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 .
Election/Restrictions
It is acknowledged that Applicant elected claims 12-14 and 24 and species: (a) CpG cg04988978 and (b) SNP rs2869675 without traverse in the reply filed July 24, 2026.
Claims 1-25 are currently pending.
Claims 1-11, 15-23, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 24, 2026.
Claims 12-14 and 24 herein been examined to the extent that they read the elected species. The additionally recited species have been withdrawn from consideration as being directed to non-elected subject matter.
Priority
Claims to benefit of provisional applications 63/496,330 and 63/455,888 are acknowledged and the effective filing date of the instant application is considered to be March 30, 2023.
Information Disclosure Statement
Information disclosure statements from 01/17/25, 08/25/25, 12/12/25, 04/21/26, and 07/24/26 have been received.
The following IDS entries have been crossed out and not considered, as they are missing a publication year:
NPL #47 from the IDS filed 01/17/25
Additionally, please note that for each of the filed IDS, the given references have been considered to the extent of their documentation which has been submitted/provided on the record in English.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12-14 and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 12-14 and 24 are rejected because it is not clear how the recited preambles of claims 12 and 24 are intended to breathe life and meaning into the claims. The preambles of the claims recite a method for “determining the presence of biomarkers in a biological sample from a subject, wherein the biomarkers are associated with detecting CVD, determining severity of CVD, estimating survival from CVD, identifying, customizing, and/or optimizing intervention(s) for CVD, managing CVD and/or monitoring CVD.” However, the method only requires active process steps of “providing” a sample/samples and “contacting” a sample/samples. Thus, it is not clear if the Applicant intends to cover only a method of “providing” and “contacting” samples with reagents, OR if the method is somehow intended to require more in order to accomplish the goal(s) set forth in the preamble. If it is the latter, then it appears that the claims are incomplete, as they fail to provide active steps that clearly accomplish the goal(s) set forth by the preambles to the claims.
Furthermore, claims 12 and 24 recite the limitation "the percentage" in the last wherein clause. There is insufficient antecedent basis for this limitation in the claims.
Claim 14 is rejected for the recitation of “the window of incidence” because it lacks antecedent basis and is unclear. Claim 12, on which it depends, does not recite “a window of incidence” nor any active steps which inherently require the existence of ‘a window of incidence,’ and it is unclear what is being required by the claim. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claim 24 is rejected for the recitation of “a biological sample from a subject” in the preamble and “a biological sample from the subject at risk for or having CVD” because it is unclear if these samples are the same. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claim 24 is rejected for the recitation of “subject at risk for or having CVD” because it is unclear how being "at risk" is assessed or defined. CVD is a possibility in any individual of a species susceptible to the condition, and thus a subject would inherently be ‘at risk’ for developing CVD. If Applicant intended to indicate that the method be used for prognosis of CVD or assessing the likelihood that a subject will develop CVD, the Applicant must amend the language of the claims to indicate that meaning.
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 12-14 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for some combinations of biomarkers for some applications, as elaborated below, does not reasonably provide enablement for all possible combinations regarding a method for determining the presence of biomarkers in a biological sample from a subject, wherein the biomarkers are associated with detecting CVD, determining severity of CVD, estimating survival from CVD, identifying, customizing, and/or optimizing intervention(s) for CVD, managing CVD and/or monitoring CVD.
The embodiments which are enabled are (see embedded Table and discussion below):
Human subjects between the ages of 35-80
Blood samples
Determination of biomarkers/diagnosis for coronary heart disease using:
16-biomarker panel
Individual CpG biomarkers: cg04988978, cg03725309, cg12586707, cg17901584
Estimating mortality risk using:
The 6-biomarker panel and the 3-biomarker panel
The embodiments which are not enabled are:
ALL subjects
ALL types of samples
Determination of ALL recited clinical associations (i.e. determining severity, optimizing interventions, etc.) using ALL individual CpG or ALL possible pairs of the CpG/SNPs
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
Claims 12-14 and 24 are drawn to a method of determining the presence of biomarkers in a biological sample from a subject, wherein the biomarkers are associated with detecting CVD, determining severity of CVD, estimating survival from CVD, identifying, customizing, and/or optimizing intervention(s) for CVD, managing CVD and/or monitoring CVD. In view of the recitation of “sample,” the claims broadly encompass ANY type of sample. Claim 13 limits the sample types to blood and saliva. In view of the recitation of “subject,” the claims broadly encompass both human AND non-human subjects of ANY age.
The claims recite first steps of providing a sample or samples and contacting a first portion of a sample with oligonucleotide primers for detection of any of six CpG dinucleotides. Claims 12-14 additionally recite a step of contacting a second portion of the sample with primers for detecting the identity of any of ten SNPs. The claims recite that the identity of the SNP and/or the percentage of methylation of the CpG dinucleotide is/are associated with detecting CVD or estimating survival from CVD.
The nature of the invention requires reliable correlations between the identity of ANY of the ten SNPs and/or the percentage of methylation of ANY of the six CpG dinucleotides in ANY combination and detecting CVD, determining severity of CVD, estimating survival from CVD, identifying, customizing, and/or optimizing intervention(s) for CVD, managing CVD and/or monitoring CVD.
Teachings in the Specification and Examples
The specification teaches that biomarkers and associated models were determining using the Framingham Heart Study (FHS) Offspring Cohort (par. 232) and validated using two additional cohorts. The FHS study included human subjects within the ages of approximately 55-80 (Table 1). The FHS study collected information regarding coronary heart disease status comprising patient clinical data and blood samples. Genome-wide methylation data from 2,567 human subjects was obtained using the Illumina Infinium HumanMethylation450 BeadChip Array (par. 233). After quality control, a total of 2,560 were retained, and methylation data was obtained from 403,192 loci. Genome-wide genotype data was obtained using the Affymetrix GeneChip HumanMapping 500K array. Of the samples remaining from methylation analysis, after quality control, 2,295 samples and 472,822 SNPs were assessed.
Several validation cohorts were described. The Intermountain Healthcare Cohort comprised 252 human subjects between the ages of approximately 48-80 (par. 234; Table 2). Subjects had undergone coronary angiography and were defined as having or not having CHD on the basis of percentage stenosis upon angiography. Illumina Infinium MethylationEpic Beadchip array and the Illumina Infinium Multi-Ethnic Global BeadChip array were used to obtain methylation and SNP data (par. 236). Please note that the SNP array recited here is distinct from the SNP array recited for the training cohort. The Iowa cohort was a second validation cohort having 167 human subjects between the ages of approximately 37-77, although controls in this cohort skewed younger than cases and subjects having heart disease were between the ages of 51-77 (par. 237; Table 3). Subjects were assessed as having or not having coronary heart disease using medical records.
All data mining, feature selection, model development/tuning based on FHS training set (par. 238). Analyses led to selection of a 16-marker set comprised of six methylation loci and ten SNPs which had the best combined performance as measured by AUC, sensitivity, and specificity (par. 239). The specification states that Kaplan-Meier survival curves and Cox Proportional Hazard models were fitted to display CHD as a function of high vs low predicted genetic-epigenetic profile (par. 240), though this data is not shown. The overall model, comprising the 16-marker set, was termed the PrecisionCHD model. This 16-biomarker model demonstrated > 75% AUC in each overall cohort, with an average of 81% AUC in validation cohorts (Table 4). The average sensitivity and specificity in validation cohorts were 80% and 75% (par. 244).
The specification does not disclose how individual biomarkers were assessed as predictors for CVD (how they were tested and validated, etc.). Appendix A shows the AUC for individual biomarkers, including the elected species cg04988978, which is listed as having an AUC of ~0.62. There is no information regarding the individual performance of the elected SNP rs2869675, even in Appendix C (which lists SNPs “associated with CVD”). The specification states that these biomarkers are “associated with CVD” (par. 245), which is interpreted to mean that the biomarkers are associated with the presence or absence of CVD.
The specification describes further assessment of biomarker performance regarding mortality risk (par. 266). The six methylation markers from the 16-marker set were used for this purpose and termed the PrecisionCHD-Epi panel (par. 265). 244 subjects from the FHS cohort between the ages of approximately 62-82, all diagnosed as having CHD, were analyzed regarding their percentage methylation at these methylation sites and whether or not they died within the follow-up period (par. 268). Standard proportional modelling using all six markers predicted survival, and an optimized model of three markers was also predictive. However, the specifications states that “stepwise removal of non-significant markers resulted in a model of three markers, cg04988978, cg21161138, ch12655112,” and thus it is unclear if different subsets of markers from the 6-marker panel (including the individual biomarkers) would be sufficiently predictive of survival (par. 268).
The specification states that "Overall, those in the lower two deciles of cg04988978 methylation were four times (28 of 50 vs 7 of 50) more likely to die during the follow-up period than those in the two highest deciles" with “similar, yet less powerful” effects observed for cg12655112 and cg21161138 (par. 269). The specification indicates that Fig. 5A-C shows the relationship between each of the three-marker panel biomarkers and mortality status (par. 48) and that Fig. 6A-C indicates their individual relationship to survival (days to death; par. 49). However, no indication of the statistical or practical significance of these relationships is indicated. The specification does state that no significant relationship exists between cg04988978 and survival time in those who died in the follow up period (Fig. 6A), while cg12655112 and cg21161138 were significantly associated with survival time (par. 269). Data regarding significance (e.g. p-values, AUC, sensitivity, and/or specificity) are not indicated.
State of the Art and the Unpredictability of the Art
While methods of determining methylation percentage at a CpG site and of detecting the identity of a SNP are known in the art, methods of correlating methylation percentage and SNP identity with phenotypes such as CVD detection, severity, survival, CVD-associated intervention, management, and/or monitoring are unpredictable.
The unpredictability will be discussed below.
The claims broadly encompass assessing the relationship between CVD and biomarkers in ANY human or non-human subject. However, the specification’s data regarding this relationship is based on analysis of samples from human subjects. The prior art teaches that there is a large amount of unpredictability with regard to comparing results from epigenetic modifications (such as methylation patterns) in humans to animals. For example, Woo et al. (Woo & Li. Evolutionary conservation of histone modification in mammals. Mol Biol Evol. 2012 Jul; 29(7):1757-67) found that a particular methylation pattern of regulatory sites which was shared between cell types in humans was not highly shared between mice and humans. Only ~20% of regulatory sites with H3K4me1 modifications which were shared between cell types in humans were also shared between mice and humans (pg. 1759: col. 2, last par.). This supports the finding that there is no predictable means for determining whether differential methylation which is diagnostic or prognostic of CVD in humans will also be predictive in a representative number of non-human subjects. Furthermore, Perlman (published May 21, 2016; Perlman RL. Mouse models of human disease: An evolutionary perspective. Evol Med Public Health. 2016 May 21;2016(1):170-6) teaches that mice and humans have different genotype-phenotype relationships, which means that “the relationships between genotype and disease are also likely to differ” between the two species (pg. 174, col. 1). This supports the finding that there is no predictable means for determining whether the identity of a SNP which is diagnostic or prognostic of CVD in humans will also be predictive in a representative number of non-human subjects. The specification only provides support for human subjects.
The claims broadly encompass assessing the relationship between CVD and biomarkers in subjects of ANY age. However, the specification allows that the diagnostic panels of the invention are intended for use in subjects between the ages of 35-80 (par. 248). The cohort subjects having CVD were of ages of approximately 50-80 years and subjects in the cohorts overall were between the ages of approximately 37-82 (see discussion of cohorts above; Tables 1-3). The prior art teaches that there is a large amount of unpredictability with regard to comparing methylation data between different ages. For example, Nemoda teaches (published online April 20, 2020; Nemoda. 2020.The Use of Saliva for Genetic and Epigenetic Research. In: Granger, D., Taylor, M. (eds) Salivary Bioscience. Springer, Cham.) that methylation patterns at some CpG sites are subject to significant age-related changes (pg. 130, par. 1). This supports the finding that there is no predictable means for determining whether CpG methylation which is indicative of CVD status in older adults would also be predictive of CVD status in younger subjects. The specification only provides support for human subjects between the ages of 35-80.
The claims broadly encompass assessing the relationship between CVD and biomarkers using ANY type of sample. Claim 13 restricts the sample type to blood or saliva. The specification only provides examples of analyses based on blood samples. Nemoda teaches (published online April 20, 2020; Nemoda. (2020). The Use of Saliva for Genetic and Epigenetic Research. In: Granger, D., Taylor, M. (eds) Salivary Bioscience. Springer, Cham.) that many studies report high correlations in methylation levels at CpG sites between blood-derived and salivary DNA samples (pg. 130, par. 2), supporting the use of both blood and salivary samples in the claimed invention. However, Woo (published 2012; Woo & Li. Mol Biol Evol. 2012 Jul; 29(7):1757-67) teaches that the fraction of genomic sites which experience the same epigenetic modification in multiple cell types even in the same species is relatively low (Fig. 2). Therefore, it is not clear if nucleic acid methylation levels observed in blood and saliva samples could be extrapolated to other sample types (such as lymph, urine, tissue, etc.), as encompassed by the claims. Absent evidence to the contrary, it is highly unpredictable if the level of epigenetic modification present in nucleic acids from blood and saliva samples which is useful for diagnosis and prognosis of CVD would also be found in other sources of nucleic acids (such as lymph, urine, tissue, etc.). The specification itself provides support only for the use of the percentage methylation of the recited CpG sites in blood samples.
The claims broadly encompass clinical predictions of CVD using ANY pair of recited CpG dinucleotide and SNP (60 possibilities) or ANY individual CpG dinucleotide (6 possibilities). The specification (par. 245) states that Appendix A shows “a list of CpGs whose methylation is associated with CVD”, and Appendix C shows “a list of SNPs associated with CVD.” These Appendices list the AUC associated with a given individual SNP or CpG, presumably as a measurement of the discriminatory ability of the biomarker as it related to detecting the presence of CVD. There appears to have been no validation of these individual biomarkers in cohorts other than the FHS training data cohort (par. 242). The information in the Appendices as it relates to the claimed biomarkers is listed in the table below.
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Of the claimed biomarkers, 2 of 6 CpG sites are not listed in Appendix A and 5 of 10 SNPs are not listed in Appendix C. Values of AUC under 0.6 generally indicate poor discriminatory ability. Thus, at least all of the individual SNPs appear to have poor discrimination of CVD status (i.e. diagnosis). Given that the Appendices are said to list biomarkers associated with CVD, and that AUC values in these tables range only as low as ~0.48 (the AUC for an unclaimed SNP rs2312949), it seems possible that the biomarkers without a stated individual AUC value could have low AUC and thus lower discriminatory capacity. As the biomarkers relate to survival (e.g. mortality risk vs diagnosis or detection of CVD), the specification only addresses the predictive ability of the six methylation markers. The specification provides support only for the predictive ability (of mortality risk) of the six-marker panel and a three-marker panel optimized to remove ‘non-significant markers’ (composed of cg04988978, cg21161138, ch12655112; par. 268). While the specification states that the relationship between each of the individual three biomarkers and survival is ‘strong,’ it does not provide any data regarding practical or statistical significance which supports the use of any of the individual six markers as predictors of survival, as required by claims 12-14 and 24.
Therefore, given the teachings of the instant specification and barring evidence to the contrary, it is highly unpredictable whether ANY individual CpG biomarker or ANY pair of SNP/CpG biomarkers (as recited in the claims), would be equally associated with CVD status and/or survival. The specification supports only the following associations:
CVD diagnosis/status
16-marker panel
Individual CpG biomarkers: cg04988978, cg03725309, cg12586707, cg17901584
CVD mortality risk
6-marker panel, 3-marker panel
The claims broadly encompass determination of ANY recited clinical association and methylation of any of six recited CpG or methylation/identity of any pair of recited CpG/SNPs. However, it is highly unpredictable as to whether a given SNP and/or methylation status of a given CpG site would be associated with ANY clinical feature recited by the claims (i.e. CVD detection, severity, survival, CVD-associated intervention, management, and/or monitoring). For example, the specification explicitly allows that cg04988978 may be useful for predicting overall survival/mortality risk but not useful for predicting days survived (par. 269). Thus, in the absence of evidence to the contrary, it is highly unpredictable if any CpG biomarker or any pair of SNP/CpG biomarkers recited by the claims which are predictive of one clinical outcome (e.g. detection of CVD) would also be predictive of any other clinical outcome encompassed by the claims (e.g. response to treatment).
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to determine ANY recited clinical outcome (“detecting CVD, determining severity of CVD, estimating survival from CVD, identifying, customizing, and/or optimizing intervention(s) for CVD, managing CVD and/or monitoring CVD”) in ANY type or age of subject (human or non-human animals) using ANY individual CpG or ANY recited pair of CpG/SNPs.
In order to practice the breadth of the claimed invention one of skill in the art would first have to gather samples from human and non-human subjects having a representative range of ages and a representative number of cardiovascular diseases with a variety of clinical features (i.e. severities, treatment courses, etc.). The status of a representative number of individual biomarkers or biomarker combinations (>60 possible combinations) would have to be determined. Then, sophisticated data analysis would have to be conducted to determine which biomarker(s) would be predictive of CVD diagnosis, severity, response to intervention, and prognosis (survival in days, mortality risk, etc.). The specification has merely provided an invitation for further experimentation. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even "a considerable amount of experimentation is permissible," as long as it is "merely routine" or the specification "provides a reasonable amount of guidance" regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360- 61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is "not without bounds." Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation "would be excessive, e.g., that it would involve testing for an unreasonable length of time." 707 F .3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a "diverse and relatively poorly understood group of microorganisms," with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years' work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a "predictable" factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
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 12-14 and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4, Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite a correlation between the percentage of methylation of CpG dinucleotides and/or the identity of a SNP and predicting CVD (e.g. diagnosis, prognosis, survival estimation). This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. The claims recite “determining” severity of CVD or the presence of biomarkers, “estimating” survival from CVD, “identifying, customizing, and/or optimizing” interventions, and/or “monitoring” CVD. Neither the specification nor the claims set forth a limiting definition for these processes, and the claims do not set forth how the process(es) is/are accomplished. These processes broadly encompass mental processes. For example, one may “determine” the severity of CVD by looking at a patient’s data and thinking about how severe their CVD is. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exception(s) into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or a technological field;
An additional element that applies or used a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing;
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, the preambles of the claims recite optionally “managing” CVD. However, no active step of “managing” CVD is set forth in the claims, and while “managing” CVD could be considered administration of a treatment, the treatment is both optional (i.e. not required by the claims) and not particular (i.e. specifically identified so that it does not encompass all applications of the judicial exceptions). “Managing” CVD is merely intention to apply the exception in generic ways. Thus, the limitation does not recite any elements that integrates the judicial exception so as to practically apply the judicial exception.
In addition to the judicial exceptions, the claims recite a step of “providing” a sample or portions of a sample. This step is not considered to integrate the judicial exceptions into a practical application because it merely adds insignificant extra-solution activity (data gathering) to the judicial exceptions.
In addition to the judicial exceptions, the claims recite a step of “contacting” a sample or a portion of a sample with an oligonucleotide primer. This step is not considered to integrate the judicial exceptions into a practical application because it merely adds insignificant extra-solution activity (data gathering) to the judicial exceptions.
In addition to the judicial exceptions, the claims recite various wherein clauses which set forth limitations of the primer (claim 12b,c; 24), the sample (claim 12a, 14; 24a), and the analysis (claim 12, 14). These elements fail to meaningfully limit the claims and are the equivalent of adding the words “apply it” to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides and Inventive Concept
In addition to the judicial exceptions, the claims recite “managing” CVD, “providing” a sample or samples, “contacting” a sample or samples with a primer, and various wherein clauses which limit the primer, sample, and analysis. These steps do not amount to significantly more because they simply append well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
These steps are recited a high level of generality. Managing CVD, providing a sample or samples, and contacting a sample or samples with a primer merely instruct a scientist or clinician to use any known technique. These steps (and the various wherein clauses which limit the primer, sample, and analysis) do not require the use of any particular non-conventional reagents or equipment or methodology. When recited at this high level of generality, there is no meaningful limitation that distinguishes these elements from well-understood, routine, and conventional activities engaged in by scientists and clinicians prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well-understood, routine, and conventional nature of additional elements because it teaches that the additional elements are well-known or commercially available. For example, the specification teaches the following:
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Further, it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, and conventional activity in the life science arts when they are claimed in a merely generic manner (e.g. at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
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 12-14 and 24 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Dogan (published Aug. 29, 2019; Patent Application Publication No. US 20190264286 A1).
Regarding claim 12, Dogan recites a method of determining the presence of biomarkers in a biological sample from a subject, wherein the biomarkers are associated with detecting CVD (par. 175), identifying, customizing, and/or optimizing intervention(s) for CVD, managing CVD and/or monitoring CVD (par. 321). Dogan recites that the method comprises: (a) providing a first portion of the biological sample and a second portion of the biological sample, wherein the nucleic acid from at least the first portion is bisulfite converted; (b) contacting the first portion of the biological sample with a first oligonucleotide primer at least 8 nucleotides in length, complementary to a sequence that comprises a first CpG, wherein the first nucleic acid primer detects a methylated or unmethylated CpG dinucleotide; and (c) contacting the second portion of the biological sample with a nucleic acid primer at least 8 nucleotides in length that is complementary to a DNA sequence or a bisulfite-converted DNA sequence of a first SNP (par. 140-141, 191).
Regarding claim 24, Dogan recites a method of determining the presence of biomarkers in a biological sample from a subject, wherein the biomarkers are associated with detecting CVD (par. 175), identifying, customizing, and/or optimizing intervention(s) for CVD, managing CVD and/or monitoring CVD (par. 321). Dogan recites that the method comprises: (a) providing a biological sample from a subject having CVD, wherein the nucleic acid from at least a portion is bisulfite converted; (b) contacting the bisulfite converted nucleic acids with a first oligonucleotide primer at least 8 nucleotides in length, complementary to a sequence that comprises a first CpG dinucleotide, wherein the first nucleic acid primer detects a methylated or unmethylated CpG dinucleotide (par. 140-141, 191).
Regarding claims 12 and 24, Dogan does not explicitly recite that a first primer is complementary to cg04988978 or that a second primer is complementary to rs2869675. However, Dogan uses the HumanMethylation450 BeadChip Array for methylation analysis and the Affymetrix GeneChip HumanMapping 500K array for SNP analysis (e.g. par. 406-407). Use of these commercial arrays fulfills the requirements of the claim, as they contain primers (>8nt in length) which are complementary to the appropriate sites. See table below.
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Regarding claims 12 and 24, Dogan does not explicitly recite that the percentage of methylation of the CpG dinucleotide at the GC locus cg04988978 and the identity of the nucleotide at the first SNP rs2869675 are biomarkers associated with detecting CVD or estimating survival from CVD. However, Applicants are reminded that method claims are analyzed with respect to their positively recited process steps and that claim scope is not limited by claim language such as wherein clauses which suggest or make optional but do not require steps to be performed to reach any unspecified percentage. As the prior art in Dogan teaches the recited steps of the claimed method (the active process steps and appropriate primers for performing those steps), the claim is considered to have been anticipated.
Regarding claim 13, Dogan recites the use of blood samples or saliva samples (par. 23, 141).
Regarding claim 14, Dogan does not explicitly teach a window of incidence which is three years. However, method claims are analyzed with respect to their positively recited process steps. Claim scope is not limited by claim language such as wherein clauses which suggest or make optional but do not require steps to be performed. Thus, as the limitations of claim 14 do not give meaning or purpose to the manipulative steps recited in the claims, the limitations have no patentable weight.
Conclusion
No claims are allowed.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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