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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/08/2026 has been entered.
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Claims 1, 11-13, 16-22 and 24-39 are pending; claims 16-20 and 25 (drawn to non-elected species) are withdrawn; claims 3-10, 14, 15 and 23 are canceled.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Withdrawn Objections/Rejections
The previous rejection of claims under 35 U.S.C. 112(a), regarding scope of enablement, is withdrawn in response to further consideration and amendments to the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1, 11-13, 21, 22, 24, 26-30 and 33-38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter
later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of
possession has been furnished in the disclosure of the application. These include: (1) Actual
reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient
relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with known or disclosed, and correlation between function and structure), (4) Method of making claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
The claims are drawn to a method of diagnosing heart functional or structural abnormality preceding heart failure comprising measuring the concentration of cardiac troponin marker or a variant thereof. The claims encompass a genus of biomarker, namely variants of cardiac troponin T (see as discussed under 35 U.S.C. 112(b), the broad language “a cardiac troponin T marker, based on the originally filed specification, appears to still encompass variants of cardiac troponin T) (claims 1). For example, rather than reciting the language “concentration of cardiac troponin T or fragments thereof”, the claimed language recites the article “a” (i.e., “a cardiac troponin T”), in the present case, the article “a” recited implies or suggests there are multiple possible species of “cardiac troponin T” biomarkers encompassed by the claimed invention, and turning to the originally filed specification for meaning and understanding, it appears that encompassed under “a cardiac troponin T” is both variants and fragments of this protein (see discussed further below, with reference to para [0181]).
The instant specification (see e.g. para [0181]) indicates that the variants encompassed by the claimed invention include variants with the same essential biological and immunological properties as the specific cardiac troponins (see para [0181], “ “cardiac Troponin” encompasses also variants of the aforementioned specific Troponins, such as Troponin I and Troponin T. Such variants have at least the same essential biological and immunological properties as the specific cardiac Troponins.”). The specification as cited indicates the variants are detectable by the same specific assays, using antibodies that specifically recognize cardiac troponins. A variant is described as differing by at least one amino acid sequence due to substitution, deletion, and/or addition, wherein the variant is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% identical with the sequence of specific troponin. Further at para [0181] the variant may be allelic variants or other species specific homologs, paralogs, or orthologs. Variants include fragments of specific cardiac troponins, and further variants may include degradation products, or variants that differ due to post translation modifications.
The amended claims therefore cover methods of measuring/detecting the biomarker in heart structural or functional abnormality preceding heart failure. The species encompassed by this genus are not structurally specified as they may encompass any possible substitution, deletion, addition, etc., that still accommodates the required functional ability specified by the claim (while still capable detected/measured with an antibody having affinity for an epitope).
The claimed genus of biomarker (with respect to variants of a cardiac troponin T) is characterized by reference to a desired functional limitation. With respect to structure, although the claims are somewhat limited by definitions provided in the specification at para [0181] (e.g., at least about 50% identical with sequence specific troponin, etc.), the number of amino acid sequences encompassed by the claim language (particularly those comprising deletions, substitutions and/or addition) is enormous. The potential species meeting the structural requirements could be any variant (including fragments) having at least one different amino acid residue.
The instant specification fails to convey possession of the entire genus of biomarkers, as it does not adequately describe what molecules would possess the necessary recited function, i.e. what protein variants of troponin T are actually present in vivo in a patient sample in the context of heart structural or functional abnormality preceding heart failure, the subject apparently healthy with respect to heart failure.
The specification provides examples wherein heart structural or functional abnormality preceding heart failure-specific proteins are detectable/measurable as potential diagnostic markers are identified in serum and plasma. See e.g. para [00346] and Example 1 starting at para [00351] wherein Troponin T is determined. See e.g. para [00359], data showed that levels of Troponin T were higher in subjects with functional/structural abnormality of the heart, and further levels keep on augmenting as subjects proceed to heart failure. The examples in the specification only use troponin T for diagnostic purposes (in combination with the other additional makers, e.g. insulin-like growth factor-binding protein 7, i.e., these are the markers expected present/detectable in this specific population). However, the examples do not clearly indicate exactly which additional species of the genus of “a cardiac troponin T” are being detected beyond the full length protein itself (there is no evidence of the detection/presense of variants as encompassed by the claims).
The disclosure therefore fails to convey evidence of possession of the entire genus, which would encompass a large number of potential variants, including fragments, varying both in length and amino acid sequence.
Even with the aid of a computer, it would be difficult to ascertain all possible variants of cardiac troponin that would meet the structural requirements of the claims. Furthermore, it is not possible to envision, based on the specification, which variants actually exist in vivo and are present in a patient sample in detectable amounts that would correlate with this subject population. In other words, it is not possible to envision which species of the genus are actually measurable/detectable in this specific subject, as is required of the claims. The specification fails to describe what species of variants could serve as biomarkers, as it does not provide relevant, identifying details beyond the full length cardiac troponin T marker.
In remarks to previous rejection (see discussed in more detail below under response to remarks), Applicant specifically references particular epitopes, suggesting antibodies binding these specific epitope residues, however it is noted that the present claims are not limited, for example to any particular fragments or variants that conserve these residues as in the specification. The claims broadly encompass any possible variants meeting the functional requirements of the claim (detectable/measurable in a subject having functional and/or structural abnormality preceding heart failure and is apparently healthy with respect to heart failure, detectable by antibody).
Accordingly, the claimed genus has not been adequately described such to convey Applicant was in possession of the entire encompassed claimed genus; one skilled in the art would not be able to predict whether a cardiac troponin protein variant would fall within the scope of the claim or not. As such, the claims are much broader in scope than what Applicant’s specification supports was in Applicant’s possession.
In summary regarding the claimed genus of biomarker, the finding of cardiac troponin T per se in a sample such as serum or plasma fails to convey evidence of possession of the entire genus as claimed in regards to variants of cardiac troponin T, as a biomarker measurable in a specific subject as claimed (having heart structural and/or functional abnormality preceding heart failure, and apparently healthy with respect to heart failure).
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 1, 11-13, 21, 22, 24 and 26-39 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.
The claims were previously amended earlier in prosecution in order to replace the language “a cardiac troponin marker or variant thereof” with the language “a cardiac troponin T marker”. The recited language “a cardiac troponin T marker” is indefinite because it is unclear exactly what is and is not covered by “a cardiac troponin T marker”. Based on the originally filed specification (see referring to para [0181] discussed previously above), it appears “a cardiac troponin T marker” is broad terminology which could encompass “variants” of cardiac troponin T as well as fragments of cardiac troponin T, see for example paras [00216]-[00217] “cardiac troponin is selected from troponin T or a variant thereof” (which, see maintained in detail above, the language regarding variants thereof raises issue under 35 U.S.C. 112(a), regarding written description). It is suggested that Applicant amend the claims in order to recite at the preamble “detecting an increased concentration of cardiac troponin T or fragments thereof” in order to clarify any ambiguity regarding what is and is not encompassed by the claims.
Claim 13 recites the limitation "the cardiac troponin T reference value" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. The claim language at independent claim 1 from which 13 is amended and no longer recites a reference value.
Claim 27 recites the limitation "the cardiac troponin T reference value" in lines 1-2 (see also claims 28-30 recite “the cardiac troponin T reference value). There is insufficient antecedent basis for this limitation in the claim. The claim language at independent claim 22 (from which claim 27 depends) is amended and no longer recites a reference value.
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 marker in a subject” (preamble) and “detecting an increased amount or concentration of the cardiac troponin T marker in the sample”. Regarding claim 1, the claim encompasses measuring the amount or concentration of the marker 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 marker 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 marker 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 marker 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 marker and detecting binding between the cardiac troponin T marker and the antibody” (see claims 1, 22 and 33). However, the 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). 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 marker”, and claim 33 recites “measuring a cardiac troponin T marker”, 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 01/08/2026 have been fully considered but they are not persuasive for the following reasons.
At remarks page 8 applicant indicates that claim 25 is not withdrawn as directed to non-elected species of invention because it is analogous to claim 11 which recites “the subject is known to suffer from one of hypertension and diabetes”. However, in response see the Restriction requirement mailed on 02/12/2025, page 4, Applicant was asked to elect a pre-condition as originally presented at original claim 11. See Applicant’s response (04/11/2025, page 7), Applicant indicated and election of the species “hypertension” without traverse. Claim 11 is examined as this claim recites both species in alternative, i.e., “known to suffer from one of hypertension and diabetes”. Newly recited claims directed to the non-elected pre-condition species are withdrawn. As such, 25 is withdrawn, as claim 25 recites only “from diabetes”, the non-elected species.
Regarding the rejection of claims under 35 U.S.C. 112(a), written description, Applicant argues that “a cardiac troponin T” is not indefinite, asserting that it is clear that this terminology does not encompass variants of cardiac troponin T. Specifically, Applicant argues that because the specification recites “troponin T or a variant thereof” throughout the specification it is clear that the claim language does not intend to cover variants. However, this argument is not persuasive, for example, the claim also does not recite “fragments thereof”, but based on Applicant’s further dependent claims reciting that the protein is the full length protein (dependent claims considered to further limit/narrow) it appears that “a cardiac troponin T” encompasses fragments of protein. The language is ambiguous, and since it appears to encompass “fragments”, this also raises further question as to whether or not this language would also encompass variants of the protein. Since it is not readily clear, and because the English language article “a” recited before the terminology suggest there are multiple possible cardiac troponins encompassed by the claimed invention, the rejection is maintained. For example, there is no clear and limiting definition in the specification for “a cardiac troponin T” which limits this to only the protein and fragments thereof and not variants. As such, it is suggested that applicant amend the recited language to improve clarity of the record.
Applicant further argues at remarks page 9 that even if the language was considered to encompass variants, there is sufficient written description because the specification discloses antibodies binding specific epitopes at positions 125-131 and 136-147 of cardiac troponin T. However, this argument is not persuasive, notably the claimed species of “a cardiac troponin T” recited at the claims is not limited to only fragments or variants containing conserved residues as these positions of cardiac troponin T. Even further, it appears if amended in such a way, the claims would require additional consideration under 112(a) (would require additional consideration regarding claims limited to an antibody by what it binds, i.e., function, rather than structure). However, regarding the instant claims and this argument, the claims are not limited to protein/fragments containing the argued structure.
Applicant further argues the rejection of claims under 35 U.S.C. 112(a), scope of enablement, Applicant refers to arguments above, the claimed invention does not encompass variants of the marker (remarks pages 10-11), although this particular argument is not persuasive for the reasons discussed in detail above, the rejection is withdrawn upon further consideration. The claims as amended are no longer directed to methods of diagnosing, but rather methods of detecting and measuring, and the rejection is withdrawn.
Regarding the rejection of claims under 35 U.S.C. 112(b) (remarks pages 12-16), Applicant’s arguments assert that there is sufficient reasonable certainty regarding the claimed language, remarks suggesting at page 14 that it’s clear from the recited language that “variants” is not included in the claimed scope. Further, remarks page 15-16 Applicant argues the claims are amended to recite measurement method by contacting with an antibody having affinity for an epitope, Applicant argues that the claim must therefore encompass biomarker having the epitope recognized by the antibodies. However, as noted in response to arguments above, the claims are not limited, for example to any particular species of cardiac troponin T containing any particular epitope/epitope residues. For these reasons, and those discussed previously above, Applicant’s amendments to the claims do not overcome the rejection.
Regarding the rejection of claims under 35 U.S.C. 101 (remarks pages 16-18), Applicant asserts that as amended the claims no longer recite calculating and comparing and as such the basis for the rejection is no longer present. However, see the amended grounds of rejection as detailed above, the claims indicated above in the rejection recite abstract ideas (namely the comparing- specifically by referring to an increase, or to a reference value, the claims are considered to encompass a comparison step). As such, Applicant’s remarks are not persuasive.
Regarding the rejection of claims under 35 U.S.C. 102, Applicant argues that the cited art does not teach every element of the claims, see at remarks page 19 Applicant argues Wienhues-Thelen does not teach providing a sample from a subject as claimed, having a functional and/or structural abnormality of the heart preceding heart failure and is apparently healthy with respect to heart failure, wherein the sample is blood, serum or plasma. However, this argument is not persuasive, see as cited in detail above (amended grounds of rejection), some of the subjects as in this reference include subjects with such a claimed abnormality, who are asymptomatic.
Further at remarks page 20, Applicant argues the cited reference does not teach detecting with an antibody, specifically arguing that example 6.2 merely (in passive voice) indicates the marker is evaluated, asserting that the rejection speculates about its detection. However, regarding the reference as a whole, one having ordinary skill in the reading the reference as a whole understands that the reference is referring to immunological detection of markers which include markers IGFBP7 and cardiac troponins, see for example as is supported by page 9, “Proteins or polypeptides used as a marker in the present invention are contemplated to include naturally occurring fragments of said protein in particular, immunologically detectable fragments”. See further page 33, which references embodiments of the invention including troponin T, particularly at liens 14-28, Weinhues-Thelen teach “A marker panel according to the present invention is preferable measured using a protein array technique…Array as sued herein refers to any immunological assay with multiple addressable markers. In one embodiment the addressable markers are antigens…Antigen used herein refers to any molecule that can bind specifically to an antibody” (this citation indicates their methods encompass immunological assay, i.e. antibody binding assays). Even further, importantly, see page 49, Example 6.2 recites “troponin T as measured by commercially available assay (Roche Diagnostics, troponin T assay (Cat. No. 210 76 44 for Elecsys® Systems immunoassay analyzer)”, which is referring to an immunoassay that detects the marker using an antibody, antibodies having an affinity to cardiac troponin T epitope. Applicant has provided no evidence that this immunoassay kit is not an immunoassay (no evidence that there is no antibody that binds with affinity). Immunoassay suggest intrinsically an antibody with affinity that binds a target.
Further the arguments that the cited art focuses on IGFBP7, not cardiac troponin T is not persuasive. The cited reference teaches both markers consistent as claimed, as such the arguments at remarks pages 20-21 are not persuasive.
At remarks page 21, Applicant further argues that Weinhues-Thelen teaches heart failure assessment, not abnormalities preceding heart failure. However, as amended the claimed invention is merely directed to detecting/measuring the marker in subjects as limited by the claims, which see as cited above, the cited art is teaching measuring in subjects who exhibit a structural and/or functional abnormality as claimed, who are otherwise asymptomatic (i.e., apparently healthy). As amended, the claimed invention is no longer directed to methods of “detecting abnormalities that precede heart failure” as asserted in arguments (remarks page 21).
Further, at remarks pages 21-22 Applicant argues the cited art is not teaching subjects “apparently healthy with respect to heart failure”, however this is not persuasive because the method is detecting in those who are asymptomatic. See for example, amendments to the grounds of rejection set forth in detail above, samples were obtained from subjects who appear to meet the claimed criteria as amended.
Further, regarding remarks at page 22-23, as noted above, the claimed invention is no longer recited as a diagnostic method, but rather a method of measuring/detecting a marker in a specific subject population. As such, the arguments are not persuasive.
Regarding the further rejections of dependent claim limitations under 35 U.S.C. 103, Applicant argues the rejections lack articulated reasoning as to why it would have been routine optimization to arrive at the claimed value of 20% compared to the reference. In response, see as noted in the rejections under 35 U.S.C. 112 and 35 U.S.C. 101, and further response to remarks under 101 (the argument that the claimed no longer recited comparing to a reference), see as indicated the claims as amended omit reference to a reference value from the independent claims, but still refer “the reference” at dependent claims, and also although the word “reference value” is omitted from independent claim 1, the claims till encompasses a comparison step because the claim refers to an increase.
In response to the argument that there is no articulated reasoning, see as noted above under the grounds of rejection, it is noted that although the cited prior art reference fails to teach specifically at least 20% greater as indicative of “elevated”, it is understood from the reference that the user/practitioner performing the method sets a reference value to indicate a positive result, i.e., selects/chooses an amount considered to representative of a positive result (which further supports taking such action is well within the skill level of one of ordinary skill). Specifically, this is referred to at page 20 of Wienhues-Thelen et al. where the reference teaches “setting” a level to indicate positive results, a value outside the reference range and its higher end is considered elevated.
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, see specifically as noted the cited art clearly directs to “setting” this level in order to indicate the outcome as a positive result. As a result of the cited portion of the reference, 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.
Further regarding the citation of Jackowski, Applicant argues there is not motivation to combine and that the references address different clinical contexts (remarks pages 24-25 and also page 27). However, these arguments are not persuasive. In response, the motivation is that regarding such biomarker assay methods, 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 is maintained, that based on the cited art, 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.
Applicant also argues (remarks page 25) that even if Weinhues-Thelen recognized cardiac troponin as a general marker of cardiac injury, it would not establish obviousness using the marker to detect subclinical abnormalities. However, see as indicated in response previously above, as amended the claimed invention is no longer detecting or diagnosing subclinical abnormalities. As amended, the claims are directed to merely methods of measuring or detecting the biomarker(s) in the claimed subjects.
Applicant also asserts impermissible hindsight reasoning (remarks page 26), however, this argument is not persuasive for the reasons discussed in detail above, it is maintained that the rejection relies only on that which was taught by the cited prior art in establishing the claimed measurement/detection methods are obvious.
Additionally, at remarks pages 27-28 Applicant asserts routine optimization is not supported because there is no reasonable expectation of success that 20% threshold would be effective for detecting elevation of cardiac troponin in apparently healthy subjects, citing Jackowski as teaching a 2 fold (200%) threshold is needed for statistical significance (referring to Jackowski col. 14, lines 16-18.
This argument is not persuasive, referring to this citated portion of Jackowski (quoted here), “The term "above normal" or "above threshold" are used herein to refer to a level of a marker that is greater than the level of the marker observed in normal individuals. For some markers, no or infinitesimally low levels of the markers may be present. For other markers, notably myoglobin, detectable levels may be present normally in blood. Thus, the terms further contemplate a level that is significantly above the level found in patients. The term "significantly" refers to statistical significance, and generally means at least a two-fold greater level of the marker is present. However, a significant difference between levels of markers depends on the sensitivity of the assay employed, and must be taken into account for each marker assay.” This citation from Jackowski does not require 200% increase, and further does not even limit to only 2-fold as being limited to what is meant by “statistically significant”.
It is maintained that one having ordinary skill in the art would have a reasonable expectation of success modifying Wienheus-Thelen with Jackowski, namely success optimizing a reference value through routine experimentation because Wienhues-Thelen et al. (primary cited reference) specifically teach the skilled artisan would choose/select a cutoff so as to match the diagnostic question of interest. From the teachings of both of these references taken together, one having ordinary skill in this relevant art (assay art) would understand this is a value that is optimizable in order to distinguish what is considered to be “elevated” clinically. Even further this supported by Wienhues-Thelen at page 10, lines 34 to page 11, line 5, which for diagnostic purposes, refer to choosing or establishing a reference value (also page 11, lines 14 and 15).
Further, although Applicant cites Maynard as supporting unpredictability in threshold selection, this interpretation does not necessarily appear accurate. These references were originally introduced when the claims were not limited to any one particular troponin.
Referring to how these references were cited in the previous office action, each were cited regarding state of the prior art in rejection under 35 U.S.C. 112(a) and how different isoforms of troponin are not necessarily diagnostically interchangeabel. Maynard et al., Troponin T or troponin I as cardiac markers in ischemic heart disease, Heart, 83, (2000), p. 371-373 (IDS entered 03/02/2021), was cited as establishing that cTnI and cTnT are not interchangeable biomarkers, rather each is a different marker, each having different molecular weights and each coded by a separate gene (see Maynard et al., page 371, col. 1, para 3, troponin T (39 kD), troponin I (26 kD), troponin C (18 kD)). The art recognized that there are different isoforms of the specific troponins (also col. 1, para 3), and also that the different species of troponin vary regarding their levels expressed in samples, see e.g., concentrations of cTnT and cTnI both begin to rise 4-8 hours following injury and peak at 12-24 hours, but cTnT may remain raised for more than two weeks and cTnI for more than 5-7 days.
Welsh et al., Cardiac Troponin T and Troponin I in the General Population, Circulation, 139, (2011), p.2754-2764, similarly establish that the two markers are not interchangeable. Welsh teach (see page 2758, col. 2) regarding MI and coronary heart disease, only cTnI, not cTnT, was associated with myocardial infarction and coronary heart disease (see also page 2759, col. 1, para 2). See also page 2760, col. 2, Discussion, Welsh teach that it was surprising that cTnT showed no association with MI or CHD, and cTnI did. See at page 2760, col. 2, Discussion, Welsh teach their results suggest different upstream causes of elevated cTnI and cTnT in the general population. Welsh acknowledges the differences in these markers, despite also acknowledging that it is known that the source of both markers is cardiac injury (see Discussion, col. 2, last paragraph). Welsh further supports the position that cTnI and cTnT, while both being markers related to cardiac injury, are not predictably interchangeable markers for diagnoses consistent with that presently claimed (the very specific diagnosis claimed presently of a functional and/or structural abnormality of the heart preceding heart failure, wherein the abnormality is an increased septum diameter).
Neither of these references were cited with regard to a particular teaching specific to setting or determining a threshold or cutoff value Further, as noted previously and above, Wienhues-Thelen specifically teach such a value is specifically chosen/selected relative to the diagnostic goal. The unpredictability that Applicant refers to in the previous rejection regarding enablement had to do with the predictability that one marker (referring to cTnI and cTnT) could be used in place of the other, not regarding predictability in selecting threshold/reference values.
For all of these reasons Applicant’s arguments are not persuasive and the rejections are as indicated in detail above.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677