DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-16 are pending and examined herein.
Priority
The present application, filed 04/26/2024, claims benefit of U.S. Provisional Patent Application 63/462,804, filed 04/28/2023. Claims 1–14 are entitled to the 04/28/2023 filing date. The provisional expressly supports the claimed CHD detection methods using sST2, Galectin-3, and NT-proBNP in dried blood samples; comparison to normal newborn controls; immunoassays; sampling times; pulse oximetry; physical and physiological characteristics; the claimed kits and antibodies; and the computer-implemented scoring method. In particular, provisional claims 1–14 substantially correspond to present claims 1–14, with additional support provided at provisional [0009]–[0036].
However, claims 15 and 16 are not entitled to the 04/28/2023 filing date and have an effective filing date of 04/26/2024. Although provisional claim 15 discloses providing “pulse oximetry data,” “physical characteristics,” and “physiological characteristics,” it does not require normalization of the biomarker level with respect to those categories. The provisional’s normalization disclosure is narrower: [0075] states that biomarker levels were normalized using “birth weight, GA week of delivery, sex of newborn, and day of testing” as underlying cofactors, while POX was separately used “as a pre-screen.” The provisional does not disclose normalizing biomarker levels with respect to POX data or the disclosed physiological-characteristic genus. By contrast, the 04/26/2024 specification expressly adds this broader normalization subject matter. It states that assay results may be normalized with respect to physical and/or physiological characteristics and provides detailed normalization embodiments at [0013] and [0130]–[0140]. Present claim 15 therefore includes subject matter not adequately supported throughout its scope by the provisional. Claim 16 contains an additional unsupported limitation. The provisional does not disclose algorithmically comparing a normalized patient biomarker level with a normal-newborn standard that is itself normalized with respect to the same data. The 04/26/2024 specification expressly introduces that relationship at [0021]–[0022] and [0234]–[0237], including normalized reference datasets, and Figure 13 specifically depicts “compare the normalized assay result to a normalized standard.” Accordingly, the effective filing dates are: Claims 1–14: April 28, 2023 and Claims 15–16: April 26, 2024.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 07/18/2024 and 04/03/2026 are acknowledged and have been considered.
Specification
The disclosure is objected to because of the following informalities: Paragraph [0041] states that FIG. 6D demonstrates an AUC of 0.96 with a 95% confidence interval of (0.83, 0.98), whereas FIG. 6D identifies the AUC as 0.96 with a confidence interval of [0.93, 0.98]. Applicant is required to amend the specification and/or drawings, as appropriate, so that the disclosure is internally consistent. Appropriate correction is required.
Claim Objections
Claim 10 is objected to because of the following informalities: the phrase “the one or more reagents comprises” is grammatically incorrect because the subject “reagents” is plural. For example, “the one or more reagents comprises” should be amended to “the one or more reagents comprise.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-8 and 13-16 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.
More particularly, although the specification provides procedures for measuring sST2, Galectin-3, and NT-proBNP in dried blood samples and reports cohort-level analyses using prospectively enrolled controls and retrospectively identified CHD cases, as well as pooled analyses comparing biomarker measurements between CHD and control groups, the specification does not provide sufficient teaching demonstrating that the recited biomarker measurements can be used according to the claimed steps to detect CHD in an individual newborn human patient without undue experimentation. The disclosed pooled analyses establish statistical discrimination between groups under particular experimental conditions, but do not establish an enabled diagnostic relationship by which an increased sST2 and/or Galectin-3 level, alone or in the claimed combinations, can be applied to an individual newborn human patient to detect CHD as required by the claims. This deficiency is further compounded by the heterogeneous congenital heart defects encompassed by the claims, the variable performance of the disclosed biomarkers, and the unpredictability of pediatric cardiovascular biomarker behavior demonstrated by the state of the art.
The enablement requirement is such that the specification of the described invention in such terms that one skilled in the art can make and use the invention to ensure that the invention is communicated to the interested public in a meaningful way (MPEP 2164).
The standard for determining whether the specification satisfies the enablement requirement is determined in view of the Wands factors (MPEP 2164.01(a)), to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation needed to make or use the invention based on the content of the disclosure, (2) the amount of direction provided by the inventor, (3) the existence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the level of one of ordinary skill, (7) the level of predictability in the art, and (8) the breadth of the claims. While all of these factors are considered a sufficient amount for a prima facie case are discussed below.
The breadth of the claims
Claim 1 broadly recites detection of congenital heart defect, CHD, in a newborn human patient based on an assay for one or more biomarkers selected from sST2 and Galectin-3, comparison of the determined biomarker level with a standard representing a normal newborn control without CHD, and a determination in which an increased biomarker level indicates detection of CHD. Thus, claim 1 does not merely require measuring a biomarker or demonstrating a statistical difference between populations. Rather, the claim requires using the biomarker level obtained from the newborn human patient, relative to the recited normal-newborn standard, such that an increased biomarker level indicates detection of CHD in that patient. The specification must therefore enable the skilled artisan to use the claimed biomarker relationship for the recited diagnostic determination, rather than merely establish that the biomarkers can be measured or that their distributions may differ between pooled CHD and control populations.
Claim 1 does not limit the claimed CHD to any particular congenital lesion, hemodynamic abnormality, ventricular morphology, disease severity, pathophysiology, or mechanism responsible for altering the recited biomarker. The breadth of CHD expressly contemplated by Applicant is substantial. The specification states that the term congenital heart defect as used herein refers to critical congenital heart defects including, but not limited to: coarctation of the aorta, double-outlet right ventricle, d-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia (with intact septum), single ventricle, total anomalous pulmonary venous return, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus ([0061], p. 13).
The specification therefore itself establishes that CHD encompasses numerous structurally and physiologically different cardiac abnormalities, including obstructive lesions, defects involving abnormal pulmonary or systemic circulation, single-ventricle physiology, conotruncal abnormalities, and defects having materially different ventricular loading conditions. Moreover, the disclosed examples do not establish that the claimed individual-patient diagnostic relationship is operative throughout the materially different CHDs encompassed by the claimed subject matter, nor do they demonstrate that an increased level of either biomarker recited alternatively by claim 1 reliably indicates CHD in an individual newborn across the claimed subject matter.
The breadth is further amplified because the specification defines an increased biomarker level very broadly. Applicant states that the term increased level as used herein refers to a detectable increase compared to the standard. The increase may be an increase of about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, about 100%, or more, such as about 150%, i.e. 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, or more, compared to the standard ([0072], p. 16). Thus, the disclosure does not restrict the operative increase to a single validated diagnostic threshold. Rather, Applicant expressly encompasses numerous degrees of biomarker elevation. The specification therefore leaves the skilled artisan to determine which increases, standards, thresholds, and biomarker configurations actually permit the claimed detection of CHD in an individual newborn patient.
Dependent claims 2–3 add NT-proBNP and specific biomarker combinations but still broadly encompass detection of the entire claimed CHD genus. Claim 4 merely specifies an immunoassay. Claim 5 permits sampling at numerous postnatal times extending from the day of birth through one week after birth or later. Claims 6–8 add POX or assessment of physical or physiological characteristics but likewise do not restrict the underlying CHD genus.
Independent claim 13 encompasses computer-implemented detection of CHD broadly through a score generated by algorithmically comparing sST2 and/or Galectin-3 levels to standards representing normal newborn controls. Claims 14–16 broaden the analytical implementations to encompass NT-proBNP, POX data, physical and physiological characteristics, normalization, and comparison with normalized standards. These additional analytical limitations do not supply the underlying experimentally established relationship necessary to determine CHD in the individual newborn patient. Instead, the claimed computer implementation depends upon the same biomarker-to-CHD relationship that must first be established before the resulting score can reliably perform the claimed diagnostic function.
The nature of the invention
The invention is directed to a biomarker-based diagnostic technology comprising measuring the presence or amount of sST2, Galectin-3, or NT-proBNP or a combination thereof, in a dried blood sample from a newborn human patient and using the result to diagnose congenital heart defect (CHD). CHD, as defined in the specification at paragraph [0061], encompasses numerous heterogeneous congenital defects. The invention further comprises using a computer to assign a score to the patient based upon the measured level of the biomarkers, and providing one or more vital data to make a diagnosis of CHD.
The amount of direction provided by the inventor / the existence of working examples
The specification provides working examples and procedural guidance for measuring the biomarkers. However, the disclosed studies principally establish retrospective, pooled, or aggregate statistical relationships between groups of CHD cases and controls rather than demonstrating prospective application of the claimed diagnostic method to an individual newborn human patient whereby a measured increase in sST2 and/or Galectin-3 relative to the recited normal-newborn standard is used to detect CHD in that patient.
Example 1 describes a pooled case-control investigation rather than an individual-patient diagnostic demonstration. Applicant states prospectively enrolled controls were compared to retrospectively identified CHD cases from pediatric cardiac surgical centers in Sweden and that blinded DBS batch analysis obtained during day 2-7 of life was performed for amino-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) and soluble Suppression of Tumorigenicity 2 protein (sST2) ([00189], p.39). Thus, the experiment demonstrates that biomarker measurements can be obtained from DBS specimens and statistically compared between previously characterized groups; it does not prospectively validate the claimed diagnostic relationship by applying the recited biomarker comparison to an unknown individual newborn human patient and demonstrating detection of CHD in that patient.
Example 2 likewise relies on a pooled cohort. Applicant states that the analysis contained 81 controls and 47 cases born at 36-42 weeks gestation, who passed POX without signs of CHD ([00194], p. 40), and reports an AUC of 0.96 [0.91-0.99] ([00195], p. 40; Fig. 1B). Again, the reported AUC characterizes discrimination between populations in the analyzed cohort; it does not itself establish a validated individual-patient decision rule showing that an increased level of the alternatively recited biomarkers permits detection of CHD in a newborn human patient according to claim 1.
Example 3 provides additional assay and analytical guidance, but likewise operates on pooled CHD and non-CHD samples. Applicant states that data analysis values obtained from these assays for NT-proBNP, sST2, and Galectin-3 were compared between CHD and non-CHD samples, and that group medians, averages and distributions were compared ([00219], p. 42). Applicant further states that levels were normalized with known underlying co-factors, such as birth weight, Gestational age (GA) week of delivery, sex of newborn, and day of testing after birth, for possible bias effects ([00219], p. 42), and that risk assessment was done with sample concentration, normalized or not, using a single or multiple cut-off values ([00219], p. 42). Applicant further evaluated binary, linear, and non-linear models with or without co-factor normalization ([00219], p. 42). Applicant states that an algorithm to estimate overall risk was applied to all samples in this example in order to separate CHD and non-CHD samples, and that POX (pulse oximetry) was used as a pre-screen to remove those picked up with it and used biochemical markers, i.e. NT-proBNP, sST2, and Galectin-3, to separate remaining CHD from non-CHD cases ([00219], p. 42). These disclosures provide evidence that Applicant investigated aggregate classification models and biomarker distributions. However, they do not identify an adequately validated diagnostic rule by which the skilled artisan can take the recited biomarker measurement from an individual newborn human patient, compare it to the claimed normal-newborn standard, and determine from the recited increase that the newborn has CHD. Nor do the examples establish that such a relationship is operative for the numerous materially different CHDs encompassed by Applicant’s definition in paragraph [0061].
The drawings further demonstrate this limitation. Figure 5A reports pooled NT-proBNP, 112 cases & 89 controls with AUC = 0.91 [0.87,0.95] (Fig. 5A). Figure 5B likewise reports pooled sST2, 112 CHD cases & 89 controls with AUC = 0.91 [0.87,0.95] (Fig. 5B). Figure 5C reports pooled Galectin-3, 112 cases & 89 controls with only AUC = 0.69 [0.62,0.76] (Fig. 5C). These results demonstrate population-level discriminatory performance under the tested conditions, but they do not establish that each biomarker alternative recited by claim 1 provides an enabled individual-patient diagnostic determination.
The Galectin-3 result is particularly important because claim 1 expressly permits Galectin-3 alone as the biomarker whose increased level indicates detection of CHD. Yet Applicant’s own Figure 5C shows substantial overlap and only modest overall discriminatory performance in the pooled cohort. The weakness persists after POX-positive cases are removed. Figure 5F reports Galectin-3, 52 cases & 81 controls, POX=1 and AUC = 0.7 [0.62,0.8] (Fig. 5F). Accordingly, even at the pooled-population level, Applicant’s own data demonstrate materially variable performance among the biomarker alternatives encompassed by the claims. The disclosure does not explain how the skilled artisan is to convert the Galectin-3 measurements, in particular, into the claimed reliable individual-newborn CHD determination without further empirical validation.
Applicant does disclose illustrative thresholds. For example, the specification states when sST2 is found to be greater than 5 ng/mL in a DBS from a newborn human patient, the level of sST2 is determined to be increased and the newborn human patient is thereby determined to have increased risk of CHD ([00110], p. 24), and when Galectin-3 is found to be greater than 800 ng/ml in a DBS from a newborn human patient, the level of Galectin-3 is determined to be increased and the newborn human patient is thereby determined to have increased risk of CHD ([00111], p. 24). However, the specification does not demonstrate that these illustrative thresholds were prospectively validated for detecting CHD in individual newborn human patients, establish the associated false-positive and false-negative performance necessary to apply those thresholds diagnostically, or demonstrate that either threshold provides the claimed diagnostic relationship for the materially different CHDs encompassed by paragraph [0061]. Accordingly, the disclosed thresholds do not remedy the absence of an enabled individual-patient diagnostic rule.
The state of the prior art / the level of predictability in the art
The state of the prior art and the level of predictability further demonstrate why the gap between Applicant’s pooled statistical observations and the claimed individual-patient diagnostic determination could not have been bridged by the skilled artisan without substantial additional experimentation. Cantinotti et al. (The Potential and Limitations of Plasma BNP Measurement in the Diagnosis, Prognosis, and Management of Children with Heart Failure Due to Congenital Cardiac Disease: An Update. Heart Failure Reviews. Vo. 19, No. 6, November 2014), Hauser et al. (Diagnostic Performance and Reference Values of Novel Biomarkers of Paediatric Heart Failure. Heart. Vol. 102, No. 20, October 2016), Wierzbicka et al. (A Scoping Review of Galectin-3 as a Biomarker of Cardiovascular Diseases in Pediatric Populations. International Journal of Environmental Research and Public Health. Vol. 19, No. 7, April 2022), and Meeusen et al. (Soluble ST2 and Galectin-3 in Pediatric Patients without Heart Failure. Biocehmistry. Vol. 48, No. 18, December 2015) collectively demonstrate that pediatric cardiovascular biomarker concentrations and diagnostic performance vary with, or are materially affected by, factors including age, hemodynamics, underlying cardiac/lesion physiology, disease state, and the particular biomarker being considered. These references therefore show that a skilled artisan could not simply take the population-level associations disclosed by Applicant and predict that a particular increase in sST2 and/or Galectin-3 relative to a normal-newborn standard would reliably detect CHD in an individual newborn patient.
Cantinotti et al. is particularly relevant to the predictability of natriuretic peptide measurements, including the NT-proBNP embodiments of claims 2–3, 11, and 14–16. Cantinotti expressly reports that BNP values are age and method dependent, even in pediatric populations and that regardless of age, there is great variability in BNP/NT-proBNP values within CHD characterized by different hemodynamic and clinical conditions (p. 727). This directly demonstrates that the biomarker signal varies within the very disease genus that Applicant claims broadly. Cantinotti further states that BNP plasma concentrations fluctuate widely and according to patho-physiologic stimuli and cardiovascular hemodynamic both in healthy subjects and in patients with heart failure (p. 728). The reference also reports significant infra-individual biological variability (CVi), ranging from 30 to 50 % (pp. 728–729). The newborn period is particularly variable. Cantinotti states that plasma BNP concentrations are very high during the first 4 days of life and then rapidly fall during the first week, with a further slower progressive reduction throughout the first month of life (p. 729). Most importantly for the breadth of CHD, Cantinotti expressly divides congenital defects by materially different cardiac physiology, including increased volume overload, pressure overload involving the left ventricle or the right ventricle, and complex cyanotic CHD (pp. 729–731). The reference then reports that BNP concentrations are higher in those with left ventricular volume overload as compared to those with right ventricular volume or pressure overload and further that BNP values are higher in diseases characterized by left ventricular pressure overload than in diseases with right ventricular pressure overload (p. 731). Thus, even a well-established cardiovascular biomarker does not behave identically across different congenital lesions.
Cantinotti likewise explains that reliable diagnostic cutoffs depend on age. For neonates 0–7 days, the reviewed prospective study used 170 pg/mL, whereas the older age group used 41 pg/mL, and Cantinotti states higher accuracy measures, for example, may be attained if multiple cutoffs are determined by age group, especially during the early infancy (p. 732). Further, Cantinotti reports that, in patients with univentricular heart, data being still controversial in this patient setting and that BNP was variable but within a normal range in the majority of patients and only weakly correlated with clinical and functional status (p. 733). Even for tetralogy of Fallot, Cantinotti reports correlation between BNP and RV function was discordant among various studies (p. 736). Ultimately, Cantinotti concludes that the pediatric evidence supported BNP/NT-proBNP as an adjunctive marker, not a stand-alone test and states that the indications were based on studies generally conducted on limited populations and that further prospective studies are needed (p. 737). Cantinotti therefore provides strong evidence that pediatric cardiovascular biomarker behavior is lesion-, age-, and physiology-dependent and that even NT-proBNP, a substantially more established biomarker, required contextual interpretation rather than a universal CHD rule.
Hauser is highly probative with respect to Applicant’s claimed sST2 embodiments. Hauser identifies pediatric CHD as the large and heterogeneous group of congenital heart diseases (CHD) (p. 1633). The reference further cautions that findings from adults cannot be extrapolated to children as they fail to reflect important differences in pathophysiology and compensatory reserve inherent to this group (p. 1633). This is directly relevant because Applicant seeks to extrapolate a biomarker relationship across a heterogeneous pediatric CHD genus. Hauser’s study population itself demonstrates that heterogeneity. The CHD-containing population included Functional single ventricle, Pulmonary/right-sided obstruction, Aortic/left-sided obstruction, Ventricular septal defect, Tetralogy of Fallot, Atrioventricular septal defect, Patent arterial duct, and Mixed lesion/other (Table 1, p. 1634). Importantly, sST2 did not show the same diagnostic performance as the natriuretic peptides. Hauser reports NT-proBNP and MR-proANP showed very good accuracy, whereas the remaining parameters did not perform sufficiently (p. 1635). Hauser further explains the biological unpredictability underlying those results. The authors state that in children, where CHD is the leading cause, the importance and prevalence of such fibrotic processes in different lesions are still poorly understood and that this may partly explain the lack of diagnostic performance observed for sST2 (p. 1637). The limitations section likewise states that the inhomogeneity of our cohort in terms of underlying aetiology may have obscured condition-specific associations and explains that outcome trajectories vary substantially between different diseases in the paediatric age group (p. 1638). Hauser therefore concludes further research is required to investigate whether and how reliably these novel biomarkers can predict outcome or treatment response in a more narrowly defined population and larger case numbers are needed (Hauser, p. 1638). The relevance is not that Hauser proves sST2 can never discriminate CHD. Rather, Hauser demonstrates that the diagnostic significance of sST2 in pediatric cardiac disease was sufficiently dependent upon the underlying population and disease physiology that the skilled artisan could not infer the claimed individual-newborn biomarker-to-CHD diagnostic relationship merely from Applicant’s pooled sST2results.
Wierzbicka similarly demonstrates unpredictability for Galectin-3. At the outset, the reference states that Galectin-3 has not yet been established in the pediatric population as a biomarker in daily clinical practice and that the available results were based on small cohort studies (p. 1). Most significantly, the reference states that the evidence for the usefulness of galectin-3 in the assessment of such pathologies as idiopathic dilated cardiomyopathy, coarctation of the aorta, functionally univentricular heart or tetralogy of Fallot were not completely confirmed (p. 1). These disease types overlap directly with defects encompassed by Applicant’s broad CHD definition, including coarctation of the aorta, single-ventricle physiology, and tetralogy of Fallot. The individual studies summarized in the reference reinforce that unpredictability. For aortic coarctation, Table 1 reports no linear relationship of G3 and LVMI or RWT in post-op nor in the follow-up (1-year post-op) period (Table 1, p. 5). For right-heart pressure or volume overload associated with pulmonary valve disease after tetralogy of Fallot repair, Table 1 reports no significant correlations between G3 and right heart hemodynamic measurements, both invasive and MRI derived (Table 1, p. 5). For young patients having Fontan circulation, Table 1 reports no relation of G3 and cardiac function nor long-term outcome and no potential of G3 in risk stratification of patients who have undergone the Fontan procedure (Table 1, p. 6).
The authors characterize the overall surgical-CHD evidence as the data is inconsistent and state that the data regarding aortic coarctation and tetralogy of Fallot are less promising (p. 7). The review further reports that in Fontan patients galectin-3 showed no relation to cardiac function nor long-term postoperative outcome in this cohort (p. 7). Although the reference acknowledges some positive Galectin-3 results in pediatric heart failure, it expressly concludes that the data are still sparse, and further trials are necessary to evaluate the value of the biomarker and its relationship to hemodynamical dysfunction (p. 8). The reference further notes that a study of patients after tetralogy of Fallot repair did not find any correlation between galectin-3 plasma concentration and right ventricular invasive hemodynamical parameters, nor measurements derived by cardiac magnetic resonance and states that those results raise doubt of whether galectin-3 may be a useful marker of myocardial damage of the right ventricle in patients after correction of congenital heart diseases (p. 9). The conclusion is particularly significant. The authors state there is still insufficient data to be able to introduce galectin-3 in clinical practice guidelines and further investigations should doubtlessly focus on multicenter studies consisting of larger cohorts (p. 11). They further identify heterogeneous data and small sample sizes as limitations of the evidence (p. 11). Accordingly, Wierzbicka demonstrates that Galectin-3 behavior differed among pediatric congenital cardiac conditions and that the field itself regarded the evidence as incomplete and heterogeneous.
Meeusen further supports the unpredictability of the claimed sST2 and Galectin-3 diagnostic relationships while distinguishing the ability to measure the biomarkers from the ability to use them predictably for disease-specific pediatric diagnosis. Meeusen expressly states that soluble ST2 (ST2) and galectin-3 (Gal3) are biomarkers of myocardial fibrosis and remodeling and explains that the study provides a foundation for the use of ST2 and Gal3 in pediatric patients by assessing values of these biomarkers among children without heart failure (p. 1337). The study evaluated sera from 240 children without heart failure and states that serum ST2 and Gal3 were measured by ELISA (p. 1337). Thus, the reference demonstrates that measuring sST2 and Galectin-3 and developing normal pediatric reference distributions were technically feasible. However, Meeusen expressly characterizes the pediatric state of the art as one in which treatment is hindered by the absence of biomarkers to monitor patient response to therapy or identify risk of progression and states clearly, further studies are needed in cardiac biomarkers for pediatric patients (p. 1337). The study further states that noting the paucity of biomarkers available in pediatric heart failure, we sought to provide a foundation for the use of ST2 and Gal3 in pediatric patients by assessing values of these biomarkers among children without heart failure (p. 1337). Most significantly, after establishing pediatric reference values for the biomarkers, Meeusen does not conclude that those values establish a predictable disease-specific relationship. Rather, the authors expressly state further disease specific studies are necessary in order to elucidate the relationship between these biomarkers and heart failure progression among pediatric patients (p. 1339). Meeusen further identifies potential non-cardiac sources of biomarker elevation, stating that increased ST2 and Gal3 concentrations have been reported in association with pneumonia and chronic obstructive pulmonary disease (COPD) and that this emphasizes the importance of considering non-cardiac co-morbidities and underlying inflammation in planning disease specific studies (p. 1339).
The authors ultimately conclude only that this baseline, normative data will allow for the evaluation of ST2 and Gal3 utility as biomarkers for the management of heart disease in children (p. 3), rather than establishing a generally applicable pediatric disease-detection relationship for either biomarker. Accordingly, Meeusen demonstrates that the underlying laboratory measurement of sST2 and Galectin-3 was available in the art, while the disease-specific meaning and reliability of those measurements in pediatric cardiac disease remained to be established through additional studies. This further supports that a skilled artisan could not simply extrapolate Applicant’s pooled biomarker measurements to reliable detection of the full heterogeneous CHD genus without additional disease- and lesion-specific investigation.
When Cantinotti, Hauser, Wierzbicka, and Meeusen are considered together, the prior art does not establish a simple, settled, lesion-independent relationship between an elevated cardiovascular biomarker and congenital heart defect generally. Thus, the state of the art supports substantial biological and clinical unpredictability and weighs strongly against concluding that Applicant’s pooled examples enable the entire claimed CHD genus.
The level of ordinary skill in the art
The level of ordinary skill at the effective filing date would have been relatively high, reasonably encompassing individuals having advanced education (e.g., PhD or M.D.) and substantial practical experience in pediatric cardiology, neonatal diagnostics, cardiovascular biomarker analysis, immunoassays, clinical laboratory science, and biostatistical classification. Nevertheless, the high level of skill does not remedy the absence of lesion-specific or generally applicable diagnostic guidance. A skilled artisan would understand how to obtain a dried blood sample, perform an immunoassay, measure the concentration of sST2, Galectin-3, or NT-proBNP, and perform statistical analyses. The specification provides substantial procedural guidance for those tasks. The missing teaching lies elsewhere: the artisan is not supplied with a sufficiently established diagnostic rule showing how an increased sST2 and/or Galectin-3 level relative to the recited normal-newborn standard can be used to detect CHD in the individual newborn human patient as claimed. Nor does the disclosure establish that such a diagnostic relationship operates for the materially different congenital heart defects encompassed by the claims.
That problem cannot be resolved merely through technical skill because the prior art itself demonstrates substantial variability in pediatric cardiovascular biomarker behavior and diagnostic performance. Thus, even a highly skilled artisan would need to generate additional empirical clinical evidence to establish the operative thresholds, decision rules, sensitivity and specificity, and patient- and disease-related conditions under which the claimed diagnostic determination can reliably be made.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The quantity of experimentation necessary to make and use the claimed diagnostic invention would be extensive. The specification establishes that the biomarkers can be measured and provides pooled CHD-versus-control analyses, but does not provide sufficient teaching establishing how the claimed biomarker increase is to be applied to an individual newborn human patient to detect CHD as claimed. A person of ordinary skill would therefore need to conduct substantial additional clinical experimentation to establish and validate the diagnostic relationship itself. Such experimentation would include, at minimum, prospective or otherwise adequately powered clinical validation, including prospective validation as appropriate, in newborn patients; determination of diagnostically operative biomarker distributions and thresholds; establishment of appropriate normal-newborn control distributions; determination of sensitivity, specificity, false-positive rates, and false-negative rates; assessment of postnatal age effects; assessment of gestational age, birth weight, sex, and testing-day effects; evaluation of disease severity and hemodynamic state; determination of whether and how the biomarker relationship differs among the numerous CHD lesions encompassed by paragraph [0061]; and validation of the claimed biomarker combinations and computational models.
For the Galectin-3-alone embodiment, the need for such additional work is particularly apparent because Applicant’s own Figure 5C reports only AUC = 0.69 [0.62,0.76] for 112 cases & 89 controls (Fig. 5C), and Figure 5F reports only AUC = 0.7 [0.62,0.8] after POX screening (Fig. 5F). These data do not provide the skilled artisan with an adequately validated rule for using an increased Galectin-3 level to detect CHD in an individual newborn as expressly encompassed by claim 1. For sST2, although Applicant reports stronger pooled sST2 discrimination, pooled cohort discrimination does not itself establish the individual-patient diagnostic rule recited by the claim, particularly where the state of the art demonstrates that sST2 performance varies with pediatric cardiac disease context and underlying physiology. For claims involving NT-proBNP, the artisan would additionally have to resolve the age-, hemodynamic-, and lesion-dependent effects documented by Cantinotti, including the fact that different congenital loading states produce materially different BNP responses and that optimal diagnostic thresholds vary with age.
Claims 13–16 require additional experimentation because algorithmic scoring and normalization cannot remedy the absence of an adequately established underlying biomarker-to-CHD diagnostic relationship. Although Applicant discloses binary, linear, and non-linear models with or without co-factor normalization ([00219], p. 42), the specification does not provide sufficient validation demonstrating that the resulting score permits the claimed detection of CHD in an individual newborn patient. Nor does the specification establish an operative model applicable to the materially different congenital defects encompassed by the claims. Accordingly, practicing the full scope would not involve merely repeating a disclosed protocol or undertaking routine optimization. Rather, it would require substantial clinical investigation across multiple disease phenotypes, patient variables, biomarker thresholds, assay combinations, and statistical models to determine which portions of the broad genus actually work for the claimed CHD-detection purpose. That quantity of experimentation is undue.
Therefore, considering the Wands factors as a whole, the specification demonstrates that sST2, Galectin-3, and NT-proBNP can be measured in dried blood samples and reports statistical discrimination between certain pooled CHD and control cohorts. However, those disclosures do not provide sufficient teaching to enable a person of ordinary skill in the art to use the claimed biomarker increase to detect CHD in an individual newborn human patient as required by claims 1–8 and 13–16 without undue experimentation. Applicant’s cohort-level and pooled analyses, including analyses using prospectively enrolled controls and retrospectively identified CHD cases, do not themselves establish an adequately validated individual-patient diagnostic rule, and Applicant’s own results demonstrate materially variable performance among the claimed biomarker alternatives, particularly Galectin-3.
Moreover, the specification encompasses numerous materially different congenital heart defects without demonstrating that the claimed diagnostic relationship is operative throughout the materially different congenital heart defects encompassed by the claims, while the state of the art demonstrates that pediatric cardiovascular biomarker concentrations and diagnostic performance vary with, or are materially affected by, factors including age, cardiac lesion, hemodynamics, physiology, and disease state. A skilled artisan would therefore be required to conduct substantial additional clinical experimentation to establish the operative thresholds, standards, diagnostic performance, patient-variable effects, lesion-dependent effects, and analytical models necessary to make the claimed diagnostic determination. Such experimentation constitutes undue experimentation rather than routine implementation of an enabled diagnostic method.
Accordingly, the specification does not enable the claimed diagnostic invention, and claims 1–8 and 13–16 are rejected under 35 U.S.C. 112(a).
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 1-8 and 13-16 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to judicial exceptions, specifically a law of nature and an abstract idea in the form of mental processes, without significantly more. Claims 1–8 recite the naturally occurring relationship between increased levels of the cardiovascular biomarkers sST2 and/or Galectin-3, optionally together with NT-proBNP, and congenital heart defect (CHD) in a newborn human patient, and recite evaluating measured biomarker information relative to a normal newborn standard to determine whether CHD is detected. Claims 13–16 recite the same natural relationship and further recite abstract evaluation of biomarker information through scoring, algorithmic comparison, normalization, and comparison with standards.
This rejection is made in accordance with Patent Subject Matter Eligibility as set forth in MPEP §2106. Analysis of subject-matter eligibility under 35 U.S.C. §101 requires consideration under these steps as followed:
Step 1 – Statutory Category (Refer to MPEP §2106.03): Claims 1-8 and 13-16 are drawn to a process, which falls within a statutory category under 35 U.S.C. §101.
Step 2A, Prong One – Recitation of a Judicial Exception (Refer to MPEP §2106.04): Regarding claim 1, the claim recites assaying a dried blood sample from a newborn human patient for one or more CHD biomarkers selected from sST2 and Galectin-3; determining the level of the biomarker; comparing that level with a standard representing a normal newborn human control patient without CHD; determining whether the biomarker level is increased or decreased compared with that standard; and providing that an increased level indicates detection of CHD. The claim therefore recites a law of nature, namely the naturally occurring relationship between an increased level of sST2 and/or Galectin-3 in the newborn and the presence of CHD. The claimed biomarker concentration is a naturally occurring biological characteristic of the patient, and the diagnostic significance assigned to an increased concentration is based upon the natural physiological relationship between the biomarker and the patient’s cardiac condition. The claim does not create that relationship; rather, the claim detects and evaluates it. Claim 1 additionally recites an abstract idea in the mental-process grouping. Once the measured biomarker value and the normal reference value are available, the recited acts of comparing the values, determining whether the measured level is increased or decreased, and determining from that comparison that CHD is detected constitute evaluation and judgment of information. Such evaluation is the type of mental-process activity identified in MPEP § 2106.04(a)(2).
Claim 2 incorporates the judicial exceptions of claim 1 and additionally recites assaying NT-proBNP as a CHD biomarker. The claim therefore additionally relies upon the naturally occurring relationship between NT-proBNP level and cardiac condition while retaining the same comparison and diagnostic evaluation. Claim 3 specifies combinations of sST2, Galectin-3, and NT-proBNP, but likewise retains the naturally occurring biomarker-to-CHD relationship and the evaluation of measured biological information relative to normal controls. Merely evaluating two or more naturally occurring biomarker concentrations rather than one does not remove the judicial exceptions. Claim 4 specifies that the assay comprises an immunoassay. The immunoassay is a physical laboratory technique used to obtain the biomarker information subsequently evaluated under the recited natural relationship; it does not remove the law of nature or the mental-process limitations from the claim. Claim 5 specifies the timing at which the biological sample is obtained. That limitation defines when the data used in the diagnostic evaluation are collected but leaves unchanged the recited natural relationship and subsequent comparison and diagnostic determination. Claims 6-8 similarly add POX assessment and assessment of physical and physiological characteristics. These limitations provide additional observations and information for diagnostic assessment but retain the law of nature and mental evaluation recited by claim 1. Accordingly, claims 1–8 recite judicial exceptions in the form of a law of nature and mental processes
Independent claim 13 recites a computer-implemented method of detecting CHD by providing a determined level of one or more biomarkers selected from sST2 and Galectin-3 in a dried blood sample and, responsive to that level, assigning a score representative of detection of CHD by algorithmically comparing the determined biomarker level with one or more standards representing normal newborn human control patients without CHD. Claim 13 recites the same law of nature as claim 1: the naturally occurring relationship between the patient’s sST2 and/or Galectin-3 level and the presence of CHD. Claim 13 also expressly recites an abstract mental process, namely evaluating biological information by assigning a score and comparing the determined biomarker level with normal reference information to reach a diagnostic determination. The fact that the method is characterized as computer-implemented and that the comparison is characterized as algorithmic does not, without more, remove the underlying evaluation from the mental-process grouping. Current MPEP guidance specifically recognizes that computer implementation does not preclude a mental-process characterization where the underlying evaluation can be conceptually performed by a human, and further cautions that merely using the term algorithm does not itself establish a particular mathematical concept unless the claim actually sets forth or describes the mathematical calculation.
Claim 14 adds the determined level of NT-proBNP and therefore retains the same judicial exceptions while adding another naturally occurring cardiovascular biomarker as an input to the analysis. Claim 15 adds POX data, physical characteristics, physiological characteristics, and a normalized determined biomarker level with respect to the recited data. The normalization limitation constitutes additional evaluation and manipulation of information to account for selected patient variables and does not remove the underlying natural relationship. The resulting normalized biomarker information is still used to make the claimed diagnostic determination. Claim 16 further recites algorithmically comparing the normalized determined biomarker level with standards representing normal newborn controls normalized with respect to the recited data. This limitation further specifies the information comparison used to reach the diagnostic conclusion but remains an evaluation of patient information against reference information. Accordingly, claims 13–16 recite both the naturally occurring biomarker/CHD relationship and abstract evaluation of biological information.
Step 2A, Prong Two – Integration into a Practical Application (Refer to MPEP §2106.04 (d)): Regarding claim 1, the additional physical activity is principally the assaying of a dried blood sample to obtain the sST2 and/or Galectin-3 level used in the comparison. That assay is data gathering necessary to observe the naturally occurring biomarker relationship. The claim does not recite an improvement in assay technology, an improved dried-blood-spot structure, an improved immunoassay architecture, or another technological improvement attributable to the claimed method. Rather, the measured biomarker value supplies the information upon which the natural correlation and abstract comparison operate. The dried blood sample does not meaningfully integrate the judicial exceptions merely because the diagnostic information originates from a physical specimen. The claim uses the sample to acquire the biological information required for the subsequent comparison and diagnostic inference. The claimed result remains detection of CHD based upon the naturally occurring biomarker relationship. The claim also does not recite administering a drug, performing surgery, altering treatment, changing a newborn’s management, or otherwise applying the diagnostic determination to effect a particular treatment or prophylaxis for CHD. Unlike a treatment claim in which a natural relationship is used to select and administer a particular therapy, claim 1 ends with the diagnostic determination itself.
Claim 2’s additional NT-proBNP measurement and claim 3’s biomarker combinations likewise provide further biological information to be evaluated. They do not impose an action upon the newborn resulting from the diagnostic conclusion. Claim 4’s immunoassay specifies the laboratory technique used to collect the biomarker information. The claim does not improve immunoassay technology; rather, the immunoassay functions as the mechanism for obtaining the input used to apply the judicial exceptions. Claim 5’s sampling-time limitations merely define when the biological information is collected. They do not apply the natural relationship in a meaningful manner beyond the diagnostic field of use. Claim 6’s POX assessment similarly provides another diagnostic measurement. The claim does not require treatment responsive to the POX or biomarker result. It merely supplements the information considered in detecting CHD. Claims 7 and 8 add assessments of physical and physiological characteristics. Those additional observations likewise supply information rather than impose a treatment or technological transformation responsive to the claimed diagnostic determination. When claims 1–8 are considered as a whole, the additional limitations therefore do not meaningfully apply the naturally occurring biomarker relationship or mental evaluation beyond obtaining and assessing the information required to detect CHD. Accordingly, the judicial exceptions are not integrated into a practical application.
Regarding claim 13, identifying the method as computer-implemented does not, as claimed, improve the functioning of a computer or another technology. The claim does not specify a new computer architecture, new processor operation, new data structure, improved storage mechanism, or technical improvement in computational performance. Instead, the computer performs the claimed scoring and comparison of biomarker information. Current MPEP guidance explains that a generic computer used merely as a tool to perform an exception does not itself establish a practical application, whereas an actual improvement in computer capabilities or another technological field may do so. Here, claim 13 uses computer implementation to perform the diagnostic information evaluation itself rather than reciting a technological improvement to the computer or assay.
Claim 14 merely adds NT-proBNP information to the analysis. Claim 15 adds POX, physical, and physiological information and normalization of biomarker levels with respect to that information. These limitations refine the data supplied to and processed by the diagnostic analysis but do not require any particular treatment or other action responsive to the resulting score. Claim 16 further refines the comparison by requiring normalized patient values and normalized normal-control standards. This is an additional manner of evaluating the information rather than an improvement in the operation of a computer or another technical field. Accordingly, considering claims 13–16 as a whole, the computer and additional patient information are used to perform and refine the claimed diagnostic evaluation rather than to integrate the judicial exceptions into a practical application.
Step 2B, Inventive Concept (Refer to MPEP §2106.05): The additional elements are considered individually and as an ordered combination to determine whether they amount to significantly more than the judicial exceptions. One consideration is whether the additional elements merely constitute well-understood, routine, conventional activities previously engaged in within the relevant field. The evidence discussed below is relied upon for this limited Step 2B purpose. The references are not relied upon to establish the judicial exceptions themselves, but rather to demonstrate the conventional nature of the additional laboratory, screening, reference-comparison, normalization, and computer-analysis activities surrounding those exceptions.
Regarding claim 1, the additional activity of obtaining and assaying a newborn dried blood sample does not supply an inventive concept. Clausen et al. (Evaluation of Circulating Cardiovascular Biomarker Levels for Early Detection of Congenital Heart Disease in Newborns in Sweden, JAMA Network Open. Vol. 3, No. 12, December 2020 – IDS dated 07/18/2024) demonstrates that the DBS analysis has been part of neonatal screening programs around the world for many decades (p. 2), while Meeusen et al. (refer to full citation above) demonstrates quantitative immunoassay measurement of the exact sST2 and Galectin-3 biomarkers at issue. The use of a normal reference also does not provide significantly more. Meeusen expressly established ST2 and galectin-3 reference values in pediatric patients without heart failure (Table 2, p. 1338) and reports baseline, normative data for ST2 and Gal3 in children (p. 1337).
Claim 2’s NT-proBNP assay likewise does not supply significantly more. Clausen was already quantitatively testing NT-proBNP in newborn dried blood spots and comparing the resulting measurements between newborn controls and newborns with CHD (p. 1). Claim 3 merely requires specified combinations of the same biomarker information. Combining multiple biomarker measurements does not transform the otherwise conventional acquisition of biological data into an inventive concept when the claimed combination is subsequently used to perform the recited diagnostic evaluation. Claim 4’s immunoassay limitation is particularly well supported as routine laboratory activity by Meeusen’s express use of a quantitative monoclonal sandwich ELISA 96-well microtiter plate format for sST2 and a quantitative 2-site ELISA approved for clinical diagnostics for Galectin-3 (p. 1338). Claim 5’s sample-time limitation does not amount to significantly more. Clausen expressly reports that newborn DBS screening using standard protocols was conducted more than 48 hours after birth during the first week of life (p. 3). Claim 6’s POX limitation likewise does not provide an inventive concept because Clausen expressly characterizes POX as a widespread tool for detecting critical CHD in many health care systems (p. 2). Claims 7–8 add physical and physiological characteristics as additional diagnostic information. Considered in the context of the claims as a whole, these observations provide further patient data for the same diagnostic assessment rather than a technological improvement or treatment step.
Regarding claim 13, the computer implementation does not supply an inventive concept merely by automating the scoring and comparison of biomarker information. Clausen demonstrates that newborn cardiovascular biomarker information was already entered into an electronic database for statistical analysis using SPSS, version 26 (IBM); TIBCO Spotfire, version 7.11.1 (TIBCO Software Inc); and R, version 3.5.1 (R Foundation for Statistical Computing) (p. 4). Madsen et al. (Reference Curves for Pediatric Endocrinology: Leveraging Biomarker Z-Scores for Clinical Classifications, Journal of Clinical Endocrinology & Metabolism. Vol. 107, No. 7, July 2022) further demonstrates computer-based processing and classification of pediatric biomarker information using established software and analytical frameworks. The reference used the LMS framework implemented in R, generated covariate-adjusted biomarker z-scores, and used a random-forest model to perform computerized classification (pp. 2005 – 2012).
Claim 14 merely adds NT-proBNP as another determined biomarker level. Clausen demonstrates quantitative NT-proBNP analysis in newborns and statistical comparison of those results in the CHD-screening environment (p. 1). Claim 15’s use of POX data and patient characteristics likewise does not supply significantly more. Clausen demonstrates established POX screening in newborn CHD assessment (pp. 2-4), while Madsen demonstrates quantitative adjustment of biomarker information according to patient covariates. Madsen specifically teaches adjustments for gender, age, BMI, and other clinically relevant features when evaluating patient biomarker levels (p. 2013). Claim 16 further specifies comparison with normalized normal-control standards. Madsen demonstrates the established use of reference curves against which individual pediatric biomarker measurements are benchmarked and normalized according to covariates (p. 2013). The claimed use of normalized reference information therefore does not, by itself, transform the natural relationship and abstract comparison into significantly more.
When the additional limitations of claims 13–16 are considered as an ordered combination rather than in isolation, the claims still amount to obtaining biomarker and patient information, adjusting that information according to patient characteristics/reference information, and using a computer to score or compare the resulting information to reach the diagnostic conclusion dictated by the claimed natural relationship. No unconventional technical arrangement or improvement in computer functionality is recited. Accordingly, the ordered combination does not provide an inventive concept sufficient to transform the claimed judicial exceptions into patent-eligible subject matter.
Ultimately, claims 1–8 and 13–16 are therefore rejected under 35 U.S.C. 101 because the claimed inventions are directed to a law of nature and an abstract idea without additional elements that integrate the judicial exceptions into a practical application or amount to significantly more than the exceptions themselves.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 9-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Snider (US 9,239,333 B2).
Regarding claim 9, Snider teaches kits containing an antibody that specifically binds to ST2, an antibody that specifically binds to galectin-3, and instructions for using the kit (col. 24, p. 23). Snider further expressly states that any of the kits described herein may also be provided as an ELISA assay and may include one or more secondary antibodies and/or a substrate for detection (col. 24, p. 23). Also, Snider explains that ST2 exists as a soluble receptor that is detectable in serum and that in general, in the methods described herein, the soluble form of ST2 polypeptide is measured (col. 12, p. 17) The recitation that the kit is for detection of CHD in a newborn human patient and that the assay is performed in a dried blood sample obtained from the newborn human patient, these limitations recite the intended use and environment of the claimed kit and do not require the newborn patient or dried blood sample to constitute a structural component of the kit. Snider nevertheless expressly teaches that the sample may be serum, blood, or plasma (col. 3, p. 13), and teaches that the level of ST2 and galectin-3 may be measured in blood, serum, and plasma (col. 17, p. 20). The different intended clinical use or source/condition of the external sample does not structurally distinguish the claimed assay-reagent kit from Snider’s expressly disclosed kit.
Regarding claim 10, as discussed above, Snider teaches kits containing an antibody that specifically binds to ST2, an antibody that specifically binds to galectin-3 (col. 24, p. 23). Snider further teaches that these antibodies may be polyclonal, monoclonal, recombinant, e.g., a chimeric or humanized, fully human, non-human, e.g., murine, monospecific, or single chain antibody (col. 24, p. 23).
Regarding claim 11, Snider expressly teaches the further limitation that the kit comprises one or more antibodies specific for NT-proBNP. Specifically, Snider teaches that any of the kits described herein may also include one or more additional antibodies for additional markers including NT-proBNP (col. 24, p. 23). Snider further expressly states that antibodies for ST2, galectin-3, NT-proBNP are commercially available (col. 24, p. 23). Accordingly, Snider expressly provides the same ST2/Galectin-3 kit of claims 9 and 10 with an additional NT-proBNP-specific antibody as required by claim 11.
Accordingly, Snider discloses, expressly or inherently, each and every limitation of claims 9-11. Accordingly, claims 9-11 are anticipated under 35 U.S.C. 102.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Snider in view of Saleh et al. (Value of Galectin-3 Assay in Children with Heart Failure Secondary to Congenital Heart Diseases: A Prospective Study. BMC Pediatrics. Vol. 20, No. 1, November 2020).
With respect to the teachings of Snider, see the discussion above, which applies equally here. However, Snider does not expressly teach that the kit further comprises one or more reagents or devices for one or more of collection, drying, transport, and storage of a blood sample.
Regarding one or more reagents or devices for one or more of collection, drying, transport, and storage of a blood sample, Saleh expressly teaches these additional sample-handling components in the same Galectin-3 assay context. Specifically, Saleh teaches that for the assay of serum galectin-3, blood samples were collected in plastic syringes, and rapidly conveyed to chilled tubes and that the serum was separated by centrifugation at 4 °C for 20 min and stored at -80 °C (Methods, p. 2). Saleh further teaches that serum galectin-3 was measured using ELISA kit that is manufactured for research use only (Methods, p. 2). Thus, Saleh expressly demonstrates the use of physical devices for collection and handling of a blood sample—plastic syringes and chilled tubes—and preservation by storage prior to performing the Galectin-3 assay.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Snider’s Galectin-3/ST2 assay kit by further including a blood-sample collection device, such as the plastic syringe taught by Saleh, and associated sample-handling components such as the chilled tube to provide the physical means for collecting and maintaining the blood specimen prior to biomarker analysis. A skilled artisan would have been motivated to make this modification because Snider provides a kit for measuring Galectin-3, while Saleh expressly teaches in the same Galectin-3 assay context that the specimen used for that assay is collected in plastic syringes and rapidly conveyed to chilled tubes before being stored at -80 °C and subsequently measured using a Galectin-3 ELISA kit. Accordingly, Saleh provides a direct teaching and suggestion to provide the Galectin-3 assay workflow with the conventional blood-collection and sample-preservation devices necessary to obtain and maintain the specimen before assay. One of ordinary skill in the art would have had a reasonable expectation of success because Saleh actually employed those same devices to collect and handle the blood specimen before subsequent Galectin-3 measurement, demonstrating that the modification performs its established collection and sample-maintenance functions without changing the ordinary biomarker-assay function of Snider’s kit.
Conclusion
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 August 27, 2026
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