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 the instant application is the filing date 03/28/2013.
Election/Restrictions
Applicant’s election of the species of additional biomarker iv. Brain natriuretic peptides and cardiac troponin in the reply filed on 10/29/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 6 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/29/2025.1
Information Disclosure Statement
Information disclosure statement (IDS) filed 04/07/2025 is considered, initialed and is attached hereto.
The information disclosure statement filed 08/19/2022 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
See for example, for IDS filed 08/19/2022, no copy has been provided for non-patent literature reference nos. 8, 10, 19, 30 and 36.
Non-patent literature no. 39 is lined through because it is a duplicate (duplicate of citation no. 38).
The information disclosure statement filed 09/26/2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered.
See for example, non-patent literature citation no. 2 is not provided in the English language.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
In the present case the title is “Identification of Patients with Abnormal Fractional Shortening”, however, as amended the claims are now directed at “A Method of Predicting Risk of Mortality and/or a Cardiovascular Event”. The title is no longer descriptive for the claims.
Claim Objections
Claim 2 is objected to because of the following informalities:
Claim 2 recites the abbreviations IGFBP7 and FGF-23. It is suggested that in the first instance of an abbreviation, that the abbreviation be accompanied by the full term (i.e., “full term (abbreviation)”).
Claim 2 also recites parenthesis in the claims, e.g. "(or the amounts)” and “(or to reference amounts)”. Although Applicant’s intended meaning is understood by the Examiner, the use of parenthesis in the present claims may present confusion because the parenthesis raise question as to whether or not the limitation within the parenthesis is actually required by the claim.
Appropriate correction is required.
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 15-17 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.
Claim 15 recites “indicates that the subject to be tested is elevated risk”, the language “subject to be tested” is indefinite because it raises question as to whether the claim language is referring to the subjected that is tested (i.e., measured for) for the claimed biomarker(s), or rather if the language is suggesting that the subject is to be further tested for some other parameter. The language is not consistent with previous language used to refer to the subject (see for example, previously, independent claim 2 recites “in a subject”, the subject is not previously referred to as a “subject to be tested”).
Claim 16 recites “reference amount derived from a subject or group of subjects known to have reduced risk of mortality and/or of a cardiovascular event”; however, it is not clear what is encompassed by this language, for example, it is unclear if this refers to subjects otherwise considered to be healthy/free of disease, or rather if there is some other standard of measured used to indicate those subjects are subjects considered to be at reduced risk. While the specification does provide literal support for this limitation, the specification does not clarify how to distinguish those reference subjects who are considered to be those known to have reduced risk of mortality and/or cardiovascular event.
Claim 17 recites “essentially identical”, however, the limitation “essentially” is indefinite because it is not clear what is and is not encompassed by “essentially” beyond numbers that are identical to the reference amount. The specification fails to provide any standard of measure for what would and would not be considered “essentially identical”.
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 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”, the method “determining…the amount of IGFBP7 and/or FGF-23” and “comparing the amount (or amounts) as determined… to a reference amount (or reference amounts), whereby the risk of mortality and/or a cardiovascular event in said subject is predicted”. See further the claims recite additional biomarkers, namely brain natriuretic peptide (BNP or NT-proBNP) and/or cardiac troponin (T or I).
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 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 (or amounts) as determined… to a reference amount (or reference amounts), whereby the risk of mortality and/or a cardiovascular event in said subject is predicted” is also 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 determining the amount of the biomarker(s) and comparing to a reference amount(s).
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.
As noted the dependent claims also fail to recite additional steps/elements, other than those that further narrow the judicial exceptions themselves.
Notably claim two merely recite “determining, in a 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). Further determining/measuring the claimed biomarkers was well-known, routine and conventional in the assay art, 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 biomarker(s).
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 and 16 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) (see also page 20, lines 10-22, investigating
individuals that are clinically "normal", i.e. stage A according to ACA/ACC classification).
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).
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). 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) (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 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).
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
1 Examiner notes that the original claims do not appear present in the filed application; however, it is clear from the amended claims filed 08/19/2022 and 10/29/2025 that it is the 10/29/2025 claims which are the most recent claims which Applicant intends to pursue.