DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Herein, “the previous Office action” refers to the Final Rejection filed 5/29/2025.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/29/2025 has been entered.
Priority
As detailed on the Filing Receipt filed 6/6/2019, the instant application claims priority to as early as 4/18/2016. At this point in prosecution, all claims are accorded the earliest claimed priority date.
Claim Status
Claims 2, 5, 10-14, 16-17, 19 and 22-24 are canceled.
Claims 1, 3-4, 6-9, 15, 18, 20-21 and 25-32 are pending, and examined herein.
Withdrawn Rejections
The rejections of claim 5 are hereby withdrawn in view of Applicant’s cancelation of the claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 USC §§ 102 and 103 is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 USC § 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 USC § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 USC § 102(b)(2)(C) for any potential 35 USC § 102(a)(2) prior art against the later invention.
Claims 1, 3-9, 18, 20, 25, and 27-28 are rejected under 35 USC § 103 as being unpatentable over Zaugg et al (previously cited), in view of Hunt et al (previously cited) and Coglianese et al (previously cited). This rejection is maintained from the previous Office action, and has been revised to address the amended claims (filed 8/29/2025).
Claim 1 recites a method for identifying a subject who is at risk of progressing to left ventricular hypertrophy, comprising:
a) measuring an amount of soluble sST2 (sST2) in a sample from the subject, wherein the subject does not suffer from heart failure;
b) comparing the amount to a reference amount derived from a subject or group known to be at risk of progressing to LVH;
c) identifying the subject who is at risk of progressing to LVH based on the result of the comparison, when the amount of sST2 in the subject is equal to or increased as compared to the reference amount; and
d) administering one or more angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), aldosterone antagonists, and beta blockers.
With respect to claim 1, Zaugg discloses “a method for identifying a subject as being eligible to the administration of at least one medicament… based on” (Abstract):
a) “determination of the amount of at least one biomarker selected from the group consisting of… soluble ST2 (sST2)… in a sample from a subject” (Abstract);
b) “comparing the, thus, determined amount with a reference amount” (Abstract), wherein the reference amount is “an amount of a suitable reference source” (pg. 14, para. 0171) and is “derived from a subject or group of subjects known to be eligible to the administration of said at least one medicament” (pg. 17, para. 0208);
c) “identifying a subject being eligible to the administration of at least one medicament” (pg. 3, para. 0040), wherein “an amount (or amounts) of the biomarker (or biomarkers) in the test sample which is (or are) essentially the same, or which is (or are) increased as compared to the reference amount (or to the reference amounts) is (or are) indicative for a subject who is eligible” (pg. 17, para. 0208); and
d) “administration of at least one medicament selected from the group consisting of a beta blocker, an aldosterone antagonist… and an inhibitor of the renin-angiotensin system” (Abstract) wherein “Inhibitor[s] of the renin-angiotensin system include angiotensin converting enzyme (ACE) inhibitors, [and] angiotensin II receptor blockers…ARBs” (pg. 6, para. 0107).
Zaugg discloses that “a subject who is eligible to the administration of said at least one medicament will benefit from the administration… [and] a subject benefits… if the administration… reduces the risk of mortality of said subject and/or reduces the risk of hospitalization of said subject, in particular within a window period… after the sample has been obtained… due to heart failure” (pg. 5, para. 0090), thus, “by identifying a subject who is eligible… it can be assessed whether a subject will benefit from the administration (i.e., from the initial administration or intensification of administration, in particular the administration at a higher dosage), or not” (pg. 5, para. 0092). In other words, the disclosed steps identify a subject who is at risk of progression to heart failure of severity sufficient to result in hospitalization, and/or death, within a time interval based on the result of the comparison.
Zaugg further discloses that “Heart failure is a complex clinical syndrome that can
result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood and to… supply [the body] with blood/oxygen. In such cases, the body tries to compensate… by structural changes of the myocardium (e.g. hypertrophy eventually leading to fibrosis, apoptosis, necrosis)… aimed at maintaining the required supply” (pg. 1, para. 0004). Zaugg thereby discloses that progression of myocardial hypertrophy is a biological response to underlying cardiac dysfunction, yet in turn exacerbates cardiac dysfunction.
Additionally, Zaugg discloses that “HF can be classified into various degrees of severity… patients with coronary artery disease, hypertension, or diabetes mellitus who do not yet demonstrate impaired left ventricular (LV) function, [or] hypertrophy… would be considered stage A… As used herein, the term ‘heart failure’… refers to stages B, C, and D of the ACC/AHA classification” (pg. 7, para. 0116-117).
In this way, Zaugg discloses identifying a subject as known to be eligible for administration of at least one disclosed medicament (i.e., at risk of progression to heart failure of severity sufficient to result in hospitalization, or death), by comparing measured amounts of sST2 to a suitable reference amount derived from a subject or group of subjects known to be eligible. Zaugg further discloses that progression to left ventricular hypertrophy is biologically correlated with progression to and worsening of symptomatic heart failure.
Zaugg does not disclose utilizing a reference amount derived from a subject or a group thereof known to be at risk of progressing to LVH; or identifying the subject who is at risk of progressing to LVH.
Hunt discusses “diagnosis and management of chronic HF” (pg. e5, r. column), and teaches that “Left ventricular dysfunction… is generally a progressive process, even in the absence of a new identifiable insult to the heart. The principal manifestation of such progression is a change in the geometry and structure of the LV, such that the chamber dilates and/or hypertrophies… [which] increases the hemodynamic stresses on the walls of the failing heart and depresses its mechanical performance... sustain[ing] and exacerbat[ing] the remodeling process. Cardiac remodeling generally precedes the development of symptoms [of HF] (occasionally by months or even years), continues after the appearance of symptoms, and contributes substantially to worsening of symptoms” (pg. e7, r. column). Hunt, like Zaugg, thus teaches that progression of LV remodeling (i.e., progression to and worsening of LVH) is biologically correlated with progression to and worsening of symptomatic heart failure.
Hunt further teaches that “physicians should monitor patients closely for… worsening signs and symptoms of HF… Such patients generally respond favorably to intensification of conventional therapy” (pg. e32, r. column), and “incidence of HF can be reduced by… retarding the evolution and progression of LV remodeling. Initial appropriate measures include those listed as class I recommendations for patients in Stage A” (pg. e19, l. column), i.e., patients who have not yet progressed to LVH. Said conventional therapy and appropriate measures, earlier described by Hunt, comprise administration of ACE inhibitors, ARB, aldosterone antagonists and/or beta blockers (pg. e16, Table 3). In other words, these medications function to retard LV remodeling (e.g., progression to and worsening of LVH), and thereby lower risk of heart failure.
The teachings of Hunt indicate that a subject at risk of progressing to LVH is necessarily at risk of worsening heart failure. The teachings of Hunt further indicate that the treatments disclosed by Zaugg function to treat heart failure by treating LV remodeling (i.e., when applied to a subject who has not yet progressed to LVH, retarding progression to LVH).
In this way, the teachings of Hunt provide evidence that the particular treatment methods of Zaugg have clinical utility for treatment of subjects at risk of progressing to LVH. However, the combined teachings of Zaugg and Hunt do not indicate a predictive role for ST2 regarding risk of progression to LVH.
Coglianese discusses “Soluble ST2 (sST2)… a cardiac biomarker whose concentration rises in response to myocardial strain… [and] its distribution and correlates in community-based populations” (pg. 1673, Background), and teaches “measur[ing] sST2… [and] identify[ing] covariates associated with sST2 in [a] general sample” (pg. 1673, Methods) wherein “Candidate covariates included… LV hypertrophy” (pg. 1675, l. column). Coglianese describes selection and assessment of “A healthy reference sample… from which participants with the following characteristics were excluded… heart failure… [and] LV dysfunction” (pg. 1674, l. column), and presents findings that “sST2 values previously linked with a higher risk for cardiovascular outcomes in patients with established heart disease… generally represented values at or above the 95th-percentile concentration in our general population” (pg. 1679, r. column).
Coglianese concludes: “[M]uch like other biomarkers of risk in the general population… there are ‘apparently well’ subjects with values of sST2 associated with considerable risk… sST2 (alone or in combination with other cardiovascular biomarkers) predicts incident cardiovascular disease… Our results imply that… concentrations of the biomarker”, i.e., sST2, “are detectable in most (and likely all) apparently healthy individuals” (pg. 1679, r. column – pg. 1680, l. column).
In this way, Coglianese teaches comparing amounts of sST2 measured in a general population, including subjects who do not suffer from heart failure, to reference amounts derived from subjects known to be at risk of cardiovascular outcomes.
Coglianese also teaches that “Loss of intact IL-33/ST2L signaling results in unchecked remodeling of ventricular myocardium characterized by excessive myocyte hypertrophy, fibrosis, and worsening of left ventricular (LV) function”, i.e., left ventricular hypertrophy, “along with a higher risk of death from ventricular failure… In contrast to ST2L, sST2 may act as a ‘decoy’ receptor for IL-33, and when present in large enough amounts, sST2 likely interferes significantly with the actions of IL-33” (pg. 1673, r. column). In this way, Coglianese teaches a biological link between sST2 and progression of left ventricular hypertrophy.
In this way, Coglianese provides evidence for a causative (and thus, predictive) role of sST2 with respect to development of LVH. Hunt and Coglianese provide evidence that the method of Zaugg has clinical utility for identification and treatment of subjects at risk of progressing to LVH, and therefore the combination of Zaugg, Hunt and Coglianese is viewed as teaching and/or suggesting the limitations of comparing the amount of sST2 to a suitable reference amount derived from a subject or a group thereof known to be at risk of progressing to LVH; and identifying the subject who is at risk of progressing to LVH.
With respect to claim 3, Zaugg discloses that “Samples… can be obtained by well-known techniques and include… more preferably, samples of blood, plasma or serum” (pg. 8, para. 0121).
With respect to claim 4, Coglianese describes selection and assessment of “A healthy reference sample” (pg. 1674, l. column), and concludes therefrom that “[M]uch like other biomarkers of risk in the general population… there are ‘apparently well’ subjects with values of sST2 associated with considerable risk… sST2 (alone or in combination with other cardiovascular biomarkers) predicts incident cardiovascular disease… Our results imply that… concentrations of the biomarker”, i.e., sST2, “are detectable in most (and likely all) apparently healthy individuals” (pg. 1679, r. column – pg. 1680, l. column).
Coglianese thus teaches comparing amounts of sST2 measured in a general population, including apparently healthy subjects, to reference amounts derived from subjects known to be at risk of cardiovascular outcomes.
With respect to claim 6, Coglianese discloses participant age groups including 35-44 years (pg. 1677, Table 2).
With respect to claim 7, Zaugg discloses “determination of the amount of at least one biomarker selected from the group consisting of… a cardiac Troponin, [and/or] a BNP-type peptide” (Abstract) such as a “pre-proBNP, proBNP, NT-proBNP and BNP” (pg. 8, para. 0122).
Claim 18 recites a method comprising:
a) measuring an amount of a BNP-type peptide selected from… pre-proBNP, proBNP, NT-proBNP and BNP and an amount of sST2 in a sample from a subject;
b) comparing the measured amounts to reference amounts of the BNP-type peptide and sST2;
c) predicting that the subject is at short-term risk of progressing to LVH, wherein:
1. short-term risk is risk on a time interval of from 1 month to 3 years, and
2. short-term risk is predicted based on the amount of BNP-type peptide being above the corresponding reference amount and the amount of sST2 being above the corresponding reference amount; and
d) administering to the subject an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-II receptor blocker (ARB), an aldosterone antagonist and/or a beta blocker.
With respect to claims 8-9 and 25, Coglianese discloses measurements of “estimated glomerular filtration rate (GFR)” (pg. 1674, l. column) and “systolic blood pressure” (pg. 1675, l. column; see pg. 1676, Table 1).
With respect to claim 18, Zaugg discloses “a method… based on” (Abstract):
a) “determination of the amount of at least one biomarker selected from… a BNP-type peptide… [and] soluble ST2 (sST2)… in a sample from a subject” (Abstract), wherein BNP-type peptides include “pre-proBNP, proBNP, NT-proBNP and BNP” (pg. 8, para. 0122);
b) “comparing the, thus, determined amount with a reference amount” (Abstract), wherein “the reference amount… may be the same for the respective marker. Accordingly, the amount of the biomarker as determined… is, preferably, compared to… a reference amount for the individual marker” (pg. 20, para. 304);
c) “identifying a subject being eligible to the administration of at least one medicament” (pg. 3, para. 0040) wherein “a subject who is eligible… will benefit from the administration… [and] a subject benefits… if the administration… reduces the risk of mortality… and/or reduces the risk of hospitalization of said subject… due to heart failure”, i.e., predicting that the subject is at risk,
1. “in particular within a window period of 18 months or 3 years after the sample has been obtained” (pg. 5, para. 0090), and
2. “amounts of the [biomarkers] in the test sample… which [are] increased as compared to the reference [amounts are] indicative for a subject who is eligible” (pg. 17, para. 0208);
d) “administration of at least one medicament selected from the group consisting of a beta blocker, an aldosterone antagonist… and an inhibitor of the renin-angiotensin system” (Abstract) wherein “Inhibitor[s] of the renin-angiotensin system include angiotensin converting enzyme (ACE) inhibitors, [and] angiotensin II receptor blockers…ARBs” (pg. 6, para. 0107).
With respect to claim 20, Zaugg discloses that “the subject, preferably, shall not suffer from renal hypertension” (pg. 7, para. 0118). Additionally, Coglianese discloses “excluding individuals with… hypertension” (pg. 1673, Methods).
With respect to claim 27, Coglianese teaches selection of “A healthy reference sample… from which participants with the following characteristics were excluded… hypertension… [and] diabetes” (pg. 1674, l. column).
With respect to claim 28, Coglianese teaches selection of “A healthy reference sample… from which participants with the following characteristics were excluded… LV dysfunction… valve disease… hypertension… diabetes… atrial fibrillation… heart failure… or coronary heart disease (myocardial infarction, angina pectoris, or coronary insufficiency)” (pg. 1674, l. column).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have utilized the biomarker comparison method of Zaugg to treat a subject who is at risk of progressing to LVH, because the teachings of Hunt provide evidence that risk of worsening heart failure (i.e., that which is predicted by the method of Zaugg) is biologically correlated with risk of LVH (pg. e7, r. column), and treatments administered to lower risk of worsening heart failure (e.g., those administered by the method of Zaugg) can be administered to lower risk of LVH (pg. e16, Table 3; pg. e19, l. column). Said practitioner would have had a reasonable expectation of success because Zaugg and Hunt both discuss analysis of cardiac risk, LVH, and treatment.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have utilized the biomarker comparison method of Zaugg to identify a subject who is at risk of progressing to LVH, because the teachings of Coglianese provide evidence that sST2 (i.e., that which is measured by the method of Zaugg) is biologically correlated with progression to LVH (pg. 1673, r. column).
Additionally, said practitioner would have derived samples from subjects who are not suffering from heart failure, apparently healthy, and of ages between 30 and 50 years, and implemented measurement of estimated glomerular filtration rate (eGFR) and systolic blood pressure, to enhance the biomarker comparison method of Zaugg, in view of Hunt, because Coglianese teaches that sST2, eGFR and systolic blood pressure can all be measured in such subjects and used in combination to predict cardiovascular outcomes (pg. 1674, l. column, pg. 1675, l. column; pg. 1677, Table 2; pg. 1679, r. column; pg. 1680, l. column).
Said practitioner would have had a reasonable expectation of success because Zaugg and Coglianese both discuss measurement of ST2 levels in subject blood samples, LVH, and comparative analysis of heart condition risk.
In this way the disclosure of Zaugg, in view of Hunt and Coglianese, makes obvious the limitations of claims 1, 3-4, 6-9, 18, 20, 25, and 27-28. Thus, the invention is prima facie obvious.
Response to Arguments - Claim Rejections Under 35 USC § 103
In the reply filed 8/29/2025, Applicant traverses the rejections under 35 USC § 103 and presents supporting arguments.
Applicant asserts that the Office has failed to establish a prima facie case of obviousness, citing guidance from KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007; hereafter “KSR”) that analysis supporting a rejection should be made explicit (see 550 U.S. at 418), guidance from In re Zurko, 258 F.3d 1379 (Fed. Cir. 2001) that appeals to “basic knowledge or common sense” cannot remedy reference deficiencies (258 F.3d at 1385), and guidance from In re Lee, 277 F.3d 1338 (Fed. Cir. 2002) that “conclusory statements… do not fulfill the agency’s obligation” (277 F.3d at 1344, citing to In re Zurko), and alleges that the Office provides no rationale beyond conclusory reasoning for why one would adapt Zaugg’s methods for existing heart failure patients to predict future LVH in subjects without heart failure (pg. 8, paras. 1-3).
As an initial matter, In re Zurko (2001) and In re Lee (2002) were decided in the context of a strict in-reference evidentiary requirement which was superseded by the Supreme Court decision in KSR (2007). KSR reinforced a more flexible approach to obviousness, requiring that the Office present “some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness’” (550 U.S. at 418, quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)) while elaborating numerous potential bases for that reasoning (e.g., market forces) beyond teachings, suggestions, or motivations in the prior art itself. As held in In re Soli, 317 F.2d 941 (CCPA 1963), the rationale to support a rejection under 35 USC § 103 may rely on scientific principle with evidentiary support.
Although the prior art references of record in the instant application may not contain express teachings, suggestions or motivations that would instruct one of ordinary skill in the art in their combination or modification such that said practitioner would arrive at the claimed invention, the rejections of record do not in fact rely on mere conclusory statements without articulated reasoning or evidentiary support and are considered to meet the KSR standards for a prima facie case of obviousness. Thus, the argument is found unpersuasive.
Applicant points to Coglianese’ s establishment of reference values using healthy populations that exclude cardiovascular disease patients, and asserts distinction of the claimed invention in utilizing reference values derived from subjects known to be at risk of progressing to LVH (pg. 9, para. 4 – pg. 10, para. 2).
The method of Zaugg involves comparison of measured sST2 values to reference values indicative for subjects who are known to be eligible for the administration of heart medication, i.e., known to be at risk of mortality and/or hospitalization due to heart failure, to assess whether a tested subject would benefit from administration of particular medications (paras. 0090, 0092, 0171 and 0208). In other words, Zaugg uses reference sST2 values derived from subjects known to be at risk of particular cardiovascular outcomes, which can be reduced by administration of particular medications, to predict individual risk of those outcomes and thus benefit from administration of those medications.
One of ordinary skill in the art would understand that application of the sST2 measurement and analysis of Zaugg to predict risk of progression to LVH, rather than risk of mortality and/or hospitalization due to heart failure as disclosed, would necessitate usage of reference values from subjects known to be at risk of progression to LVH, rather than subjects known to be at risk of mortality and/or hospitalization due to heart failure as disclosed.
Coglianese is not relied upon for establishing the reference comparison framework of Zaugg, but for providing evidence for scientific principles that would lead one of ordinary skill in the art to apply the method of Zaugg to the prediction of LVH. Thus, the argument is found unpersuasive.
Applicant asserts that the previous Office action fails to establish specific motivation to combine the references, and improperly relies on a biological correlation between heart failure and LVH that is absent from the references themselves (pg. 10, para. 3 – pg. 11, para. 2).
The rejections under § 103 outline relevant teachings from the cited references, and provide rationale regarding motivation for their combination. A finding of reasonable expectation of success is considered implicit to that rationale in light of the level of skill in the art (Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1377 (Fed. Cir. 2023)). Thus, the argument is found unpersuasive.
Applicant asserts that one skilled in the art would have not had a reasonable expectation of success, as the prior art provides no guidance regarding the critical parameters of the claimed method (e.g., the use of reference amounts from subject known to be at risk of progressing to LVH) and such guidance can only be found through use of Applicant’s disclosure (pg. 11, para. 3 – pg. 12, para. 2).
The method of Zaugg involve comparison of measured sST2 values to reference values indicative for subjects who are known to be eligible for the administration of heart medication, i.e., known to be at risk of mortality and/or hospitalization due to heart failure, to assess whether a tested subject would benefit from administration of particular medications (paras. 0090, 0092, 0171 and 0208). In other words, Zaugg uses reference sST2 values derived from subjects known to be at risk of particular cardiovascular outcomes, which can be reduced by administration of particular medications, to predict individual risk of those outcomes and thus benefit from administration of those medications.
Zaugg discloses comparison of measured values with reference values corresponding to the predicted condition. Coglianese provides evidence for scientific principles that would lead one of ordinary skill in the art to apply the method of Zaugg to the prediction of risk of progression to LVH. One of ordinary skill in the art would understand that application of the sST2 measurement and analysis of Zaugg to predict risk of progression to LVH, rather than risk of mortality and/or hospitalization due to heart failure as disclosed, would necessitate usage of reference values from subjects known to be at risk of progression to LVH, rather than subjects known to be at risk of mortality and/or hospitalization due to heart failure as disclosed. Thus, the argument is found unpersuasive.
Applicant asserts that the Office rationale impermissibly relies on hindsight reconstruction, particularly noting that “none of the references suggest adapting methods for heart failure patients to predict disease progression in non-heart failure subjects” (pg. 12, para. 3 – pg. 13, para. 3).
A judgment of obviousness is proper, albeit in a sense necessarily a hindsight
reconstruction, so long only relies upon knowledge which was within the level of ordinary
skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure (In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971)). Relevant teachings from the applied combination of references are outlined in the rejections, and Applicant’s own disclosure is not relied upon as a source of knowledge therein.
For example, Coglianese notes that “sST2 values [were] previously linked with a higher risk for cardiovascular outcomes in patients with established heart disease” (pg. 1679, r. column) and “sST2 has been established as a potentially useful biomarker for risk prediction in patients with established heart disease” (pg. 1680, l. column). Based on their presented findings, Coglianese teaches that sST2 is additionally a “biomarker[] of risk in the general population… there are ‘apparently well’ subjects with values of sST2 associated with considerable risk… [and] sST2 (alone or in combination with other cardiovascular biomarkers) predicts incident cardiovascular disease” (pg. 1679, r. column – pg. 1680, l. column).
In this way, Coglianese is considered to suggest applying measurement and analysis of sST2 testing, with known predictive utility for patients with established heart disease (e.g., heart failure patients), to predict risk of incident cardiovascular disease (i.e., cardiovascular disease progression) in apparently healthy subjects (e.g., non-heart failure patients). Thus, the argument of improper hindsight reconstruction is found unpersuasive.
Applicant asserts that the instant specification demonstrates unexpected results not predictable from the cited references, namely the early predictive capability of sST2 regarding LVH outcome, and points to Example 4 of the specification (at pp. 38-40) for evidentiary support (pg. 13, para. 4- pg. 14, para. 1).
Examiners must consider comparative data in the specification which is intended to illustrate the claimed invention in reaching a conclusion with regard to the obviousness of the claims (In re Margolis, 785 F.2d 1029 (Fed. Cir. 1986)). The cited Example 4 has been considered. Its evidentiary weight in supporting an assertion of unexpected results is uncertain, for at least the following reasons:
The Example data does not regard predictive accuracy of the claimed invention, but rather statistical analysis of clinical measurements not involving any actual risk prediction;
The provenance of the Example data as derived from prior art (e.g., the article “Siest et al 2008” mentioned on pg. 31, Example 1 Legend), or original relative to prior art (e.g., derived from original measurements of preserved STANISLAW cohort samples), is unclear;
There is no comparison to closest prior art, and it is unclear whether the observed correlations represent differences in results between the claimed invention and comparable prior art that are unexpected or unobvious;
The practical significance of the Example data (i.e., the purported correlation between sST2 amounts and later LVH status) is unclear, particularly as the depicted data itself indicates non-linear fluctuation in amounts of the key biomarker (sST2) over time in both the case (‘LVH’) and control (‘No LVH’) groups of the tested cohort;
Applicants may rebut obviousness by providing objective evidence of unexpected results, but “have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness” (Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992)). The Examiner suggests submitting an affidavit or declaration clarifying the listed issues. See MPEP 716.01(c) and 716.02-716.02(e).
Applicant asserts that claim 18 is separably patentable, as the cited art does not teach predicting short-term LVH progression using the specific dual biomarker pattern claimed (pg. 14, para. 3 – pg. 15, para. 3).
The differences between claim 1 and claim 18 are: additional measurement, and subsequent analysis, of a selected one of a recited group of biomarkers (BNP-type peptides) including NT-proBNP; predicting risk on a time interval from one month to three years; and predicting risk when the amount of both sST2 and the BNP-type peptide are above the reference amounts.
Zaugg teaches measuring both sST2 and BNP-type peptides (including NT-proBNP), and sST2, comparing to reference amounts, and identifying subjects as eligible for a medication within a window period of 18 months to 3 years when both markers are elevated. Coglianese provides evidence for biological correlation between sST2 and progression of LVH, and Applicant has previously stated that “NT-proBNP… is a known marker for LVH” (Remarks filed 12/27/2023 at pg. 12, para. 3). The teachings of the cited art are considered to make obvious the limitations of claim 18, and the argument is found unpersuasive.
Applicant asserts that the cited references fail to teach risk stratification between near-term and distant LVH progression, while the claimed invention provides this ability as elevated sST2 with normal BNP was discovered to indicate longer-term risk (pg. 16, paras. 2-3).
Assessment of long-term risk as described is a unique feature of claim 15 and dependents thereof, which are indicated as allowable. The argument is considered moot and found unpersuasive regarding the pending rejections.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Instant claims 1, 3-4, 6-9, 20 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 8 of US Patent No. 10,557,858 (hereafter, “‘858”) in view of Coglianese and Hunt. ‘858 shares joint inventors (Dirk Block, Ursula-Henrike Wienhaus-Thelen, and Christian Zaugg) and a common assignee (Roche Diagnostics Operations, Inc.) with the instant application. This rejection is maintained from the previous Office action, and has been revised to address the amended claims (filed 8/29/2025).
Instant claim 1 recites a method for identifying a subject who is at risk of progressing to left ventricular hypertrophy, comprising:
a) measuring an amount of soluble sST2 (sST2) in a sample from the subject, wherein the subject does not suffer from heart failure;
b) comparing the amount to a reference amount derived from a subject or group known to be at risk of progressing to LVH;
c) identifying the subject who is at risk of progressing to LVH based on the result of the comparison, when the amount of sST2 in the subject is equal to or increased as compared to the reference amount; and
d) administering one or more angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), aldosterone antagonists, and beta blockers.
With respect to instant claim 1, ‘858 discloses “[a] method for predicting the risk of a human subject of progressing to chronic heart failure… comprising” (claim 8):
a) “measuring… the level from the human subject of… soluble ST2 (sST2)” (claim 8), wherein
b) “comparing the level… to a reference level, wherein said subject does not suffer from left ventricular hypertrophy” (claim 8);
c) “predicting the risk of a subject of progressing to chronic heart failure… and/or of death… wherein a level… above the reference level indicates that the subject is at risk” (claim 8); and
d) “administering a medicament selected from the group consisting of an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor antagonist (ARB)”, i.e., angiotensin II receptor blocker, “an aldosterone antagonist… and a beta blocker” (claim 8).
As the disclosed method predicts the risk of a human subject of progressing to chronic heart failure, one of ordinary skill in the art would find it obvious to apply the method to assessment of a subject who does not suffer from heart failure.
‘858 also discloses that “said subject does not suffer from left ventricular hypertrophy” (claim 8), but does not disclose utilizing a reference amount derived from a subject or group known to be at risk of progressing to LVH; or identifying the subject who is at risk of progressing to LVH.
Hunt discusses “diagnosis and management of chronic HF” (pg. e5, r. column), and teaches that “Left ventricular dysfunction… is generally a progressive process, even in the absence of a new identifiable insult to the heart. The principal manifestation of such progression is a change in the geometry and structure of the LV, such that the chamber dilates and/or hypertrophies… [which] increases the hemodynamic stresses on the walls of the failing heart and depresses its mechanical performance... sustain[ing] and exacerbat[ing] the remodeling process. Cardiac remodeling generally precedes the development of symptoms [of HF] (occasionally by months or even years), continues after the appearance of symptoms, and contributes substantially to worsening of symptoms” (pg. e7, r. column). Hunt thus teaches that progression of LV remodeling (i.e., progression to and worsening of LVH) is biologically correlated with progression to and worsening of symptomatic heart failure.
Hunt further teaches that “physicians should monitor patients closely for… worsening signs and symptoms of HF… Such patients generally respond favorably to intensification of conventional therapy” (pg. e32, r. column), and “incidence of HF can be reduced by… retarding the evolution and progression of LV remodeling. Initial appropriate measures include those listed as class I recommendations for patients in Stage A” (pg. e19, l. column), i.e., patients who have not yet progressed to LVH. Said conventional therapy and appropriate measures, earlier described by Hunt, comprise administration of ACE inhibitors, ARB, aldosterone antagonists and/or beta blockers (pg. e16, Table 3). In other words, these medications function to retard LV remodeling (e.g., progression to and worsening of LVH), and thereby lower risk of heart failure.
The teachings of Hunt indicate that a subject at risk of progressing to LVH is necessarily at risk of worsening heart failure. The teachings of Hunt further indicate that the treatments disclosed by ‘858 function to treat heart failure by treating LV remodeling (i.e., when applied to a subject who has not yet progressed to LVH, retarding progression to LVH).
In this way, the teachings of Hunt provide evidence that the particular treatment methods of ‘858 have clinical utility for treatment of subjects at risk of progressing to LVH. However, the combined teachings of ‘858 and Hunt do not indicate a predictive role for ST2 regarding risk of progression to LVH.
Coglianese discusses “Soluble ST2 (sST2)… a cardiac biomarker whose concentration rises in response to myocardial strain… [and] its distribution and correlates in community-based populations” (pg. 1673, Background), and teaches “measur[ing] sST2… [and] identify[ing] covariates associated with sST2 in [a] general sample” (pg. 1673, Methods) wherein “Candidate covariates included… LV hypertrophy” (pg. 1675, l. column).
Coglianese teaches that “Loss of intact IL-33/ST2L signaling results in unchecked remodeling of ventricular myocardium characterized by excessive myocyte hypertrophy, fibrosis, and worsening of left ventricular (LV) function”, i.e., left ventricular hypertrophy, “along with a higher risk of death from ventricular failure… In contrast to ST2L, sST2 may act as a ‘decoy’ receptor for IL-33, and when present in large enough amounts, sST2 likely interferes significantly with the actions of IL-33” (pg. 1673, r. column). In this way, Coglianese teaches a biological link between sST2 and progression of left ventricular hypertrophy.
In this way, Coglianese provides evidence for a causative (and thus, predictive) role of sST2 with respect to development of LVH. Hunt and Coglianese provide evidence that the method of ‘858 has clinical utility for identification and treatment of subjects at risk of progressing to LVH, and therefore the combination of ‘858, Hunt and Coglianese is viewed as teaching and/or suggesting the limitations of comparing the amount of sST2 to a suitable reference amount derived from a subject or a group thereof known to be at risk of progressing to LVH; and identifying the subject who is at risk of progressing to LVH.
With respect to instant claim 3, ‘858 discloses “measuring the level… from a blood, serum or plasma sample” (claim 1).
With respect to instant claim 4, ‘858 discloses that “said subject does not show symptoms of heart failure” (claim 2) and “said subject does not suffer from left ventricular hypertrophy” (claim 8).
Coglianese describes selection and assessment of “A healthy reference sample”, wherein “participants with the following characteristics were excluded… heart failure… [and] LV dysfunction” (pg. 1674, l. column). Coglianese concludes therefrom that “[M]uch like other biomarkers of risk in the general population… there are ‘apparently well’ subjects with values of sST2 associated with considerable risk… sST2 (alone or in combination with other cardiovascular biomarkers) predicts incident cardiovascular disease… Our results imply that… concentrations of the biomarker”, i.e., sST2, “are detectable in most (and likely all) apparently healthy individuals” (pg. 1679, r. column – pg. 1680, l. column).
Coglianese thus teaches assessment of apparently healthy subjects, and furthermore suggests consideration of subjects who do not show symptoms of heart failure or suffer from LVH (i.e., those assessed according to the method of ‘858) as ‘apparently healthy’.
Like ‘858, Coglianese describes exclusion of participants with heart failure or LVH. This suggests that Coglianese considers subjects satisfying these criteria to be ‘apparently healthy’.
With respect to instant claim 6, Coglianese discloses participant age groups including 35-44 years (pg. 1677, Table 2), i.e., subjects between 30 and 50 years of age.
With respect to instant claim 7, ‘858 discloses “measuring the level of at least one biomarker selected from… a B-type natriuretic peptide (BNP) or N-terminal pro B-type peptide (NT-proBNP)… [or] a cardiac Troponin… [and] comparing the level of said at least one biomarker to a reference level” (claim 1).
With respect to instant claims 8-9 and 25, Coglianese discloses measurements of “estimated glomerular filtration rate (GFR)” (pg. 1674, l. column) and “systolic blood pressure” (pg. 1675, l. column; see pg. 1676, Table 1).
With respect to instant claim 20, Coglianese discloses “excluding individuals with… hypertension” (pg. 1673, Methods).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have utilized biomarker comparison method of ‘858 to treat a subject who is at risk of progressing to LVH, because the teachings of Hunt provide evidence that risk of worsening heart failure (i.e., that which is predicted by the method of ‘858) is biologically correlated with risk of LVH (pg. e7, r. column), and treatments administered to lower risk of worsening heart failure (e.g., those administered by the method of ‘858) can be administered to lower risk of LVH (pg. e16, Table 3; pg. e19, l. column). Said practitioner would have had a reasonable expectation of success because ‘858 and Hunt both discuss analysis of heart condition risk, LVH, and cardiac therapy.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have utilized the biomarker comparison method of ‘858 to identify a subject who is at risk of progressing to LVH, because the teachings of Coglianese provide evidence that sST2 (i.e., that which is measured by the method of ‘858) is biologically correlated with progression to LVH (pg. 1673, r. column).
Additionally, said practitioner would have derived samples from subjects who are apparently healthy (e.g., do not suffer from heart failure) and of ages between 30 and 50 years, and implemented measurement of estimated glomerular filtration rate (eGFR) and systolic blood pressure, to enhance the biomarker comparison method of ‘858, because Coglianese teaches that sST2, eGFR and systolic blood pressure can all be measured in such subjects and used in combination to predict cardiovascular outcomes (pg. 1674, l. column, pg. 1675, l. column; pg. 1677, Table 2; pg. 1679, r. column; pg. 1680, l. column).
Said practitioner would have had a reasonable expectation of success because ‘858 and Coglianese both discuss measurement of ST2 levels in subject blood samples and comparative analysis of heart condition risk.
In this way the disclosure of ‘858, in view of Hunt and Coglianese, makes obvious the limitations of instant claims 1, 3-4, 6-9, 20 and 25. Thus, the invention is prima facie obvious.
Additionally, instant claims 1, 3-4, 6-9, 20 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-6 and 8 of US Patent No. 10,684,291 (hereafter, “‘291”) in view of Coglianese and Hunt. ‘291 shares joint inventors (Dirk Block, Ursula-Henrike Wienhaus-Thelen, and Christian Zaugg) and a common assignee (Roche Diagnostics Operations, Inc.) with the instant application. This rejection is maintained from the previous Office action, and has been revised to address the amended claims (filed 8/29/2025).
Instant claim 1 recites a method for identifying a subject who is at risk of progressing to left ventricular hypertrophy, comprising:
a) measuring an amount of soluble sST2 (sST2) in a sample from the subject, wherein the subject does not suffer from heart failure;
b) comparing the amount to a reference amount derived from a subject or group known to be at risk of progressing to LVH;
c) identifying the subject who is at risk of progressing to LVH based on the result of the comparison, when the amount of sST2 in the subject is equal to or increased as compared to the reference amount; and
d) administering one or more angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), aldosterone antagonists, and beta blockers.
With respect to instant claim 1, ‘291 discloses “[a] method for identifying a patient who is eligible for an intensification of heart failure therapy”(claim 5), comprising:
a) “measuring the level of at least one marker… in a sample from the patient” (claim 5) wherein “the patient is human” (claim 8);
b) “comparing the level (or levels) of the at least one marker… to a reference level (or reference levels)” (claim 5);
c) “identifying a patient who is eligible for intensification of heart failure therapy based on the results” (claim 5), wherein “a level of the at least one marker in the sample from the patient which is above the reference level for said marker… is indicative for a patient who is eligible for intensification of heart failure therapy” (claim 6); and
d) “intensifying heart therapy for the patient… compris[ing] administration of at least one medicament selected from the group consisting of… angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers and aldosterone antagonists” (claim 5).
‘291 does not disclose measuring an amount of soluble ST2 in a sample from a subject who does not suffer from heart failure; utilizing a reference amount derived from a subject or group known to be at risk of progressing to LVH; or identifying the subject who is at risk of progressing to LVH.
Hunt discusses “diagnosis and management of chronic HF” (pg. e5, r. column), and teaches that “Left ventricular dysfunction… is generally a progressive process, even in the absence of a new identifiable insult to the heart. The principal manifestation of such progression is a change in the geometry and structure of the LV, such that the chamber dilates and/or hypertrophies… [which] increases the hemodynamic stresses on the walls of the failing heart and depresses its mechanical performance... sustain[ing] and exacerbat[ing] the remodeling process. Cardiac remodeling generally precedes the development of symptoms [of HF] (occasionally by months or even years), continues after the appearance of symptoms, and contributes substantially to worsening of symptoms” (pg. e7, r. column). Hunt thus teaches that progression of LV remodeling (i.e., progression to and worsening of LVH) is biologically correlated with progression to and worsening of symptomatic heart failure.
Hunt further teaches that “physicians should monitor patients closely for… worsening signs and symptoms of HF… Such patients generally respond favorably to intensification of conventional therapy” (pg. e32, r. column), and “incidence of HF can be reduced by… retarding the evolution and progression of LV remodeling. Initial appropriate measures include those listed as class I recommendations for patients in Stage A” (pg. e19, l. column), i.e., patients who have not yet progressed to LVH. Said conventional therapy and appropriate measures, earlier described by Hunt, comprise administration of ACE inhibitors, ARB, aldosterone antagonists and/or beta blockers (pg. e16, Table 3). In other words, these medications function to retard LV remodeling (e.g., progression to and worsening of LVH), and thereby lower risk of worsened heart failure.
The teachings of Hunt indicate that a subject at risk of progressing to LVH is necessarily at risk of worsening heart failure. The teachings of Hunt further indicate that the treatments disclosed by ‘291 function to treat worsening heart failure by treating LV remodeling (i.e., when applied to a subject who has not yet progressed to LVH, retarding progression to LVH).
In this way, the teachings of Hunt provide evidence that the particular treatment methods of ‘291 have clinical utility for treatment of subjects at risk of progressing to LVH. However, the combined teachings of ‘291 and Hunt do not indicate a predictive role for ST2 regarding risk of progression to LVH.
Coglianese discusses “Soluble ST2 (sST2)… a cardiac biomarker whose concentration rises in response to myocardial strain… [and] its distribution and correlates in community-based populations” (pg. 1673, Background), and teaches “measur[ing] sST2… [and] identify[ing] covariates associated with sST2 in [a] general sample” (pg. 1673, Methods) wherein “Candidate covariates included… LV hypertrophy” (pg. 1675, l. column). Coglianese describes selection and assessment of “A healthy reference sample… from which participants with the following characteristics were excluded… heart failure… [and] LV dysfunction” (pg. 1674, l. column), and presents findings that “sST2 values previously linked with a higher risk for cardiovascular outcomes in patients with established heart disease… generally represented values at or above the 95th-percentile concentration in our general population” (pg. 1679, r. column).
Coglianese concludes: “[M]uch like other biomarkers of risk in the general population… there are ‘apparently well’ subjects with values of sST2 associated with considerable risk… sST2 (alone or in combination with other cardiovascular biomarkers) predicts incident cardiovascular disease… Our results imply that… concentrations of the biomarker”, i.e., sST2, “are detectable in most (and likely all) apparently healthy individuals” (pg. 1679, r. column – pg. 1680, l. column).
In this way, Coglianese teaches comparing amounts of sST2 measured in a general population, including subjects who do not suffer from heart failure, to reference amounts derived from subjects known to be at risk of cardiovascular outcomes.
Coglianese teaches that “Loss of intact IL-33/ST2L signaling results in unchecked remodeling of ventricular myocardium characterized by excessive myocyte hypertrophy, fibrosis, and worsening of left ventricular (LV) function”, i.e., left ventricular hypertrophy, “along with a higher risk of death from ventricular failure… In contrast to ST2L, sST2 may act as a ‘decoy’ receptor for IL-33, and when present in large enough amounts, sST2 likely interferes significantly with the actions of IL-33” (pg. 1673, r. column). In this way, Coglianese teaches a biological link between sST2 and progression of left ventricular hypertrophy.
In this way, Coglianese provides evidence for a causative (and thus, predictive) role of sST2 with respect to development of LVH. Hunt and Coglianese provide evidence that the method of ‘291 has clinical utility for identification and treatment of subjects at risk of progressing to LVH, and therefore the combination of ‘291, Hunt and Coglianese is viewed as teaching and/or suggesting the limitations of comparing the amount of sST2 to a suitable reference amount derived from a subject or a group thereof known to be at risk of progressing to LVH; and identifying the subject who is at risk of progressing to LVH.
With respect to instant claim 3, ‘291 discloses that “the sample is a blood, serum or plasma sample” (claim 8).
With respect to instant claim 4, Coglianese describes selection and assessment of “A healthy reference sample” (pg. 1674, l. column), and concludes therefrom that “[M]uch like other biomarkers of risk in the general population… there are ‘apparently well’ subjects with values of sST2 associated with considerable risk… sST2 (alone or in combination with other cardiovascular biomarkers) predicts incident cardiovascular disease… Our results imply that… concentrations of the biomarker”, i.e., sST2, “are detectable in most (and likely all) apparently healthy individuals” (pg. 1679, r. column – pg. 1680, l. column). In this way, Coglianese teaches assessment of apparently healthy subjects.
With respect to instant claim 6, Coglianese discloses participant age groups including 35-44 years (pg. 1677, Table 2).
With respect to instant claim 7, ‘291 discloses “measuring the level of a BNP or NT-proBNP in a sample from a patient… [and] comparing the level of the BNP OR NT-proBNP… to a reference level (or reference levels)” (claim 5).
With respect to instant claims 8-9 and 25, Coglianese discloses measurements of “estimated glomerular filtration rate (GFR)” (pg. 1674, l. column) and “systolic blood pressure” (pg. 1675, l. column; see pg. 1676, Table 1).
With respect to instant claim 20, Coglianese discloses “excluding individuals with… hypertension” (pg. 1673, Methods).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have utilized the biomarker comparison method of ‘291 to treat a subject who is at risk of progressing to LVH, because the teachings of Hunt provide evidence that risk of worsening heart failure (i.e., that which is predicted by the method of ‘291) is biologically correlated with risk of LVH (pg. e7, r. column), and treatments administered to lower risk of worsening heart failure (e.g., those administered by the method of ‘291) can be administered to lower risk of LVH (pg. e16, Table 3; pg. e19, l. column). Said practitioner would have had a reasonable expectation of success because ‘291 and Hunt both discuss analysis of cardiac risk, LVH, and treatment.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have utilized the biomarker comparison method of ‘291 to identify a subject who is at risk of progressing to LVH, because the teachings of Coglianese provide evidence that sST2 (i.e., that which is measured by the method of ‘291) is biologically correlated with progression to LVH (pg. 1673, r. column).
Additionally, said practitioner would have derived samples from subjects who are apparently healthy (e.g., do not suffer from heart failure) and of ages between 30 and 50 years, and implemented measurement of estimated glomerular filtration rate (eGFR) and systolic blood pressure, to enhance the biomarker comparison method of ‘291, because Coglianese teaches that sST2, eGFR and systolic blood pressure can all be measured in such subjects and used in combination to predict cardiovascular outcomes (pg. 1674, l. column, pg. 1675, l. column; pg. 1677, Table 2; pg. 1679, r. column; pg. 1680, l. column).
Said practitioner would have had a reasonable expectation of success because ‘291 and Coglianese both discuss measurement of ST2 levels in subject blood samples and comparative analysis of heart condition risk.
In this way the disclosure of ‘291, in view of Coglianese and Hunt, makes obvious the limitations of instant claims 1, 3-4, 6-9, 20 and 25. Thus, the invention is prima facie obvious.
Response to Arguments - Double Patenting
In the reply filed 8/29/2025, Applicant requests that the Office hold the rejections on the grounds of nonstatutory double patenting in abeyance until resolution of the inventiveness rejection (pg. 17, paras. 2-3).
“A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer… with a reply to the Office action… Such a response is required… [and] should not be held in abeyance. Only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated” (MPEP 804 § I.B.1).
Applicant has neither filed an appropriate terminal disclaimer nor filed showings that the claims subject to rejection are patentably distinct from the indicated claims of the reference patents (US 10,557,858 and US 10,684,291) in view of Coglianese and Hunt. Accordingly, the double patenting rejections are maintained with respect to the pending claims.
Allowable Subject Matter
Claims 15, 21, 26 and 29-32 are allowable.
Conclusion
At this point in prosecution, claims 15, 21, 26 and 29-32 are allowable.
At this point in prosecution, claims 1, 3-9, 18, 20, 25, and 27-28 are rejected.
The following prior art, made of record and not relied upon, is considered pertinent to applicant's disclosure:
Manzano-Fernández et al (Am J Cardio 107(2): 259-267; published 1/15/2011) examines associations between risk of mortality, sST2 concentration and left ventricular ejection fraction (a conventional estimate of LVH).
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/T.C.S./Examiner, Art Unit 1685
/JESSE P FRUMKIN/ Primary Examiner, Art Unit 1685 March 26, 2026
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