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, filed 01/29/2021 is a continuation of 14/549,632, filed 11/21/2014 (US Patent 10,942,175), which is a continuation of 13/776,314, filed 02/25/2013 (abandoned), which is a continuation of PCT/EP2011/063398, filed 08/03/2011. Acknowledgement is also made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application Nos. 10174182.5, filed 08/26/2010 and 10186710.9, filed 10/06/2010.
Status of the Claims
Claims 1, 11-13, 16-22 and 24-39 are pending; claims 16-20 and 25 (drawn to non-elected species) are withdrawn; claims 1, 13, 22, 27, 29-33, 36, 38 and 39 are amended; claims 3-10, 14, 15 and 23 are canceled. Claims 1, 11-13, 21, 22, 24 and 26-39 are examined below.
Withdrawn Objections/Rejections
The previous rejection of claims under 35 U.S.C. 112(a), regarding written description, is withdrawn in response to Applicant’s amendments to the claims.
The previous rejections of claims under 35 U.S.C. 112(b), other than those of 11, 24 and 34 maintained below, are withdrawn in response to Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(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 11, 24 and 34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 11, 24 and 34 each recite that the subject is known to suffer from hypertension (hypertension, Applicant’s elected species). However, the independent claims from which these claims depend from, each recite that the subject is “apparently healthy with respect to heart failure”. See the originally filed specification which supports that those with known hypertension are not considered “apparently healthy with respect to heart failure”, particularly at paras [0020]-[0022], para [0021] recites “Untreated hypertension is associated with an increased risk to develop heart failure”. As a result, claims 11, 24, and 34 contradict the limitations recited at the independent claims, and therefore the claims are indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 11-13, 21, 27, 28-31, 36, 37, 38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and to laws of nature/natural phenomena 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
Independent claim 1 recite(s) a method of “detecting an increased amount or concentration of a cardiac troponin T or fragments thereof in a subject” (preamble) and “detecting an increased amount or concentration of the cardiac troponin T or fragments thereof in the sample”. Regarding claim 1, the claim encompasses measuring the amount or concentration of the biomarker and determining the amount is increased, detecting an “increase” amounts to performing a comparison, namely comparison to some standard or reference.
See further claim 13 recites “wherein the cardiac troponin T reference value is an amount at least 20% greater than a concentration of the cardiac troponin T or fragments thereof of a population of healthy individuals”, claim 13 supporting the position stated above, that an “increase” encompasses comparing reference/target data.
Claim 21 recites “detecting an increased concentration of insulin-like growth factor-binding protein (IGFBP-7) in the subject”.
Similarly claims 27 (depending from claim 22), and claim 36 (depending from claim 33), also recite “wherein the cardiac troponin T reference value is an amount at least 20% greater than a concentration of the cardiac troponin T or fragments thereof of a population of healthy individuals”.
Claim 28 (depends from claim 22) recites “detecting an increased concentration of insulin-like growth factor-binding protein (IGFBP-7) in the subject”.
Claims 29 (depends from claim 1) and claim 30 (depends from claim 22) each recites “wherein the concentration of the cardiac troponin T or fragments thereof is at least 20% greater than the cardiac troponin T reference value”.
Further, the above indicated “comparing” steps (implied/suggested by the “increase” and “reference value” language noted above), is categorized as abstract ideas, namely mental processes/concepts performed in the human mind (such as a practitioner simply thinking about the calculated/measured concentration in relation to the reference value and making an evaluation, judgement or opinion). The claims, under their broadest reasonable interpretation, cover performance of the diagnosing solely within the human mind, or by a human using a pen and paper. Comparing information regarding a sample to a control/reference or target data (i.e., the reference value) 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. See also MPEP 2106.04(a).
Step 2A, Prong 2
The above discussed steps limitations (indicated to be directed to judicial exceptions) are insufficient to integrate into a practical application because steps corresponding to mental activity, which could be performed in a practitioner’s head, are insufficient to constitute a practical application. In the present case, calculating, comparing, diagnosing/determining a need based on a diagnostic result, represent judicial exceptions and not a practical applications thereof.
In addition to the above indicated judicial exceptions, the claims also recite steps of “providing a sample from the subject…, wherein the sample is blood, serum or plasma” and “detecting an increased amount or concentration…by contacting the sample with an antibody having specific binding affinity of an epitope of the cardiac troponin T or fragments thereof and detecting binding between the cardiac troponin T or fragments thereof and the antibody” (see claims 1, 22 and 33). However, the steps of providing a sample and detecting binding to detect the biomarker are steps necessarily performed to obtain data, these steps are considered presolution activity, a data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015) (see also MPEP 2106.05). Furthermore, as amended, the step of measuring is generic and not limited, for example to any particular assay/immunoassay, rather it is recited at a high level of generality and are not tied, for example, to any particular machine or transformation (merely requires antibody binding).
The claims fail to recite any additional steps/elements (either at the independent claim or dependent claims) that further apply, rely on or use the judicial exception in such a way to amount to a practical application of the judicial exception.
Claims 11, 12, further limit the subject from which the sample is obtained. However, none of the dependent claims which further depend from the above indicated claims containing judicial exceptions, further apply, rely on or use the judicial exception in a meaningful way to amount to a practical application of judicial exception(s).
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the limitations “wherein the sample is selected from the group consisting of blood, serum and plasma”, do not add significantly more to the judicial exception(s).
The additional limitation/elements (noted above, namely providing sample, detecting by contacting with an antibody having binding affinity) fail to go beyond activity in the assay art which was considered well known routine and conventional.
For example, immunoassay methods (antibody binding methods) which involve providing a sample and performing antibody binding were well-known, routine and conventional in the assay art at the time for the specifically claimed marker (cardiac troponin T and insulin-like growth factor binding protein 7). As an example, regarding immunoassays/methods comprising contacting sample with an antibody specific for cardiac troponin T, Jin et al., US PG Pub No. 2008/0032929A1, para [0154], teaching generation of antibodies specifically recognizing cardiac troponin T, using said antibodies for screening for cTnT; and further Dave et al., US PG Pub No. 2002/0193287A1, para [0011] teaching immunoassays have been described which are specific for TnT (referring to prior art, prior to Dave et al.), Dave et al. also further recognizing the commercial availability of such assays.
See further Wienhues-Thelen et al., WO2008/089994 which teaches measuring a combination of markers including IGFBP-7 and cardiac troponin T (for example see at page 27, lines 9-14; see also e.g., page 15, page 30 detection by antibody binding).
There are no other additional active method steps performed/recited (in addition to the limitations considered to be directed to the judicial exceptions themselves) as part of the claimed methods which amount to significantly more than the judicial exception. None of the claim elements or steps, recited in addition to the judicial exception(s), when considered alone or in combination, are sufficient to add significantly more than the judicial exception. There are no additional claim elements recited in addition to the judicial exceptions that go beyond that which was considered well-known, routine and conventional in the assay art.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim(s) 1, 11, 12, 21, 22, 24, 26, 28, 31-34, 35, 37 and 39 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Wienhues-Thelen et al., WO2008/089994A1 (IDS entered 03/02/2021), as evidenced by Roche Diagnostics, Troponin T product description, (2007), 6 pages (Retrieved from www .jiscmail.ac.uk/cgi-bin/webadmin on 05/14/2014, IDS entered 03/02/2021).
Regarding claim 1 and 21, Wienhues-Thelen et al. teach methods for predicting risk of heart failure (see for example page 6, lines 16-21 and 29-30; page 7, Summary of the invention, methods predicting future risk). Wienhues-Thelen et al. teach a method to assess whether an individual is at risk of developing heart failure (i.e., subject’s preceding heart failure), namely by relying on the marker IGFBP-7 in combination with a cardiac troponin (see end of page 9 to page 10, cardiac troponin taught as another marker of heart failure, page 4, lines 10-16, page 11, lines 8-9, page 20, lines 8-9, indicating increased detection). In particular, Wienhues-Thelen teach TnT is considered (in the prior art) as a marker of acute myocardial damage (i.e., a marker of structural/functional injury to the heart muscle, see page 30, lines 12-18 and 27-34). Regarding detection, see Wienhues-Thelen teach reagents for detection of the indicated markers (page 34, lines 7-11).
Specifically, the methods of Wienhues-Thelen et al. involve providing a sample and measuring/detecting in the sample obtained from a subject, the concentration of one or more markers (see page 7, lines 23-29); comparing said concentrations to the concentrations for each established in controls sample (i.e. reference) (see also page 1, lines 2-11; page 7, lines 23-29; page 10, lines 14 to page 11, line 7; page 11, lines 10-13; and page 30, lines 19-26) preferably wherein the additional marker consists of cardiac troponin marker (see page 9, lines 27-34 and page 30, lines 7-11, and lines 19 to page 31, line 5).
See for example, at example 6.2 Wienhues-Thelen teach detection of cardiac troponin T using commercially available assay from Roche Diagnostics (i.e., Roche Diagnostics, troponin T assay, for Elecsys® Systems); as evidenced by the Troponin T assay description (5 pages), said assay is a sandwich type assay (see page 1, col. 2, Test Principle of the Roche Diagnostic evidence), comprising two antibodies for detection of cardiac troponin T, one of said monoclonal antibodies being labeled (contacting with an antibody having specific binding affinity).
Wienhues-Thelen et al. teach at page 10, lines 3- 13, that samples include any body fluid; preferably blood, serum, plasma.
In applying the method to assess whether an individual is at risk of developing heart failure (i.e., subject’s preceding heart failure), the reference as cited is providing a sample from a subject who has a functional and/or structural abnormality preceding heart failure, i.e., subjects that are asymptomatic, i.e., apparently healthy with respect to heart failure, as the method encompasses diagnosing subjects that are free of clinical symptoms (see for example, page 6, lines 15-21, see also page 20, lines 1-4 and lines 10-22). As such, the reference anticipates the claim because those subjects indicating to have the structural and/or functional abnormality, based on the biomarkers, read on the present claims.
Claims 22 and 33 are substantially similar to independent claim 1, however the preamble of claim 22 merely recites “a method of detecting a cardiac troponin T or fragments thereof”, and claim 33 recites “measuring a cardiac troponin T or fragments thereof”, the method reciting the word “measuring” rather than “detecting”.. Wienhues-Thelen et al. teach (page 6) from a clinical perspective, the disease is clinically asymptomatic in the compensatory and early decompensatory phases (completely asymptomatic in stage A with structural heart disease but no signs and symptoms of HF in stage B); that outward signs do not appear until well in the decompensatory phase. The methods of Wienhues-Thelen encompass subjects such as those that are asymptomatic, page 18, last line, page 20, line 18-19 (considered to address “apparently healthy”). For all of the reasons cited in detail above (regarding independent claim 1), the cited art is considered to anticipate the claim.
Regarding claims 11, 24 and 34, Wienhues-Thelen et al. teach at page 19, lines 28-33 preferably screening for heart failure in individuals at risk of future heart failure (i.e. preceding heart failure), such as those diagnosed with hypertension (see page 19, lines 28-33). See the rejection set forth in detail under 35 U.S.C. 112(b), regarding the contradiction between the language “apparently healthy with respect to heart failure” and those diagnosed with hypertension. The present rejection is made in the interest of compact prosecution because although though those subject with hypertension contradict the meaning of ‘apparently healthy with respect to heart failure”, the cited art does teach those who are “asymptomatic” which also reads on “apparently healthy” when given broadest reasonable interpretation.
Regarding claims 12, 26 and 35, the reference teaches methods measuring/detection in samples from subjects with a structural abnormality that is increased posterior wall thickness (for example, examples page 36, lines 5-12, significant dilation, continues to deteriorate).
Regarding claim 21, 28 and 37; dependent claim 21 specifically modifies claim 1 so that one is measuring the concentration of two biomarkers, specifically so that the method of 1 further comprises measurement of IGFBP7 as well as cardiac troponin via antibody binding methods, by contacting a sample with an antibodies specific for each of said biomarkers. As discussed in detail above, Wienhues-Thelen et al. specifically teach detection of both of said biomarkers (IGFBP7 and cardiac troponin I) for assessment of heart failure (see also page 7, lines 23-29 , measuring more than one marker to diagnose, page 11, lines 8-13, wherein marker level is above a cutoff). See further this applies to claims 28 and 37 as well (same reasons as cited above apply to these claims).
Regarding claims 31, 32 and 39, Wienhues-Thelen encompasses full length cardiac troponin T (see for example page 30, lines 7-18).
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 29, 30 and 38 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Wienhues-Thelen et al.
Regarding claims 29, 30 and 38, Wienhues-Thelen et al. teach (page 11) a level elevated above the 90-percentile of the reference range as indicative of increased (90 percentile representing a significant increase as compared to the reference/control, see further page 11 teaching up to 97.5% percentile of the reference range.
However, Wienhues-Thelen et al. fails to teach “at least 20% greater” than the reference value.
Regarding positive indicators, see further page 20, Wienhues-Thelen et al. teach “setting” a level to indicate positive results, a value outside the reference range and its higher end is considered elevated.
Although the reference fails to teach specifically at least 20% greater as indicative of “elevated”, it is understood from the reference that the user sets a reference value to indicate a positive result, i.e., selects/chooses an amount considered to representative of a positive result. The difference (the selected amount about the threshold) is considered a result-effective variable, namely a variable that achieves a recognized result, namely distinguishes what is considered elevated/or increased compared to a control/reference data. As a result, it would have been prima facie to one having ordinary skill prior the effective filing date of the claimed invention, to have arrived at a value of 20% compared to the reference value as an amount to indicate an increased/elevated level as an obvious matter of routine optimization of experimental parameters of Wienhues-Thelen, in order to achieve the optimum results for indicating those with increased levels correlating with the abnormality. One having ordinary skill would have a reasonable expectation of success because the reference already suggests using values well above the control data to indicate an increase, and because the prior art recognizes “setting” such a value.
Claims 13, 27 and 36 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Wienhues-Thelen et al. in view of Jackowski et al. US Patent No. 5,604,105 (1997) (IDS entered 03/02/2021) and as evidenced by Roche Diagnostic.
Wienhues-Thelen et al. is as discussed in detail above (see rejection of claim1 under 35 U.S.C. 102(b)), teaching a method substantially as claimed.
Wienhues-Thelen et al. also teach at page 10, lines 14 to page 7, line 11, with regard to comparing a measured concentration to a control, that a control can be from healthy individuals (i.e. free of the condition). At page 11, line 10-14 Wienhues-Thelen et al. teach wherein measured values of a marker in a control are used to establish a cutoff value or a reference range; that a value above such cut-off or outside the reference range and its higher end is considered as elevated. At page 11, lines 14-15, teach that such cutoff is chosen to match the diagnostic question of interest. Thereby Wienhues-Thelen et al. is indicating that the selection of a cutoff is merely routine experimentation within the skill of the ordinary artisan.
However, Wienhues-Thelen et al. fail to specifically teach wherein the cardiac troponin reference value is an amount at least 20% greater than a concentration of the cardiac troponin marker of a population of healthy individuals.
Jackowski et al. teach a method which involves detecting cardiac markers (see abstract); one of said markers may be Troponin T (see e.g. col. 11, lines 3-5). Jackowski et al. teach (see e.g. claim 1, step B, correlating marker with a diagnostic result. Jackowski et al. teach (see e.g. col. 9, lines 52-56, in particular embodiments of the invention, the markers are detected whereby a presence above normal enables differentiation. Jackowski et al.t each that "above normal" or "above threshold" are used to refer to a level of marker that is greater than the level of a marker observed in normal individuals; the terms contemplating a level that is significantly above the level found in patients (at least a 2-fold greater level of the marker being present) (see e.g. col. 14, lines 9-21. Furthermore, Jackowski et al. teach normal patients will have a basal level of some cardiac markers in their blood at all times; that according to the invention, a diagnostic test must determine when levels are above a basal level, further teaching comparison of levels against a normal population (i.e. the reference are a healthy, normal population of controls) (see col. 36, lines 1-9.
It would have been prima facie obvious to the ordinarily skilled artisan at the time of the invention to have established a cutoff/threshold concentration above that measured in a normal, control population (i.e. healthy population), as taught by Jackowski et al., when performing the method of Wienhues-Thelen et al., because Jackowski et al. taught that normal patients typically have a basal level of a given marker in their sample, that it is necessary to measure that basal level and establish a concentration "above normal" (i.e. above a normal population) in order to perform a differential diagnosis. It would be well within the skill of the ordinary artisan to establish a threshold that is 20% above a normal healthy population as a matter of routine experimentation in the course of defining an optimum cutoff value that would achieve an affirmative diagnostic result. Jackowski et al. teach a threshold level considered to be statistically significant is a level that is at least 2 fold greater than the basal level of the normal population; the ordinarily skilled artisan would appreciate that this number would not be arbitrarily chosen, but chosen through experimentation, in order to establish what threshold would define between diagnostically relevant positive results from negative results. The ordinarily skilled artisan would have a reasonable expectation of success optimizing a reference value through routine experimentation because Wienhues-Thelen et al. specifically teach the skilled artisan would choose a cutoff so as to match the diagnostic question of interest.
Response to Arguments
Applicant's arguments filed 06/03/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding remarks at pages 8-11, see as indicated above, the previous rejection of claims under 35 U.S.C. 112(a), regarding written description, is withdrawn in response to Applicant’s amendments to the claims.
Regarding remarks at pages 11-16, the previous rejections of claims under 35 U.S.C. 112(b), other than those of 11, 24 and 34 maintained above, are withdrawn in response to Applicant’s amendments to the claims.
Regarding remarks at page 14, Applicant argues the limitations as claimed 11, 24 and 34 do not contradict the limitation “apparently healthy”, arguing that not showing signs of heart failure is considered to be “apparently healthy”, that subjects can still bear risk of heart failure, such as hypertension or diabetes, and be “apparently healthy”. Applicant refers to specific paragraphs in the originally filed specification where it expressly states that subjects “bear risk factors for heart failure”, including hypertension and diabetes, and who “does not show overt signs and/or symptoms of heart failure” (para [0029]). Further where language “does not show signs of heart failure” is interpreted as meaning “apparently healthy”, that those subjects be classified into ACC/AHA Stage A (para [0103]). Additionally, Applicant notes paragraph [00105] where “the individual bearing risk factors of developing heart failure is an individual which has been classified into ACC/AHA stage A prior to carrying out the methods according to the present disclosure. The individual classified in stage A may have experienced physiological changes towards pathophysiological states belonging to ACC/AHA stage B (i.e. functional and/or structural abnormalities of the heart preceding heart failure). In the context of the present disclosure, this state is referred to as "early stage of functional and/or structural abnormalities of the heart preceding heart failure" (early stage B) and is different from a "late stages of functional and/or structural abnormalities of the heart preceding heart failure" (late stage B). According to some embodiments, the individual does not show obvious symptoms of heart failure. According to some embodiments the individual does not show left ventricular hypertrophy (i.e. the individual is apparently healthy).” Further, para [00176] “shall not exhibit symptoms and/or physical signs known to be associated with HF (i.e., the subject is apparently healthy”.
The cited paragraphs support “does not show overt signs and/or symptoms of heart failure” as meaning the subject is “apparently healthy”, and although places other than those indicating that “does not show overt signs and/or symptoms of heart failure”, indicate subjects may bear risk factors such as hypertension and/or diabetes, there is no clear definition or singular citation that indicates “apparently healthy” means those subjects both exhibit hypertension or diabetes and do not show over signs and/or symptoms of heart failure. The language “apparently healthy” is confusing when used as claimed because each of hypertension and diabetes are specific conditions that negatively impact an individual’s health with respect to heart failure, and generally a subject known to have one of these conditions is not considered to be “healthy”. It is suggested that if it is Applicant’s intention, that “apparently healthy with respect to heart failure” be those subjects who have no overt signs and/or symptoms of heart failure, then Applicant amend the claims accordingly to omit this relative terminology, because “apparently healthy” with regard to one’s heart failure status is not clear considering these are disease/conditions known to adversely impact heart health.
Regarding the rejection of claims under 35 U.S.C. 101 (remarks pages 16-22), Applicant argues claims 22 and 23 are not subject to rejection (remarks page 17), and argues that claim 1 should be eligible for the same reasoning that supports eligibility for claims 22 and 23. Applicant argues the language “detecting an increased amount or concentration” characterizes a physical result observed in the claimed population, not a mental comparison performed by the practitioner. Applicant argues that “increased” read as an implicit mental comparison would improperly import limitations that the claims do not recite.
However, this argument is not persuasive. The claim recites “detecting an increased amount or concentration of the cardiac troponin T or fragment there in the sample”, the language “an increased amount” generally means greater in size, amount or intensity, it specifically indicates something has gone up relative to some standard of measure/baseline, which specifically suggests a comparison is being performed (i.e., increased relative to some measure). The claims are literally directed to the action of the practitioner detecting an increase in the amount of the naturally occurring marker, and as such the claims are considered to recite a judicial exception, and as such are subject to the two prong analysis required when considering eligibility under 35 U.S.C. 101. It is suggested that Applicant amend the language to omit the language if it is not Applicant’s intention to recite a step that amounts to performing action encompassing a comparison.
Applicant further argues the claims integrate any judicial exception into a practical application under step 2A, Prong 2 (remarks page 19), as the claims recite a specific laboratory protocol involving (i) provisions of a defined biological sample from a subject having a defined physiological condition, (ii) physical contact of the sample with an antibody having specific binding affinity for an epitope of cardiac troponin T or fragments thereof, and (iii) physical detection of the binding between the antibody and the analyte. Applicant asserts that this ordered combination of physical steps is a concrete diagnostic methodology applied to a defined patient population for the purpose of identifying a specific physiological state.
However, this argument is not persuasive for the following reasons. Prong 2 requires identifying whether there are any additional elements in the claim beyond the judicial exception (i.e., not including the judicial exception(s) themselves, but recited in addition to the judicial exceptions). Further, “Integration into a practical application” requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. None of the ordered combination referenced above by Applicant further apply, rely on or use the judicial exception (the detected increase) in this way as indicated as required for “integration into a practical application”. The claimed steps of providing a sample and detecting binding to detect the marker are steps necessarily performed to obtain data, these steps are considered presolution activity, a data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015) (see also MPEP 2106.05); such steps do not apply, rely on or use the “detected increase” as claimed.
Applicant further argues (page 19) that antibody-based detection step as recited is not generic, as it requires a specific physical interaction with a defined molecular analyte (cardiac troponin T or fragments thereof retaining the recited epitopes) using a specific class of binding reagent (an antibody having specific affinity). Applicant argues the detection step is not a preliminary to any further analytical process, rather that it is the technical contribution to the method itself. However, this argument is not persuasive because the binding assay is the step necessarily performed in order to achieve “detection an increased amount”. See MPEP 2106.05(g), indicating examples of activities the courts have found to be insignificant extra-solution activity, including determining the level of a biomarker in blood.
Applicant also argues the claims are anchored to a specific patient population (those who have functional and/or structural abnormalities of the heart preceding heart failure). Applicant argues that the recited combination of physical detection steps applied to this specific patient population was not previously known or recognized in the art. Applicant asserts NT-proBNP is a well established marker for heart failure which failed to identify subjects with first structural changes to the left ventricle and/or diastolic dysfunction, that the claimed method surprisingly found that troponin levels can identify subjects at early stage B even before hypertrophy becomes apparent (referring to specification paras [0024] and [00363]). However, the patient population, while specific, imparts not distinguishing element/step on how the assay itself is performed. Limitations pertaining to the subject population fail to constitute a technical advancement or improvement in the method or the art. Such limitations do not constitute a technical advancement or improvement, and further it is not the case that the active method steps would be performed any differently (referring to the action of contacting with antibody having specific binding affinity for an epitope) depending on the limitations pertaining to the subject population.
Arguing that the biomarker surprisingly identifying subjects at early stage B even before hypertrophy is an argument directed to a natural correlation, and further directed to limitations not present in the claims (referring to claim 1, the claim recites no steps/elements that amount to identifying (i.e., diagnosing) such subjects based on the detected increase. The argued “technical contribution” is not recited at the claims.
For these reasons, Applicant’s arguments are not persuasive.
Applicant also argues (remarks pages 20-21) the Office has applied improper evidentiary support for the consideration under step 2B, under Berkheimer. Applicant argues that under Berkheimer, the WURC inquiry is directed to whether the specific claimed combination is well understood, routine and conventional. In response to these arguments, the rejection is maintained, as this consideration takes into account the claimed steps/elements recited in addition to the judicial exception(s) themselves. It is maintained that the cited evidence supports the claimed active steps, i.e., those steps recited in addition to the judicial exception itself, are routine and conventional in the assay art. Abstract idea limitations and/or limitations directed to the natural correlation of the claimed marker with a particular conditions/diagnostic outcome is not sufficient establish more than what was well-known, routine or conventional in the prior art at the time. Limitations regarding the subject population upon whom the method is performed does not clearly go beyond insignificant presolution activity, e.g., a mere data gathering step necessary to use the correlation. See Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015):
Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art.
Applicant further argues claims 11, 12, 21 and 28 each add limitations that add further concrete physical or quantitative steps that integrate any judicial exception into a practical application such to constitute significantly more than any judicial exception (remarks page 22). However, none of these additionally recited limitations either amount to integration of the judicial exception claimed into a practical application thereof, or amount to significantly more than that which was routine and conventional in the assay prior art.
Regarding the rejection of claims under 35 U.S.C. 102, Applicant argues (pages 23-28), Applicant initially argues that the present claims require detection of cardiac troponin T or fragments thereof in a specific patient population, Applicant argues Wienhues-Thelen fails to recite in a single embodiment, antibody-based detection of cardiac troponin T or fragments in a sample who is asymptomatic with respect to heart failure and has a functional and/or structural abnormality. Applicant argues (remarks page 24) that the reference does not teach independent detection or measurement of cardiac troponin T as the primary analyte for any diagnostic purpose. However, in response, this is not persuasive as the claims fail to require a method consisting of only a measure of cardiac troponin T or fragments there of (claim 1 recites the language “comprising”, the method does not consist of measurement of cardiac troponin T only, nor are there any limitations/elements that amount to cardiac troponin T as a sole or independent biomarker).
Regarding remarks at page 25, while cardiac troponin T has been recognized in the prior art as a marker related to myocardial infarction, it is still the case that Wienhues-Thelen teach a method to assess whether an individual is at risk of developing heart failure (i.e., subject’s preceding heart failure), namely by relying on the marker IGFBP-7 in combination with a cardiac troponin (see end of page 9 to page 10, cardiac troponin taught as another marker of heart failure, page 4, lines 10-16, page 11, lines 8-9, page 20, lines 8-9, indicating increased detection). In particular, Wienhues-Thelen teach TnT is considered (in the prior art) as a marker of acute myocardial damage (i.e., a marker of structural/functional injury to the heart muscle, see page 30, lines 12-18 and 27-34). Regarding detection, see Wienhues-Thelen teach reagents for detection of the indicated markers (page 34, lines 7-11). While the focus of reference that is cited as prior art is not the same as the claimed invention, the prior art still addresses the claim as currently presented (referring to the broad language recited by the instant claim and the citations specific to the prior art above).
Further, regarding remarks, Wienhues-Thelen does teach cardiac troponin as a marker (not merely as Example 6.2 (page 47), see end of page 9-10, page 4, lines 10-16, page 11, lines 8-9, page 20, lines 8-9, page 30 and 34), however, argued example 6.2 is merely cited in supporting that the reference is teaching detection of this marker using commercially available immunoassay (see previous action at page 16). As such, arguments at page 25, that example 6.2 is a different patient population are not persuasive, as 6.2 is not the only patient population to which this reference limits their assay.
The arguments (remarks pages 25-26) are similarly that Wienhues-Thelen is teaching screening related to the use of IGFBP7, however, this argument is not persuasive for the reasons as indicated in detail above, specifically that Wienhues-Thelen teaches IGFBP7 in combination with cardiac troponin, and the claims of the instant application do not exclude IGFBP7.
At remarks pages 26-27 Applicant argues impermissible combination of disparate teachings of Wienhues-Thelen, arguing there is not embodiment that combines cardiac troponin and IGFPB-7 using antibody based binding, however, referring to response to arguments and citations from this reference above, this argument is not persuasive.
Applicant further argues (remarks pages 27) that the cited prior art does not teach detecting “an increased amount or concentration”, that the cited art fails to teach cardiac troponin T levels are elevated in apparently healthy subjects with subclinical functional or structural abnormalities preceding heart failure. This argument is not persuasive, as indicated previously above, the reference is indicating IGFBP-7 as just one marker of a HF marker combination for HF screening purposes (see page 20, lines 5-8), the reference also teaches cardiac troponin T (see page 20, lines 10-22, “one or more marker(s)” and “clinically “normal”, asymptomatic patients having structural heart disease). See page 27, lines 9-21, the reference as a whole encompasses IGFBP-7 and other markers, including cardiac troponin T. The reference does support increased amounts of markers as correlating with disease, in addition to citations above, see for example page 30, lines 27-33 “the release into the blood of troponin I and T from damaged heart muscle can be specifically related to damage of cardiac tissue”. See also page 31, lines 1-5, a preferred marker used in combination with IGFBP-7 is cardiac troponin T.
The instant claim 1 merely encompasses detecting an increased amount of cardiac troponin T in subjects with functional and/or structural abnormality of the heart proceeding heart failure, a subject “apparently healthy with respect to heart failure”, Wienhues-Thelen is directing practitioners to perform detection on this subject population (as discussed above, the reference is performing such assays on subjects classified as early stage, i.e., with damage who appear clinically normal). The present claims are not reciting diagnostic limitations (i.e., there is no correlation with a particular diagnosis).
For these reasons, Applicant’s arguments through page 28 are not persuasive.
Applicant also argues the rejection of claims under 35 U.S.C. 103 (remarks pages 28-30), arguing that the reference does not render the 20% threshold obvious. Applicant argues the cited passages of the reference are for setting a threshold for IGFBP-7, not cardiac troponin T.
Referring to the rejection, Regarding claims 29, 30 and 38, Wienhues-Thelen et al. teach (page 11) a level elevated above the 90-percentile of the reference range as indicative of increased (90 percentile representing a significant increase as compared to the reference/control, see further page 11 teaching up to 97.5% percentile of the reference range. This cited portion of the reference is referring to markers in general, not limited to IGFBP-7. See for example, end of page 9 to page 10, the reference is referring to markers including cardiac troponin. See last paragraph of page 10 to page 11 is referring to the expression “comparing the concentration... to the concentration in a control sample”. This portion of the reference is giving direction for assessing marker levels in a test sample as compared to a control sample, generally.
However, Wienhues-Thelen et al. fails to teach “at least 20% greater” than the reference value.
Regarding positive indicators, see further page 20, Wienhues-Thelen et al. teach “setting” a level to indicate positive results, a value outside the reference range and its higher end is considered elevated. This citation is referring to their primary marker, IGFBP7-7. However, this taken in conjunction with the citation referenced above, one of ordinary skill would understand this is direction is applicable to the markers (plural), that one of ordinary skill would appreciate threshold is a variable to be selected to indicate a positive result (the reference teaching both IGFBP-7 and cardiac troponin T as markers).
Although the reference fails to teach specifically at least 20% greater as indicative of “elevated”, it is understood from the reference that the user sets a reference value to indicate a positive result, i.e., selects/chooses an amount considered to representative of a positive result. The difference (the selected amount about the threshold) is considered a result-effective variable, namely a variable that achieves a recognized result, namely distinguishes what is considered elevated/or increased compared to a control/reference data. As a result, it is maintained that it would have been prima facie to one having ordinary skill prior the effective filing date of the claimed invention, to have arrived at a value of 20% compared to the reference value as an amount to indicate an increased/elevated level as an obvious matter of routine optimization of experimental parameters of Wienhues-Thelen, in order to achieve the optimum results for indicating those with increased levels correlating with the abnormality. One having ordinary skill would have a reasonable expectation of success because the reference already suggests using values well above the control data to indicate an increase, and because the prior art recognizes “setting” such a value.
Regarding arguments at page 31, that the reference does not recognize the magnitude of cardiac troponin T elevation in the claimed subject population and as such does not establish the variable (cutoff) as a result effective variable, these arguments are not persuasive, given the direction and guidance in Wienhues-Thelen regarding comparison of test and control samples, and the direction that a practitioner performing an assay selects a cutoff to indicate a positive result. It is understood from the reference as a whole that a cutoff is a user selected variable which achieves a recognized result, distinguishing two populations.
Furthermore, the rejections applied also rely on Jackowski et al., who teach a method which involves detecting cardiac markers (see abstract); one of said markers Troponin T (see e.g. col. 11, lines 3-5). Jackowski et al. teach (see e.g. claim 1, step B, correlating marker with a diagnostic result. Jackowski et al. teach (see e.g. col. 9, lines 52-56, in particular embodiments of the invention, the markers are detected whereby a presence above normal enables differentiation. Jackowski et al.t each that "above normal" or "above threshold" are used to refer to a level of marker that is greater than the level of a marker observed in normal individuals; the terms contemplating a level that is significantly above the level found in patients (at least a 2-fold greater level of the marker being present) (see e.g. col. 14, lines 9-21. Furthermore, Jackowski et al. teach normal patients will have a basal level of some cardiac markers in their blood at all times; that according to the invention, a diagnostic test must determine when levels are above a basal level, further teaching comparison of levels against a normal population (i.e. the reference are a healthy, normal population of controls) (see col. 36, lines 1-9).
It is maintained that it would be well within the skill of the ordinary artisan to establish a threshold that is 20% above a normal healthy population as a matter of routine experimentation in the course of defining an optimum cutoff value that would achieve an affirmative diagnostic result. Jackowski et al. teach a threshold level considered to be statistically significant is a level that is at least 2 fold greater than the basal level of the normal population; the ordinarily skilled artisan would appreciate that this number would not be arbitrarily chosen, but chosen through experimentation, in order to establish what threshold would define between diagnostically relevant positive results from negative results. The ordinarily skilled artisan would have a reasonable expectation of success optimizing a reference value through routine experimentation because Wienhues-Thelen et al. specifically teach the skilled artisan would choose a cutoff so as to match the diagnostic question of interest. The argument that Jackowski is a fundamentally different clinical context is not persuasive, Jackowski, like Wienhues-Thelen is referring to the use of diagnostic biomarkers compared to a reference/control in order to indicate a particular diagnostic result (like Wienhus-Thelen), as such arguments through page 35 are not persuasive.
Further, regarding remarks at page 35, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). It is maintained that the pending grounds of rejection only takes into account that which within the level of ordinary skill at the time, see as indicated above, the rejection relies on the cited prior art.
For all of these reasons, Applicant’s arguments are not persuasive.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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