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 .
DETAILED ACTION
Claims 1-27 are pending.
Priority
This application, filed on 6/12/2024, is a 371 of PCT/EP2022/085557 filed on 12/13/2022, and claims priority to EUROPEAN PATENT OFFICE 21214104.8 filed on 12/13/2021. The effective filing date of the instant application is December 13, 2021.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-19, 21-23 and 26, in the reply filed on June 12, 2026 is acknowledged.
Claims 20, 24-25 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 12, 2026.
Claims 20, 24-25 and 27 are not in compliance with 37 CFR 1.121(c), which states: the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered). Claims 20, 24-25 and 27 should be identified as (Withdrawn) for being directed towards non-elected inventions.
Claim Objections
Claims 1-19 and 23 are objected to because of the following informalities:
Claim 1 recites “Method for treating a subject” in line 1, which is missing an article in front of “Method” and should be amended to recite “A method for treating a subject”.
Claims 2-19 and 23 recite “Method according to claim 1” in line 1, which is missing an article in front of “Method” and should be amended to recite “The method according to claim 1”.
Claim 16 recites “determining the levels PAPP-A2 or fragments thereof” in lines 1-2, which is missing the word “of” after levels, and should be amended to recite “determining the levels of PAPP-A2 or fragments thereof”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-19, 21-23, and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 1 recites a method for treating a subject to reduce the risk of preterm birth (PTB) comprising:
determining a level of one or more biomarkers in a sample that has been isolated from said pregnant subject, wherein the one or more biomarkers comprise at least one of matrix metallopeptidase 9 (MMP9) or fragment(s) thereof and Pappalysin-2 (PAPP-A2) or fragment(s) thereof; wherein the level of the one or more biomarkers in the sample is indicative of the presence or absence of a subsequent PTB, and
treating said subject to decrease the risk of PTB, which is a process (Step 1: Yes).
Claim 26 recites a method for determining a level of matrix metallopeptidase 9 (MMP9) or fragment(s) thereof and/or Pappalysin-2 (PAPP-A2) or fragment(s) thereof in a sample that has been isolated from a pregnant subject suspected to be at risk of preterm birth (PTB),comprising:
a. determining a level of matrix metallopeptidase 9 (MMP9) or fragment(s) thereof and/or Pappalysin-2 (PAPP-A2) or fragment(s) thereof in a sample that has been isolated from said pregnant subject,
b. wherein the sample is isolated from a subject in the first, second or third trimester of pregnancy, and
c. treating said subject to decrease the risk of PTB, which is a process (Step 1: Yes).
The claims set forth the judicial exception of measuring the level of one or more biomarkers selected from matrix metallopeptidase (MMP9) and Pappalysin-2 (PAPP-A2) (Step 2A prong one: Yes) and correlate the level of the biomarker with the presence or absence of a subsequent preterm birth (PTB). The additional elements do not integrate the judicial exception into practical application because the recitation of the additional step of treating said subject to decrease the risk of PTB is recited at such generality, that it does not integrate the judicial exception into a practical application (Step 2A Prong two: No).
Dependent claims 2-19, and 21-23 do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The dependent claims are directed towards limiting features of the subject, the biomarker, the sample collection, and do not recite any additional active method steps.
The measurement of MMP-9 in a sample from a pregnant subject is well-understood, routine and conventional in the art (Step 2B: No) as shown by Poon et al. (“First-trimester maternal serum matrix metalloproteinase-9 (MMP-9) and adverse pregnancy outcome”, Prenatal Diagnosis, 2009, Vol. 29, Issue 6, pp.553-559). Poon et al. teaches the serum concentration of MMP-9 in the first trimester of pregnancy can provide useful prediction for subsequent development of preeclampsia and spontaneous early preterm delivery (p.553, 2nd column last paragraph). Poon teaches approximately 10mL of blood was drawn from patients, centrifuged and the supernatant serum was collected and stored until analysis. Poon further teaches measuring MMP-9 concentration in the prediluted sample or control (p.554, 2nd column – Sample analysis). Poon teaches that the maternal serum concentration of MMP-9 at 11+0 – 13+6 weeks’ gestation is increased in pregnancies that resulted in spontaneous early delivery (p.558, 1st column 1st paragraph). Thus, the step of determining a level of MMP-9 in a sample that has been isolated from a pregnant subject is well-known, routine, and conventional in the field.
The step of correlating the level of the biomarker to the presence or absence of a subsequent PTB is a mere instruction to apply an exception. This judicial exception is not integrated into a practical application (Step 2A prong two: No) because the claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception (Step 2B: No).
Claims 1 and 26 recite a step of “treating said subject to decrease the risk of PTB”. However, the step is recited at such generality that it does not integrate the judicial exception into a practical application (Step 2A prong two: No), because the claims do not affirmatively recite an action that effects a particular treatment or prophylaxis to decrease the risk of preterm birth (Step 2B: No).
Thus, claims 1-19, 21-23 and 26 are rejected under 35 U.S.C. 101.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 16 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 16 recites: a method according to claim 15, comprising determining the levels PAPP-A2 or fragment(s) thereof in a sample that has been isolated in the second. The incomplete sentence “a sample that has been isolated in the second” is indefinite.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-19, 21-23 and 26 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
Applicant is referred to MPEP 2163(II)(A)(3)(a)(i and ii), which states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
Claim 1 is drawn to a method comprising determining a level of one or more biomarkers in a sample that has been isolated from a pregnant subject, wherein the one or more biomarkers comprise at least one of matrix metallopeptidase 9 (MMP9) or fragment(s) thereof and Pappalysin-2 (PAPP-A2) or fragment(s) thereof.
Claim 11 is drawn to at least one of MMP9 and Pappalysin-2 (PAPP-A2) or fragment(s) thereof, and optionally one or more of LTF, CGA, INHA, ACTA, NOTUM, PAPP-A, PSG3, MST1L, SHBG, sFlt-1, ADA12 and FCN3, P1GF, PCT, MR-proADM, MIP-1a, MIP-1b, estriol, TNF-a, IL-6, IL-8, IL-1b, AFP, fFN, PAMG1, phIGFBP1, MMP8, or fragment(s) thereof.
Claim 12 is drawn to MMP9 or fragment(s).
Claim 13 is drawn to levels of MMP9 or fragment(s) thereof in a sample.
Claim 14 is drawn to determining the levels of MMP9 or fragment(s) thereof and at least one of NOTUM, PAPP-A, PAPP-A2, MST1L, PSG3, ACTA,ADA12 and FCN3 or fragment(s) thereof.
Claim 15 is drawn to PAPP-A2 or fragment(s).
Claim 16 is drawn to levels [of] PAPP-A2 or fragment(s) thereof.
Claim 17 is drawn to determining the levels of PAPP-A2 or fragment(s) thereof and at least one of MMP9, LFT, CGA, INHA, PAPP-A, SHBG, sFlt-1 and MST1L or fragment(s) thereof.
Claim 26 is drawn to a method comprising determining a level of matrix metallopeptidase 9 (MMP9) or fragment(s) thereof and Pappalysin-2 (PAPP-A2) or fragment(s) thereof in a sample that has been isolated from a pregnant subject.
The current specification defines fragments thereof as “having any length, e.g. at least about 5, 10, 20, 30, 40, 50 or 100 amino acids, so long as the fragment allows the unambiguous determination of the level of the respective biomarker or fragment thereof” (p.36, lines 20-25). The specification identifies MMP-9 as an 82-kDa enzymatically active enzyme (p.37, lines 15-16). The current specification identifies pappalysins PAPP-A and PAPP-A2 are the only two known members of the pappalysin family of metalloproteinases, sharing 45% amino acid identity (p.38, lines 4-6). The current specification identifies procalcitonin peptide (PCT) fragments as at least 12 amino acids, preferably more than 50 amino acids, more preferably more than 110 amino acids (p.44, lines 10-13). The specification identifies fragments of the proADM peptides or fragments of the MR-proADM can comprise, for example, at least about 5, 10, 20, 30 or more amino acids (p.44, lines 35-36).
The current specification does not provide any guidance on the structure-function relationship of MMP-9; PAPP-A2 or any of LTF, CGA, INHA, ACTA, NOTUM, PAPP-A, PSG3, MST1L, SHBG, sFlt-1, ADA12 and FCN3, P1GF, PCT, MR-proADM, MIP-1a, MIP-1b, estriol, TNF-a, IL-6, IL-8, IL-1b, AFP, fFN, PAMG1, phIGFBP1, MMP8. The current specification does not provide any information on what amino acids are critical to identify a fragment as an MMP-9 fragment, a PAPP-A2 fragment, or any of LTF, CGA, INHA, ACTA, NOTUM, PAPP-A, PSG3, MST1L, SHBG, sFlt-1, ADA12 and FCN3, P1GF, PCT, MR-proADM, MIP-1a, MIP-1b, estriol, TNF-a, IL-6, IL-8, IL-1b, AFP, fFN, PAMG1, phIGFBP1, MMP8.
The current specification does not provide any information on how a 5-amino acid fragment could provide any identifying information about what biomarker it is from and serves as an indicator of preterm birth. The specification does not provide any working examples of using fragments of MMP-9, PAPP-A2, or any of LTF, CGA, INHA, ACTA, NOTUM, PAPP-A, PSG3, MST1L, SHBG, sFlt-1, ADA12 and FCN3, P1GF, PCT, MR-proADM, MIP-1a, MIP-1b, estriol, TNF-a, IL-6, IL-8, IL-1b, AFP, fFN, PAMG1, phIGFBP1, MMP8 to identify biomarker levels in a sample that has been isolated from a pregnant subject. Based on the lack of art-recognized structure-function relationships of 5-amino acid fragments and determining which biomarker the fragment represents, it is highly unpredictable what minimum fragment length would be able to provide the required function of indicating the presence or absence of preterm birth.
The lack of disclosure of examples containing a fragment of MMP-9, PAPP-A2, or any of LTF, CGA, INHA, ACTA, NOTUM, PAPP-A, PSG3, MST1L, SHBG, sFlt-1, ADA12 and FCN3, P1GF, PCT, MR-proADM, MIP-1a, MIP-1b, estriol, TNF-a, IL-6, IL-8, IL-1b, AFP, fFN, PAMG1, phIGFBP1, MMP8 is not considered to constitute a representative number of species of the genus of MMP-9 fragments; the genus PAPP-A2 fragments; or the genus of fragments for each of LTF, CGA, INHA, ACTA, NOTUM, PAPP-A, PSG3, MST1L, SHBG, sFlt-1, ADA12 and FCN3, P1GF, PCT, MR-proADM, MIP-1a, MIP-1b, estriol, TNF-a, IL-6, IL-8, IL-1b, AFP, fFN, PAMG1, phIGFBP1, MMP8. Thus, one of ordinary skill in the art could not conclude that Applicant was in possession of any of the species of the claimed genera of fragments for the biomarkers listed above. This disclosure does not constitute a representative number of species of the genus in view of the potential breadth and variability of the genus, and so there is a failure to satisfy the written description requirement for the genus.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 and 18 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 recites “method according to claim 1, wherein the sample has been isolated from the pregnant subject in the first, second or third trimester of pregnancy”. Claim 6 depends from claim 1, which requires a pregnant subject. A pregnancy must have a term falling into the first, second, or third trimester of pregnancy, as there are no other time frames categorized for a pregnancy term. Thus, claim 6 does not further narrow claim 1 from which it depends, and therefore is an improper dependent claim.
Claim 18 recites “method according to claim 1, wherein the method additionally comprises treating a subject with an increased risk of PTB”. Claim 18 depends from claim 1, which recites “treating a subject to decrease the risk of PTB”. Since treating a subject to decrease the risk of PTB would necessarily occur for patients with increased risk of PTB, claim 18 does not further narrow claim 1 from which it depends, and therefore is an improper dependent claim.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 10, 12-13, 18-19, 21-23 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Poon et al. (“First-trimester maternal serum matrix metalloproteinase-9 (MMP-9) and adverse pregnancy outcome”, Prenatal Diagnosis, 2009, Vol. 29, Issue 6, pp.553-559) in view of Tarca et al. (US 2018/0328937 A1, published on November 15, 2018) and Bertagnolli et al. (“Preterm Birth and Hypertension: Is There a Link?”, Current Hypertension Reports, 2016, Vol. 18, Articles 28, 8 pages).
Regarding claim 1, Poon teaches the serum concentration of MMP-9 in the first trimester of pregnancy can provide useful prediction for subsequent development of preeclampsia and spontaneous early preterm delivery (p.553, 2nd column last paragraph). Poon teaches approximately 10mL of blood was drawn from patients, centrifuged and the supernatant serum was collected and stored until analysis (i.e. sample isolated from pregnant subject) (p.554, 1st column – Study population). Poon further teaches measuring MMP-9 concentration in the prediluted sample or control (p.554, 2nd column – Sample analysis).
Poon teaches that the maternal serum concentration of MMP-9 at 11+0 – 13+6 weeks’ gestation is increased in pregnancies that resulted in spontaneous early delivery (p.558, 1st column 1st paragraph).
Poon does not teach treating said subject to decrease the risk of PTB.
However, Tarca teaches biomarker tests which can be used to predict a positive or negative risk of preeclampsia (abstract). Tarca teaches assessing the presence or risk of preeclampsia in a female to determine the need for a treatment regimen including:
determining levels of one or more biomarkers including MMP-7 in a biological sample obtained from the female;
generating a dataset based on the determined levels;
assessing the presence or risk of developing preeclampsia in the female based on the dataset; and, in particular embodiments,
determining a treatment regimen based on the assessed presence or risk (p.1, [0009]).
Tarca teaches the method further comprising initiating a therapeutic intervention, when a positive risk of preeclampsia is detected; where the therapeutic intervention is selected from antiplatelet drugs; antihypertensive drugs; dietary supplementation with antioxidants and/or calcium; rest; and or exercise (p.20, claims 61 and 62).
Bertagnolli teaches that preeclampsia is one of the leading causes of preterm birth and is recognized as an antecedent for around 20 to 30% of all preterm births (p.2, 2nd column, 2nd paragraph). Bertagnolli further teaches that the risk is greatest in early onset preeclampsia, diagnosed before 34 weeks of gestation, which generally results in preterm birth (p.2, 2nd column 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the methods of Poon and Tarca to further determine a treatment regimen based on the assessed presence or risk taught by Tarca after determining the concentration of MMP-9 in the sample as taught by Poon, because Bertagnolli teaches that preeclampsia is one of the leading causes of preterm birth. Each of Poon and Tarca teach the detection of biomarkers in pregnant female to determine risk. One of ordinary skill in the art would have been motivated to determine a treatment regiment, because Poon teaches the maternal serum concentration of MMP-9 is increased in pregnancies that resulted in spontaneous early delivery, and Bertagnolli teaches that diagnosis of preeclampsia before 34 weeks of gestation generally results in preterm birth. One of ordinary skill in the art would have found it beneficial to treat the patient and decrease the risk of spontaneous early delivery.
Regarding claims 2 and 21, Poon teaches in the preterm delivery group, compared to the controls, MMP-9 was significantly higher (p.556, 1st column).
Regarding claim 3, Poon teaches that the maternal serum concentration of MMP-9 at 11+0 – 13+6 weeks’ gestation is increased in pregnancies that resulted in spontaneous early delivery (p.558, 1st column 1st paragraph).
Regarding claim 4, Poon teaches the concentrations of MMP-9 were measured at 11+0 – 13+6 weeks in cases of spontaneous early preterm delivery (abstract).
Regarding claims 5 and 22, Poon teaches measuring MMP-9 in samples from 57 patients with spontaneous preterm delivery before 34 weeks’ gestation (p.554, 1st column – Study population).
Regarding claim 6, Poon teaches first-trimester maternal serum MMP-9 (title) and that samples were measured at 11+0 – 13+6 weeks (abstract).
Regarding claim 7, Poon identifies patients as being nulliparous or parous (p.556, Table 1 – Maternal characteristics).
Regarding claim 8, Poon teaches that the findings of this study demonstrate that maternal serum concentration of MMP-9 at 11+0 – 13+6 weeks’ gestation is increased in pregnancies that subsequently develop preeclampsia and in those resulting in spontaneous early delivery (i.e. asymptomatic subject) (p.558, 1st column 1st paragraph).
Regarding claims 10 and 23, Poon teaches approximately 10mL of blood was drawn from patients, centrifuged and the supernatant serum was collected and stored until analysis (p.554, 1st column – Study population).
Regarding claims 12 and 13, Poon teaches the serum concentration of MMP-9 in the first trimester of pregnancy can provide useful prediction for subsequent development of preeclampsia and spontaneous early preterm delivery (p.553, 2nd column last paragraph).
Regarding claim 18, Poon does not teach treating a subject with an increased risk of PTB.
However, Tarca teaches the method further comprising initiating a therapeutic intervention, when a positive risk of preeclampsia is detected; where the therapeutic intervention is selected from antiplatelet drugs; antihypertensive drugs; dietary supplementation with antioxidants and/or calcium; rest; and or exercise (p.20, claims 61 and 62).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to initiate a therapeutic invention taught by Tarca after determining a risk in the method of Poon, because Poon teaches that the serum concentration of MMP-9 can provide a useful prediction for spontaneous early preterm delivery. One of ordinary skill in the art would have been motivated to initiate a therapeutic intervention to prevent spontaneous early preterm delivery in a patient.
Regarding claim 19, Poon teaches performing screening for adverse pregnancy outcomes in women attending for routine assessment of risk for chromosomal abnormalities (p.554, 1st column – Study Population). Poon further teaches that gestational hypertension is defined as diastolic pressure higher than 90 mmHg or more on at least two occasions 4h apart developing after 20 weeks’ gestation in previously normotensive women in the absence of significant proteinuria (p.554, 2nd column top paragraph).
Poon does not disclose how many samples were collected.
However, Tarca teaches that maternal plasma samples were collected throughout gestation with a median number of 2 samples (p.8, [0088]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Poon to collect more sample throughout gestation as taught by Tarca. One of ordinary skill in the art would have found it beneficial to collect additional samples later in the pregnancy to determine if the risk of adverse pregnancy outcomes increased during gestation after 20 weeks’ gestation as disclosed by Poon.
Regarding claim 26, Poon teaches the serum concentration of MMP-9 in the first trimester of pregnancy can provide useful prediction for subsequent development of preeclampsia and spontaneous early preterm delivery (p.553, 2nd column last paragraph). Poon teaches approximately 10mL of blood was drawn from patients, centrifuged and the supernatant serum was collected and stored until analysis (i.e. sample isolated from pregnant subject) (p.554, 1st column – Study population). Poon further teaches measuring MMP-9 concentration in the prediluted sample or control (p.554, 2nd column – Sample analysis).
Poon teaches that the maternal serum concentration of MMP-9 at 11+0 – 13+6 weeks’ gestation is increased in pregnancies that resulted in spontaneous early delivery (i.e. sample isolated in the first trimester) (p.558, 1st column 1st paragraph).
Poon does not teach treating said subject to decrease the risk of PTB.
However, Tarca teaches biomarker tests which can be used to predict a positive or negative risk of preeclampsia (abstract). Tarca teaches assessing the presence or risk of preeclampsia in a female to determine the need for a treatment regimen including:
determining levels of one or more biomarkers including MMP-7 in a biological sample obtained from the female;
generating a dataset based on the determined levels;
assessing the presence or risk of developing preeclampsia in the female based on the dataset; and, in particular embodiments,
determining a treatment regimen based on the assessed presence or risk (p.1, [0009]).
Tarca teaches the method further comprising initiating a therapeutic intervention, when a positive risk of preeclampsia is detected; where the therapeutic intervention is selected from antiplatelet drugs; antihypertensive drugs; dietary supplementation with antioxidants and/or calcium; rest; and or exercise (p.20, claims 61 and 62).
Bertagnolli teaches that preeclampsia is one of the leading causes of preterm birth and is recognized as an antecedent for around 20 to 30% of all preterm births (p.2, 2nd column, 2nd paragraph). Bertagnolli further teaches that the risk is greatest in early onset preeclampsia, diagnosed before 34 weeks of gestation, which generally results in preterm birth (p.2, 2nd column 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the methods of Poon and Tarca to further determine a treatment regimen based on the assessed presence or risk taught by Tarca after determining the concentration of MMP-9 in the sample as taught by Poon, because Bertagnolli teaches that preeclampsia is one of the leading causes of preterm birth. Each of Poon and Tarca teach the detection of biomarkers in pregnant female to determine risk. One of ordinary skill in the art would have been motivated to determine a treatment regiment, because Poon teaches the maternal serum concentration of MMP-9 is increased in pregnancies that resulted in spontaneous early delivery, and Bertagnolli teaches that diagnosis of preeclampsia before 34 weeks of gestation generally results in preterm birth. One of ordinary skill in the art would have found it beneficial to treat the patient and decrease the risk of spontaneous early delivery.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Poon et al. (“First-trimester maternal serum matrix metalloproteinase-9 (MMP-9) and adverse pregnancy outcome”, Prenatal Diagnosis, 2009, Vol. 29, Issue 6, pp.553-559) in view of Tarca et al. (US 2018/0328937 A1, published on November 15, 2018) and Bertagnolli et al. (“Preterm Birth and Hypertension: Is There a Link?”, Current Hypertension Reports, 2016, Vol. 18, Articles 28, 8 pages) as applied to claim 1 above, and further evidenced by Wang et al. (“Temporal Trends in the Rates of Singletons, Twins and Higher-order Multiple Births Over Five Decades Across Racial Groups in the United States”, International Journal of Maternal and Child Health and AIDS, 2020, Vol. 9, Issue 3, pp.257-259).
The teachings of Poon et al., Tarca et al., and Bertagnolli et al. are discussed above.
Regarding claim 9, Poon, Tarca and Bertagnolli do not identify whether the pregnant subjects have a singleton pregnancy.
However, as evidenced by Wang et al., 97% of births from 1971 to 2018 were singleton births (p.258, 1st column – 2nd paragraph). Thus, the subjects of Tarca and Poon are singleton pregnancies.
Claims 11 and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Poon et al. (“First-trimester maternal serum matrix metalloproteinase-9 (MMP-9) and adverse pregnancy outcome”, Prenatal Diagnosis, 2009, Vol. 29, Issue 6, pp.553-559) in view of Tarca et al. (US 2018/0328937 A1, published on November 15, 2018) and Bertagnolli et al. (“Preterm Birth and Hypertension: Is There a Link?”, Current Hypertension Reports, 2016, Vol. 18, Articles 28, 8 pages) as applied to claim 1 above, and as evidenced by Barrios et al. (“Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease”, Cells, 2021, Vol. 10, Issue 12, article 3576, 22 pages).
The teachings of Poon et al., Tarca et al. and Bertagnolli et al. are discussed above.
Regarding claims 11 and 14-17, the limitation “PAPP-A2 or fragment thereof” is being interpreted to require an amino acid sequence having at least 5 amino acids that are identical to PAPP-A2.
Regarding claims 11, 14 and 17, Poon teaches measuring maternal serum free PAPP-A at 11+0 – 13+6 weeks’ gestation (p.554, 1st column – 1st paragraph). Poon further teaches measuring MMP-9 and PAPP-A in each adverse outcome group with controls, which includes preterm delivery (p.557, Table 2).
As evidenced by Barrios, PAPP-A2 shares 45% homology of its residues and the three LNR and five motifs responsible for the enzymatic activity with PAPP-A. Thus, PAPP-A can be considered a fragment of PAPP-A2.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to detect the presence of MMP-9 and PAPP-A taught by Poon as the biomarkers in the method of Poon and Tarca, because Poon teaches measuring MMP-9 and PAPP-A in each adverse outcome group, including preterm delivery. One of ordinary skill in the art would have found it beneficial to select a combination of biomarkers known to help predict an increased risk of preterm delivery in a pregnant subject.
Regarding claims 15 and 16, Poon teaches measuring maternal serum free PAPP-A at 11+0 – 13+6 weeks’ gestation (p.554, 1st column – 1st paragraph). Poon further teaches measuring MMP-9 and PAPP-A in each adverse outcome group with controls, which includes preterm delivery (p.557, Table 2).
As evidenced by Barrios, PAPP-A2 shares 45% homology of its residues and the three LNR and five motifs responsible for the enzymatic activity with PAPP-A. Thus, PAPP-A can be considered a fragment of PAPP-A2.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Poon to replace MMP-9 with PAPP-A taught by Poon. Poon teaches measuring two biomarkers in pregnant subjects to determine adverse outcomes. One of ordinary skill in the art would reasonably expect that substituting PAPP-A for MMP-9 would predictably result in the detection of a biomarker in a sample that was isolated from a pregnant subject, because it would amount to a simple substitution of one known biomarker for another, and it was known in the art at the time of invention that each of MMP-9 and PAPP-A could be detected in the serum of a pregnant subject.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEEPA MISHRA whose telephone number is (571) 272-6464. The examiner can normally be reached Monday - Friday 9:30am - 3:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise W. Humphrey can be reached at (571) 272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/DEEPA MISHRA/Examiner, Art Unit 1657
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