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 .
This Office Action is in reply to Applicants’ correspondence of 12/08/2025.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 05/27/2025 Applicants elected, without traverse, the invention of Group 1 (claims 28-43), and the particular miRNA that is hsa-miR-6737-3p
Claim 44-46 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as set forth on pages 2 of the Office Action of 07/07/2025.
Withdrawn Objection to the Specification
The objections to the disclosure, as set forth on page 3 of the Office Action of 07/07/2025, are withdrawn in light of the amendments to the specification of 12/08/2025 as provided by the Applicants which are entered.
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Withdrawn Objection to the Drawings
The objection to the drawings, as set forth on page 3-4 of the Office Action of 07/07/2025, is withdrawn in light of Applicants reply indicating that colors in the drawings are not intended to be a part of any published patent resulting from the instant application.
Claim Objections
Claim 40 is objected to because of the following informalities: line 8 and 14 of the claim recite “comprised”, where the term “compromised” is likely intended. Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Indefiniteness
Maintained and Newly Applied as Necessitated by Claim Amendments
Claims 28, 29 and 31-43 are 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.
Claims 28, 29, and 31-43 are unclear over recitation of the phrase “segregating the patient population of pregnant human beings into the first characteristic group and a second characteristic group on the basis of expression of the at least one miRNA”, as recited in step b) of claim 28, from which claims 31-43 depend. The phrase is unclear because there is no indication as to what constitutes “on the basis of expression” within the context of the claims. It is unclear if the claims are intended to require some compared level of expression, and if so what is that standard for comparison, and what result of the comparison is required for the first or second group. Or if the claims only require any detection of any level of the miRNA to be put into some particular group. In the case of the instant claims, it is entirely unclear as to how the segregation of the patient population is intended to be performed. Even with regard to the limitations set forth in claim 29, it is unclear how the steps are intended to be performed because the segregating, which creates a first and second group, is based on an expression being higher or lower in the first and second group, respectively; but in this regard it appears that the samples must already have been segregated in order to determine what is require for higher or lower expression levels.
Claim 40 is unclear over recitation of the phrase “the segregating is carried out by calculating a HC ratio of expression of said at least one miRNA,” because it is unclear “calculating …a …ratio” is a mathematical process, but the process itself does not result in any “segregating” of a population into two characteristic groups.
Claim 42 is unclear over recitation of the limitations “said miRNA exhibits a signal consistency of at least about 85%; a mean signal strength of at least 5.0; and a p value of less than 0.05 (p<0.05)” because the claims do not set forth any steps related to measuring any consistency, signal strengths, or p-values. And so, it is entirely unclear what measurements are required to determine that the miRNA meets these requirements.
Response to Remarks
Applicants have Remarks (p.9-10 of the Remarks of 12/08/2025) addressing the rejections of claims under 35 USC 112(b) have been considered but are not persuasive to withdraw the rejections as maintained above. Applicants have asserted that the amendments to the claims sufficiently clarify the claimed subject matter such that it would be clear to one of ordinary skill in the art. The claims remain rejected for the reasons set forth above.
Maintained Claim Rejections – Improper Markush Group
Claims 28, 29 and 31-43 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the miRNAs recited in the alternative in claim 28 directing the claims to any combinations or subcombinations of those different recited miRNAs is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Here each species is considered to be a different method requiring the analysis and detection of a distinct gene product (transcript), and combinations thereof.
The recited alternative elements do not share a single structural similarity, as each method relies on the detection of a different biomolecule (i.e.: a unique polynucleotides sequence that is distinct form other sequences and allows the identification of the specific transcript). Each transcript arising from a particular gene has a different chemical structure in that it consists of a different polynucleotide sequence context. And transcript has a different biological activity in that it codes for the expression of a different miRNA having a different biological function in a cell. Thus, these different species do not share a single structural similarity or biological activity. The only structural similarity present is that all of the transcripts may be present as cell-free nucleic acids (as relevant to the claimed methods). The fact that the transcripts comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because this property (i.e.: being a cell-free nucleic acid) mainly responsible for the asserted common activity of being a biomarker for a reproductive disorder (e.g.: there are thousands of miRNAs in immune cells in a pregnant subject that are not in fact associated with any reproductive disorder). Accordingly, while the different transcripts are asserted be associated with reproductive disorders, they do not share a single structural similarity essential to this activity.
Here it is clear that the asserted common use does not flow from any broadly ascribed common structure (see MPEP 2117 II B). The common use of being a related reproductive disorder diagnosis is particular to each different transcript because of the role in gene regulation of each particular transcript, not based on some particular common structural feature shared among the different transcripts themselves.
Response to Remarks
Applicants have traversed the rejection of claims as directed to an improper Markush style grouping of alternatively useable elements. Applicants’ arguments (p.10-12 of the Remarks of 12/08/2025) have been fully and carefully considered but are not persuasive to withdraw the rejection. Applicants have argued that the different nucleic acid molecules, each with a distinct sequence, are share a single structural similarity because they all contain an miRNA core. This argument is not persuasive because the broadly described “core”, as set forth in para 0113 of the specification as referenced in the Remarks, is not a structure that is mainly responsible for the functionality of the different claimed miRNAs in segregating groups of subject, some of which can be treated for a placental bed disorder. As noted in the rejection, the functionality of each individual miRNA is based on its particular sequence; Applicants argument would require that all miRNAs (i.e.: each and every miRNA that possesses the argued “core”) are suitable for the establishing of a characteristic group that is treatable for a placental bed disorder.
Furthermore, it is noted that the instantly application is a 371 national stage application, and so it is relevant to consider unity of invention among the different elements of the Markush group. In this regard the Exmainer maintains that the different elements of the group do not each contain a common structure (i.e.: a common sequence). And the Examiner maintains that the different miRNAs are not a "recognized class of chemical compounds", which means that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. With regard to Applicants Remarks, where the argument is that the miRNA all contain a “core”, there is not an expectation that all members of the class (i.e.: all miRNAs) will have an expression level that: (1) allows for some classification/segregation of subject; and/or (2) is associated with treatability of a placental bed disorder.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims under 35 U.S.C. 101 as set forth on pages 9-10 of the Office Action of 07/07/2025 is withdrawn in light of the amendments to the claims to include treating that “is performed by administering an anti-inflammatory drug to the pregnant human being”.
Claim Rejections - 35 USC § 112 – Scope of Enablement
Maintained in Part, Modified as Necessitated by Claim Amendments
Claims 28, 29 and 31-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (as consonant with the election):
methods comprising treating preeclampsia in a pregnant human subject, comprising the detection of an increased level of hsa-miR-6737-3p in a peripheral blood cell sample from the subject as compared to the level of expression of hsa-miR-6737-3p in peripheral blood cell samples from a population of control pregnant human subjects that do not have preeclampsia
does not reasonably provide enablement for the methods as claimed which encompass the detection of any level of has-miR-6737-3p (as consonant with the election) for the identification of any placental bed disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the invention and the breadth of the claims
The rejected claims are directed to methods of identifying reproductive disorder in a subject quantifying an hsa-miR-6737-3p (as consonant with the election) level in a sample to identify presence or any risk of a placental bed disorder. The claims include the detection of any level of expression level of hsa-miR-6737-3p in a sample from the subject, and a diagnosis of any placental bed disorder based on any level of expression.
Direction provided by the specification and working example
The instant application provides an example of the analysis (p.25) of the analysis of detected miRNA expression levels in control subjects (pregnant human females with normal pregnancy) and cases (pregnant human females with preeclampsia). The data of the analysis is directed to miRNA expression in blood samples of preeclampsia patients, and does not address any predictive analysis of gene expression (e.g.: gene expression elevated prior to preeclampsia).
The specification asserts that the expression level of hsa-miR-6737-3p is increased in the preeclampsia subjects versus the normal controls (e.g.: Fig. 10).
The specification does not teach any other associations between hsa-miR-6737-3p and any other conditions (i.e.: other than preeclampsia) or any analysis of non-human subjects.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to the analysis of gene expression profiles in any sample is high, the unpredictability in associating any gene expression level with a phenotype or risk is Higer. Such unpredictability is demonstrated by the related art and the instant specification.
Because the claims broadly and generically encompass any expression levels as a basis for identification of a subject with a placental bed disorder, it is relevant to point out that the prior art of Cheung et al (2003) teaches that there is natural variation in gene expression; so it is unpredictable if any comparison to any reference gene, as generically encompassed by the claims are indicative of a placental bed disorder.
Because the claims generically encompass any reproductive disorder, or any placental bed disorder, it is relevant to point out that Ali et al (2021) teaches that miRNAs that are differentially expressed in some pregnancy-related disorders are not differentially expressed in other different pregnancy-related disorders.
Quantity of experimentation required
A large and prohibitive amount of experimentation would be required to make and use the claimed invention. Such experimentation would require case:control analysis of samples from any subjects of interest to try to establish the broadly required associations of the claims. Even if such experimentation were to be performed, given the unpredictability of the subject matter of the claims, there is no assurance that the required associations would beyond those specifically disclosed in the application would be detected.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the lack of guidance by the applicant and the particular examples, it is the conclusion that an undue amount of experimentation would be required to make and use the invention in the full scope as claimed.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112(a) as encompassing non-enabled subject matter, as maintained above. Applicants’ arguments (p.12-13 of the Remarks of 12/08/2025) have been fully and carefully considered but are not persuasive to withdraw the rejection. Initially it is noted that in light of the amendments to the claim to be directed to human subjects, the rejection as it was previously applied to the generic breadth of the claims encompassing non-human subjects has been withdrawn. Applicants have argued that the claims are directed to treatment of a “placental bed disorder”. But, as set forth in the rejection, the teachings of the application appear to be directed to the analysis of case:control samples related specifically to preeclampsia. Additionally, as set forth in the rejection, the claims are broadly directed to any measure/detection of miRNA in any classification/segregation, whereas the, the teachings of the application appear to be directed specifically to detecting an increased level of hsa-miR-6737-3p in the presence of preeclampsia as compared to non-preeclampsia controls.
Maintained 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 28, 29, and 31-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/027,095 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the detection of expression level of the same analyte (i.e.: hsa-miR-6737-3p) for the identification of the same disorders (e.g.: placental bed disorder) as the methods of the rejected claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Remarks
Applicants have acknowledged (p.13 of the Remarks of 12/08/2025) the rejection of claims for issues related to double patenting.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683