnancy. In all 18 subjects
studied, the levels of PAPP-A rose from first detection in the first trimester until delivery at term.
The development of these assays now permit the evaluation of PAPP-A measurement as a diagnostic test of early pregnancy and as an index of fetal well-being throughout gestation (see
for example, the abstract at page 910). Folkersen et al establish a reference curve of reference PAPP-A values taken serially from 18 subjects at timepoints ranging from 6-42 weeks of gestation (see for example, figures 4a-b and their caption at page 912).
Qin et al and Folkersen et al do not explicitly teach antibodies that are explicitly taught to bind heterotetrameric PAPP-A/proMBP and/or homodimeric (dimeric) PAPP-A.
However, Hytest teaches antibodies that bind heterotetrametic PAPP-A and dimeric (synonymous with homodimeric) PAPP-A “see the two appended screen captures of Hytest where specificity is discussed”.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to measure PAPP-A according to art known means and would have found it obvious to correlate a measured PAPP-A
level from a serum sample to a reference value, such as the reference curve/value of PAPP-A
taken at a known point in gestation, such as the curve/values taught by Folkersen et al in order to
determine/classify the gestational age of the pregnancy from which the PAPP-A serum sample was taken. Note that, the MPEP provides that,
“A person of ordinary skill in the art is also a person of ordinary creativity, not an
automaton.”KSR, 550 U.S. at 421, 82 USPQ2d at 1397. “[I]n many cases a person of
ordinary skill will be able to fit the teachings of multiple patents together like pieces of a
puzzle.”Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account “the
inferences and creative steps that a person of ordinary skill in the art would
employ.”Id. at 418, 82 USPQ2d at 1396,”
(see MPEP § 2141 (ii)(c)). The artisan would have found it obvious to use art-known antibodies binding one or more of the heterotetrameric or homodimeric proteoforms of PAPP-A (such as the antibodies of Hytest) using a standard/calibration curve of known PAPP-A concentration (such as the curve at Figure 1 of page 476 of Qin et al) and/or a reference curve such as that of Folkersen et al (reading on step (aiv) of claim 31) to classify/determine the GA (see also the enumerated claims of refence A motivating measuring a PAPP-A concentration where G is impliedly determined as being less than 70 days if the measured concentration of PAPP-A is lower than a predetermined threshold level for PAPP-A making the subject eligible for medical abortion such that performance to the eligible, consenting subject is obvious; see alternatively the above enumerated claims of ‘636 motivating performing prenatal care or preclinical treatment, such as medical abortion, for a subject where GA by a method comprising measurement of PAPP-A concentration). Note that the recited cutpoints are only described throughout the specification as being weeks of gestation where a cutpoint of 5-42 weeks is made obvious by Folkersen et al teaching detection of PAPP-A at 5-42 weeks of gestation (see for example, figures 2-3 and their captions at page 911, figures 4a-b and their captions at page 912, and column to of page 913) (reading on step b of claim 31). It would have been obvious to the person having ordinary skill in the art to classify a GA as less than a comparative GA “cutpoint” where the measured PAPP-A is less than the reference/cutpoint associated PAPP-A concentration. It would have been obvious to the person having ordinary skill in the art to classify a GA as higher/older than a comparative GA “cutpoint” where the measured PAPP-A is higher than the reference/cutpoint associated PAPP-A concentration. It would have been obvious to the person having ordinary skill in the art to classify a GA as equal to a comparative GA “cutpoint” where the measured PAPP-A is equal to the reference/cutpoint associated PAPP-A concentration. This reads upon step c of claim 31. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 32, as noted above the recited cutpoints are only described throughout the specification as being weeks of gestation where a cutpoint of 5-42 weeks is made obvious by Folkersen et al teaching detection of PAPP-A at 5-42 weeks of gestation (see for example, figures 2-3 and their captions at page 911, figures 4a-b and their captions at page 912, and column to of page 913) (reading on step b of claim 31).
Regarding claim 71, as discussed above, either of reference A or ‘636 in view of Qin et al, Folkersen et al, and Hytest teach and make obvious the method of instant claim 31.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use the method made obvious by either of reference A or ‘636 in view of Qin et al, Folkersen et al, and Hytest to classify determine if the sample gestational age was less than, equal to, or greater than 10 weeks (70 days) by comparison to a standard/reference PAPP-A predetermined concentration corresponding to the 10 week (70 days) time period as claimed by reference A and ‘636. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 72, the only addition over claim 71 is that the prenatal care or clinical treatment is performed. Reference A and ‘636 both claim performing medical abortion, as discussed above.
Regarding claim 74, as discussed above, the combined references make obvious a method of determining the gestational age (GA) of a pregnancy by detecting PAPP-A in a biological sample from a pregnant subject using an immune assay according to the steps recited in part (a) of claim 74 (see for example, the rejection of claims 31-32 above). The key distinction of claim 74 from claims 31-32 is the addition in step (b) of claim 74, that the determining comprises providing the degree of the detectable signal assessed from the test sample as input to a process that uses the degree of the detectable signal assessed from the test sample to predict GA. Accordingly, Qin et teach the use of a process where the detectable signal assessed from the test sample (time-resolved fluorescence data) is input into a process (an autoanalyzer; the Victor analyzer) or where the assay is entirely conducted in an all-in-one (AIO) immunoanalyzer) (see for example, column 2 of page 474 at the Instrumentation section, column 2 of page 476 at the Assay Procedure section).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use a process where PAPP-A detectable signal is the input andGA is the output because Qin et al teach that GA and PAPP-A concentration (and logically detectable signal related thereto) are positively correlated. This process would have been an obvious matter of choice yielding no more than predictable results. The artisan would have had a reasonable expectation of success prior to the effective filing date in light of the combined references.
Regarding claim 76, the key distinction between claim 74 and 76 is that the concentration of PAPP-A measured in the sample is input into a process that uses PAPP-A concentration as a continuous predictor of GAs. The process of Qin et al yields a PAPP-A concertation concordance result as a continuous variable output resulting from a regression analysis, where detected PAPP-A concentration was the input (see for example, the citations from the rejections of claims 31 and 74 above as well as column 2 of page 478 and Figure 7 and its caption at page 479).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use a process such as that in Qin et al where Qin et al teach a process where PAPP-A concentration is the input, it would have been obvious to the artisan to modify the process to arrive at GA as the output where Qin et al teach that GA and PAPP-A concentration are positively correlated. The regression process of Qin et al, taking PAPP-A concentration input clearly yields a continuous output. Where the output is GA, which is positively correlated with PAPP-A concentration, such an output would be a continuous predictor of GA as instantly recited. This process would have been an obvious matter of choice yielding no more than predictable results. The artisan would have had a reasonable expectation of success prior to the effective filing date in light of the combined references.
Regarding claim 92, as discussed above, reference A and/or ‘636, Qin et al, Folkersen et al, and Hytest teach and make obvious the method of instant claim 74. As discussed above (in the rejection of instant claim 71 under 35 USC §103, for example), the artisan would have been motivated to use the method made obvious by reference A and/or ‘636, Qin et al, Folkersen et al, and Hytest to classify determine if the sample gestational age was less than, equal to, or greater than 10 weeks (70 days) by comparison to a standard/reference PAPP-A predetermined concentration corresponding to the 10 week (70 days) time period in order to determine eligibility for a medical abortion (with eligibility/treatment being favored where the sample gestational age is classified/determined to be less than the 70 day/10 week cutpoint and disfavored where the sample gestational age is classified/determined to be equal to or greater than the 70 day/10 week cutpoint) as taught and motivated by the cited claims of reference A and/or ‘636, thus selecting a prenatal treatment or prenatal clinical treatment (medical abortion) for the consenting subject with a GA of less than 70 days (10 weeks). The artisan would have further found it obvious to input the measured data into a process, such as an autoanalyzer and/or regression model, as taught by Qin et al, the process being a matter of obvious choice yielding no more than predictable results, to arrive at an optimized process for determining/predicting GA (as discussed above in the rejection of instant claim 74 above under 35 USC §103). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 93, where the combined references make obvious the method of claim 92, as discussed above, the addition of claim 92 is performing the medical abortion, the method for which is taught by the enumerated claims of reference A and/or ‘636, as discussed above.
Regarding claims 94-95, as discussed above, reference A and/or ‘636 in view of Qin et al, Folkersen et al, and Hytest teach and make obvious claim 71, wherein the prenatal care or prenatal clinical treatment is a medical abortion and reference A and ‘636 each claim performing a medical abortion, as discussed above.
For the foregoing reasons, claims 31-32, 71-72, 74, 76, and 94-95 are made obvious in light of the combined teachings of Qin et al, Folkersen et al, Hytest and either of reference A and/or ‘636.
Regarding claim 140, the only added limitation over claim 76 is selection of a prenatal care or prenatal clinical treatment for the pregnant subject based on the GA of the pregnancy. As discussed above, reference A and/or ‘636 in view of Qin et al, Folkersen et al, and Hytest teach and make obvious the method of instant claim 76. As discussed above, the artisan would have been motivated to use the method made obvious by the combined references to classify/determine if the sample gestational age was less than, equal to, or greater than 10 weeks (70 days) by comparison to a standard/reference PAPP-A predetermined concentration corresponding to the 10 week (70 days) time period in order to determine eligibility for a medical abortion (with eligibility/treatment being favored where the sample gestational age is classified/determined to be less than the 70 day/10 week cutpoint and disfavored where the sample gestational age is classified/determined to be equal to or greater than the 70 day/10 week cutpoint) as taught and motivated by reference A, thus selecting a prenatal treatment or prenatal clinical treatment (medical abortion) for the consenting subject with a GA of less than 70 days (10 weeks). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references and would have been motivated to provide medical abortion to consenting, care-seeking pregnant subjects with a GA or 70 days/10 weeks or less as claimed by reference A and/or ‘636.
Regarding claim 141, as discussed above, where the combined references make obvious the method of claim 140, as discussed above, the addition of claim 141 is performing the medical abortion, as discussed above which in one of the treatments/interventions to be done to consenting pregnant persons with a sample having a GA less than or equal to 70 days (10 weeks) as claimed by reference A and/or’636.
Claim 40 is rejected over claims 1-8 of U.S. Patent No. 12066432 (reference A) in view Qin et al, Folkersen et al, and Hytest as applied to claims 31-32, 71-72, 74, 76, 92-95, and 140-141 above on the grounds of nonstatutory double patenting.
Regarding claim 40, the above enumerated claims of reference A are directed to a method for performing a prenatal care or prenatal clinical treatment on a pregnant subject, wherein the prenatal care or prenatal clinical treatment is a medical abortion or early aspiration, the method comprising:
(a) measuring the concentration of PAPP-A from a sample from a pregnant subject seeking the medical abortion or early aspiration, wherein:
the concentration of PAPP-A is measured by an immunoassay; and
the sample is a whole blood or serum sample;
(b) determining the gestational age (GA) of the pregnancy as less than 70 days, wherein
the subject is determined to have a GA of less than 70 days if the measured concentration of PAPP-A is lower than a predetermined threshold level for PAPP-A; and
the pregnant subject with GA classified as less than 70 days is eligible for a medical abortion or early aspiration; and
(c) performing the medical abortion or early aspiration on the pregnant subject (see for example, claim 1 of reference A), wherein the predetermined threshold level of PAPP-A is a value between at or about 3 ng/mL and at or about 10 ng/mL, inclusive (see for example, claim 2 of reference A), wherein the sample may be a serum sample (see for example, claim 8 of reference A).
3 ng/mL is within the recited range of 1-70 ng/mL.
It is noted that measurement of PAPP-A concentration using different units (such as U/mL in Folkersen et al) is known in the art. The choice of units employed by the artisan would appear to be a routine matter of choice, whereby use of measured concentrations associated with samples from a known timepoint in gestation (gestational age) such as the curves taught in Qin et al and/or Folkersen et al would have been obvious to the artisan. Therefore, while the Examiner believes arriving at one or more pre-determined PAPP-A concentrations as predetermined for use as a reference value would have been a mere matter of optimizing a method of gestational aging yielding no more than predictable results, this rationale is not relied upon at this time.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use this pre-determined PAPP-A concentration (3 ng/ml) as taught by reference A in view of Qin et al, Folkersen et al, and Hytest. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claim 40 is provisionally rejected over claims 5-6, 13, 48, 52, 77-78, 80-83, and 86 of copending Application No. 18/767,636 (‘636), Qin et al, Folkersen et al, and Hytest as applied to claims 31-32, 71-72, 74, 76, 92-95, and 140-141 above, in further view of Bischof et al (BJOG: An International Journal of Obstetrics & Gynaecology, 89: 358-363. https://doi.org/10.1111/j.1471-0528.1982.tb05078.x1982) on the grounds of nonstatutory double patenting.
As discussed above, the combined references make obvious instant claim 31.
It is noted that measurement of PAPP-A concentration using different units (such as U/mL in Folkersen et al) is known in the art. The choice of units employed by the artisan would appear to be a routine matter of choice, whereby use of measured concentrations associated with samples from a known timepoint in gestation (gestational age) such as the curves taught in Qin et al and/or Folkersen et al would have been obvious to the artisan. Therefore, while the Examiner believes arriving at one or more pre-determined PAPP-A concentrations as predetermined for use as a reference value would have been a mere matter of optimizing a method of gestational aging yielding no more than predictable results, this rationale is not relied upon at this time.
However, the combined references do not explicitly teach a predetermined PAPP-A concentration of 1-70 ng/mL for determining GA.
However, Bischof et al make obvious a predetermined concentration of 69-70ng/mL which is included/overlaps with the claimed range of 1-70ng/mL (see MPEP §2144.05 which states that “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 reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive
at the claimed invention from the disclosures of the combined references before the effective
filing date of the claimed invention. The artisan would have been motivated to use this pre-determined PAPP-A concentration (70ng/ml) as indicative of 8 weeks of gestation as taught by Bischoff et al in view of ‘636, Qin et al, Folkersen et al, and Hytest. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Citations 9, 18, 26, and 28 under Non-Patent literature on the 04/12/2024 IDS and citations 1-2 under Non-Patent literature on the 05/22/2024 IDS are deemed relevant to the claimed subject matter.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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