Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This is the Final Action for application 18/028235 response filed 04/27/2026.
Claims 1-12 & 16-27 have been fully examined.
Claims 13 & 15 are withdrawn from prosecution.
Claim 14 is cancelled.
Claims 22-27 are newly added.
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 1-12 & 16-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature (natural correlation) without significantly more.
Step 1—are the claims directed to a statutory category of invention:
Yes, Independent Claim 1 is directed towards a method.
Yes, Independent Claim 22 is directed towards a method.
Step 2A, Prong One—do the claims recite a judicial exception?
Yes, independent Claim 1 recites both natural correlations and abstract ideas. “Diagnosing,” atrial fibrillation based on the amount of total NT-proBNP and the amount of unglycoslyated NT-proBNP (the amounts are given by a score), is a natural correlation.
The examiner notes that this is more of a discovery of the natural correlation than a patent eligible invention. Examiner also notes that this discovery is not used in a practical application, such as administration of a particular treatment.
See Mayo Collaborative Services v. Prometheus Labs. Inc & also Example 29 of the USPTO subject matter eligibility examples.
Independent Claim 1 also recites the abstract ideas of “calculating a score,” and “comparing,” which are both abstract ideas which are math and mental processes.
Also—as claimed through BRI the claimed “determining,” steps can also be interpreted as mental processes since no specific detection or measurement is claimed and this can be read as “determining,” by looking at a table or similar (which would be a mental process).
Mathematical concepts and mental processes are enumerated abstract idea s(MPEP § 2106.04(a)).
Independent Claim 22 has the same/similar analysis to that of Claim 1 as shown above. In Claim 22, the word diagnosing/diagnosis is not used however it states that the detection of elevated amounts is “indicative of atrial fibrillation,” which is the same thing as diagnosing atrial fibrillation. Further, the claim comparing is done in Claim 22, which is still an abstract idea and part of the natural correlation.
Step 2A, Prong Two—do the claims integrate the judicial exception/s into a practical application:
For independent Claim 1, these judicial exceptions are not integrated into a practical application because after the comparison and diagnosis which are judicial exceptions, nothing further is done. The contacting of a sample with a first antibody or antigen binding fragment thereof “which specifically detects total NT-proBNP,” or a second antibody “which specifically detects unglycosylated NT-proBNP,” does not change these matters as this does nothing to practically apply and is still used for data-gathering. Therefore, there is no practical application and the answer is no.
Further even if the claimed “determining,” steps were limited to be concrete but general measurement by ways like mass spectrometry, as claimed this would be considered data gathering to perform the judicial exception. Data gathering has been shown to be insignificant extra-solution activity and therefore also does not practically apply. See MPEP 2106.05 (g).
Independent Claim 22 has the same/similar analysis to that of Claim 1 as shown above. Nothing further is done after the claimed comparison step, so there is no practical application. Further, instead of claiming that the contacting of a sample with a first antibody or antigen binding fragment thereof “which specifically detects total NT-proBNP,” or a second antibody “which specifically detects unglycosylated NT-proBNP,” is it claimed that the first antibody or antigen binds to an epitope comprising amino acid residues 13 to 16 of human NT-proBNP, and the second antibody specifically binds to an epitope comprising amino acid residues 42 to 46 of human NT-proBNP. The examiner maintains that this binding/detection does not change the matters above and therefore this does nothing to practically apply and is still used for data-gathering. Therefore, there is no practical application and the answer is no.
Step 2B—is there anything additional which amounts to significantly more than the judicial exceptions:
There are no additional steps claimed, which are not part of the judicial exceptions. Therefore, the answer is no.
For Claim 1, the claimed contacting of a sample with a first antibody or antigen binding fragment thereof which detects total NT-proBNP or a second antibody which specifically detects unglycosylated NT-proBNP does not change these matters, as generally claimed antibodies specific to the compounds which are being detected are well understood, routine and conventional (WURC) in the art and therefore are not significantly more.
Independent Claim 22 has the same/similar analysis to that of Claim 1 as shown above. For Claim 22, instead of claiming that the contacting of a sample with a first antibody or antigen binding fragment thereof “which specifically detects total NT-proBNP,” or a second antibody “which specifically detects unglycosylated NT-proBNP,” is it claimed that the first antibody or antigen binds to an epitope comprising amino acid residues 13 to 16 of human NT-proBNP, and the second antibody specifically binds to an epitope comprising amino acid residues 42 to 46 of human NT-proBNP. Contacting with such antibodies is still well understood, routine and conventional (WURC) in the art and therefore are not significantly more.
Even if the “determining,” steps were limited to be concrete but general measurement by ways like mass spectrometry, if only routine and conventional steps were added like that measuring is done by mass spectrometry, this would still be considered well understood routine and conventional (WURC) in the art. This is generally the case the more generally measurement steps are claimed in claims which heavily recited judicial exceptions. See MPEP 2106.05(d).
The examiner notes it is evidences by BORGY in US 20060110776 that detecting as claimed using the two different antibodies, MAB 17.3.1 which has the advantage of reacting with all the proBNP molecules present in a serum sample so having advantage of giving total proBNP, and MAB 1.21.3 which has advantage in only detecting a fraction of this total proBNP (BORGYA, paragraph 0047) is WURC.
With respect to Claim 2, it adds that the subject is human the sample is blood, serum or plasma. Using human subjects and body fluid samples does nothing to practically apply at step 2 A, 2. Further it is WURC at step 2B so does not add significantly more.
With respect to Claim 3, “suspecting,” that a subject suffers from a condition is a mental process. This does nothing to practically apply at step 2 A, 2. Further having hypothesis, opinions before testing is WURC at step 2B so does not add significantly more.
With respect to Claim 4, it further specifies what the unglycosylated NT-proBNP compound is. This further specified biomarker is still part of the natural correlation. Therefore, this does nothing to practically apply at step 2 A, 2. Further having hypothesis, opinions before testing is WURC at step 2B so does not add significantly more.
With respect to Claim 5, it further specifies what the unglycosylated NT-proBNP compound is. This further specified biomarker is still part of the natural correlation. Therefore, this does nothing to practically apply at step 2 A, 2. Further having hypothesis, opinions before testing is WURC at step 2B so does not add significantly more.
With respect to Claim 6, it further specifies that the unglycosylated NT-proBNP compound is detected by using an antibody or antigen binding or fragment of. As generally claimed this detecting is still used to gather data to perform the judicial exception and therefore is insignificant extra solution activity and therefore does nothing to practically apply at step 2 A, 2. Further using anitbodies or antigens to aid in detection is WURC at step 2B so does not add significantly more.
With respect to Claim 7, it further specifies that the unglycosylated NT-proBNP compound is detected by using an antibody or antigen binding or fragment of which is a epitope that comprises amino acid residues 42 to 46 of NT-proBNP. As generally claimed this detecting is still used to gather data to perform the judicial exception and therefore is insignificant extra solution activity and therefore does nothing to practically apply at step 2 A, 2. Further using anitbodies or antigens which specifically bind to the compound which is being detected (in this case NT- proBNP) to aid in detection is WURC at step 2B so does not add significantly more.
With respect to Claim 8, it further defines what applicant considered the “total,” NT-proBNP. With respect to this—this is still a natural biomarker and part of the claimed judicial exception. Therefore, it does nothing to practically apply at step 2A, 2 and also does nothing to add significantly more at step 2B since it is part of a judicial exception itself.
With respect to Claim 9, it further specifies that the antibody or antigen binding or fragment of, binds to a region of human NT-proBNP which does not have an o-glycosylation site. As generally claimed this detecting is still used to gather data to perform the judicial exception and therefore is insignificant extra solution activity and therefore does nothing to practically apply at step 2 A, 2. Further using anitbodies or antigens that bind at (and do not bind at) at specific sites to aid in detection is WURC at step 2B so does not add significantly more.
With respect to Claim 10, it specifies what ratios indicate disease (atrial fibrillation) or not. This is part of the claimed natural correlation and abstract idea judicial exceptions themselves and therefore does nothing to practically apply at step 2A, 2, nor does it add significantly more at step 2B.
With respect to Claim 11, it specifies what ratios indicate disease (atrial fibrillation) or not based on comparison. This is part of the claimed natural correlation (diagnosis) and abstract idea (mental processes comparison) judicial exceptions themselves and therefore does nothing to practically apply at step 2A, 2, nor does it add significantly more at step 2B.
With respect to Claim 12, it specifies what type the atrial fibrillation is—that is it paroxysmal or persistent atrial fibrillation. This is part of the natural correlation judicial exception itself and therefore does nothing to practically apply at step 2A, 2, nor does it add significantly more at step 2B.
With respect to Claims 16 & 18, it/they further specify that the unglycosylated NT-proBNP compound is detected by using an antibody, or an antigen thereof. As generally claimed this detecting is still used to gather data to perform the judicial exception and therefore is insignificant extra solution activity and therefore does nothing to practically apply at step 2 A, 2. Further using antibodies or antigens to aid in detection is WURC at step 2B so does not add significantly more. Claim 18 specifies that the epitope of the antibody comprises amino acid residues 13 to 16 of human NT-proBNP. However, this still does nothing to practically apply the judicial exceptions and further using antibodies with epitopes comprising amino acid residues 13 to 16 of human NT-proBNP (the residues of NT-proBNP applicant would detect) is WURC. This is especially at the level of generality instantly claimed.
With respect to Claims 17,19, & 23, they specify that the antibody is monoclonal (man-made) MAB 1.21.3 or MAB 17.3.1. However, this still does nothing to practically apply the judicial exceptions and further using monoclonal antibodies MAB 1.21.3 and MAB 17.3.1 (antibodies that bind to proBNP) are WURC, especially at the level of generality claimed.
With respect to Claim 20, it further specifies that an antibody or antigen binding or fragment of is used as a capture antibody in combination with at least one other antibody that binds to an epitope of NT-proBBP As generally claimed this detecting is still used to gather data to perform the judicial exception and therefore is insignificant extra solution activity and therefore does nothing to practically apply at step 2 A, 2. Further using capture antibodies or antigens in combination with others to aid in detection is WURC at step 2B so does not add significantly more.
With respect to Claim 21, “suspecting,” that a subject suffers from a condition is a mental process. This does nothing to practically apply at step 2 A, 2. Further having hypothesis, opinions before testing is WURC at step 2B so does not add significantly more.
Claims 24-27 were also evaluated, however in these claims the focus is clearly on a method of measuring or detecting and not on a combination of diagnoses, comparisons, and calculations, so Claims 24-27 are not rejected under 101.
Claim Rejections - 35 USC §103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11, 16-20 & 22-27 are rejected under 35 U.S.C. 103 as being obvious over BORGYA in US 20060110776 in view LEWIS in ProBNP that is not Glycosylated at Threonine 71 is Decreased with Obesity in Patients with Heart Failure in view of and further in view of BLOCK in US 20160334419.
With respect to Claim 1, BORGYA teaches of methods for detecting proBNP and related compounds as they are related to heart failure (abstract). BORGYA teaches that in a preferred embodiment both a first antibody and a second antibody are used (paragraph 0070-0072).
BORGYA more specifically teaches of detecting N-terminal (NT) proBNP (1-76) or fragments thereof (paragraph 0034) and also of using MAB (monoclonal antibodies) to detect the NT-proBNP fragments and specifically MAB 17.3.1 to detect the NT-proBNP which binds to epitope comprising amino acid residues 13-16, and also of using MAB 1.21.3, which binds to an epitope having amino acid residues 42-46 (paragraph 0131). The examiner notes that in following the claim tree in the instant application--- MAB 17.3.1 detects total NT-proBNP (so this reads on Claim 1 first antibody) and MAB 1.21.3 detects unglycosylated NT-proBNP (so this reads on Claim 1 second antibody). What the antibodies bind to is a material property of the antibodies used and the sample used. So, since the sample used and the two antibodies used are the same as what is claimed--- they would necessarily detect the claimed “total NT-proBNP,” and “unglycosylated NT-proBNP,” although the unglycosylated part is not called out in the reference.,
BORGYA teaches that the sample used is blood, serum, plasma, urine, or saliva (paragraph 0089).
BORGYA further teaches that MAB 17.3.1 has the advantage of reacting with all the proBNP molecules present in a serum sample so having advantage of giving total proBNP, and MAB 1.21.3 has advantage in only detecting a fraction of this total proBNP (BORGYA, paragraph 0047).
BORGYA teaches of the compounds detected associated with heart failure, but does not specifically call out atrial fibrillation. BORGYA also does not specifically teach of calculating a score of total NT-proBNP and the unglycosylated NT-proBNP including that scoring is responsible for the diagnosis or comparison of score to a reference, and though they use a MAB that detects unglycosylated pro-BNP, they do not call out specifically detection of unglycosylated NT-proBNP (though this is what the claimed antibody in BORGYA would detect based on material property).
LEWIS is used to remedy this and teaches of a method of detection of heart failure and associated conditions in obesity patients (title). LEWIS teaches that the heart failure can be associated with conditions including atrial enlargement and atrial fibrillation (Page 1122, column 2, line 3, Page 1123, column 1, paragraph 3).
LEWIS further teaches of detection of total proBNP an dNT-proBNP (glycosylated and non-glycosylated proBNP, “unglycosylated,” as claimed), proBNP not glycosylated (unglycosylated) at threonine 71 (NG-T71) (unglycosylated) and proBNP not glycosylated (unglycosylated) in the central region (NG-C) in samples from heart failure (HF) patients (Page 1116, column 1, paragraph 2-3).
LEWIS teaches that the concentrations of proBNP, NG-T71 and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. So- with respect to the instant claims, LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios, which can be considered scores (see instant application Claim 11) of the compounds to one another and also determination of a z-score using these detected compounds (Page 1120, column 2, first paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to calculate the concentration of both glycosylated and more specifically nonglycosylated NT-proBNP as is done in LEWIS in the method of BORGYA due to the advantages both NT-proBNP, as well as their precursor proBNP have for determination of the degree of cardiac dysfunction and clinical severity (Page 1115, column 2, first paragraph, lines 6-11) and due to the need in the art for better methods of measuring non glycosylated forms of NT-proBNP due to the disadvantage that prior methods have in underestimating the nonglycosylated form/s(Page 1116, column 1, paragraphs 1-2).
BORGYA and LEWIS do not specifically teach that scoring is responsible for the diagnosis.
BLOCK is used to remedy this and further teaches of a method of monitoring natriuretic peptides in heart failure patients (abstract), which includes measurement of NT-proBNP (paragraph 0006), and of performing analysis which results in calculation of Hazard Ratios and Wald scores (which evaluate/show if explanatory variables are significant)—therefore showing if the explanatory variable/biomarker (NT-proBNP) is indicative for disease (paragraph 0288, Table 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use a score to diagnosis/determine indication of disease as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage these scores offer for showing indication of hospitalization or death of the condition in patients (BLOCK, paragraph 0288, Table 2).
With respect to Claim 2, BORGYA teaches that the sample used is blood, serum, plasma, urine, or saliva (paragraph 0089) and that it is from a human (paragraph 0046).
With respect to Claim 3, LEWIS teaches that the heart failure and the patient can be associated or suspected of possibly having with including atrial enlargement and atrial fibrillation (Page 1122, column 2, line 3, Page 1123, column 1, paragraph 3).
With respect to Claim 4, BORGYA teaches of the method as shown above. BORGYA does not teach of un or not glycosylated detection, or specifically call it out.
LEWIS is used to remedy this and teaches that the concentrations of proBNP, NG-T71 (not glycosylated at T71) and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios of the compounds to one another and determination of score (z-score) using these detected compounds (Page 1120, column 2, first paragraph). See reason for combination from Claim 1.
With respect to Claim 5, BORGYA teaches of the method as shown above. BORGYA does not teach of un or not glycosylated.
LEWIS teaches that the S44 site can be glycosylated or non glycosylated and of detection of these site with antibodies (Page 1115, column 2, last paragraph). See reason for combination from Claim 1.
With respect to Claim 6, BORGYA teaches of the method as shown above. BORGYA does not teach of un or not glycosylated detection with an antibody.
LEWIS is used to remedy this and teaches that the concentrations of proBNP, NG-T71 (not glycosylated at T71) and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios of the compounds to one another and determination of score (z-score) using these detected compounds (Page 1120, column 2, first paragraph).
LEWIS also teaches of detection antibodies "16F3" binding to epitope NT-proBNP13-20, i.e. binding to total NT- proBNP, and to antibody "24E11" binding to epitope NT-proBNP 67-76, i.e. binding to unglycosylated NT-proBNP, see LEWIS abstract; page 1116, right- column, section "development of the proBNP, NG-T71, and NG-C assays". Reference to the antibodies "16F3" and "24E11" of LEWIS is made in figure 2 of the present application. See reason for combination from Claim 1. Also, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use the detection antibodies as is done in LEWIS in the method of BORGYA due to the advantage these detection antibodies offer for rapid determination of glycosylated versus non- glycosylated proBNP(Page 1116, column 1, 3 paragraphs from bottom).
With respect to Claim 7, BORGYA teaches of the method as shown above including detection of total proBNP in circulation (paragraph 0024). BORGYA does not teach of un or not glycosylated detection with an antibody.
LEWIS is used to remedy this and teaches that the concentrations of proBNP, NG-T71 (not glycosylated at T71) and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios of the compounds to one another and determination of score (z-score) using these detected compounds (Page 1120, column 2, first paragraph).
LEWIS teaches of detection antibodies "16F3" binding to epitope NT-proBNP13-20, i.e. binding to total NT- proBNP, and to antibody "24E11" binding to epitope NT-proBNP 67-76, i.e. binding to unglycosylated NT-proBNP, see LEWIS abstract; page 1116, right- column, section "development of the proBNP, NG-T71, and NG-C assays". Reference to the antibodies "16F3" and "24E11" of LEWIS ( these sites do not have an o-glycosylation site). LEWIS teaches that the S44 site can be glycosylated or non glycosylated and of detection of these site with antibodies (Page 1115, column 2, last paragraph). See reason for combination from Claims 1 & 6.
With respect to Claim 8, LINZI teaches of the invention as shown above wherein circulating NT-proBNP is total NT-proBNP. LEWIS also teaches of detection go total NT-proBNP(Page 1120, column 2, 2nd paragraph). “Total,” means whole or entire (so including all kinds).
With respect to Claim 9, L BORGYA teaches of the method as shown above. BORGYA does not teach of un or not glycosylated detection with an antibody.
LEWIS is used to remedy this and teaches that the concentrations of proBNP, NG-T71 (not glycosylated at T71) and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios of the compounds to one another and determination of score (z-score) using these detected compounds (Page 1120, column 2, first paragraph).
LEWIS teaches of detection antibodies "16F3" binding to epitope NT-proBNP13-20, i.e. binding to total NT- proBNP, and to antibody "24E11" binding to epitope NT-proBNP 67-76, i.e. binding to unglycosylated NT-proBNP, see LEWIS abstract; page 1116, right- column, section "development of the proBNP, NG-T71, and NG-C assays". Reference to the antibodies "16F3" and "24E11" of LEWIS (these bind to a region which does not have an o-glycosylation site). See reason for combination from Claims 1 & 6.
With respect to Claim 10, BORGYA teaches of the method as shown above. BORGYA does not teach of un or not glycosylated detection with an antibody.
LEWIS is used to remedy this and teaches that the concentrations of proBNP, NG-T71 (not glycosylated at T71) and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3).
LEWIS further teaches that O-glycosylation sites have been reported for proBNP on serine (S) or threonine (T) residues (T36, S37, S44, T48, S53, T58, and T71) (21, 22), with low abundance sites at S5 and either T14 or T15 (23 ). Each of these sites could also be nonglycosylated (23 ) (Page 1115, column 2, last paragraph). LEWIS specifically teach that the assays contain antibodies directed to epitopes located at these portions of proBNP(Page 1116, column 1, paragraph 1).
LEWIS teaches of detection antibodies "16F3" binding to epitope NT-proBNP13-20, i.e. binding to total NT- proBNP at amino acid residue 16, and to antibody "24E11" binding to epitope NT-proBNP 67-76, i.e. binding to unglycosylated NT-proBNP, see LEWIS abstract; page 1116, right- column, section "development of the proBNP, NG-T71, and NG-C assays". Reference to the antibodies "16F3" and "24E11" of LEWIS ( these sites do not have an o-glycosylation site). See reason for combination from Claim 1 & 6.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to calculate the concentration of both glycosylated and not glycosylated NT-proBNP using antibodies and epitopes as is done in LEWIS in the method of BORGYA due to the advantages both NT-proBNP, as well as their precursor proBNP have for determination of the degree of cardiac dysfunction and clinical severity (Page 1115, column 2, first paragraph, lines 6-11) and due to the need in the art for better methods of measuring non glycosylated forms of NT-proBNP(Page 1116, column 1, paragraphs 1-2) and due to the advantage that different antibodies have for conferring specificity(Page 1116, column 1, paragraph 4).
With respect to Claim 11, BORGYA in view of LEWIS teaches of detecting atrial fibrillation with NT-proBNP as shown above for Claim 1. BORGYA does not teach of determining the amount of unglycosylated NT-proBNP, calculating a score which is a ratio of total NT-proBNP and the unglycosylated NT-proBNP and diagnosing based on the score comparison to a reference.
LEWIS is used to remedy this and teaches of a method of detection of heart failure and associated conditions in obesity patients (title). LEWIS teaches that the heart failure can be associated with conditions including atrial enlargement and atrial fibrillation (Page 1122, column 2, line 3, Page 1123, column 1, paragraph 3).
LEWIS further teaches of detection of total proBNP (glycosylated and non-glycosylated proBNP), proBNP not glycosylated (unglycosylated) at threonine 71 (NG-T71) (unglycosylated) and proBNP not glycosylated (unglycosylated) in the central region (NG-C) in samples from heart failure (HF) patients.
LEWIS teaches that the concentrations of proBNP, NG-T71 and NT-proBNP were greater in heart failure patients compared with controls/reference, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3) when compared to references. NG, stands for non/not glycosylated. So- with respect to the instant claims, LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios, which can be considered scores (see instant application Claim 11) of the compounds to one another and also determination of a z-score using these detected compounds. LEWIS teaches that a difference in the amounts of the compounds and ratios in comparison to the controls indicate that the patient has the cardiac disease, which makes this for atrial fibrillation obvious (Page 1120, column 2, first paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to calculate the concentration of both glycosylated and not glycosylated NT-proBNP in ratios in comparison to references as is done in LEWIS in the method of BORGYA due to the advantages both NT-proBNP, as well as their precursor proBNP have for determination of the degree of cardiac dysfunction and clinical severity (Page 1115, column 2, first paragraph, lines 6-11) and due to the need in the art for better methods of measuring non glycosylated forms of NT-proBNP(Page 1116, column 1, paragraphs 1-2).
With respect to Claim 16, BORGYA teaches of the method as shown above. BORGYA does not teach of un or not glycosylated detection with an antibody.
LEWIS is used to remedy this and teaches that the concentrations of proBNP, NG-T71 (not glycosylated at T71) and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios of the compounds to one another and determination of score (z-score) using these detected compounds (Page 1120, column 2, first paragraph).
LEWIS teaches of detection antibodies "16F3" binding to epitope NT-proBNP13-20, i.e. binding to total NT- proBNP, and to antibody "24E11" binding to epitope NT-proBNP 67-76, i.e. binding to unglycosylated NT-proBNP, see LEWIS abstract; page 1116, right- column, section "development of the proBNP, NG-T71, and NG-C assays". Reference to the antibodies "16F3" and "24E11" of LEWIS (these sites do not have an o-glycosylation site). See reason for combination from Claims 1 & 6.
With respect to Claim 17, BLOCK teaches of using binding antigens which are monoclonal antibodies which is any antibody which specifically binds to the corresponding target molecules (paragraphs 0124-0125). BLOCK even more specifically state the monoclonal antibodies detect the N-terminal part (1-76) of pro BNP (1-108) (paragraph 0295), which reads on the claimed MAB 1.21.3. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use the monoclonal antibodies and adjust them to one which specifically binds as is instantly done as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage this offers for specific binding and detection of the target or marker in the samples (BLOCK, paragraphs 0123-0127).
With respect to Claim 18, BORGYA teaches of the method as shown above. BORGYA does not teach of un or not glycosylated detection with an antibody.
LEWIS is used to remedy this and teaches that the concentrations of proBNP, NG-T71 (not glycosylated at T71) and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3).
LEWIS further teaches that O-glycosylation sites have been reported for proBNP on serine (S) or threonine (T) residues (T36, S37, S44, T48, S53, T58, and T71) (21, 22), with low abundance sites at S5 and either T14 or T15 (23 ). Each of these sites could also be nonglycosylated (23 ) (Page 1115, column 2, last paragraph). LEWIS specifically teach that the assays contain antibodies directed to epitopes located at these portions of proBNP(Page 1116, column 1, paragraph 1).
LEWIS teaches of detection antibodies "16F3" binding to epitope NT-proBNP13-20, i.e. binding to total NT- proBNP at amino acid residue 16, and to antibody "24E11" binding to epitope NT-proBNP 67-76, i.e. binding to unglycosylated NT-proBNP, see LEWIS abstract; page 1116, right- column, section "development of the proBNP, NG-T71, and NG-C assays". Reference to the antibodies "16F3" and "24E11" of LEWIS ( these sites do not have an o-glycosylation site). See reason for combination from Claim 1 & 6.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to calculate the concentration of both glycosylated and not glycosylated NT-proBNP using antibodies and epitopes as is done in LEWIS in the method of BORGYA due to the advantages both NT-proBNP, as well as their precursor proBNP have for determination of the degree of cardiac dysfunction and clinical severity (Page 1115, column 2, first paragraph, lines 6-11) and due to the need in the art for better methods of measuring non glycosylated forms of NT-proBNP(Page 1116, column 1, paragraphs 1-2) and due to the advantage that different antibodies have for conferring specificity(Page 1116, column 1, paragraph 4).
With respect to Claim 19, BLOCK teaches of using binding antigens which are monoclonal antibodies which is any antibody which specifically binds to the corresponding target molecules (paragraphs 0124-0125). BLOCK even more specifically state the monoclonal antibodies detect the N-terminal part (1-76) of pro BNP (1-108) (paragraph 0295) and also monoclonal antibodies of IL, Fab, GDF, Gal and other peptides (paragraph 0068, 0088, 0116, 0123-0124, 0295-0296), which reads on the claimed MAB 17.3.1. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use the monoclonal antibodies and adjust them to one which specifically binds as is instantly done as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage this offers for specific binding and detection of the target or marker in the samples (BLOCK, paragraphs 0123-0127).
With respect to Claim 20, BORGYA and LEWIS teach of the invention as shown above, but do not teach of using sandwich assays.
BLOCK is used to remedy this and teaches of the invention as shown in Claim 1. BLOCK further teaches of using antibodies (plural) for sandwich assays (paragraphs 0109-0110, 0295, 0299, 0302, 0303, 0304). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use a sandwich assay with multiple binding sites as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage this offers in that it offers two binding sites for the assaying (BLOCK, paragraph 0109).
With respect to Claim 22, BORGYA teaches of methods for detecting proBNP and related compounds as they are related to heart failure (abstract). BORGYA teaches that in a preferred embodiment both a first antibody and a second antibody are used (paragraph 0070-0072).
BORGYA more specifically teaches of detecting N-terminal (NT) proBNP (1-76) or fragments thereof (paragraph 0034) and also of using MAB (monoclonal antibodies) to detect the NT-proBNP fragments and specifically MAB 17.3.1 to detect the NT-proBNP which binds to epitope comprising amino acid residues 13-16, and also of using MAB 1.21.3, which binds to an epitope having amino acid residues 42-46 (paragraph 0131). The examiner notes that in following the claim tree in the instant application--- MAB 17.3.1 detects total NT-proBNP (so this reads on Claim 1 first antibody) and MAB 1.21.3 detects unglycosylated NT-proBNP (so this reads on Claim 1 second antibody). What the antibodies bind to is a material property of the antibodies used and the sample used. So, since the sample used and the two antibodies used are the same as what is claimed--- they would necessarily detect the claimed “total NT-proBNP,” and “unglycosylated NT-proBNP,” although the unglycosylated part is not called out in the reference. BORGYA teaches that all of the measured compounds are compared to a reference or standard amounts (paragraph 0031, 0039, 0038, 0062). BORGYA teaches that an increase in the measured amounts indicates advanced disease or disease progression (paragraph 0136).
BORGYA teaches that the sample used is blood, serum, plasma, urine, or saliva (paragraph 0089).
BORGYA further teaches that MAB 17.3.1 has the advantage of reacting with all the proBNP molecules present in a serum sample so having advantage of giving total proBNP, and MAB 1.21.3 has advantage in only detecting a fraction of this total proBNP (BORGYA, paragraph 0047).
BORGYA teaches of the compounds detected associated with heart failure, but does not specifically call out atrial fibrillation. BORGYA also does not specifically teach of calculating a score of total NT-proBNP and the unglycosylated NT-proBNP including that scoring is responsible for the diagnosis or comparison of score to a reference, and though they use a MAB that detects unglycosylated pro-BNP, they do not call out specifically detection of unglycosylated NT-proBNP (though this is what the claimed antibody in BORGYA would detect based on material property).
LEWIS is used to remedy this and teaches of a method of detection of heart failure and associated conditions in obesity patients (title). LEWIS teaches that the heart failure can be associated with conditions including atrial enlargement and atrial fibrillation (Page 1122, column 2, line 3, Page 1123, column 1, paragraph 3).
LEWIS further teaches of detection of total proBNP an dNT-proBNP (glycosylated and non-glycosylated proBNP, “unglycosylated,” as claimed), proBNP not glycosylated (unglycosylated) at threonine 71 (NG-T71) (unglycosylated) and proBNP not glycosylated (unglycosylated) in the central region (NG-C) in samples from heart failure (HF) patients (Page 1116, column 1, paragraph 2-3).
LEWIS teaches that the concentrations of proBNP, NG-T71 and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. So- with respect to the instant claims, LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios, which can be considered scores (see instant application Claim 11) of the compounds to one another and also determination of a z-score using these detected compounds (Page 1120, column 2, first paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to calculate the concentration of both glycosylated and more specifically nonglycosylated NT-proBNP as is done in LEWIS in the method of BORGYA due to the advantages both NT-proBNP, as well as their precursor proBNP have for determination of the degree of cardiac dysfunction and clinical severity (Page 1115, column 2, first paragraph, lines 6-11) and due to the need in the art for better methods of measuring non glycosylated forms of NT-proBNP due to the disadvantage that prior methods have in underestimating the nonglycosylated form/s(Page 1116, column 1, paragraphs 1-2).
BORGYA and LEWIS do not specifically teach that scoring is responsible for the diagnosis.
BLOCK is used to remedy this and further teaches of a method of monitoring natriuretic peptides in heart failure patients (abstract), which includes measurement of NT-proBNP (paragraph 0006), and of performing analysis which results in calculation of Hazard Ratios and Wald scores (which evaluate/show if explanatory variables are significant)—therefore showing if the explanatory variable/biomarker (NT-proBNP) is indicative for disease (paragraph 0288, Table 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use a score to diagnosis/determine indication of disease as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage these scores offer for showing indication of hospitalization or death of the condition in patients (BLOCK, paragraph 0288, Table 2).
With respect to Claim 23, BORGYA teaches of using MAB 1.21.3 detects unglycosylated NT-proBNP (so this reads on Claim 1 second antibody).
With respect to Claim 24, BORGYA teaches of methods for detecting proBNP and related compounds as they are related to heart failure (abstract). BORGYA teaches that in a preferred embodiment both a first antibody and a second antibody are used (paragraph 0070-0072).
BORGYA more specifically teaches of detecting N-terminal (NT) proBNP (1-76) or fragments thereof (paragraph 0034) and also of using MAB (monoclonal antibodies) to detect the NT-proBNP fragments and specifically MAB 17.3.1 to detect the NT-proBNP which binds to epitope comprising amino acid residues 13-16, and also of using MAB 1.21.3, which binds to an epitope having amino acid residues 42-46 (paragraph 0131). The examiner notes that in following the claim tree in the instant application--- MAB 17.3.1 detects total NT-proBNP (so this reads on Claim 1 first antibody) and MAB 1.21.3 detects unglycosylated NT-proBNP (so this reads on Claim 1 second antibody). What the antibodies bind to is a material property of the antibodies used and the sample used. So, since the sample used and the two antibodies used are the same as what is claimed--- they would necessarily detect the claimed “total NT-proBNP,” and “unglycosylated NT-proBNP,” although the unglycosylated part is not called out in the reference.
BORGYA teaches that the sample used is blood, serum, plasma, urine, or saliva (paragraph 0089).
BORGYA further teaches that MAB 17.3.1 has the advantage of reacting with all the proBNP molecules present in a serum sample so having advantage of giving total proBNP, and MAB 1.21.3 has advantage in only detecting a fraction of this total proBNP (BORGYA, paragraph 0047).
BORGYA teaches of the compounds detected associated with heart failure, but does not specifically call out atrial fibrillation. BORGYA also does not specifically teach of calculating a score of total NT-proBNP and the unglycosylated NT-proBNP including that scoring is responsible for the diagnosis or comparison of score to a reference, and though they use a MAB that detects unglycosylated pro-BNP, they do not call out specifically detection of unglycosylated NT-proBNP (though this is what the claimed antibody in BORGYA would detect based on material property).
LEWIS is used to remedy this and teaches of a method of detection of heart failure and associated conditions in obesity patients (title). LEWIS teaches that the heart failure can be associated with conditions including atrial enlargement and atrial fibrillation (Page 1122, column 2, line 3, Page 1123, column 1, paragraph 3).
LEWIS further teaches of detection of total proBNP an dNT-proBNP (glycosylated and non-glycosylated proBNP, “unglycosylated,” as claimed), proBNP not glycosylated (unglycosylated) at threonine 71 (NG-T71) (unglycosylated) and proBNP not glycosylated (unglycosylated) in the central region (NG-C) in samples from heart failure (HF) patients (Page 1116, column 1, paragraph 2-3).
LEWIS teaches that the concentrations of proBNP, NG-T71 and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. So- with respect to the instant claims, LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios, which can be considered scores (see instant application Claim 11) of the compounds to one another and also determination of a z-score using these detected compounds (Page 1120, column 2, first paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to calculate the concentration of both glycosylated and more specifically nonglycosylated NT-proBNP as is done in LEWIS in the method of BORGYA due to the advantages both NT-proBNP, as well as their precursor proBNP have for determination of the degree of cardiac dysfunction and clinical severity (Page 1115, column 2, first paragraph, lines 6-11) and due to the need in the art for better methods of measuring non glycosylated forms of NT-proBNP due to the disadvantage that prior methods have in underestimating the nonglycosylated form/s(Page 1116, column 1, paragraphs 1-2).
BORGYA and LEWIS do not specifically teach that scoring is responsible for the diagnosis.
BLOCK is used to remedy this and further teaches of a method of monitoring natriuretic peptides in heart failure patients (abstract), which includes measurement of NT-proBNP (paragraph 0006), and of performing analysis which results in calculation of Hazard Ratios and Wald scores (which evaluate/show if explanatory variables are significant)—therefore showing if the explanatory variable/biomarker (NT-proBNP) is indicative for disease (paragraph 0288, Table 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use a score to diagnosis/determine indication of disease as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage these scores offer for showing indication of hospitalization or death of the condition in patients (BLOCK, paragraph 0288, Table 2).
With respect to Claim 25, BORGYA teaches of the claims as shown above. LEWIS further teaches of detection of total proBNP an dNT-proBNP (glycosylated and non-glycosylated proBNP, “unglycosylated,” as claimed), proBNP not glycosylated (unglycosylated) at threonine 71 (NG-T71) (unglycosylated) and proBNP not glycosylated (unglycosylated) in the central region (NG-C) in samples from heart failure (HF) patients (Page 1116, column 1, paragraph 2-3).
BORGYA and LEWIS do not specifically teach that scoring is responsible for the diagnosis.
BLOCK is used to remedy this and further teaches of a method of monitoring natriuretic peptides in heart failure patients (abstract), which includes measurement of NT-proBNP (paragraph 0006), and of performing analysis which results in calculation of Hazard Ratios and Wald scores (which evaluate/show if explanatory variables are significant)—therefore showing if the explanatory variable/biomarker (NT-proBNP) is indicative for disease (paragraph 0288, Table 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use a score to diagnosis/determine indication of disease as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage these scores offer for showing indication of hospitalization or death of the condition in patients (BLOCK, paragraph 0288, Table 2).
With respect to Claim 26, BORGYA teaches of methods for detecting proBNP and related compounds as they are related to heart failure (abstract). BORGYA teaches that in a preferred embodiment both a first antibody and a second antibody are used (paragraph 0070-0072).
BORGYA more specifically teaches of detecting N-terminal (NT) proBNP (1-76) or fragments thereof (paragraph 0034) and also of using MAB (monoclonal antibodies) to detect the NT-proBNP fragments and specifically MAB 17.3.1 to detect the NT-proBNP which binds to epitope comprising amino acid residues 13-16, and also of using MAB 1.21.3, which binds to an epitope having amino acid residues 42-46 (paragraph 0131). The examiner notes that in following the claim tree in the instant application--- MAB 17.3.1 detects total NT-proBNP (so this reads on Claim 1 first antibody) and MAB 1.21.3 detects unglycosylated NT-proBNP (so this reads on Claim 1 second antibody). What the antibodies bind to is a material property of the antibodies used and the sample used. So, since the sample used and the two antibodies used are the same as what is claimed--- they would necessarily detect the claimed “total NT-proBNP,” and “unglycosylated NT-proBNP,” although the unglycosylated part is not called out in the reference.,
BORGYA teaches that the sample used is blood, serum, plasma, urine, or saliva (paragraph 0089).
BORGYA further teaches that MAB 17.3.1 has the advantage of reacting with all the proBNP molecules present in a serum sample so having advantage of giving total proBNP, and MAB 1.21.3 has advantage in only detecting a fraction of this total proBNP (BORGYA, paragraph 0047).
BORGYA teaches of the compounds detected associated with heart failure, but does not specifically call out atrial fibrillation. BORGYA also does not specifically teach of calculating a score of total NT-proBNP and the unglycosylated NT-proBNP including that scoring is responsible for the diagnosis or comparison of score to a reference, and though they use a MAB that detects unglycosylated pro-BNP, they do not call out specifically detection of unglycosylated NT-proBNP (though this is what the claimed antibody in BORGYA would detect based on material property).
LEWIS is used to remedy this and teaches of a method of detection of heart failure and associated conditions in obesity patients (title). LEWIS teaches that the heart failure can be associated with conditions including atrial enlargement and atrial fibrillation (Page 1122, column 2, line 3, Page 1123, column 1, paragraph 3).
LEWIS further teaches of detection of total proBNP an dNT-proBNP (glycosylated and non-glycosylated proBNP, “unglycosylated,” as claimed), proBNP not glycosylated (unglycosylated) at threonine 71 (NG-T71) (unglycosylated) and proBNP not glycosylated (unglycosylated) in the central region (NG-C) in samples from heart failure (HF) patients (Page 1116, column 1, paragraph 2-3).
LEWIS teaches that the concentrations of proBNP, NG-T71 and NT-proBNP were greater in heart failure patients compared with controls, whereas heart failure patients with obesity had lower NT-proBNP and NG-T71 concentrations and higher proBNP/ NT-proBNP and proBNP/NG-T71 ratios (Page 1115, column 1, paragraph 3). NG, stands for non/not glycosylated. So- with respect to the instant claims, LEWIS teaches of detecting concentrations of both glycosylated, not glycoysylated and total NT-proBNP forms and of forming ratios, which can be considered scores (see instant application Claim 11) of the compounds to one another and also determination of a z-score using these detected compounds (Page 1120, column 2, first paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to calculate the concentration of both glycosylated and more specifically nonglycosylated NT-proBNP as is done in LEWIS in the method of BORGYA due to the advantages both NT-proBNP, as well as their precursor proBNP have for determination of the degree of cardiac dysfunction and clinical severity (Page 1115, column 2, first paragraph, lines 6-11) and due to the need in the art for better methods of measuring non glycosylated forms of NT-proBNP due to the disadvantage that prior methods have in underestimating the nonglycosylated form/s(Page 1116, column 1, paragraphs 1-2).
BORGYA and LEWIS do not specifically teach that scoring is responsible for the diagnosis.
BLOCK is used to remedy this and further teaches of a method of monitoring natriuretic peptides in heart failure patients (abstract), which includes measurement of NT-proBNP (paragraph 0006), and of performing analysis which results in calculation of Hazard Ratios and Wald scores (which evaluate/show if explanatory variables are significant)—therefore showing if the explanatory variable/biomarker (NT-proBNP) is indicative for disease (paragraph 0288, Table 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use a score to diagnosis/determine indication of disease as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage these scores offer for showing indication of hospitalization or death of the condition in patients (BLOCK, paragraph 0288, Table 2).
With respect to Claim 27, BORGYA teaches of the claims as shown above. LEWIS further teaches of detection of total proBNP an dNT-proBNP (glycosylated and non-glycosylated proBNP, “unglycosylated,” as claimed), proBNP not glycosylated (unglycosylated) at threonine 71 (NG-T71) (unglycosylated) and proBNP not glycosylated (unglycosylated) in the central region (NG-C) in samples from heart failure (HF) patients (Page 1116, column 1, paragraph 2-3).
BORGYA and LEWIS do not specifically teach that scoring is responsible for the diagnosis.
BLOCK is used to remedy this and further teaches of a method of monitoring natriuretic peptides in heart failure patients (abstract), which includes measurement of NT-proBNP (paragraph 0006), and of performing analysis which results in calculation of Hazard Ratios and Wald scores (which evaluate/show if explanatory variables are significant)—therefore showing if the explanatory variable/biomarker (NT-proBNP) is indicative for disease (paragraph 0288, Table 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use a score to diagnosis/determine indication of disease as is done in BLOCK in the methods of BORGYA and LEWIS due to the advantage these scores offer for showing indication of hospitalization or death of the condition in patients (BLOCK, paragraph 0288, Table 2).
Claims 12 & 21 are rejected under 35 U.S.C. 103 as being obvious over BORGYA in US 20060110776 in view LEWIS in ProBNP that is not Glycosylated at Threonine 71 is Decreased with Obesity in Patients with Heart Failure in view of and further in view of BLOCK in US 20160334419 and further in view of LINZI in Association of N-terminal natriuretic peptide (NT-proBNP) change with the risk of atrial fibrillation in the ARIC.
With respect to Claim 12, BORGYA in view of LEWIS in view of BLOCK teach of the invention as shown above. They do not teach of persistant atrial fibrillation.
LINZI is used to remedy this and teaches of a method of detecting circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) (total NT-proBNP) and using it to predict/diagnosis atrial fibrillation (Page 119, background).
LINZI teaches that samples are obtained from patients and then of assaying/conducting assays to determine the amount of NT-proBNP in the samples (Page 121, column 2, assessment of NT-proBNP). LINZI teaches of comparing the measured NT-proBNP levels over several doctor’s office visits. This can be considered to be the claimed comparison to a reference or control (Page 121, column 2, assessment of NT-proBNP).
LINZI further teaches of the atrial fibrillation being persistent atrial fibrillation (AF) (Page 126, column 1, last paragraph, last line).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to diagnose persistant atrial firbrilation as is done in LINZI in the methods of BORGYA LEWIS and BLOCK due to the need in the art to better diagnose atrial fibrillation as it is responsible for increased cardiovascular and cerebrovascular morbidity and mortality (LINZI, page 2, introduction, paragraph 1).
With respect to Claim 21, BORGYA in view of LEWIS in view of BLOCK teach of the invention as shown above. They do not teach of a history of atrial fibrillation.
LINZI teaches of the subject being suspected of suffering from atrial fibrillation in that the subject at the being does not have prevalent atrial fibrillation, and then determining if the risk of atrial fibrillation increases over time with NT-proBNP level (Page 119, methods and results). See reason for combination from Claim 12.
Response to Arguments
Applicant's arguments filed 04/27/2026 have been fully considered but they are not persuasive.
The prior 112 rejections were overcome due to amendments made 04/26/2026.
The 101 rejected is maintained for the significantly amended claims as shown above. Please see the rejection above.
With respect to the 101 rejection--- applicant argues that the instant claims are drawn towards a specific laboratory protocol. The examiner disagrees with respect to this as not actual specific measurement apparatus or technique is claimed. Further, nothing that practically applies or adds significantly more is added to the claims.
The examiner does not that some of the new claims which are clearly directed to a method of detecting/measuring and not a judicial exception are found to the patent eligible. Please see the rejection above.
Further with respect to the 101 rejection, applicant argues that the specification demonstrates a concrete technical improvement that supports eligibility. With respect to this--- the examiner notes that applicant seems to be arguing that the technical achievement is a diagnostic result. The examiner maintains that the claimed score calculation and comparison and the diagnosis and judicial exceptions themselves, especially when claimed all together in the instantly claimed methods for diagnosing or identifying a disease condition.
Further with respect to the 101 rejection, applicant argues that the office failed to provide evidentiary support for it’s WURC findings. The examiner notes that this is done as shown above. The examiner notes though that they do not need to show evidentiary support for the calculating of a score and the diagnostic part as these are parts of the judicial exception themselves and not the additional steps.
The examiner notes that it is evidenced by BORGYA in US 20060110776 that detecting as claimed using the two different antibodies, MAB 17.3.1 which has the advantage of reacting with all the proBNP molecules present in a serum sample so having advantage of giving total proBNP, and MAB 1.21.3 which has advantage in only detecting a fraction of this total proBNP (BORGYA, paragraph 0047) is WURC.
With respect to the 101 rejection, applicant further argues that the dependent claims add further specific limitations that support eligibility and that the new claims are patent eligible. The examiner disagrees that the dependent claims add further limitations that make the claims patent eligible and instead maintains that the dependent claims are ineligible as shown in the rejection above. This is particularly with the cited BORGYA reference showing the MAB’s claimed are WURC and which would detect the claimed epitopes.
Further with respect to the 101 rejection, the examiner notes that some of the newly added claims have been shown as patent eligible in light of 101, however that prior art rejections in light of 103 still apply.
Applicant’s arguments with respect to the prior art and claim(s) have been considered but are moot because the new ground of rejection does not rely on the combination of references and particularly not the currently cited primary reference which is new due to amendments made 04/27/2026 and subsequent grounds of rejection as applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
All claims remain rejected.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
GUDIM in US 20220042978 teaches of a method by which NT-proBNP can be determined in a biological sample using at least one antibody which recognizes an epitope of NT-proBNP in both a glycosylated and non-glycosylated form of NT-proBNP. Said antibody is preferably an isolated polyclonal antibody or a mixture of monoclonal antibodies coated onto a particle, preferably coated onto said particle in a coating ratio of 6-60%, forming a layer or multiple layers of antibodies on said particle. The assay, realized in the form of a nephelometric or turbidimetric assay, can be applied to a wide range of automated clinical analyzers (abstract).
GUDIM further teaches of detection of nonglycosylated NT-proBNP( 0026, 0043, 0069, 0079, 0104, 0122, 0124, 0182, table 2).
NISHIKIMI in US 20130260480: NISHIKIMI teaches of a method and kit for determining the overload or atrium or ventricle in a subject, comprising at least a step of measuring levels of proBNP-108 in a sample from the subject. The method further provides for diagnosis, prevention and/or treatment of cardiac diseases, particularly heart failure, aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, and atrial fibrillation (abstract).
NISHIKIMI teaches that the term proBNP-108 refers to precursor of BNP, which includes “glycosylated pro-BNP 108.” NISKIKIMI further teaches that after secretion of proBNP-108 from the ventricular monocyte, it is cleaved into proBNP [7-108] (BNP-32), and N-terminal proBNP[1-76] (NT-proBNP-76)(paragraph 0027).
LEE in US 20160299154: LEE teaches of methods and kits for the prognosis and/or diagnosis of cardiac disorders. LEE further teaches of determining atrial fibrillation (paragraph 0021), by detection of NT-proBNP (paragraph 0046, 0048, 0051).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
Prosecution Insights