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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/23/2026 has been entered.
Status of the Claims
Claim 2 has been cancelled by Applicant. Claims 1, 6, and 13 have been amended by Applicant. Claims 1, 3, 6-7, and 13 are pending and examined herein.
Priority
This application, filed 09/27/2022, is a 371 of PCT/KR2021/004557, filed 04/12/2021, which claims benefit of REPUBLIC OF KOREA 10-2020-0043706, filed 04/10/2020. The benefit is acknowledged and the claims examined herein are treated as having an effective filing date of 04/10/2020.
Withdrawn Rejections/Objections
The rejection under 35 U.S.C. 112(b) of claims 1-3, 6-7, and 13 is withdrawn in response to Applicant’s amendments.
The rejection under 35 U.S.C. 112(d) of claim 2 is withdrawn in response to Applicant’s cancellation of the claim.
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, 3, 6-7, and 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and 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 § 2106.0S(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
Claim 1 recites “A method of diagnosing renal fibrosis in a subject…wherein the pg amphiregulin/mg Cr ratio value of 6.55 or more is indicative of renal fibrosis”. Claim 6 recites “A method of diagnosing renal fibrosis…wherein a pg amphiregulin/mg creatinine ratio value of 6.55 or more is indicative of renal fibrosis”. Claim 13 recites “A method of predicting likelihood of progression to end-stage renal disease…wherein a pg amphirgulin/mg creatinine ration value of 39.905 or more is indicative of likelihood of progression to end-stage renal disease”.
Claims 1, 6, and 13 are directed to the natural correlation between levels of amphiregulin and creatinine in urine and renal fibrosis and end-stage renal disease.
The natural relationship to which the claims are directed (i.e. between levels of amphiregulin and creatinine in urine and renal fibrosis and end-stage renal disease) is a law of nature.
Similar concepts have been held by the courts to constitute law of nature/natural phenomena, as in the identification of a correlation between the presence of in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those as in Mayo as they involve a “relation itself [which] exists in principle apart from any human action” (id. at 77), namely the relationship between the naturally occurring level of amphiregulin and creatinine in bodily fluid (urine) and the presence of impaired kidney function.
The correlation as indicated is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that amphiregulin and creatinine levels are different in relation to kidney function (namely renal fibrosis and likelihood to progress to end-stage renal disease).
Further claim 6 recites “determining a pg amphiregulin/mg creatinine ratio value” and claim 13 recites “determining a pg amphiregulin/mg creatinine ratio value”. Regarding these limitations, “determining” is categorized as an abstract idea, namely it is a mental process performed in the human mind. For example, “determining” encompasses a practitioner simply observing the results and thinking about the quantified result. The claims, under broadest reasonable interpretation, cover performance of these steps solely within the human mind.
Step 2A, Prong 2
Independent claim 1 further recites “detecting an amount of amphiregulin” and “measuring creatinine in the urine sample”. Claim 6 recites “treating a urine sample with a kit comprising an antibody that specifically detects amphiregulin”. Claim 13 recites “treating a urine sample with a kit comprising an antibody that specifically detects amphiregulin”. These steps are considered to be insignificant extra-solution activity, as they are mere data gathering steps (necessary in order to gather the data, namely the steps are merely to perform the immunoassay).
Dependent claim 3 is directed to limiting the version of amphiregulin to be detected, which limits the insignificant extra-solution activity of claim 1 and fails to amount to a practical application of the judicial exception. Similarly, dependent claim 7 is directed toward the characterization of the kit used in the insignificant extra-solution activity of claim 7 and fails to amount to a practical application of the judicial exception
ELIGIBILITY OF STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN “INVENTIVE CONCEPT”
Further, the additional elements of the claims (the active method steps/limitations recited in addition to the judicial exceptions themselves) do not add significantly more to the judicial exception(s); the additional recited claim elements are recited at a high level of generality, and are not, for example, limited to any particular testing technique or platform as claimed.
In this case, it was well-understood, routine and conventional to determine the levels of amphiregulin and creatinine in urine samples to diagnose kidney disease. See US 2014/0147864, “METHODS AND COMPOSITIONS FOR DIAGNOSIS AND PROGNOSIS OF RENAL INJURY AND RENAL FAILURE” (IDS dated 10/16/2022. Published 05/29/2014. Referred herein as Anderberg), as cited in more detail below under 35 U.S.C. 103, supports that measuring amphiregulin and creatinine in urine by immunoassay to diagnose kidney disease (abstract, para. 0014, lines 1-10) and predict likelihood to end-stage renal disease (para. 0014, lines 11-20) was routine and conventional activity previously performed by those of skill in the art. Further, Kefaloyianni et al., “Proximal Tubule–Derived Amphiregulin Amplifies and Integrates Profibrotic EGF Receptor Signals in Kidney Fibrosis” JASN (IDS dated 04/11/2024, published December 2019, referred to herein as Herrlich) teaches that amphiregulin could specifically be used for the diagnosis of renal fibrosis (p. 2381, col. 2, para. 2, lines 1-7).
It does not appear to be the case that the active steps recited, which are performed in order to gather the data or perform the assay, are steps recited or performed in an unconventional or non-routine way, such to provide an inventive concept under step 2B.
The claimed limitations as currently presented fail to recite limitations that add a feature that is more than well-understood, conventional or routine in the field of diagnostics and biochemical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than the judicial exception(s).
Amended Claim Rejections - 35 USC § 103
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.
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, 3, 6-7, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0147864 A1, “METHODS AND COMPOSITIONS FOR DIAGNOSIS AND PROGNOSIS OF RENAL INJURY AND RENAL FAILURE” (published 05/29/2014, referred to herein as Anderberg) in view of Kefaloyianni et al., “Proximal Tubule–Derived Amphiregulin Amplifies and Integrates Profibrotic EGF Receptor Signals in Kidney Fibrosis” JASN (IDS dated 04/11/2024, published December 2019, referred to herein as Herrlich) as evidenced by Watson (Evaluation of novel urinary tract infection biomarkers in children. Pediatric Research. Vol. 79, No. 6, June 2016).
Regarding claims 1 and 6-7, Anderberg teaches teaches using an antibody (para. 0042, lines 1-3) detecting amphiregulin (para. 0013, line 8-9) in an immunodiagnostic kit (para. 0045, lines 1-5) for diagnosing kidney disease in subjects with reduced renal function (para. 0014, lines 7-10) in urine (para. 0042, lines 7-8). Anderberg teaches combining the detection of biomarkers with urine creatinine concentration (para. 0043, line 28).
Regarding claim 3, Anderberg teaches amphiregulin from a polypeptide (Anderberg SEQ ID NO: 10, para. 0072), which is identical to claimed SEQ ID NO: 1.
Regarding claim 13, Anderberg teaches using an antibody (para. 0042, lines 1-3) detecting amphiregulin (para. 0013, line 8-9) for predicting the risk of progression to acute renal failure, i.e. end stage renal disease (para. 0014, lines 11-20). Anderberg teaches combining the detection of biomarkers with urine creatinine concentration (para. 0043, line 28).
Regarding the use of measured biomarkers, such as amphiregulin, to diagnose kidney fibrosis or predict a likelihood of progression to end-stage renal failure, Anderberg teaches that “the measured concentrations may be compared to a threshold value. For a positive going marker, when the measured concentration is above the threshold, a worsening of renal function may be assigned to the subject” (para. 0034, lines 7-11). Relating to the determination of the threshold value(s), Anderberg teaches “the threshold value may be determined from a ‘diseased’ population of subjects…by selecting a concentration the 75th, 85th, 90th, 95th, or 99th percentile of a kidney injury marker measured in such subjects” (para. 0037, lines 7-14) in order to “provide an acceptable level of specificity and sensitivity in separating a population of subjects” (para. 0040, lines 7-9). Anderberg teaches picking a range of amphiregulin cutoff concentrations, from 5.56 – 97.1 pg/mL which result in a range of sensitivity from 18-92% and a range of specificity from 11-81% (para. 0154). Anderberg teaches that the selection of various amphiregulin thresholds has a large impact on the sensitivity and selectivity of the biomarker for distinguishing between populations (para. 0154). Regarding the claimed units of pg/mgCr, Anderberg discloses amphiregulin concentrations in pg/mL (para. 0142, line 8), but teaches that “additional variables or other clinical indicia may be included in the methods” (para. 0043, lines 4-5) including “a urine creatinine concentration” (para. 0043, line 28). A measurement of urine creatinine concentration is common and well-understood measure of urine dilution, as evidenced in Watson et al. ("Evaluation of novel urinary tract infection biomarkers in children." Pediatric research 79.6 (2016): 934-939.) “to account for urine dilution, concentrations of [biomarkers] were normalized to urine creatinine concentration” (p. 938, col. 2, para. 5, lines 12-14).
It would have been obvious to one of ordinary skill in the art at the before the effective filing date of the claimed invention to arrive at the claimed threshold values based on the disclosure of Anderberg. The ordinary artisan would have understood that various thresholds could be determined in order to maximize the sensitivity and selectivity of the assay, as taught by Anderberg. As taught in the instant specification, the threshold values were chosen which “maximizes the sum of sensitivity and specificity” (para. 151, lines 10-12). Further, as evidenced in Watson, the use of mgCr or mL urine both account for urine dilution due to changes in volume; therefore, an ordinary artisan would recognize the use of one or the other as a preferential choice by the practitioner. An artisan would have a reasonable expectation of success because the determination of the threshold, as taught in Anderberg, is decided based on the levels of specificity and selectivity for the assay, as is common in the field of biomarker diagnostics.
Anderberg does not teach the specific diagnosis of kidney fibrosis.
However, Herrlich teaches that amphiregulin could be used as a “diagnostic target in kidney injury and fibrosis” (p. 2381, col. 2, para. 2, lines 1-7). Herrlich teaches that measurement of “sAREG serum/urine levels” could be useful as a “diagnostic target in kidney injury and fibrosis” (p. 2381, col. 2, para. 2, lines 1-7).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method taught by Anderberg for diagnosing kidney disease to specifically diagnose renal fibrosis as taught by Herrlich. An artisan would be motivated to use the method to diagnose renal fibrosis because of the suggestion by Herrlich that amphiregulin could be a good biomarker for renal fibrosis, which is a hallmark of chronic kidney disease (CKD, p. 2370, col. 1, para. 1, lines 7-10). An artisan would have a reasonable expectation of success because antibody-based biomarker detection is a well-known method of biochemical detection in the art and Herrlich teaches that amphiregulin could be used to diagnose kidney fibrosis.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive for the following reasons:
Regarding the remarks on pages 6 and 7 on the rejection of claims 1-3, 6-7, and 13 under 35 U.S.C. 112(b), the rejection has been withdrawn in response to Applicant’s amendment.
Regarding the remarks on page 8 on the rejection of claim 2 under 35 U.S.C. 112(d), the rejection has been withdrawn in response to Applicant’s cancellation of the claim.
Regarding the remarks on pages 9 and 10 on the rejection of claims 1-3, 6-7, and 13 under 35 U.S.C. 103, Applicant argues that the method by which the Applicant’s derived the cutoff values for diagnosing renal fibrosis and predicting likelihood of progression to end-stage renal disease is not described in the prior art.
This argument is not persuasive. As discussed above regarding the rejection under 35 U.S.C. 103, the selection of specific cutoff values based on specificity and sensitivity is a process taught by Anderberg, even if the specific cutoff value selected by the Applicant is different than those taught by Anderberg. The selection of the cutoff values by Applicant is not considered to have any specific critical significance beyond what is to be expected by selecting a cutoff value by routine, well-known processes of detecting biomarkers and choosing cutoff values for diagnosis based on optimized specificity and sensitivity values, such as the process taught by Anderberg.
Regarding the remarks on page 10, Applicant argues that neither Anderberg nor Herrlich contains measured amphiregulin values for end-stage renal disease patients.
This argument is not persuasive. Anderberg does measure amphiregulin levels (para. 0154) and teaches that this method of measuring amphiregulin can be used for predicting the risk of progression to acute renal failure, i.e. end stage renal disease (para. 0014, lines 11-20).
Regarding the remarks on page 10, Applicant argues that Anderberg does not show any experimental results or specific concentration values for amphiregulin as a marker for renal injury.
This argument is not persuasive. Anderberg does measure amphiregulin levels and teaches specific values (para. 0154) in subjects with renal injury.
Regarding the remarks on page 11, Applicant argues that the values of pg/ml, as taught by Anderberg, and “pg/mgCr (creatinine-adjusted pg/mL)” are completely different.
This argument is nor persuasive. The unit of pg/mgCr is equivalent to pg/ml which has been adjusted for creatinine levels in urine, as disclosed in the remarks, and are closely related. Anderberg discloses amphiregulin concentrations in pg/mL (para. 0142, line 8), but teaches that “additional variables or other clinical indicia may be included in the methods” (para. 0043, lines 4-5) including “a urine creatinine concentration” (para. 0043, line 28), which would result in an equivalent unit to pg/mgCr.
Regarding the remarks on page 11, Applicant argues that Anderberg does not provide specific guidance for the diagnosis of renal fibrosis or end-stage renal disease or the use of pg/mgCr in para. 0072.
This argument is not persuasive. Para. 0072 of Anderberg merely describes the sequence of amphiregulin that is measured in their assay, which is identical to Seq ID No. 1 of the instant application, and is not relied upon for the disclosure of diagnosis of renal fibrosis or end-stage renal disease or the use of pg/mgCr.
Further regarding the remarks on page 11, Applicant argues that Herrlich does not teach using the pg/mgCr unit or the specific cutoff values.
This argument is not persuasive. Herrlich is not relied upon in the rejection under 35 U.S.C. 103 for the teaching of these limitations.
Further regarding the remarks on page 11, Applicant argues that the teaching of Herrlich to use amphiregulin as a biomarker for renal injury and fibrosis is not sufficient to achieve the specific threshold values of the invention.
This argument is not persuasive. The teaching of Herrlich in the rejection under 35 U.S.C. 103 is only used to motivate an artisan to use the method taught by Anderberg of amphiregulin detection and threshold determination for the diagnosis of renal fibrosis. The teachings of Anderberg, not Herrlich, is not relied upon to teach a method of determining the threshold values.
Further regarding the remarks on page 11, Applicant argues that Herrlich does not teach the predictive potential of amphiregulin for end-stage renal disease.
This argument is not persuasive. Herrlich is not relied upon in the rejection under 35 U.S.C. 103 for the teaching of this limitation.
Regarding the remarks on page 12, Applicant argues that Watson does not teach using the pg/mgCr unit or the specific cutoff values.
This argument is not persuasive. Watson is not relied upon in the rejection under 35 U.S.C. 103 for the teaching of these limitations.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Yilmaz et al., “Higher urine heat shock protein 70/creatinine ratio in type 1 diabetes mellitus” (published 01/28/2016) supports that, when detecting urinary diagnostic and predictive biomarkers for renal injury, the use of pg/mgCr unit value is routine and well-understood (Abstract, lines 6-17).
No claims are allowable.
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/C.E./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 16, 2026
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