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
Applicant’s election without traverse of claims 1-7 and 16-18 in the reply filed on April 17, 2026 is acknowledged.
Claims 8-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 13-15 are cancelled.
Claims 1-7 and 16-18 are examined herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink http://broadcvdi.org/home/portalHome (pg. 105, par. 1). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 1-7 and 16-18 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is directed to determining, diagnosing, and/or prognosing an individual's risk of suffering from cardiovascular disease the method comprising:
a. detecting, in a sample obtained from an individual, the expression level, amount
and/or activity of two or more biomarkers selected from a group consisting of: Tumor Necrosis Factor (TNF)-a; Glutathione S-Transferase Alpha 1 (GSTAl); N-terminal-pro hormone BNP (NT-proBNP); Retinoic Acid Receptor-Related Orphan Receptor Alpha (RORA); Tenascin C (TNC); Growth Hormone Receptor (GHR); Alpha-2-Macroglobulin (A2M); Insulin Like Growth Factor Binding Protein 2 (IGFBP2); Apolipoprotein B (APOB); Selenoprotein P (SEPPI); Trefoil Factor (TFF3); Interleukin 6 (IL6); Chitinase 3 Like 1 (CHI3Ll); Hepatocyte Growth Factor Receptor (MET); Growth Differentiation Factor 15 (GDF15); Chemokine (C-C Motif) Ligand 22 (CCL22); Tumour Necrosis Factor Receptor Superfamily, Member 11 (TNFRSFl 1); Angiopoietin 2 (ANGPT2); and v-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A Nuclear Factor-kappa B (ReLA NF-KB);
b. comparing the expression level, amount, and/or activity of the biomarker with a
reference from a healthy control population; and
c. determining, diagnosing and/or prognosing the risk of an individual suffering
from cardiovascular disease if the expression level, amount, and/or activity of the biomarker deviates from the reference from a healthy control population.
Claims 5 and 16-17 are similar to claim 1, but recite at least 3, 5, and 10 of the biomarkers respectively.
Claims 1, 5, and 16-17 are interpreted broadly as requiring at least 2, 3, 5, and 10 of the biomarkers respectively in any combination.
Nature of the invention – the invention is directed to diagnosing and/or prognosing an individual's risk of suffering from cardiovascular disease using measured biomarker levels.
State of the prior art & level of predictability in the art. The art of using biomarkers for diagnosing and/or prognosing an individual's risk of suffering from cardiovascular disease is highly unpredictable. Some prior art references teach biomarker trends contradicting those of instant invention. For example, Dragut et al. (Atherosclerosis, 235e239) teach that increased plasma levels of TNF alpha is associated with increased cardiovascular risk (e239, col. 1, last par.), which contradicts claim 2 reciting that a decrease in TNF alpha levels is indicative of an individual having a higher risk of suffering from cardiovascular disease or a negative prognosis.
Amount of direction and example provided by the inventor.
The specification is silent with respect to specific data related to recited biomarkers and evidence of correlations with cardiovascular outcomes. For example, the specification fails to provide any evidence of corresponding p-values, which is the key parameter characterizing a biomarker for its suitability in diagnostic applications. No biomarkers and corresponding p-values are disclosed. No combinations of the biomarkers and corresponding p-values for these combinations are disclosed.
Most of the disclosure is about network-related subject matter and computational analysis. For example, some figure titles:
Figure 1 shows after the disease network identification;
Figures 2A-2C and Figures 8A-8F show the networks of molecular entities that were prioritized in the overconnectivity analyses;
Figures 3A-3E show that the molecular signatures of population sub-types
relate to CVD progression;
Figures 4A-4C show cox-regression results presented as Hazard rations (HR) with confidence intervals;
Figures 9A-9C show Kaplan-Meier survival estimates by patient clusters for the measured CV outcomes in Caucasian and Latinos.
The specification provides only two examples.
Example 1 - identification of biomarkers and biomarker networks. However, bulk of this example is a disclosure of genotype-related subject matter and SNPs related to non-elected claims 8-12. For example: section “Genotyping quality control and population stratification analysis” (pg. 95-96) and section “Genome-wide association analyses” (pg. 96-97).
Example 2 - detection of SNPs associated with CVD risk – this example is entirely related to the non-elected claims.
The specification fails to demonstrate actual expression levels, amounts, or activities of the recited biomarkers for the healthy control population and the individuals suffering from cardiovascular disease. The disclosure makes references to data not present in the specification. For example: Supplementary Table S1 (Patient Stratification, pg. 102), Supplementary Table S2 (ORIGIN GWAs results, pg. 105), Supplementary Table S3 (CVD disease network prioritization, pg. 105), Supplementary Table S5 (last line, pg. 105). Page 112 lists titles of all six Supplementary Tables, but the tables are not present in the specification.
The prior art reference of Gerstein et al. (IDS; Circulation. 2015 Dec 15; 132(24) :2297-304) is the most closely related reference to instant disclosure. However, Gerstein fails to teach diagnostic potentials/performances of each of the biomarkers recited in claim 1, both as individual biomarkers and as combinations of the biomarkers.
Additionally, Gerstein teaches a set of 10 biomarkers for the cardiovascular composite outcome “Ten novel biomarkers were identified that were each independent determinants of the 1405 CV composite outcomes of nonfatal myocardial infarction, nonfatal stroke, or CV death” (section “Clinical perspective”, last page). However, Gerstein fails to teach these 10 biomarkers as independent biomarkers, instead there are presented as a singular cardiovascular composite outcome or a set. Fig. 1B supports the 10 biomarkers as a set “Similar curves based on the fifths of the risk probability estimated from a model that that includes the baseline clinical variables plus the levels of the 10 identified biomarkers in Table 3” (Fig. 1B legend) – Fig. 1B does not show any individual biomarker.
Finally, Gerstein teaches only a fraction of the claimed biomarkers: N-terminal pro-B-type natriuretic peptide, trefoil factor 3, apolipoprotein B, angiopoietin-2, a-2-macroglobulin, glutathione S transferase a, growth/differentiation factor 15, and hepatocyte growth factor receptor. Dragut et al. (Atherosclerosis, 2014. 235e239) and Lorbeer et al. (Heart. 2015 Feb;101(3):178-84) teach angiopoietin-2 and RORA. The remaining 10 biomarkers of claim 1 are not disclosed as cardiovascular biomarkers.
Finally, claims 1, 5, and 16-17 recite measuring expression level, amount, and/or activity of the biomarkers. The specification fails to disclose measurements of the activity of any of the biomarkers.
Claims 2-7 and 16-18 are rejected because they depend from rejected claim 1.
Based on the above findings, one of ordinary skill in the art would conclude that Applicant did not have possession of the claimed invention.
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.
Claim 7 is 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.
Claim 7 recites “the sample comprises blood, urine or tissue”. The claim is indefinite because it uses the open “comprises” language.
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 1-7 and 16-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring correlation, without significantly more.
Claim 1 is directed to a process, which belong to the four statutory categories.
The claim is related to a method of determining, diagnosing and/or prognosing an individual's risk of suffering from cardiovascular disease, which is categorized as a naturally occurring correlation, and therefore it is a judicial exception.
Step (b) of the claim recites comparing the measured expression level, amount, and/or activity of the biomarker with a reference from a healthy control population. Step (c) recites determining, diagnosing and/or prognosing the risk of an individual suffering from cardiovascular disease if the expression level, amount, and/or activity of the biomarker deviates from the reference from a healthy control population. These limitations fall into the “mental process” groupings of abstract ideas and therefore are judicial exceptions.
Claim 1 recites additional elements of detecting, in a sample obtained from an individual, the expression level, amount and/or activity of two or more biomarkers. The additional element of “detecting” is an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
When considering the elements in combination, the claim as a whole does not integrate the recited exceptions into a practical application. Claim 1 does not recite any practical applications of the recited method. Thus, claim 1 is directed to the judicial exception.
Additional elements of measuring the biomarker levels and considered insignificant extra-solution activities are recited at a high level of generality and have been recognized as routine laboratory techniques. The techniques for measuring biomarker levels are known in the art. For example, it was routine and conventional to measure the same biomarker levels in the ORIGIN trial using the LUMINEX 100/200 platforms (Gerstein et al. (IDS; Circulation. 2015 Dec 15; 132(24) :2297-304); pg. 2298, col. 2, par. 2). Therefore, the claim as a whole does not amount to significantly more than the recited exception, because there are no additional elements, or combination of additional elements, that add an inventive concept to the claim.
The dependent claims 2-7 and 16-18 fail to add additional elements, or combination of additional elements, that contribute to an inventive concept to the claim. For example: claims 2-4 recite directions of the biomarker levels correlating with a higher risk of suffering from cardiovascular disease, which are merely results of the measuring step; and claims 5 and 16-17 recite detecting at least 3, 5, and 10 biomarkers respectively. Claims 1-7 and 16-18 fail to recite any practical applications of the recited method.
For these reasons, claims 1-7 and 16-18 are ineligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7 and 16-17 are rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Gerstein et al. (IDS; Circulation. 2015 Dec 15; 132(24) :2297-304; a better-quality copy is uploaded), as evidenced by Dragut et al. (Atherosclerosis, 2014. 235e239) and Lorbeer et al. (Heart. 2015 Feb;101(3):178-84).
Regarding claim 1, Gerstein teaches detecting, in a sample obtained from an individual, the expression level of two biomarkers NT-proBNP and angiopoietin 2 (Table 3 and pg. 2301, col. 1, par. 2).
The reference teaches analysis of the biobanked serum samples from 8494 participants with dysglycemia (pg. 2297, Background) without a healthy control group. However, the study was set to identify biomarkers of the composite outcome of myocardial infarction, stroke, or CV death. One of ordinary skill in the art would have recognized that the participants with the outcomes of myocardial infarction, stroke, or CV death were necessarily compared to the participants without the outcomes of myocardial infarction, stroke, or CV death. The participants without the outcomes of myocardial infarction, stroke, or CV death functioned as an internal control group. Therefore, Gerstein teaches step (c) - determining, diagnosing and/or prognosing the risk of an individual suffering from cardiovascular disease if the expression level, amount, and/or activity of the biomarker deviates from the reference from a control population.
Additionally, regarding step (c), Gerstein teaches that regression models were used to identify biomarkers that were each independent determinants of the composite of myocardial infarction, stroke, or CV death (pg. 2297, Methods and Results). Therefore, the identified biomarkers were “new biochemical markers of CV risk” (pg. 2297, col. 1).
Regarding claim 2, Gerstein teaches glutathione S transferase alpha levels were inversely associated with all 3 studied outcomes “Although no link between an elevated glutathione S transferase a level and reduced CV outcomes has been previously reported, higher levels may be associated with reduced oxidative stress and have been noted in response to insulin administration” (pg. 2302, col. 2, par. 2). The inverse association means decrease in the transferase amount is indicative of an individual having a higher risk of suffering from cardiovascular disease or a negative prognosis, recited in claim 2.
Regarding claim 3, Gerstein does not specifically teach an increase in expression, amount, and/or activity of GHR, A2M, IGFBP2, APOB, SEPPI, TFF3, IL6 and/or CHBL1, when compared to the reference, is indicative of an individual having a higher risk of suffering from cardiovascular disease or a negative prognosis. Regarding claim 3, Dragut teaches relationship between IL-6 and cardiovascular risk in patients with type 2 diabetes and metabolic syndrome (Title). Specifically, Dragut provides evidence that increased plasma levels of IL-6 is associated with increased cardiovascular risk in patients with type 2 diabetes and metabolic syndrome (pg. e239, col. 1, last par.), meeting the corresponding limitation of claim 3.
Regarding claim 4, Gerstein does not specifically teach a decrease in expression, amount, and/or activity of MET, GDF15, CCL22, TNFRSF11, ANGPT2 and/or ReIA NF-KB, when compared to the reference, is indicative of an individual having a lower risk of suffering from cardiovascular disease or a positive prognosis. Regarding claim 4, Lorbeer teaches relationship between circulating angiopoietin-2 and mortality in the general population (Title). Specifically, Lorbeer provides evidence that angiopoietin-2 levels were positively associated with cardiovascular mortality (pg. 1327, Methods and results and Fig. 2B), meeting the limitation of claim 4 reciting a decrease in ANGPT2 is indicative of an individual having a lower risk of suffering from cardiovascular disease or a positive prognosis.
Regarding claim 5, Gerstein teaches detecting, in a sample obtained from an individual, the expression level of at least 3 biomarkers: NT-proBNP, angiopoietin 2, and glutathione S-transferase (Table 3 and pg. 2301, col. 1, par. 2).
Regarding claim 6, Gerstein teaches the cardiovascular disease is myocardial infarction, stroke, or CV death (pg. 2297, Methods and Results) meeting the cardiovascular death, myocardial infarction, and stroke recited in claim 6.
Regarding claim 7, Gerstein teaches that the biomarkers were measured in serum samples from biobanked blood (pg. 2297, Methods and Results), meeting the limitation of claim 7 reciting blood. Serum is a derivative of blood obtained in the process of sample preparation.
Regarding claim 16, Gerstein teaches detecting, in a sample obtained from an individual, the expression level of at least 5 biomarkers: NT-proBNP, Trefoil factor 3 (TFF3), Growth differentiation factor 15 (GDF15), Apolipoprotein B (APOB), angiopoietin 2 (ANGPT2), a-2-macroglobulin (A2M), Hepatocyte growth factor receptor (MET), glutathione S-transferase (GSTA1), Tenascin C (TNC), and Selenoprotein P (SEPP1) from Table 3.
Regarding claim 17, Gerstein teaches detecting, in a sample obtained from an individual, the expression level of at least 10 biomarkers: NT-proBNP, Trefoil factor 3 (TFF3), Growth differentiation factor 15 (GDF15), Apolipoprotein B (APOB), angiopoietin 2 (ANGPT2), a-2-macroglobulin (A2M), Hepatocyte growth factor receptor (MET), glutathione S-transferase (GSTA1), Tenascin C (TNC), and Selenoprotein P (SEPP1) from Table 3.
Claim 18 is rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Gerstein, as applied to claim 1 above, in view of Zhao et al. (IDS; Exp Ther Med. 2018 Feb;15(2):1456-1464).
The teachings of Gerstein have been set forth above.
Gerstein fails to teach the detecting comprises sequencing or performing a hybridization-based method.
Regarding claim 18, Zhao teaches “Identification of potentially relevant genes for myocardial infarction using RNA sequencing data analysis” (Title). Zhao also teaches the detecting comprises sequencing. Specifically, Zhao teaches identification of genes relevant to myocardial infarction (MI) by sequencing RNA extracted from blood samples from patients with MI and normal controls to calculate the gene expression value (Abstract). A total of eight genes, including RORA, may be considered as potentially relevant genes in the pathology of MI (pg. 1456, col. 2, par. 1). RORA is the Retinoic Acid Receptor-Related Orphan Receptor Alpha of claim 1.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Gerstein for biomarkers of higher risk of suffering from cardiovascular disease with another biomarker RORA, as taught by Zhao, in order to add additional biomarker for diagnosing and/or prognosing an individual's risk of suffering from cardiovascular disease.
MPEP 2144.06 provides "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because each biomarker is measured using its own specific set of reagents and detection of one biomarker does not affect detection of another.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER ALEXANDROVIC VOLKOV/Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677
