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 .
Election/Restrictions
Applicant’s election of the particular combination that is PTX3, ADAM12 and sENG in the reply filed on 10/10/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 10-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (i.e.: specifically requiring non-elected species element),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.
Election was made without traverse in the reply filed on 10/10/2025.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 1, 6-9, 22 and 24 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, 6-9, 22 and 24 unclear over recitation of the limitations “generating a prediction value, wherein the prediction value indicates whether the subject will develop or will not develop preeclampsia during the ongoing pregnancy” and “a high PTX3, high ADAM 12 and a high sENG level … as compared with control indicates an increased probability of the subject developing preeclampsia”, as recited in claim 1 from which claims 6-9, 22 and 24 depend. The combination of the limitations is unclear, because the first limitation sets forth that a generated prediction value (i.e.: some determined amount) provides the prediction of preeclampsia; but the second limitation requires that each individual measured value as compared to some control provides the prediction. So it is unclear how the prognosis of preeclampsia is in fact intended to be performed.
The first limitation is further unclear because the limitation sets forth” “generating a prediction value”, but the claims does 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.
The second limitation is further unclear because there is no indication of what is required for any control, so it is unclear how the compared amount is established. Where the second limitation recites an apparent relative amount (i.e.: “high”), it is impossible to understand this aspect of the claim without an indication of what is intended or required for the recited “control”.
Claim 22 is rejected for recitation of the limitation “optionally wherein the multiplex platform is a microsphere-based platform, for example xMAP technology” because ‘xMAP’ appears to be a trademarked term. MPEP 2173.05(u) provides:
If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). See also Eli Lilly & Co. v. Apotex, Inc., 837 Fed. Appx. 780, 784-85, 2020 USPQ2d 11531 (Fed. Cir. 2020)
Claim Rejections – Improper Markush Group
Claims 1, 6-9, 22 and 24 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.
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, 6-9, 22 and 24 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 there are no practical steps related to the correlation of biomarker levels with the indication of preeclampsia development. 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 methods end with an asserted association (the identifying or determining) of compared biomarker levels, or generated prediction value, with preeclampsia risk.
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).
Claim Rejections - 35 USC § 112 - Enablement
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1, 6-9, 22 and 24 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.
The claims encompass the detection of any analyte (e.g.: mRNA; protein) from any sample type (e.g.: blood, sweat, nail clippings) and any measures (e.g.: a normalized relative amount; and absolute amount; a concentration) in the measuring of a biomarker level from any subject organism. 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. 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.
Because the claims encompass the analysis of any organism, whereas the instant specification provides only teachings of human biomarkers and samples, it is relevant to point out that there is a large amount of unpredictability with regard to comparing results from biomarker analysis data in humans to other even closely related animals. Enard et al (2002) teaches that large numbers of quantitative changes in gene expression can be detected between closely related mammals (p.342, middle col., last paragraph).
Then claims generically encompass any biomarker analyte, and the specification teaches that such analytes include mRNA (e.g.: p.6 of the specificaiton), whereas the specification teaches only detection methods related to protein biomarker expression levels. Thus, it is relevant to point out that Chen (2002) teaches that it is common for protein expression to be discordant with mRNA expression levels even in matched samples (e.g.: Figure 3).
The claims generically encompass any measure of a biomarker, such as a relative amount of a protein, or absolute measure of the protein level (e.g.: p.12 of the specification). But where the specification teaches only the use of values of concentrations of the biomarkers (e.g.: p.17 of the specification), it is to point out that Matzke et al (2013) teaches that different ways of presenting a protein level can provide different values of the same analyte.
Because the claims encompass examining samples from any sample source (e.g. any tissue or body fluid type, see p.9 of the specification), it is relevant to point out the unpredictability with regard to the analysis of biomarker levels obtained from different sample types. Cobb et al (2002) teaches the analysis of gene expression in spleen and liver sample from septic mice. Notably, the reference teaches that, when compared to a non-septic sample, the relevant expression profiles of the septic mouse spleen and the septic mouse liver contain different nucleic acids at different levels (Table 1; p.2714, middle col., lns.2-8). It is thus unpredictable as to how one might extrapolate gene expression levels from a blood sample (as provided in the instant specification) to the analysis of gene expression in a sample obtained from any other source (e.g. any different fluid, organ, or tissue)
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 types (e.g.: mRNA) from any sample type in any subject organism, 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.
Conclusion
No claim is allowed.
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