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 04/23/2026.
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 Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.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 10/10/2025 Applicants elected the particular combination that is PTX3, ADAM12 and sENG; the election has been treated as an election without traverse (MPEP § 818.01(a)).
In the Office Action of 01/23/2026 claim 5 was considered withdrawn as the claim requires clinical cofactors, where such elements were not part of the elected invention (see the Requirement of 08/11/2025 and Applicants election in the reply of 10/10/2025). With the amendments of 04/23/2026, claim 1 is amended to require the analysis of both protein biomarkers and at least one clinical cofactor. In the interests of customer service and compact prosecution, the species election requirement between the elected combination (i.e.: PTX3, ADAM12, and sENG) and the combinations that are PTX3, ADAM12, and sENG in combination with at least one clinical cofactor selected from gestational age, parity, and genotype of the rs4769613 SNP is withdrawn, and the claims are examined in so far as they require PTX3, ADAM12, and sENG in combination with at least one clinical cofactor.
Claims 10-21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (i.e.: specifically requiring non-elected species element), there being no allowable generic or linking claim.
Claims 10-13 require non-elected sFlt1 and non-elected parity, gestational age, and rs4769613 SNP genotype in the calculation set forth in claim 10.
Claims 14-17 require non-elected sFlt1 and non-elected parity and gestational age in the calculation set forth in claim 14.
Claims 18-21 require non-elected sFlt1 and non-elected gestational age and rs4769613 SNP genotype in the calculation set forth in claim 18.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites “as compared with control healthy individual or non-preeclampsia (non-PE) indicates” where the phrase “as compared with protein concentration levels in samples from control healthy individuals or from non-preeclampsia (non-PE) individuals indicates” is likely intended.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
Any rejections of claims under 35 USC 112(b) as set forth on pages 3-4 of the Office Action of 01/23/2026 that are not reiterated below are withdraw in light of the amendments to the claims and/or in light of Applicants’ arguments as provided on pages 8-9 of the Remarks of 04/23/2026.
Claim Rejections - 35 USC § 112 – Indefiniteness
Maintained/Newly Applied as Necessitated by Claim Amendments
Claims 1, 5, 7 and 24-25 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 1, 5, 7 and 24-25 are unclear over recitation of the limitations “generating a prediction value” that is based on the expression level of protein biomarkers and at least one clinical cofactor, as recited in claim 1, because the claims do not set forth any manner in which the value is created. There is no formula, algorithm, or calculation, and as such it is entirely unclear how the value is intended to be generated.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112(b) for being indefinite, as maintained above. Applicants’ arguments, as provided on pages 8-9 of the Remarks of 04/23/2026 have been fully and carefully considered but are not found to be persuasive to withdraw the rejection. Applicants have argued that the claims recite that a high concentration level of the protein biomarkers indicates an increased probability of developing preeclampsia. This argument is not persuasive because it only is related to comparative measures (i.e.: a higher protein level (as compared to a control) indicates an increased risk). But an “increased risk” is not a “prediction value”. A “value” is a number or quantitative measure (e.g.: 75% likely to develop preeclampsia; 3 times more likely to develop preeclampsia; a calculated value of 175 for a sample, where some value calculated from control samples is 100). The recitation of “indicates an increased risk” is related only to the individual analytes, but is only a relative indication of risk and is not any “value”.
Claim Rejections – Improper Markush Group
Maintained/Newly Applied as Necessitated by Claim Amendments
Claims 1, 5, 7 and 24-25 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 alternative useable biomarkers that are PTX3 and ADAM12 with sFlt1 and/or sENG (as encompassed by the claims, where Applicants have elected the particular combination that is PTX2, ADAM12 and sENG), as well the Markush grouping of alternatively useable clinical cofactors (i.e.: gestational age, parity, and placental or fetal genotype of the rs4769613) are each improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use.
In this regard it is noted that each different “clinical cofactor” is related to a distinct element in a subject that is not related to any other different element. Measurement and detected values for gestation age, parity and genotype are not related to each other, and any particular clinical cofactor may have a different strength of association with the phenotype (e.g.: see the different coefficients in Table 6) indicating that each individual biomarker, may be associated with a phenotype with a different level of reliability
The Markush grouping of alternative biomarkers as identified by gene symbols in the limitations recited in claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use. The different biomarkers are each unique biological molecules, with different sequences of nucleotides (for an mRNA biomarker) or amino acids (for a protein biomarker) required for their detection and analysis; and they are related to different encoded proteins with distinct biological roles in a cellular environment. Additionally, with regard to any association with the preeclampsia phenotype as set forth in the claims, any particular biomarker may have a different strength of association with the phenotype (e.g.: see the different coefficients in Table 6) indicating that each individual biomarker, may be associated with a phenotype with a different level of reliability.
Response to Remarks
Applicants have traversed the rejection of claims as being directed to an improper Markush grouping of alternative elements, as maintained above. Applicants’ arguments, as provided on pages10 of the Remarks of 04/23/2026 have been fully and carefully considered but are not found to be persuasive to withdraw the rejection. Applicants have argued that the different combinations of markers have a common use in the detection of preeclampsia risk. This argument is not persuasive because while these particular markers may be useable to predict preeclampsia risk, they are only structurally related by belonging to the broad class of biological molecules that are proteins. But it is not clear from the specification, nor is it known in the art, that all members of this class (i.e.: all proteins) are indicative of preeclampsia risk. And while the particular proteins of the claims may be associated with preeclampsia risk, they do not share among themselves any substantial structural feature that is mainly responsible for this asserted common use.
Claim Rejections - 35 USC § 101
Maintained/Newly Applied as Necessitated by Claim Amendments
Claims 1, 5, 7 and 24-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas (e.g.: mental processes) and a natural phenomenon without significantly more.
The claims are directed to methods of prognosing preeclampsia (as recited in the preamble of claim 1), and recite a step of generation a value to indicate preeclampsia and recite a correlation between a level of biomarkers as compared to a control to indicate a probability of preeclampsia. The claims are thus directed to the assessment of collected data, which is and abstract idea that is a mental process (e.g.: MPEP 2106.04(a)(2)(III)(A)); it is the observation and evaluation of information to reach a judgment or conclusion. Additionally, where the claims include generating a value, the claims in light of the specification are directed to a mathematical calculation, which is a recognized abstract idea (e.g.: MPEP 2106.04(a)(2)(I)(C)).
Additionally, where the claims include aspects of biomarker expression levels associated with preeclampsia, such associations are accepted parts of how a biological organism functions (e.g.: phenotypes associations with gene expression), and as such these elements of the claims are a natural phenomenon (e.g.: MPEP 2106.04(b)(I)).
This judicial exception is not integrated into a practical application because the claims encompass methods in which there are no practical steps related to the correlation of biomarker levels with the indication of preeclampsia development. Here it is noted that claim 1 recites “an anti-hypertensive treatment is administered to the subject if the prediction value is greater than the cut off or threshold value”. The recitation of the term “if” means that the administration of an anti-hypertensive treatment is conditional upon a prediction value that is greater than the cut off or threshold value. But there is no requirement that such a prediction value is in fact present and detected. The claims thus include embodiments in which there are no additional steps of the claims that are directed to applying or using the judicial exception(s) noted above (e.g.: MPEP 2106.04(d)(I)).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims only broadly recite steps measuring biomarkers in a sample. However, such steps were well understood, routine and convention in the prior art (e.g.: MPEP 2106.05(d)). For example, the Gene Expression Omnibus data set for Series GSE48424 teaches the detection of transcripts associated with preeclampsia using the Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Platform GPL6480), which includes probes directed to measuring expression of the genes pentraxin-3, disintegrin and metalloproteinase domain-containing protein 12, and endoglin. And Darbouret et al (WO 2011/157445) teaches the detection of protein biomarkers including sEng, ADAM12 and PTX3 (e.g.: p.8, lns.9-11; p.19, lns.25-27) and gestational age (e.g.: p.15).
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 101 as being directed to ineligible subject matter, as maintained above. Applicants’ arguments, as provided on pages 10-11 of the Remarks of 04/23/2026 have been fully and carefully considered but are not found to be persuasive to withdraw the rejection. Applicants have argued that claim 1 his amended “to incorporate an active treatment step, wherein an anti-hypertensive treatment is administered to the subject if the prediction value is greater than the threshold value”. This argument is not persuasive because, as set forth in the rejection, The recitation of the term “if” means that the administration of an anti-hypertensive treatment is conditional upon a prediction value that is greater than the cut off or threshold value. But there is no requirement that such a prediction value is in fact present and detected.
Claim Rejections - 35 USC § 112 – Enablement
Maintained/Newly Applied as Necessitated by Claim Amendments
Claims 1, 5, 7 and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Nature of the invention and breadth of the claims
The methods of the rejected claims are directed to the prediction of preeclampsia development in a subject using a generated value that is based on the expression level of PTX3, ADAM12 and sENG (as consonant with the election) and at least one additional clinical factor (gestational age, parity, and/or genotype at rs4769631). The claims encompass any calculations or algorithms used to combine the recited biomarkers/clinical factors; for example: any weighted values of the concentrations modified by any coefficients and combined according to any formula.
The claims thus require knowledge of a robust relationship between a variety of measures and the likelihood of preeclampsia.
Direction provided by the specification and working example
The specification teaches (p.18) an analysis of protein biomarkers in blood from pregnant human subjects with preeclampsia and controls without preeclampsia. The specification teaches that logistic regression models investigated associations between biomarker measurement and onset of preeclampsia, and asserts that first trimester measurements of the ADAM12, PTX and sENG were significantly higher in cases with PE (p.23; Fig. 1). Relevant to the limitations of the claims, the specification teaches (p.26) several formulae for generating a prediction value (as required by claim 1) using coefficient modified values of protein biomarker levels; but none of the formulae are disclosed as providing values using only ADAM12, PTX and sENG (as consonant with the election) in combination with as few as a single clinical cofactor (as encompassed by the claims). All of the formulae include the Flt-1 biomarkers, as well as gestation age as well as parity type and/or genotype.
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 detecting a biomarker in any particular sample is advanced, the unpredictability with regard to associating the presence of any biomarker with the presence of a pathology is high. This unpredictability is demonstrated by the related art.
The claims are directed to values that are calculated using only ADAM12, PTX and sENG (as consonant with the election) in combination with as few as a single clinical cofactor (as encompassed by the claims). But the specification does not teach that such calculations, as encompassed by the claims and consonant with the election, are reliable predictors of preeclampsia. As noted above, the specification teaches several formulae (p.26) which include the analysis of each of four protein concentrations (i.e.: ADAM12, PTX, sFlt1 and sENG), and they all include at least gestational age as a clinical cofactor. And Tables 3 and 6 appear to teach that when considering only ADAM12, PTX, and sENG (as consonant with the election), the calculation requires at least one of parity or genotype in combination with gestational age. The variability in the different formula is particularly noteworthy where Table 6 teaches that different coefficients (i.e.: positive or negative values) can be applied to sENG depending upon which model/formula is used, but the claims do no require any particular coefficients.
It is further relevant to note that while the claims set forth that high levels of the biomarkers as compared to any control indicates an increased probability of preeclampsia, Grill et al (2009) provides a review of research related to biomarker levels in preeclampsia and teaches (p.6) that several studies have concluded that decreased ADAM12 is associated with the preeclampsia phenotype.
Quantity of experimentation required
A prohibitively large an amount of experimentation would be required to make and use the claimed invention. Such experimentation would include large case:control analyses of different biomarker/clinical cofactor combinations and comparison to any control reference levels. Even if such experimentation were to be performed, it is unpredictable if results required for the associations encompassed by the claims would be identified.
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 claimed invention.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112 as being directed to non-enabled scope, as maintained above. Applicants’ arguments, as provided on page 11 of the Remarks of 04/23/2026 have been fully and carefully considered but are not found to be persuasive to withdraw the rejection. Applicants have argued that claims are amended to “specify that the subject is human, the sample is blood, the biomarkers are protein biomarkers and that the concentration of said biomarkers is measured.” In this regard it is noted that the portions of the rejection, as set forth in the previous Office Action, pertaining to those aspects of the claims are withdrawn for the rejection as maintained above. Applicants have further argued that while in practicing the methods of the claims, “some experimentation may be required, it is well within the capability of the applicable skilled artisan, and is not undue”. This argument is not persuasive. As noted in the rejection, the specification provides only formulae that include markers that are not required by the claims as consonant with the election. Additionally, where the claims are directed to comparing some calculated value to a cutoff, the experimentation required to make and used the claimed methods would require large studies of control population to determine what cutoff values are suitable for making a diagnosis of preeclampsia risk. The examiner maintains that such experimentation is unpredictable, and that performing such experimentation in order to perform the claimed prognosing is undue.
Conclusion
No claim is allowed.
Applicant's amendment necessitated any 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.
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, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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