DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/23/2025 has been entered.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. The previously pending claims have been canceled, and claims 32-49 are currently pending and are examined on the merits herein.
Given that the previous claims are canceled, the previous rejections are all rendered moot. See new grounds of objection below.
Additionally, it is noted that in the Final Rejection, the specification was objected to for the use of a hyperlink. In light of Applicant’s amendments to the specification submitted 12/23/2025, this objection has been withdrawn.
Response to Applicant’s Amendments
In the interest of compact prosecution, the following comments are made regarding the instant claims in view of the teachings in the prior art:
As noted in the Advisory Action mailed 10/6/2025, Applicant’s proposed amendments to claim 14 that were not entered no longer wholly included subject matter previously noted as Free of the Prior Art. Applicant has now incorporated the limitations of claim 14 into claim 32. Claim 32 now encompasses measuring as few as one miRNA in a subject and finding a particular trend compared to a control value. Previous claim 14 was considered free of the prior art due to its dependence on previous claim 1, which recited finding a ratio between hsa-miR-374a-5p and hsa-miR-4454 – a limitation previously deemed free of the prior art. Such a limitation is not present in claim 32. Thus, this claim is rejected under the prior art below.
Claim 33 depends on claim 32 and does not further narrow the claim to require the limitations previously deemed free of the prior art, and so is also rejected under the prior art below.
Claim 34 does require measuring a decrease in hsa-miR-30e-5p expression in relation to decreased birth-weight, which was previously considered free of the prior art, and so this claim is considered free of the prior art.
Claim 35 depends on claim 32, and requires comparing amounts of hsa-miR-374a-5p and hsa-miR-4454 to one another. This comparison was previously deemed free of the prior art, and so the claim as a whole is considered free of the prior art. Claim 36 depends on claim 35, and so the same logic applies. Note that these determinations for both claim 35 and 36 are based on the correction of the objection associated with claim 35 described below concerning amending hsa-374a to hsa-374a-5p in ii).
Claim 37 depends on claim 32 and requires comparing amounts of hsa-miR-374a-5p and hsa-miR-4454 to one another and finding particular ratios. This claim is thus also considered free of the prior art.
Claim 38 depends on claim 32 and specifies particular miRNA groups that may be examined. These groups do not all include/require measuring hsa-miR-30e-5p, and so this claim is also rejected under the prior art below.
Claim 39 is considered to depend from claim 14 (which has now been canceled). As stated in the 35 USC 112(b) Rejections below, this claim will be considered to depend from claim 32. This claim states comparing the ratios of various miRNAs, but as only two miRNAs minimum may be measured, and seven miRNAs are listed, the claim encompasses not measuring a ratio of hsa-miR-374a-5p and hsa-miR-4454. Thus, this claim is also rejected under the prior art below. Similar logic is applied to (b) of claim 40, which recites similar potential ratio values. It is noted that (a) of claim 40 does not require any ratio measurements.
Claim 41 explicitly requires measuring a ratio of hsa-miR-374a-5p and hsa-miR-4454, and so is considered free of the prior art.
Claims 42, 43, and 44 depend on claim 40 and do not further limit claim 40 to aspects previously deemed free of the prior art, and so these claims are also rejected under the prior art below.
Claim 45 depends on claim 32 and does not further limit claim 32 to aspects previously deemed free of the prior art, and so this claim is also rejected under the prior art below. Claim 46 depends on claim 45, and the same logic applies to this claim.
Claims 47, 48, and 49 all depend on claim 32 and do not further limit claim 32 to aspects previously deemed free of the prior art, and so these claims are also rejected under the prior art below.
Regarding 35 USC 101, the independent claims (claims 32, 34, and 41) all include active treatment steps, and so these claims and their dependents are not rejected under this statute.
Claim objections and 35 USC 112(b) and 112(d) Rejections are addressed individually below.
Claim Objections
Claim 32 is objected to because of the following informalities: in line 2, “the subject” should read “the pregnant subject,” and between the final two miRNAs in the list of lines 3-4, “or” should be replaced with “and/or”. Appropriate correction is required.
Claim 34 is objected to because of the following informalities: in the list of miRNAs in lines 4-5, the “or” between the final two miRNAs should be replaced with “and” as all of the miRNAs are required to be measured. Appropriate correction is required.
Claim 35 is objected to because of the following informalities: in the preamble, “comprising” should read “further comprising.” Additionally, in ii), the word “expression” after “relative” can be removed in each instance. Finally, to ensure proper grammar, it is recommended that i) read “determining the ratio of the relative or absolute amount of hsa-miR-374a-5p to that of hsa-miR-4454” and that ii) read “determining the ratio of the relative or absolute amount of hsa-miR-374a-5p to the average relative or absolute amount of hsa-miR-30e, hsa-miR-107, hsa-miR-4454, and hsa-miR-7975” (emphasis is added to account for the typographical error of “hsa-374a” originally recited in ii) of the claim). Appropriate correction is required.
Claim 39 is objected to because of the following informality: in the preamble, it should read “wherein the method further comprises.” Appropriate correction is required.
Claim 40 is objected to because of the following informalities: the comma in line 3 between “subject” and “is” should be removed. Additionally, in (b), line 4, the phrase “or the ratio” after “of the same miRNAs” should be removed. Appropriate correction is required.
Claim 41 is objected to because of the following informalities: in a), the phrase “in a test sample obtained from the pregnant subject” should be added, similar to how the phrase is used in b). Additionally, in b), the word “or” should be replaced with “and/or” between the final two optional miRNAs, as any one or more of them may be used. Finally, in the final wherein clause, the word “where” after “wherein” should be removed. Appropriate correction is required.
Claim 42 is objected to because of the following informalities: lines 1-2 should read “wherein the control samples(s) is/are a sample(s) that was/were taken from” to fully account for the use of a control sample or control samples. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 32-49 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 32 recites “the baby” in line 5 without reciting “a baby” previously. Thus, this phrase lacks antecedent basis. It is recommended to amend this phrase to read “the pregnant subject’s baby.”
Claims 33, 35-40, and 42-49 are rejected due to their dependence on rejected claim 32. Note that claim 39 is being interpreted as depending from claim 32 (see the rejection of this claim below).
Claim 34 recites “the baby” in line 6 without reciting “a baby” previously. Thus, this phrase lacks antecedent basis. It is recommended to amend this phrase to read “the pregnant subject’s baby.”
Claim 36 recites “the control subject” in line 2 without reciting “a control subject” previously in the claim, or in claims 32 or 35, from which this claim depends. Thus, this phrase lacks antecedent basis. It is recommended to use the phrase “a control subject.”
Claim 37 is also rejected because it renders the criteria for determining if a baby is predicted to be born at a low birth-weight unclear. This claim depends on claim 32, which already recites that a baby is predicted to be born at a low birth-weight given that one of the criteria of a)-g) is met. Claim 37 then states that a particular ratio of hsa-miR-374a-5p to hsa-miR-4454 is required to make this low birth-weight determination. It is thus unclear if this is intended to add to or replace the criteria of claim 32. If adding to the criteria of claim 32 is intended, it is recommended to state that claim 37 utilizes the method of claim 32, and further comprises calculating the ratio of hsa-miR-374a-5p to hsa-miR-4454, and that the baby is predicted to be born at a birth-weight that is less than the 5th centile for a particular gestational age if the criteria of one of the claimed ratio values is met in addition to one of the criteria stated in claim 32.
Claim 39 is also rejected because it is stated to depend on claim 14, which has been canceled. The dependency of this claim, and what specific limitations are required by the claim, are therefore unclear. It will be interpreted as though this claim depends on claim 32.
Claim 40 recites “the ratio” in line 3 without reciting “a ratio” earlier in the claim or in claim 32, from which this claim depends. Therefore, this phrase lacks antecedent basis. Additionally, it is unclear what this ratio is referring to (i.e. what values are to be included in the ratio).
Claim 41 recites the phrase “the ratio” in the first wherein clause under step b), when “a ratio” is not recited earlier in the claim. Thus, this phrase lacks antecedent basis. Additionally, it is noted that claim 41 does not actually recite the determination/calculation of a ratio before this phrase, and only recites the determination of the amounts of particular miRNAs.
Claim 43 recites “the pregnant control subject” in line 2, but does not recite “a pregnant control subject” earlier in the claim, nor is this phrase used in claims 32 and 40, from which this claim depends. Thus, this phrase lacks antecedent basis. Additionally, the phrase “at an earlier stage in pregnancy” is unclear because it is unknown what this “earlier stage” is in comparison to. It will be interpreted that this is in comparison to the pregnancy stage of the pregnant subject.
Claim 44 is rejected due to its dependence on rejected claim 43.
Claim 44 is also unclear because it depends on claim 43 and requires the use of a single control sample taken from a control pregnant subject at substantially the same gestational age as that of the pregnant subject. However, the use of a single control sample in claim 43 is only done with a pregnant subject who is “at an earlier stage in pregnancy.” Thus, it is unclear where this single control sample originates, as multiple control samples are used with the pregnant control subject covered in options a) and b).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 37, 39-40, and 44 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 37 is rejected because, as described above in the 35 USC 112(b) Rejections, it is unclear if in claim 37, the criteria for predicting if a baby will be born at a birth-weight that is less than the 5th percentile is replacing the criteria established in claim 32. If so, then this claim would be failing to include all of the limitations of the claim upon which it depends.
Claim 39 is rejected because it does not depend upon a claim previously set forth (i.e. canceled claim 14), and so is considered an improper dependent claim. See MPEP 608.01(n).
Claim 40 is rejected because in option (a), the amount of the miRNAs measured in claim 32 may simply be compared to control values. However, claim 32 already encompasses comparing the amount of each miRNA to that of a control value. Therefore, this option fails to further limit the claim upon which it depends.
Claim 44 is rejected because, as noted above in the 35 USC 112(b) Rejections, it requires the use of a single control subject, but it is unclear which control subject of claim 43, from which this claim depends, is to be used. If the control subject is from the first option presented in claim 43, where the pregnant control subject is at an earlier stage in pregnancy, then claim 44 does not include all of the limitations of the claim upon which it depends, as claim 44 requires that the control subject be used in a pregnant subject at substantially the same gestational age as the pregnant test subject.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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 32, 38, 40, 42-47, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Rodosthenous et al. (Epigenetics, 2017), as evidenced by The Fetal Medicine Foundation (2018).
Rodosthenous teaches measuring miRNAs in association with fetal growth (Abstract). Blood samples were taken from mothers in their second trimester, from 16-22 weeks gestation (page 808, column 1, para. 2; instant claims 45-46). RNA was extracted, reverse transcribed, and amplified via PCR (pages 808-809, RNA extraction and microRNA profiling; instant claim 47). miRNA expression comparisons were made between woman who had LGA, SGA, and AGA infants using gestational age and sex of the infant (page 808, columns 1-2 joining para.; instant claims 40 and 42-44). This reference illustrates Table S4, which compares the fold change of miRNA expression between mothers of SGA and AGA infants. For hsa-miR-374a-5p, hsa-let-7d-5p, and hsa-miR-191, increased expression was associated with lower birth weight in female infants (instant claim 38). Rodosthenous also teaches the determination of the expression of hsa-miR-30d-5p (page 805, column 2, para. 3; instant claim 49).
Rodosthenous also details the average birth weight and gestational age for SGA, AGA, and LGA babies (Table 1). For the SGA group, the average birth weight was 2396 +/- 220 (g) with a gestational age of 38.2 +/- 1.0. According to the birth weight assessment chart provided by The Fetal Medicine Foundation, this would include babies at or below the 5th percentile for birth-weight. Thus, the ordinary artisan would be capable of using the pregnant subject samples and the miRNA expression data provided by Rodosthenou to predict when a baby will be SGA generally, and then can use the data provided by The Fetal Medicine Foundation to determine what portion of SGA babies from Rodosthenous are below the 5th birth-weight percentile specifically. This can then be used to predict in future samples if a baby will born at a birth weight below the 5th percentile. Though Rodosthenous teaches that SGA babies are generally below the 10th percentile (page 808, column 1, para. 2), the ordinary artisan would recognize that babies at or below the 5th birth-weight percentile would be at even greater risk for birth and early-life complications compared to SGA babies generally, and thus would be motivated to examine this group of babies. There would be a reasonable expectation of success in focusing on this group as it is utilizing the same systems and methods of Rodosthenous, but merely focusing on a smaller subset of SGA babies, and would simply involve additional mathematical calculations utilizing the information from The Fetal Medicine Foundation – this would not alter the actual sample collection and analysis methods of Rodosthenous, and would only involve additional downstream analysis methods (instant claim 32).
Claims 33 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Rodosthenous et al. (Epigenetics, 2017), in view of The Fetal Medicine Foundation (2018)., and further in view of Carney et al. (Pediatric Research, 2017).
Regarding claim 33, Rodosthenous in view of The Fetal Medicine Foundation teaches the method of claim 32, as described above, and teaches comparing miRNA expression values between SGA and AGA samples (e.g. comparing the subjects of interest and control subjects). However, this reference does not teach measuring the expression levels of hsa-miR-4454 and hsa-miR-7975.
Carney teaches measuring miRNA expression levels of maternal breast milk between mothers of premature infants and mothers of term infants (Abstract). hsa-miR-4454 and hsa-miR-7975 were two of the miRNAs examined, and it was found that expression levels of both miRNAs were lower in the preterm milk group compared to the expression levels of the term group (Table 4). Carney also teaches the general ontology pathways affected by the miRNAs differently expressed in preterm babies (Table 3).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Carney to inform additional biomarkers to use in the method of Rodosthenous in view of The Fetal Medicine Foundation. These additional biomarkers specifically include hsa-miR-4454 and hsa-miR-7975. Because changes in the expression levels of these biomarkers are associated with a shorter length of gestation (i.e. the preterm infant group, Carney page 227, column 2, para. 2), the ordinary artisan would be motivated to examine these biomarkers in relation to birth weight, as the shorter the total length of gestation, the less time a fetus has to develop, putting them at greater risk for a lower-than-average birth weight. The more clear biomarkers that exist to predict low birth rate, the higher the accuracy of said predictions, further motivating the ordinary artisan. There would be a reasonable expectation of success in adding these biomarkers to the method of Rodosthenous in view of The Fetal Medicine Foundation because these biomarkers and methods of calculating their expression are known, as evidenced by Carney.
As noted above, Rodosthenous teaches comparing SGA and AGA miRNA expression levels (page 808, columns 1-2 joining para. and Table S4). Additionally, as noted in the rejection of claim 32, Rodosthenous in view of The Fetal Medicine Foundation renders obvious predicting if a baby will be born with a weight under the 5th percentile. For hsa-miR-374a-5p and hsa-let-7d-5p, Rodosthenous showed that increased expression was associated with lower birth weight in female infants, matching the comparisons of (a) and (b) in instant claim 33. As Carney teaches that hsa-miR-4454 and hsa-miR-7975 expression levels are decreased in preterm mothers’ breast milk compared to that of term mothers, if these biomarkers are incorporated into the comparative expression methods of Rodosthenous (i.e. SGA versus AGA expression comparisons), this would match the comparisons of (c) and (d) in instant claim 33.
Thus, claim 33 is prima facie obvious over Rodosthenous, in view of The Fetal Medicine Foundation, and further in view of Carney.
Regarding claim 48, as noted above in the initial teachings of Rodosthenous, the miRNAs were evaluated with RT-PCR methods. In the combination of Rodosthenous, in view of The Fetal Medicine Foundation, and further in view of Carney, hsa-miR-374a-5p, hsa-let-7d-5p, hsa-miR-191, hsa-miR-4454 and hsa-miR-7975 are examined using the methodology of Rodosthenous, and so all of these miRNAs would be analyzed using RT-PCR.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Rodosthenous et al. (Epigenetics, 2017), in view of The Fetal Medicine Foundation (2018)., and further in view of Alevizos et al. (US 2012/0029056 A1).
Rodosthenous in view of The Fetal Medicine Foundation teaches the method of claim 32, as described above. However, these references do not teach directly comparing miRNA expression levels to one another in a ratio, as taught in claim 39.
Alevizos teaches identifying differentially expressed miRNAs associated with disease (Abstract). In an example of their method, when validating biomarkers, they teach calculating the ratio of expression values between two biomarkers. The ratio values were then used to place samples into different subgroups (Figure 5 and para. 294). These scores were then associated with differences in symptoms between patients (para. 6).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Alevizos to inform the analysis methods of Rodosthenous in view of The Fetal Medicine Foundation. Specifically, Alevizos would motivate the ordinary artisan to calculate ratios of the miRNAs found in Rodosthenous within the SGA group to determine if particular ratios were associated with any infant-weight patterns. For example, if a particular miRNA ratio was associated with the lowest birth weights, this could be a pattern of interest for clinicians to look out for so possible treatment interventions could be explored while the fetus is still in utero, preventing or mitigating birth-weight associated complications. There would be a reasonable expectation of success incorporating this method into that of Rodosthenous in view of The Fetal Medicine Foundation because Rodosthenous already teaches quantifying the expression levels of miRNAs (e.g. page 809, column 1, para. 2). Calculating ratios of expression levels would simply involve mathematically manipulating the data in a way that would be known and possible for the ordinary artisan, as evidenced by Alevizos.
Therefore, claim 39 is prima facie obvious over Rodosthenous, in view of The Fetal Medicine Foundation, and further in view of Alevizos.
Free of the Prior Art
Claims 34-37 and 41 are currently free of the prior art. These claims recite measuring and comparing hsa-374a-5p and hsa-miR-4454 in direct relation to birth weight and/or measuring a decrease in hsa-miR-30e-5p in association with lower birth weight. These were the limitations previously found to be free of the prior art in the previous Non-Final and Final Rejections, and further search and consideration has not revealed any additional relevant prior art.
Conclusion
No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/F.F.G./Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681