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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Status of Claims
Claims 1, 7, 9, 10, 12, 13, 17, 19, 24, 28, 30, 32, 35, 46-51 and 53-57 are currently pending. Claims 1, 7, 35, 49-51 and 53 have been amended by Applicants’ amendment filed 03-09-2026. No claims have been canceled by Applicant’s amendment filed 03-09-2026. Claims 55-57 have been added by Applicants’ amendment filed 03-09-2026.
Applicant's election with traverse of Group III, claims 35, 45-48 and 51, directed to a method of detecting two or more biomarkers; and the election of Species as follows:
Species (A): wherein ten (10) biomarkers SHBG (IALGGLLFPASNLR) and one or more of INHBC (LDFHFSSDR), AFAM (HFQNLGK); AOPC3 (GWVTDGFSSLK); CO5 (IEEIAAK) and/or CSH (ISLLLIESWLEPVR) (instant claims 1, 7 and 35);
Species (B): SHBG and INHBC (claims 1, 7 and 35);
Species (C): wherein the measurable feature comprises fragments or derivatives of said two or more biomarkers (claim 8);
Species (D): the method of claim 7 further comprising an additional step such as, for example, further comprising providing a biological sample from a pregnant female (claim 12);
Species (E): wherein analysis comprises using one or more analysis selected from the group (claim 19);
Species (F): wherein quantifying comprises mass spectrometry (claim 24);
Species (G): wherein detecting comprises mass spectrometry (claim 45);
Species (H): wherein the panel comprises two or more biomarkers (claim 49);
Species (I): wherein the combination of two or more biomarkers comprise SHBG and INHBC (claims 49-51); and
Species (J): wherein the combination of isolated biomarkers is IALGGLLFPASNLR for SHBG (claim 53), in the reply filed March 31, 2023 was previously acknowledged.
Claims 7-10, 12, 13, 17, 19, 24, 28, 30, 32, 33, 50 and 54 were previously withdrawn, and claim 56 is newly withdrawn, from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 03-21-2023.
Claims 47 and 48 were previously withdrawn, and claims 55 and 57 are newly withdrawn, from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement was deemed proper and was made FINAL.
Please Note: claim 55 and 57 depend from claims 1 and 35, where Applicant elected for Species (B), the combination of SHBG and INHBC in the reply filed March 31, 2023. Thus, claims 55 and 57 are withdrawn as being directed to a non-elected species.
Please Note: claim 56 depends from withdrawn claim 7, such that claim 56 is also withdrawn.
The claims will be examined insofar as they read on the elected species.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 1, 35, 46, 49, 51 and 53 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed July 2, 2020 is a CON of US Patent Application 16/107248, filed August 21, 2018 (now abandoned), which is a CON of US Patent Application No. 14/213947, filed March 14, 2014 (now abandoned), which claims the benefit of US Provisional Patent Application No. 61/798413, filed on March 15, 2013.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application 61/798,413, filed March 15, 2013, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claims 1 and 35 do not have support for: two or more biomarkers comprise SHBG and one or more biomarkers selected from Inhibin beta C chain (INHBC); monocyte differentiation antigen CD14 (CD14); afamin (AFAM); pre-pregnancy weight; the incidence and/or frequency of prior preeclampsia; and new paternity; Therefore, the priority date for the presently claimed invention is March 14, 2014, the filing date of US Patent Application 14/213,947.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 1 of the instant application.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed March 9, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or
objection not specifically addressed below are herein withdrawn.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 35, 46, 49, 51 and 53 are maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1 and 35 are indefinite for the recitation of the term “one or more risk indicium for preeclampsia” such as recited in claim 1, line 3 because it is unclear whether any history of smoking (e.g., a single cigarette, smoking 20 years before pregnancy, etc.); any past or present alcohol use (e.g., a single glass of wine in 10 years before pregnancy, etc.); and/or all intervals between pregnancies (e.g., <4 years; >10 years, etc.) are a risk indicium for preeclampsia and, thus, the metes and bounds of the claim cannot be determined.
Claims 49 and 53 are indefinite insofar as they ultimately depend from instant claim 1. Claims 46 and 51 are indefinite insofar as they ultimately depend from instant claim 35.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 35, 46, 49, 51 and 53 is maintained under 35 U.S.C. 103 as being unpatentable over Lim et al. (hereinafter “Lim”) (US Patent No. 10054599; issued August 21, 2018; WO2014/142752, filed March 12, 2014; effective filing date March 12, 2013; of record) in view of Rosenfeld et. al. (hereinafter “Rosenfeld”) (US Patent Application No. 20060094039, published May 4, 2006; of record) as evidenced by Liu et. al. (hereinafter “Liu”) (US Patent Application Publication No. 20120157378, published June 21, 2012; of record); and Boniface et al. (hereinafter “Boniface”) (US Patent Application Publication No. 20190234954, published August 1, 2019; of record).
Regarding claims 1, 35, 49, 51 and 53, Lim teaches detecting a modulated level of expression, activity or amount of one or more further pre-eclampsia biomarker polypeptides, wherein the one or more further pre-eclampsia biomarker polypeptides can be selected from the polypeptides set out in Table 1A, Table 1B and Table 1C; and wherein the one or more further pre-eclampsia polypeptides can be selected from the polypeptides set out in Table 2A, Table 2B, Table 2C, Table 3A, Table 3B, Table 4A, and Table 4B (col 3, lines 34-46). Lim teaches that as shown in Tables 1 to 4, proteome analysis reveals that in CTB-vesicles, 87 and 222 proteins are present only in pre-eclampsia patients and healthy pregnant women respectively; and that in AV-vesicles, 104 and 157 proteins are present only in pre-eclampsia and healthy pregnant women, respectively (interpreted as obtaining samples from pregnant females, claims 1 and 35) (col 6, lines 29-34). Lim teaches that the relative levels of proteins or combinations of proteins in annexin V- and CTB-binding sub-fractions in plasma are dependent on the preeclampsia status of the individuals, such that the relative levels of these proteins can be used to detect pre-eclampsia in an individual, determine whether an individual suffered from pre-eclampsia, predict whether an individual is suffering from, or is likely to suffer from pre-eclampsia, or determine the likelihood that an individual will suffer from pre-eclampsia in the future (interpreted as comprising a measurable feature and risk indicia of a history of pre-eclampsia, claims 1 and 35) (col 6, lines 35-44). Lim teaches in Table 1A the proteins comprising INHBC; Table 1B comprising CD14, and SHBG; and Table 2B comprising CD14, INHBC and SHBG (interpreted as comprising peptide fragments for SHBG, CD14, and INHBC; and proteins comprising amino acid sequences 6, 38, 55, 1164, 1202, and 1203 and 6, claims 1, 35, 49, 51 and 53) (cols 45, 46, 48, 51, 52 and 53), wherein it is known that the SHBG biomarkers consist of the peptide fragments including variant/isoform 1 (SEQ ID NO: 3) and encoded SHBG variant 2 polypeptide sequence (SEQ ID NO: 4) comprising the SHGB fragments including: LFLGALPGEDSSTSFCLNGLWAQGQR (SEQ ID NO: 1202), TWDPEGVIFYGD-TNPKDDWFMLGLR (SEQ ID NO: 1203), IALGGLLFPASNLR (SEQ ID NO: 55), and VVLSSGSGPGLDLPLVLG LPLQLK (SEQ ID NO: 38) as evidenced by Liu (paragraph [0006]; and Figure 2); and where it is known that the INHBC biomarker consists of the peptide fragment LDFHFSSDR; the CD14 biomarker consists of peptide fragment LTVGAAQVPAQLLVGALR as evidenced by Boniface (pg. 30, Table 1, lines 2 and 7; pg. 31, Table 1, line 2; and pg. 32, Table 1, line 5). Lim teaches that the method can comprise providing a sample of or from the individual; and detecting the level of expression, activity or amount of a pre-eclampsia biomarker polypeptide in a microparticle type of the sample (interpreted as obtaining a sample from a pregnant female, claims 1 and 35) (col 2, lines 64-67). Lim teaches that pre-eclampsia can develop any time after 20 weeks of gestation, such that pre-eclampsia before 32 weeks is considered early onset and is associated with increased morbidity (interpreted as obtaining a sample encompassing 17-28 weeks, claims 1 and 35) (col 32, lines 36-38). Lim teaches assaying for candidate PE biomarkers in AV-vesicles by ELISA; that that CTB- and AV-vesicles were isolated from plasma of pre-eclampsia (n=5) and matched healthy pregnant women (n=5), wherein they were then assayed for previously reported pre-eclampsia biomarkers by ELISA (interpreting ELISA as detecting comprises subjecting the biological sample to a proteomics method that utilizes a capture agent, claim 35) (col 5, lines 56-61; and Figure 5). Lim teaches that pre-eclampsia is a medical condition characterized by high blood pressure and significant amounts of protein in the urine of a pregnant woman, such that if left untreated, it can develop into eclampsia, the life-threatening occurrence of seizures during pregnancy; and while blood pressure elevation is the most visible sign of the disease, it involves generalized damage to the maternal endothelium, kidneys, and liver, with the release of vasoconstrictive factors being a consequence of the original damage (interpreted as a sample from a pregnant female; and indicia including history of hypertension or pre-eclampsia, claim 1 and 35) (col 32, lines 19-23 and 27-32). Lim teaches that known risk factors include: nulliparity, diabetes mellitus, renal disease, chronic hypertension, prior history of pre-eclampsia, age (>35 or <15), obesity, anti-phospholipid antibody syndrome, multiple gestation, and pathogenesis (interpreted as indicia including history of hypertension, diabetes, history of pre-eclampsia, age, and pregnancies, claim 1 and 35) (col 33, lines 45-55). Lim teaches in Example 2 that the mean gestation age of PE presentation for the 11 PE patients was 30.5 weeks (ranges 24-35 weeks) (interpreted as encompassing 17-28 weeks, claims 1 and 35) (col 40, lines 26-28). Lim teaches in Example 7 that mass spectrometry of pooled plasma from either 6 PE patients or 6 healthy controls were incubated with CTB or annexin V to isolate CTB- and AV-vesicles; and a full MS scan (350-1600 m/z range) was acquired in the FT-ICR cell at a resolution of 100,000, wherein the linear ion trap was used to collect peptides and to measure peptide fragments generated by CID; and for each experiment, MS/MS (dta) spectra of the eight gel fractions were combined into a single mascot generic file by a home-written program, such that protein identification was achieved by searching the combined data against the IPI human protein database (interpreted as analysis by MS, claim 35) (col 41, lines 66-67; and col 42, lines 49-60).
Regarding claim 46, Lim teaches that any suitable polypeptide whose presence, amount, mass or number etc. can be determined, wherein examples of such determination methods include mass spectrometry, spectrophotometry, UV absorption, etc. (interpreted as mass spectrometry, claim 46) (col 20, lines 13-19). Lim teaches immunoprecipitation assays (interpreted as encompassing co-IP, claim 46) (col 29, lines 4-5). Lim teaches that out of the 11 control and 11 PE patients, 6 control and 6 PE patients were processed for analyses using both mass spectrometry and commercially available array of antibodies (interpreted as mass spectrometry, claim 46) (col 40, lines 49-51).
Lim does not specifically exemplify co-IP MS (claim 46).
Regarding claim 46, Rosenfeld teaches method for the early non-invasive diagnosis of fetal aneuploidy including by identifying protein expression patterns characteristics of fetal aneuploidy in a maternal biological fluid, such as maternal serum or amniotic fluid (interpreted as a obtaining a biological sample from a pregnant female; and capturing a protein-binding molecule or agent, claims 1 and 35) (Abstract). Rosenfeld teaches that in an effort to reduce further the frequency of amniocenteses, second-trimester screening ultrasonography has been applied to Down's syndrome screening, wherein the identification of certain major fetal structural abnormalities significantly increases the risk of Down's syndrome and other aneuploidies, and is then considered an indication for invasive fetal testing, wherein this approach does not improve population screening for Down's syndrome, since 98% of fetuses in the general population do not have structural abnormalities (paragraph [0016]). Rosenfeld teaches that biomarkers including sex hormone-binding globulin (SHGB) (interpreted as detecting two or more biomarkers; encompassing SHGB sequences 38, 55, 1202 and 1203; and including 9 biomarkers, claims 1, 35, 49, 51 and 53) (paragraphs [0041]; [0201]; and [0202], Table 4; and Table 5) Rosenfeld teaches that the inventions involve the use of proteomic profiles that include at least on glycoprotein, wherein spectra of immunoprecipitated apolipoproteins are identified by immuno-MALDI-TOF-MS assay (interpreted as a proteomic work-flow; and as mass spectrometry, claims 35 and 46) (paragraphs [0051]; and [0065]). Rosenfeld teaches that Table 6 illustrates candidate material serum biomarkers in Down’s syndrome, identified from the initial areas of interest, wherein tandem MS/MS was employed to identify the specific candidate biomarkers (interpreted as a proteomic work-flow; and as mass spectrometry, claim 35) (paragraph [0062]; and Table 6). Rosenfeld teaches that differential expression profiles can have important diagnostic value, even in the absence of specifically identified proteins, wherein single protein spots or chromatographic eluents can then be detected, for example, by immunoblotting, and multiple spots, eluents, or proteins can be identified using protein microarrays (interpreted as array; and two or more biomarkers capture by a protein-binding molecule or agent, claims 1 and 35) (paragraph [0085]). Rosenfeld teaches the identification of proteins and polypeptides expressed in biological fluids; as well as, using proteome maps and the detection of proteins that are up- or down-regulated in a disease, such that these proteins can then be excised for identification and full characterization, e.g. using peptide-mass fingerprinting and/or mass spectrometry and sequencing methods, or the normal and/or disease-specific proteome map can be used directly for the diagnosis of the disease of interest, or to confirm the presence or absence of the disease (interpreted as proteins and peptides, claims 1 and 35) (paragraphs [0097]; and [0099]). Rosenfeld teaches that for protein identification, serum proteins were subjected to 2-DGE, digested with trypsin, the peptides extracted and analyzed by mass spectrometry including mass spectrometry-based immunoaffinity assay for the detection of biomarkers (interpreted as co-IP MS, claims 45 and 46) (paragraphs [0141]; [0149], lines 1-2; and [00156]).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of identifying differentially expressed protein biomarkers as exemplified by Rosenfeld, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of detecting a modulated expression, activity or amount of a pre-eclampsia biomarker polypeptides including SHBG, INHBC and CD14 in a biological sample from organism as compared to the level of expression, activity or amount of the pre-eclampsia biomarker polypeptide in the same microparticle type in a sample from an organism not suffering from pre-eclampsia as disclosed by Lim to include the methods of protein profile-based high-throughput screening including the use of a mass spectrometry-based immunoaffinity assay such as an immuno-MALDI-TOF-MS assay as taught by Rosenfeld with a reasonable expectation of success in capturing individual protein biomarkers that are differentially expressed in maternal serum; in providing protein identification and quantification data on differentially expressed proteins in control and pre-eclampsia samples; and/or in providing an early predictive test that provides sufficient time to intervene and mitigate the risks of pre-eclampsia in a pregnant female.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
Response to Arguments
Applicant’s arguments filed March 9, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Boniface does not qualify as prior art under 35 U.S.C. § 102(a)(l) or (2) because the earliest filed application to which Boniface claims priority, namely U.S. Provisional Patent Application 62/547,676, was filed on August 18, 2017, which post-dates the priority date for the presently claimed invention (Applicant Remarks, pg. 11, last full paragraph); (b) the claimed array and method are based, at least in part, upon Applicant's discovery of unexpected technical advantages of the biomarkers and biomarker combinations with SHBG as recited in the claims. For instance, the application teaches that "panels comprising one or more of these proteins and peptides can be utilized in methods of determining the probability for preeclampsia in a pregnant female with relatively high sensitivity and specificity" (specification, para. [0028]). SHBG, for example, was identified and confirmed to be one of such biomarkers that were shown to be predictive of preeclampsia (Applicant Remarks, pg. 11, last partial paragraph through pg. 12, first full paragraph); (c) Rosenfeld and Liu fail to teach INHBC, CD14 or CO5 and, therefore, cannot possibly teach the combination of biomarkers including peptide fragments of SHBG and INHBC, CD14 and CO5 (Applicant Remarks, pg. 12, last partial paragraph, lines 1-4); (d) Rosenfeld and Liu fail to provide any motivation for one of ordinary skill in the art to combine these references (Applicant Remarks, pg. 12, last partial paragraph, lines 5-6); (e) the Office Action relies upon Lim to overcome the deficiencies noted above in the teachings of Rosenfeld and Liu; however, Liu too fails to teach or suggest each and every element of the present claims, even when considered in combination with Rosenfeld and Liu. The Office Action appears to be using impermissible hindsight using the presently claimed invention as a blueprint or roadmap from which to allegedly find the components thereof in the distinct teachings of Lim without considering the teachings of Lim as a whole (Applicant Remarks, pg. 13, first full paragraph); (f) Lim teaches away from using SHBG as a biomarkers because Lim lists SHBG in Tables 1B and 2B, which are proteins of both preeclampsia and healthy pregnant women (Applicant Remarks, pg. 13, last partial paragraph through pg. 14, first partial paragraph); and (g) Lim, Rosenfeld, and Liu fail to teach CO5 and therefore the references cannot possible teach SHGB and CO5 (Applicant Remarks, pg. 14, first full paragraph).
Regarding (a), as noted in MPEP 2124, references cited to show a universal fact need not be available as prior art before applicant’s filing date. As indicated in MPEP 2124:
In certain circumstances, references cited to show a universal fact need not be available as prior art before applicant’s filing date. In re Wilson, 311 F.2d 266, 135 USPQ 442 (CCPA 1962). Such facts include the characteristics and properties of a material or a scientific truism. Some specific examples in which later publications showing factual evidence can be cited include situations where the facts shown in the reference are evidence "that, as of an application’s filing date, undue experimentation would have been required, In re Corneil, 347 F.2d 563, 568, 145 USPQ 702, 705 (CCPA 1965), or that a parameter absent from the claims was or was not critical, In re Rainer, 305 F.2d 505, 507 n.3, 134 USPQ 343, 345 n.3 (CCPA 1962), or that a statement in the specification was inaccurate, In re Marzocchi, 439 F.2d 220, 223 n.4, 169 USPQ 367, 370 n.4 (CCPA 1971), or that the invention was inoperative or lacked utility, In re Langer, 503 F.2d 1380, 1391, 183 USPQ 288, 297 (CCPA 1974), or that a claim was indefinite, In re Glass, 492 F.2d 1228,1232 n.6, 181 USPQ 31, 34 n.6 (CCPA 1974), or that characteristics of prior art products were known, In re Wilson, 311 F.2d 266, 135 USPQ 442 (CCPA 1962)." In re Koller, 613 F.2d 819, 824 n.5, 204 USPQ 702, 706 n.5 (CCPA 1980) (quoting In re Hogan, 559 F.2d 595, 605 n.17, 194 USPQ 527, 537 n.17 (CCPA 1977) (emphasis in original)). See also Amgen Inc. v. Sanofi, 872 F.3d 1367, 1375, 124 USPQ2d 1354, 1359 (Fed. Cir. 2017).
As noted in the rejection of record, Boniface is an evidentiary reference used to support the rejection of claim 53, wherein Boniface evidences that LDFHFSSDR is a peptide fragment of INHBC; and LTVGAAQVPAQLLVGALR is a peptide fragment of CD14. Because Boniface is cited to show a universal fact, it does not need be available as prior art before Applicant’s filing date (See, MPEP § 2124). The claims remain rejected for the reasons of record.
Regarding (b), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Moreover, it is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Additionally, MPEP 2112.01(I) states that:
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
MPEP 2112.01(II) indicates:
“Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. “The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty”) (underline added).
Moreover, MPEP 716.02(b) states:
the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (See also; In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).
MPEP 716.02(c) indicates:
unexpected results must be weighed against evidence supporting a prima facie obviousness. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978); and where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Applicant’s assertion that the claimed array and method are based on Applicant’s unexpected technical advantages of the biomarkers and biomarker combinations with SHBG including for determining the probability for preeclampsia in a pregnant female with relatively high sensitivity and specificity (para [0028]); and the SHBG is predictive of preeclampsia, is not found persuasive. As an initial matter,
Applicant’s has not provided any evidence of improved properties that are reasonably commensurate in scope with the claimed invention. For example, claims 1 and 35 do not recite:
That the array is predictive of preeclampsia in a pregnant female;
The structure of the array including the specific probes that bind the two or more biomarkers;
Any specific biomarker combinations indicative/predictive of preeclampsia; and
The specific changes in biomarker expression that will diagnose the presence of preeclampsia in a pregnant female, that is predictive of preeclampsia in a pregnant female, and/or that indicates an increased probability of preeclampsia in a pregnant female.
Applicant has not provided any evidence supporting the asserted unexpected results. It is completely unclear what the term “relatively high sensitivity and specificity” means given there is no comparison of the instant array to any other array of biomarkers; and no indication regarding what the two or more biomarkers as recited determine or specify.
There is no nexus or co-extensiveness between Applicant’s asserted improvements and the steps as recited in claims 1 and 35.
Evidence has not been provided that the “superior results” asserted by Applicant were unknown in the prior art. In fact, the biomarkers recited in claims 1 and 35 were clearly known in the prior art as biomarkers of preeclampsia. For example –
Pre-eclampsia biomarker polypeptides including SHBG, CD14, and INHBC were known in the art to be useful in detecting pre-eclampsia in an individual, in determining whether an individual suffered from pre-eclampsia, in predicting whether an individual is suffering from, or is likely to suffer from pre-eclampsia, and/or in determining the likelihood that an individual will suffer from pre-eclampsia in the future as evidenced by Lim (col 6, lines 35-44; and Tables 1A, 1B and 2B; of record).
It was known that reduced first trimester SHBG levels is associated with an increased risk of subsequent preeclampsia as evidenced by Wolf (Abstract).
Using microarray data to compare samples taken from healthy pregnant women with normal pregnancy outcome and those who subsequently developed severe preeclampsia based on the differentially expressed proteins including CD14 was known in the art as evidenced by Than (paragraph [0024], Figure 2; and paragraphs [0092]-[0095]).
Using a microarray comprising from two to 100,000 or more different biomolecule markers including SHBG to identify subjects having, or predisposed to having gestational diabetes, preeclampsia, and gestational hypertension was known in the art, wherein women with multiple gestations, molar pregnancy or fetal hydrops, chronic hypertension or diabetes, or a personal or family history of eclampsia or preeclampsia are known to be at an increased risk as evidenced by Thahani (Abstract; col 1, lines 21-24; and col 2, lines 18-65).
Elevated complement factor C5a concentration in maternal plasma was associated with preeclamptic pregnancy and gestational hypertension as evidenced by Denny (Abstract).
Additionally, as indicated in MPEP 2112.01(II), products of identical chemical composition cannot have mutually exclusive properties, such that any two or more biomarkers comprising peptide fragments of SHBG and one or more of INHBC, C5, and CD14 isolated from a biological sample from a pregnant female will provide the same benefits and/or results. Thus, the array of two or more biomarkers as taught by the combined references of Lim and Rosenfeld will provide the same results. The rejection is maintained.
Regarding (c) and (d), Applicant’s assertion that Rosenfeld and Liu fail to teach the biomarker including INHBC, CD14 or CO5; and there is no reason for one of skill in the art to combine the Rosenfeld and Liu reference, is not found persuasive. As an initial matter, Liu is an evidentiary reference. Applicant is respectfully reminded that the rejection is based on the combination of Lim and Rosenfeld, wherein Lim teaches biomarkers of pre-eclampsia including SHBG, INHBC, and CD14; as well as, using ELISA, immunoprecipitation assays, and MS/MS for biomarker analysis, while Rosenfeld is cited for exemplifying co-IP MS. The combined references of Lim and Rosenfeld teach all of the limitations of the claims. Thus, the rejection is maintained.
Regarding (e), Applicant’s assertion that Lim does not overcome the deficiencies of Rosenfeld and Liu; and Liu too fails to teach or suggest each and every element of the present claims, even when considered in combination with Rosenfeld and Liu, such that the Office Action appears to be using impermissible hindsight using the presently claimed invention, is not found persuasive. At the outset, in response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Moreover, please see the discussion supra regarding that the rejection is based on the combination of Lim and Rosenfeld, and that it is not based on Liu and Rosenfeld as argued by Applicant. The claims remain rejected.
Regarding (f), MPEP 2141.02(VI) states that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Moreover, a reference teaches away “when a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken” in the claim. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013). A reference that “merely expresses a general preference for an alternative invention but does not criticize, discredit, or otherwise discourage investigation into” the claimed invention does not teach away. Id. Applicant’s assertion that Lim teaches away from using SHBG as a biomarkers because Lim lists SHBG in Tables 1B and 2B, which include proteins found in both women with preeclampsia and healthy pregnant women, is not found persuasive. Because Lim does not criticize, discredit, or otherwise discourage using SHBG as a biomarker of preeclampsia, Lim does not teach away. Additionally, the Examiner respectfully points out that a biological sample (e.g., a serum or plasma sample) from any human subject will comprise SHBG, which can be detected using an array. The fact that Lim is detected in pregnant women with preeclampsia, and that it is also detected in healthy pregnant women is consistent with what is known in the art. Lim clearly teaches the biomarkers and array as recited in instant claim 1 and 35 including SHBG, wherein the biomarkers are clearly detected in a sample from a pregnant female. Thus, the rejection is maintained.
Regarding (g), Applicant’s assertion that Lim, Rosenfeld, and Liu fail to teach CO5 and therefore the references cannot possible teach SHGB and CO5, is not found persuasive. The Examiner notes that instant claims 1 and 35 recite two or more biomarkers, wherein one biomarker comprises SHBG, and the other biomarker is selected from INHBC, CD14 and CO5. The combined references of Lim and Rosenfeld teach all of the limitations as recited in claims 1 and 35. Thus, the claims remain rejected.
New Objections/Rejections
Notice of Non-Compliant Amendment (37 CFR 1.121)
The amendment to the claims filed on March 9, 2026 does not comply with the requirements of 37 CFR 1.121(c) because the status identifier and text of claims 49-51 and 53 are not submitted with markings to indicate the changes that have been made relative to the immediate prior version of claims filed on December 2, 2025.
Amendments to the claims filed on or after July 30, 2003 comply with 37 CFR 1.121(c), which states:
(c) Claims - Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing
of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims,
in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, 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).
Specifically, the amendments to claims 49-51 and 53 filed March 9, 2026 do not recite a proper status identifier. For example, claims 49-51 and 53 recites the status identifier “(Previously Presented),” while also displaying brackets and strike-throughs indicating that claims 49-51 and 53 have been amended relative to the immediate prior version of the claims.
To be fully responsible, Applicant is required to comply with the Notice of Non-Compliant Amendment (37 CFR 1.121). In the interests of compact prosecution, an action on the merits has been prepared. However, future amendments must comply with 37 CFR 1.121(c) in order to avoid a notice of non-compliant amendment.
Conclusion
Claims 1, 35, 46, 49, 51 and 53 are rejected.
THIS ACTION IS MADE FINAL. 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 AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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/AMY M BUNKER/Primary Examiner, Art Unit 1684