DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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.
Priority
The present application is a continuation of application 15/911,699, filed 03/05/208 (Patent 11,454,634); application 15/911,699 is a continuation of application 14/644,695, filed 03/11/2015 (abandoned); application 14/644,695 is a continuation of PCT/EP2013/056706, filed 03/28/2013. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 12184085.4, filed on 09/12/2012 in the European Patent Office.
However, foreign priority document EP 12184085.4 does not support a method of predicting the risk of mortality and/or a cardiovascular event in a subject who does not suffer from heart failure and/or who does not show overt signs of heart failure. Rather, the earlier filed foreign priority document only supports methods for assessing whether a subject is to be subjected to imaging based diagnostic methods, see at page 5 of EP 12184085.4 indicating that a subject who is susceptible to an imaging based diagnostic assessment is a subject with increased probability to suffer abnormal midwall fractional shortening. The present claims are much broader in scope than assessing whether a subject is to be subjected to imaging based diagnostics for determining probability to suffer abnormal midwall fractional shortening (the present claims more generally directed toward predicting future risk of mortality and/or cardiovascular event).
As a result, the earliest effective filing date of claims 2-5 and 7-18 is the filing date 03/28/2013.
Information Disclosure Statement
The information disclosure statement (IDS) filed 04/07/2026 is considered, initialed and is attached hereto.
Status of the Claims
Claims 2-21 are pending; claim 6 is withdrawn, claims 2 and 15-17 are amended, claims 19-21 are newly recited. Claims 2-5 and 7-21 are examined below.
Withdrawn Objections/Rejections
The previous objection to the specification is withdrawn in response to Applicant’s amendments to the title.
The previous objection to the claims over abbreviations in the claims is withdrawn in response to Applicant’s amendments to the claims.
The previous rejections of claims under 35 U.S.C. 112(b) are withdrawn in response to Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 11 recites “wherein the sample is a blood, serum or plasma sample”, the claim fails to further limit the subject matter of claim 1 because this limitation is recited by amended claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 2-5 and 7-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and a natural correlation, without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims recite “predicting the risk of mortality and/or a cardiovascular event in a subject … providing a sample from the subject, wherein the subject does not suffer from heart failure and/or who does not show overt signs of heart failure, wherein said subject does not suffer from left ventricular hypertrophy (LVH)”, the method “determining the amount of Insulin-like Growth Factor Binding Protein 7 (IGFBP7) and/or fibroblast Growth Factor 23 (FGF-23)”, the method “comparing the amount(s) determined…to a reference amount(s), and predicting that the subject is at elevated risk of mortality and/or a cardiovascular event when the amount(s) determined in step b) is above the reference amount(s)”.
The natural relationship to which the claims are directed (i.e., the relation between IGFBP7 and/or FGF-23 level(s), and further brain natriuretic peptide (BNP or NT-proBNP) and/or cardiac troponin (T or I), and future risk of mortality and/or a cardiovascular event) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of IGFBP7 and/or FGF-23 (and further brain natriuretic peptide (BNP or NT-proBNP) and/or cardiac troponin (T or I)) and future risk. The correlation between the claimed biomarker(s) and future risk of mortality/disease is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility.
Further, “comparing the amount(s) as determined… to a reference amount(s)”, predicting risk based on the comparison is categorized as abstract ideas, namely mental processes/concepts performed in the human mind (such as a practitioner simply thinking about the measured level(s) of the biomarkers in relation to the reference/control and making an evaluation, judgement or opinion). The claims, under their broadest reasonable interpretation, cover performance of identifying risk solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a control or target data represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo (which also involved specific numerical cutoff levels).
Claims 14-17 are further directed to limitations that merely narrow the comparison step.
Step 2A, Prong 2
The above discussed steps (namely the limitations directed to the correlation and the comparing steps) are the judicial exceptions and as such are insufficient to integrate the judicial exceptions into a practical application thereof.
There are no additional steps/elements recited at the independent claim beyond the steps of providing the sample from the subject and determining the amount of the biomarker(s) and comparing to a reference amount(s). As such, there are no additional steps considered sufficient to amount to a integration of the judicial exception(s) into a practical application.
As amended, claim 2 does further recite “wherein the subject does not suffer from heart failure and/or does not show overt signs of heart failure, wherein the subject does not suffer from left ventricular hypertrophy (LVH)”, however the limitations to the subject population on which the assay is performed fail to amount to an integration of the judicial exception into a practical application (MPEP 2106.05)
Claims 3-5, and 10-18 further limit the subject/sample which the method is performed on, or further narrow the comparison step limitations; however, limitations further narrowing the subject population do not further apply, rely on or use the judicial exception in a meaningful way such that would amount to a practical application thereof.
None of the additional recited claims further recite any additional claimed steps elements, that either alone or in combination, apply, rely on or further use the judicial exception in a way that amounts to a practical application of the judicial exception.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
See also regarding the above discussed steps limitation, steps limitations directed to the judicial exception(s) themselves fails to amount to significantly more than the judicial exception.
Regarding the active method steps of providing a sample from the subject and “determining” in the sample from said subject, the amount of IGFBP7 and/or the amount of FGF-23” (claim 2) , and further “determining” the amount of brain natriuretic peptide and/or cardiac troponin (BNP, NT-proBNP and cTnT or I, claims 7-9). Such steps of determining/measuring the claimed biomarkers were well-known, routine and conventional in the assay art at the time, see for Example Wienhues-Thelen cited in detail below (under 35 US.C. 103), which measures/determines the level of IGFBP-7 (as well brain natriuretic peptide and/or cardiac troponin). See further Applicant’s originally filed specification (pages 2-4) which supports the routine and conventional nature of determining/measuring the claimed biomarker(s), see pages 2-4, the specification refers to multiple reference citations that exhibit determining/measuring the recited biomarker(s).
Furthermore, these steps do not go beyond insignificant presolution activity, i.e., mere data gathering steps necessary in order to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Regarding these steps at the independent claim, it is also noted that the steps are recited at an extremely high level of generality, and are not for example, tied to any particular machine or apparatus, or assay for detection.
As amended, claim 2 does further recite “wherein the subject does not suffer from heart failure and/or does not show overt signs of heart failure, wherein the subject does not suffer from left ventricular hypertrophy (LVH)” (see also claims 3-5, 10, 12, 13, or further the sample, claim 11), however the limitations to the subject population also fail to amount to significantly more than the judicial exception(s) as there is no evidence to suggest that assay (the particular active steps, the wet method steps for performing the determining) would be performed any differently depending on the subject’s from which the sample is obtained. Put another way, the subject population does not impact or represent a technical advancement or improvement to the assay itself, and fails to ensure the claims amount to significantly more.
As noted the dependent claims also fail to recite additional steps/elements, other than those that further narrow the judicial exceptions themselves.
For all of these reasons, the claims fail to further integrate the judicial exception(s) into a practical application thereof, or amount to significantly more than the judicial exceptions themselves. As a result, the claims are rejected under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 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) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
Claim(s) 2, 10-12, 14, 16, 19-21 are rejected under pre-AIA 35 U.S.C. 102(a)(1) as being anticipated by Wienhues-Thelen et al., WO2008/089994A1.
Wienhues-Thelen et al. teach methods of measuring the concentration of IGFBP-7 in a sample, comparing the level determined to a reference population (see e.g. abstract), further methods comprising predicting risk of heart failure (a cardiovascular event). See page 18, lines 9-19, Wienhues-Thelen teach determining in a sample, the amount of IGFBP-7 by detecting specific binding (by immunoassay, thereby addressing by detecting specific binding of the first immunoassay reagent) and comparing the amount to a reference amount. Wienhues-Thelen teach a cardiac event relates to, for example acute heart failure (see e.g. page 21, last paragraph). Wienhues-Thelen teach early assessment of patients at risk for heart failure appears to be possible only by biochemical markers since the individual at risk at that stage is still free of clinical heart failure symptoms (see page 6, lines 16-21, and see also line 22-24 regarding the
recognition of atrial natriuretic peptide family and brain natriuretic family having value in the
assessment of HF). See e.g. page 7, lines 16-22, and also specifically lines 23-29 Wienhues-
Thelen et al. teach IGFBP-7 is also a predictive marker of heart failure (predicting risk in a
subject who does not suffer from heart failure, i.e., predict an onset of heart failure, or shows no
overt signs). Wienhues-Thelen does teach at page 2, lines 11-14, heart failure stage A represents
the subject who is asymptomatic but is at risk for developing HF, (thereby addressing the subject
who does not show overt signs of heart failure, not suffering from LVH) (see also page 20, lines 10-22, investigating individuals that are clinically "normal", i.e. stage A according to ACA/ACC classification).
Wienhues-Thelen at page 10, teach sample can be samples such as blood, serum or plasma (see also page 17, lines 21-25; see also page 43 Example 5). Also, see further page 10 of Wienhues-Thelen, teaching comparing to a reference control, see the control can include subjects known to suffer from, or known to be at risk of a given condition (i.e., those at elevated risk).
Regarding claims 10, Wienhues-Thelen does teach at page 2, lines 11-14, heart failure stage A represents the subject who is asymptomatic but is at risk for developing HF (thereby addressing the subject who does not show overt signs of heart failure) (see also page 20, lines 10-22, investigating individuals that are clinically "normal", i.e. stage A according to ACA/ACC classification).
Regarding claim 11, see Wienhues-Thelen at page 10, sample can be samples such as blood, serum or plasma (see also page 17, lines 21-25; see also page 43 Example 5).
Regarding claim 12, see for example page 11, lines 27-31, subjects such as human subjects.
Regarding claim 14, see further page 10 of Wienhues-Thelen, teaching comparing to a reference control, see the control can include subjects known to suffer from, or known to be at risk of a given condition (i.e., those at elevated risk).
Regarding claim 16, see Wienhues-Thelen at the end of page 10, and further page 10 to page 11, control sample is from a reference population that is age matched and disease free (i.e., those healthy subjects are those considered free of disease).
Regarding claims 19-21, see as cited in detail above, Wienhues-Thelen is teaching method of detecting IGFBP7 in a subject, the method comprising providing a sample from a subject that does not show overt signs of heart failure (e.g., as discussed above, for example, those in Stage A, clinically normal subjects, or see Example 6 at page 47, stage B), sample comprising sample that is blood, serum or plasma (Wienhues-Thelen at page 10, teach sample can be samples such as blood, serum or plasma (see also page 17, lines 21-25; see also page 43 Example 5). Wienhues-Thelen teach detecting IGFBP7 by contacting sample with an antibody that specifically binds and detecting the binding (see Example 6, referring to the antibody binding assays described previously, see as at page 44, also see IGFBP7 ELISA at 5.2, page 44)).
See also, page 20, lines 7-8, increased level (elevated level) indicator for increased risk.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 2, 7-12, 14 and 16-18 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Wienhues-Thelen et al., WO2008/089994A1 (IDS entered 04/07/2025).
Wienhues-Thelen et al. teach methods of measuring the concentration of IGFBP-7 in a sample, comparing the level determined to a reference population (see e.g. abstract), further methods comprising predicting risk of heart failure (a cardiovascular event) as discussed in detail above (see above referring to full citation as addressing claim 2).
See as cited in detail previously and above, Wienhues-Thelen teach early assessment of patients at risk for heart failure appears to be possible only by biochemical markers since the individual at risk at that stage is still free of clinical heart failure symptoms (see page 6, lines 16-21, and see also line 22-24 regarding the recognition of atrial natriuretic peptide family and brain natriuretic family having value in the assessment of HF).
See e.g. page 7, lines 16-22, and also specifically lines 23-29 Wienhues-Thelen et al. teach IGFBP-7 is also a predictive marker of heart failure (predicting risk in a subject who does not suffer from heart failure, i.e., predict an onset of heart failure, or shows no overt signs). Wienhues-Thelen does teach at page 2, lines 11-14, heart failure stage A represents
the subject who is asymptomatic but is at risk for developing HF (thereby addressing the subject
who does not show overt signs of heart failure) (see also page 20, lines 10-22, investigating
individuals that are clinically "normal", i.e. stage A according to ACA/ACC classification). See
page 1, lines 21-22, heart failure is a recognized cause of death (mortality); (page 6, lines 26-28)
Wienhues-Thelen also teach 50% of patients with heart failure die within two years of diagnosis,
that the 5 year survival rate is less than 30%, further suggesting that those that risk of heart
failure are simultaneously at risk of mortality.
Although Wienhues-Thelen does teach that IGFBP-7 is a predictive marker of heart failure (predicts the risk of heart failure, namely a cardiovascular event, and as such the independent claim is anticipated by Wienhues-Thelen, as indicated in detail above), the reference does not explicitly recite that IGFBP-7 is a biomarker for predicting risk of mortality (the examined claims recite predicting “risk of mortality and/or a cardiovascular event”).
Nonetheless, it would have been further prima facie obvious to one of ordinary skill in the art at the time of the invention, that by performing the method of Wienhues-Thelen, detecting IGFBP-7 and comparing it to a reference standard to predict a subject’s risk of heart failure, one would also be similarly predicting a subject’s risk of mortality because the teachings of Wienhues-Thelen indicate that those at risk of heart failure are also at risk of mortality due to heart failure (see as discussed previously above, specifically at page 1, lines 21-22, heart failure is a recognized cause of death (mortality); (page 6, lines 26-28) Wienhues-Thelen also teach 50% of patients with heart failure die within two years of diagnosis, that the 5 year survival rate is less than 30%, further suggesting that those at risk of heart failure are simultaneously at risk of mortality). One of ordinary skill would have a reasonable expectation of success relating risk of heart failure to a simultaneous risk of mortality because heart failure, untreated, can cause mortality and further because the reference teaches those at risk of heart failure are at risk of mortality.
Regarding claims 7-9, Wienhues-Thelen teach a further one or more marker that is selected from the group consisting of a natriuretic peptide marker, a cardiac troponin marker and an inflammation marker (see e.g. page 27).
It would have been prima facie obvious to one having ordinary skill in the art to have arrived at the combination of IGFBP-7, a natriuretic peptide marker and a cardiac troponin (e.g., BNP or NT-proBNP and Troponin T or I, pages 27-31), from selecting from the finite list of suitable combinations of IGFBP-7 and heart failure markers, including natriuretic peptide and cardiac troponin, taught by Weinhues-Thelen. One having ordinary skill would have a reasonable expectation arriving at this combination because Weinhues-Thelen specifically teach using the marker IGFPB-7 in combination with one or more, where the indicated two are considered preferred selected HF markers indicated above.
Regarding claims 10, Wienhues-Thelen does teach at page 2, lines 11-14, heart failure stage A represents the subject who is asymptomatic but is at risk for developing HF (thereby addressing the subject who does not show overt signs of heart failure) (see also page 20, lines 10-22, investigating individuals that are clinically "normal", i.e. stage A according to ACA/ACC classification).
Regarding claim 11, see Wienhues-Thelen at page 10, sample can be samples such as blood, serum or plasma (see also page 17, lines 21-25; see also page 43 Example 5).
Regarding claim 12, see for example page 11, lines 27-31, subjects such as human subjects.
Regarding claim 14, see further page 10 of Wienhues-Thelen, teaching comparing to a reference control, see the control can include subjects known to suffer from, or known to be at risk of a given condition (i.e., those at elevated risk).
Regarding claim 16, see Wienhues-Thelen at the end of page 10, and further page 10 to page 11, control sample is from a reference population that is age matched and disease free (i.e., those healthy subjects are those considered free of disease).
Regarding claim 17, Regarding claim 15, see at page 11, Wienhues-Thelen teach comparing to the reference control, that an increased level of IGFBP-7 is indicative of heart failure (referring to a control without risk, i.e., the reference indicates increased levels of the marker correlate with the disease/condition). Further see at page 10, Wienhues-Thelen teach comparing to a control, that embodiments encompass using the marker to determine if an individual is at risk for heart failure. Given this knowledge, that the marker can be used to indicate risk (see cited above, particularly starting at page 18), and given that increased detection of the marker correlates with disease, it would have been further obvious from the disclosure of Wienhues-Thelen, that those having measured levels essentially identical or lower than the reference would be those indicated to be at a reduced risk of cardiovascular event/mortality (mortality from cardiovascular event). One having ordinary skill in the art would have a reasonable expectation of success because the reference specifically indicates the marker usable for diagnosis of disease/condition, or for indicating increased risk of disease/condition.
Regarding claim 18, Wienhues-Thelen teach (see page 19, lines 11-20) in assessing risk, based on individuals who developed heart failure (a cardiovascular event) within 1 or 2 years (1 or 2 years falls within the claimed range of within 4 or 5, and as such addresses the claim.
Claims 3-5 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Wienhues-Thelen et al. as applied to claim 2 above, and further in view of Section 11: Evaluation and Management of Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction, Journal of Cardiac Failure, 16(6), (2016), p. e126-e133 (hereinafter referred to as JCF, IDS entered 08/19/2022).
Wienhues-Thelen does also suggest the importance of evaluating LVEF, teaching diagnostically when evaluating patients with HF, it is important to determine whether LVEF is preserved or reduced (page 5, lines 10-22).
Wienhues-Thelen does not specifically teach a subject that is known to have preserved (claim 3), LVEF that is larger 55% (claim 4), and larger than 60% (claim 5).
Journal of Cardiac Failure (JCF) teach preserved LVEF is defined as greater than 40, 45 or 50% (see e.g. page e126, col. 1 para 1), the claimed greater than 60% substantially overlaps said range disclosed by JCF. Furthermore, JCF taught that the female patients that they studied had LVEF ranging from 61% to 76%, a range which lies entirely within the claimed range of greater than 60%. JCF teach that the mortality of patients with heart failure with preserved LVEF is considerable, and in the general population of unselected patients it may be comparable to mortality in patients with HF and reduced LVEF (page e126, col. 1, last para). At page e126, col. 2, second to last para, JCF recommends careful attention to differential diagnosis in patients with HF and preserved LVEF to distinguish among a variety of cardiac disorders, because treatments may differ.
It would have been prima facie obvious to one of ordinary skill in the art to perform the diagnostic methods for predicting risk of mortality on a subject who does not show overt signs of heart failure as taught by Wienhues-Thelen et al. and further who has preserved LVEF larger than 60% (e.g. Stage A heart failure as in Wienhues-Thelen, also having preserved LVEF as in JCF) in order to predict future (or worsening) heart failure because JCF teach it is important (and therefore desirable) to be able to provide a differential diagnosis in patients with heart failure and preserved LVEF to distinguish among a variety of cardiac disorders since treatments may differ, and further because subjects with heart failure and preserved LVEF are at higher risk of mortality (JCF teaching mortality of patients with preserved LVEF is considerable). One of ordinary skill in the art would have a reasonable expectation of success predicting risk of mortality in a subject with preserved LVEF because JCF teach a substantial number of patients with HF have preserved LVEF.
It would be further obvious to predict risk of mortality in a subject having preserved LVEF larger than 60% as claimed because said subjects would be expected to have higher risk as suggested by Journal of Cardiac Failure (JCF); JCF teach preserved LVEF is defined as greater than 40, 45 or 50% (see e.g. page e126, col. 1 para 1), the claimed greater than 60% substantially overlaps said range disclosed by JCF. See (MPEP 2144.05). One skilled in the art would have found it obvious to arrive at the claimed invention out of the course of routine optimization, by selecting patients/subjects with preserved LVEF from within the ranges taught by the prior art, one of ordinary skill expecting those with heart failure and higher LVEF to be at greater risk. Furthermore, the patients of JCF have LVEF entirely within the claimed range, such that a prima facie case of obviousness exists.
Claims 13 and 15 rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Wienhues-Thelen et al. as applied to claim 2 above, and further in view of Maas et al., Gender differences in coronary heart disease, Netherlands Heart Journal, 18(12), (2010), p. 598-603.
Wienhues-Thelen et al. teach human subjects, however, the reference fails to limit the subjects to either of specifically male or female. As such, the reference does not specifically disclose predicting risk in subjects that are female human subjects.
Although the reference does not specifically specify if subjects are male or female, the reference does reference the use of mouse models in examples wherein the subjects are female mice (see for example, page 36, line 11; female mice analyzed showed identical findings as the male mice for cardiac measurements performed by echocardiography).
Maas et al. teach cardiovascular disease develops 7-10 years later in women than in men and is a major cause of death in women (abstract). Maas teach the risk of heart disease in women is often underestimated due to misperception that females are protected against cardiovascular disease (abstract). Maas teach examples of female-specific factors that put women at risk of cardiovascular events (page 599, end of col. 2 to page 600), further noting clinical presentation of coronary artery disease is less reliable in women (page 600, col. 1, para 2).
It would have been prima facie obvious to one having ordinary skill in the art to have modified Wienhues-Thelen such to perform their biomarker based methods specifically on human women subjects, one motivated to perform the methods on women because cardiovascular disease is a major cause of death in women, and often underestimated in women (Maas). Maas et al. supports that it is desirable to predict risk in women. Further because Wienhues-Thelen does not limit their methods to either of men or women, but rather generally humans, one having ordinary skill in the art would have a reasonable expectation of success applying the methods to detect risk in female human subjects.
Regarding claim 15, see as discussed previously above, Wienhues-Thelen correlates the increased marker with heart failure, and teaches the biomarker is also usable to predict future risk. Given that increased levels of the marker correlate with the disease/condition, it would have been further obvious to one having ordinary skill, applying the method for predicting future risk, that levels the same or larger indicate an elevated risk of heart failure (a cardiovascular event).
Response to Arguments
Applicant's arguments filed 04/07/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding remarks at pages 7-8, see as indicated previously above, the previous objections to the specification (regarding title) and the claims are withdrawn in response to Applicant’s amendments to the claims.
Additionally, regarding remarks pages 8-10, see as indicated above, the previous rejection of claims under 35 U.S.C. 112(b) are withdrawn in response to Applicant’s amendments to the claims.
Regarding remarks pages 10-16, Applicant argues the rejection of claims under 35 U.S.C. 101. Specifically, Applicant argues the amended claims integrate the judicial exception into a practical application and include claimed elements that amount to significantly more than the judicial exception(s) themselves. See at remarks pages 11-12, Applicant references the amendments to recite a “providing” step that requires obtaining a blood, serum, or plasma sample from a subject who meets specific clinical criteria, a “determining” step, a “comparing” step and a “predicting” step. Applicant argues the amended claims are directed to a specific technological solution to a concrete and documented unmet medical need, namely the non-invasive prediction of risk of mortality and/or cardiovascular events in clinically distinct patient population that does not suffer from heart failure and does not have LVH. Applicant specifically argues that the specification discloses that the PREDICTOR study validated IGFBP7 as a superior predictor of all cause mortality in this specific population (referring to pages 70-71), arguing this demonstrates a specific, concrete, and previously undemonstrated clinical benefit achieved by applying specific measurements of a specific biomarker in a specific biological sample from a specific patient population to achieve a specific result.
In response to these remarks, in order for integration into a practical application, the claim requires an additional element or combination of elements (i.e., in addition to the judicial exception(s) themselves) in the claim to apply, rely on or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception(s). In the present case, there is no such additionally recited element that applies, relies on or uses the judicial exception in such a way, rather the act of “predicting” itself is considered to be a judicial exception itself.
Further, the consideration as to whether the claim recites limitation/elements that go beyond that which was well known, routine or conventional, also applies to claim limitations/elements recited in addition to those that are the judicial exception(s) themselves.
In the present case, the additionally recited limitations recited in addition to the judicial exceptions themselves are the steps of obtaining and determining (i.e., obtaining sample from the claimed subject and determining an amount). Not only are these limitations considered insignificant presolution activity, necessarily performed in order to gather/obtain the data for the judicial exceptions, but it is also the case that the acts of obtaining sample and determining the amount of either of the claimed biomarkers is activity in the clinical assay art considered to be well known, routine and conventional (see the rejection detailed above).
It is also noted applicant’s remarks reiterated above are focused on that the PREDICTOR study validated IGFBP7 as a superior predictor of all-cause mortality in this specific population, however the present claims are not limited to IGFBP7 or even necessarily require measurements inclusive of IGFBP7. See for example, claim 2 recites “determining the amount of Insulin-like Growth Factor Binding Protein 7 (IGFBP7) and/or Fibroblast Growth Factor 23 (FGF-23) in the sample”, and as such, the claims encompass, for example, determining only amount of FGF-23 (because of the language and/or). The claims are not limited, for example, in a way that always includes IGFPB7, for example do not require the amount of IGFBP7, or the amount of IGFBP7 and FGF23- rather the instant claims also encompass only FGF-23.
Regarding arguments at pages 12-14, that the claims require the multi-step workflow, see the steps of the workflow as discussed in detail in the rejection and response to remarks above, the steps do not satisfy requirements under 35 U.S.C. 101 for the reasons discussed. Although the claims do recite obtaining the sample from particular subject, these limitations are not sufficient and do not amount to either an integration into a practical application or amount to significantly more for the reasons discussed in the rejection. There is no evidence to suggest that assay (the particular active steps, the wet method steps for performing the determining) would be performed any differently depending on the subjects from which the sample is obtained. Put another way, the subject population does not impact or represent a technical advancement or improvement to the assay itself, and fails to ensure the claims amount to significantly more.
Applicant further argues the dependent claims further narrow the claimed methods with additional limitations that support eligibility under 35 U.S.C. 101 (remarks page 14), however, although the limitations are further narrowing to certain limitations, see for the reasons discussed in detail above, none of the additional recited limitations satisfying the requirements with respect to integration or amount to activity that was more than well known, routine and conventional for the reasons as indicated in detail above.
Regarding remarks page 14-16 directed to the new claims, the new claims are not rejected under 35 U.S.C. 101 in the present action.
Regarding the rejections of claims under 35 U.S.C. 102, Applicant argues Wienhues-Thelen does not anticipate the claims (remarks pages 16-17), arguing because claim 2 as amended requires subjects are subjects without LVH, arguing this is a limitation not addressed by the cited reference.
However, this argument is not persuasive, see for example the reference is referring to levels in subjects classified as Stage A (i.e., those that are clinically considered normal according to ACA/ACC classification), and stage A are those subjects not considered to have LVH (see for example, this exact fact is supported by Applicant’s own originally filed specification at page 11-12, “For example, patients with coronary artery disease, hypertension, or diabetes mellitus who do not yet demonstrate impaired left ventricular (LV) function, hypertrophy, or geometric chamber distortion would be considered stage A,…”.
Additionally, in response to the argument that Wienhues-Thelen does not predict mortality (remarks pages 17-20), see as cited in detail above, the reference does address predicting a cardiovascular event and does address those without LVH (see response to this argument immediately above).
Further, regarding arguments specific the rejections of claims under 35 U.S.C. 103, Applicant argues it would not have been obvious to predict mortality. However, referring to the rationale provided at the rejection, it is maintained that it would have been further prima facie obvious to one of ordinary skill in the art at the time of the invention, that by performing the method of Wienhues-Thelen, detecting IGFBP-7 and comparing it to a reference standard to predict a subject’s risk of heart failure, one would also be similarly predicting a subject’s risk of mortality because the teachings of Wienhues-Thelen indicate that those at risk of heart failure are also at risk of mortality due to heart failure (see as discussed previously above, specifically at page 1, lines 21-22, heart failure is a recognized cause of death (mortality); (page 6, lines 26-28) Wienhues-Thelen also teach 50% of patients with heart failure die within two years of diagnosis, that the 5 year survival rate is less than 30%, further suggesting that those at risk of heart failure are simultaneously at risk of mortality). One of ordinary skill would have a reasonable expectation of success relating risk of heart failure to a simultaneous risk of mortality because heart failure, untreated, can cause mortality and further because the reference teaches those at risk of heart failure are at risk of mortality.
In response to remarks at page 21, it is not the case that the rationale is consistent with the position that any marker for any disease would predict mortality, rather in this case the prior art specifically correlates the marker with mortality, Wienhues-Thelen indicate that those at risk of heart failure are also at risk of mortality due to heart failure (see as discussed previously above, specifically at page 1, lines 21-22, heart failure is a recognized cause of death (mortality); (page 6, lines 26-28) Wienhues-Thelen also teach 50% of patients with heart failure die within two years of diagnosis, that the 5 year survival rate is less than 30%, further suggesting that those at risk of heart failure are simultaneously at risk of mortality).
Regarding remarks at pages 22-23, specific to the limitation “no LVH”, see this argument addressed previously above.
At remarks page 23 Applicant also argues IGFBP7 demonstrates unexpectedly superior predictive value for mortality compared to well established cardiac markers. However, based on the cited prior art, IGFBP7 is not an unexpected marker for predicting cardiovascular event, as is also encompassed by the claims.
Additionally, whether evidence shows unexpected results is a question of fact and the party asserting unexpected results has the burden of proving that the results are unexpected. In re Geisler, 116 F.3d 1465, 1469-70, 43 USPQ2d 1362, 1364-5 (Fed. Cir. 1997). The evidence must be (1) commensurate in scope with the claimed subject matter, In re Clemens, 622 F.2d 1019, 1035, 206 USPQ 289, 296 (CCPA 1980), (2) show what was expected, to "properly evaluate whether a … property was unexpected", and (3) compare to the closest prior art. Pfizer v. Apotex, 480 F.3d 1348, 1370-71, 82 USPQ2d 1321, 1338 (Fed. Cir. 2007).
The burden of demonstrating unexpected results rests on the party asserting them, and “it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972). Moreover, it has been long held that “even though applicant’s modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art, unless the claimed ranges ‘produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art.” In re Huang, 100 F.3d 135, 139 (Fed. Cir. 1996) (quoting In re Aller, 220 F.2d 454, 456 (1955), and citing In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990)).
Applicant has not provided evidence or argument as to why the results may be characterized as unexpected or surprising. Arguments that the marker as primarily known for its roles in cell growth, differentiation and insulin resistance is not sufficient evidence to support that the marker is not also predictive for risk of future mortality and/or cardiovascular event. Rather the cited prior art contradicts this position and does support this marker as being expected predictive in relation to cardiovascular event and/or mortality for the reasons discussed in detail above.
Regarding claims 7-9 (remarks pages 23-24) and claim 14-16 (pages 24-25), Applicant argues the claimed marker combinations and reference amounts would not have bene obvious for predicting risk in those without heart failure or LVH. However, see for the reasons discussed above, this argument is not persuasive.
Regarding claim 18, Applicant further argues the claimed prediction window (remarks page 24). However, see as cited above, Wienhues-Thelen teach (see page 19, lines 11-20) in assessing risk, based on individuals who developed heart failure (a cardiovascular event) within 1 or 2 years (1 or 2 years falls within the claimed range of within 4 or 5, and as such addresses the claim.
See also at pages 25-27, arguments return to Applicant’s position that the cited art does not address “no LVH” (see e.g., pages 26 and 27). However, see this argument as addressed in detail previously above.
For the reasons discussed in detail above, the claims are rejected as indicated in the pending grounds of rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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