DETAILED ACTION
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 .
Priority
This application was filed on 01/14/2021 and is a 35 U.S.C 371 national stage entry of PCT Application NO. PCT/IB2019/056111 filed on 07/17/2018, which claims benefit of the foreign Application No. Italy 102018000007264 filed 07/17/2018.
Claim status
Claims 2, 7, 13-14, 17 and 19-20 are canceled. Claims 1 and 6 are amended. Claims 1, 3-6, 8-12, 15-16 and 18 are pending and examined herein.
Withdrawn Objections/Rejections
The objection of claims 5 and 10 is withdrawn in view of the amendments of the claims.
The rejection of claims 13-14 under USC 112(f) is withdrawn in view of the cancelation of the claims.
The rejection of claims 1, 3-6, 8-12, and 15-16 under USC 101 is withdrawn in view of the amendment of the claims.
The rejection of claims 1, 3-6, 8-12, and 15-16 under 35 USC 103 is updated in view of the amendment of the claim and Applicant’s arguments filed on 11/06/2025.
The rejections of claim 18 under 35 USC 101 and 103 are maintained.
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.
Claim 18 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 18 recites comparing the normalized value of zinc and PSA with a respective threshold value, and “detecting prostate cancer when …”, which are judicial exceptions (abstract ideas and law of nature). The judicial exceptions are not integrated into a practical application because there is no practical application recited in the claims. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps amount to mere data gathering that does not go beyond well-understood, routine, and conventional activity; as detailed below.
Step 1 – Whether a claim is to a statutory category - YES
Claim 18 is directed a method of diagnosing a prostate cancer based on measuring biomarkers in urine sample of a subject. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) – YES
As explained in MPEP § 2106.04(II), a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
Claim 18 recites “detecting prostate cancer when a normalized value of zinc and a normalized value of PSA are each lower than a respective threshold value”. This step encompasses comparing the normalized value of zinc and PSA with a respective threshold value and assessing the comparison of expression levels of biomarkers in a test sample, and then making an evaluation or judgment as to whether the subject has a prostate cancer. These steps are judicial exceptions (abstract ideas and law of nature) because:
The “comparing” and “determining” steps could be performed in the human mind, or by a human using pen and paper, insofar as it reads on comparing levels and drawing conclusions from this about the specific health condition.
The “detecting” step can also be regarded as a law of nature, namely, the naturally occurring correlation between levels of one or more specific markers and the risk of prostate cancer.
Thus, claim 18 falls into judicial exceptions.
Step 2A Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? NO
The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claim 18 do not recite any additional element that integrate the exception into a practical application of the exception. In general, the additional steps of providing a sample, quantifying the biomarker levels, normalizing the biomarker levels, comparing the test levels with the control levels are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data.
As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP §§ MPEP 2106.04(d)(I) and 2106.05(g).
There are no subsequent steps recited after the “detecting prostate cancer” of claim 18 that would practically apply the method depending on the results of the measurements, e.g., treatment or other process steps that are performed after the subject is determined having prostate cancer.
Step 2B: Whether the additional elements contribute an “inventive concept”
In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, the claim 18 recites a/ providing a sample, b/ quantifying the biomarker levels, c/ normalizing the biomarker levels, and d/ performing prostate biopsy which do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these steps would have been routinely used by those of ordinary skill in the art.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional elements listed above are well-understood, routine, and conventional. This position is supported by Gen Hospital Corp (US 20150004711), Yoon et al. (US 20120252040) and Gaines et al. (Effect of creatinine and specific gravity normalization on urinary biomarker1,6-hexamethylene diamine, J. Environ. Monit., 2010, 12, 591–599).
Gen Hospital Corp teaches methods for determining the likelihood of a subject having prostate cancer based on assays that quantify biomarker, e.g., zinc, in samples (Abstract and par.3) comprising: a/ providing a urine sample of the individual; b/ quantitative determination of the zinc (see par.8: disclosing that quantitative determination of the zinc content in a prostate secretion urine sample obtained from the subject); c/ normalizing the zinc levels with control substance levels (see par.8: the zinc score is determined by precise quantitative determination of the zinc content in a prostate secretion urine sample obtained from the subject followed by normalizing the zinc content in the sample to a control substance, provides a clinically relevant quantitative measure of the likelihood of a subject having prostate cancer); d/ performing prostate biopsy (see par.6: current clinical diagnosis and staging of a prostate cancer relies on four core parameters: digital rectal examination (DRE), serum prostate-specific antigen (PSA), biopsy, and imaging). The teaching in paragraph 6 of Gen Hospital Corp encompasses measuring PSA and doing prostate biopsy is well-known in prostate cancer diagnosis.
Yoon discloses a method for diagnosing prostate cancer, which uses an antibody to prostate-specific antigen (PSA) to detect PSA in human urine. See Abstract. The method comprises a/ obtaining a urine sample from a subject; b/ determining the amount of PSA. See paragraph 13.
Gaines provides that urinary biomarker levels in urine can vary due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample. Therefore, urinary biomarker levels are generally normalized with urinary creatinine concentration, specific gravity, or urine volume. Creatinine has been frequently used to normalize urinary biomarker levels to allow comparison between individuals, thus excluding variations in hydration levels. See Introduction page 591.
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.
Claims 1, 11-12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Gen Hospital Corp (US20150004711 as WO 2013/126501 as cited on the IDS dated 01/26/2021) in view of Bolduc et al. (Urinary PSA: a potential useful marker when serum PSA is between 2.5 ng/mL and 10 ng/mL, CUAI vol.1 issue 4, 2007, IDS dated 01/26/2021) and Prior et al. (Use of a combination of biomarkers in serum and urine to improve detection of prostate cancer, World J Urol (2010) 28:681–686).
Regarding claims 1 and 16, Gen Hospital Corp teaches throughout the document methods for determining the likelihood of a subject having prostate cancer based on assays that quantify zinc in samples (Abstract and par.3).
The method comprises a/ providing a urine sample of the individual; b/ quantitative determination of the zinc (see par.8: disclosing that quantitative determination of the zinc content in a prostate secretion urine sample obtained from the subject); and c/ comparing the quantified value of zinc with a respective threshold value, the respective threshold value being a quantified value of the respective one of zinc in healthy individuals (see par.9: teaching that the subject is at risk of prostate cancer if a zinc score is 85% or less of the average zinc score for a population of healthy adult males).
The method further comprises d/ diagnosing the individual for performance of a prostate biopsy for prostate cancer only when the quantified value of zinc is lower than the respective threshold value (see par.9: teaching that the zinc score is equal to the concentration of zinc multiplied by the control substance concentration, e.g., creatinine concentration, wherein the subject is at risk of prostate cancer if the score is 85% or less of the average zinc score for a population of healthy adult males; see par.16: teaches that a decrease in the zinc score over time indicates the subject being at risk of having or developing prostate cancer). In other words, the subject is at risk of prostate cancer if the level of zinc is lower than that in the healthy group.
The method further comprises performing the prostate biopsy for prostate cancer on the diagnosed patient (see par.13 and par.68: teaching that if the score is less than 85% of the average zinc score for a population of healthy adult males, the subject is recommended to be treated or to undergo further testing or monitoring for prostate cancer, wherein the further testing encompasses performing a prostate biopsy). This teaching encompasses step e of claim 1.
The limitation in claim 16, “80% of individuals with prostate cancer have a zinc value below the respective threshold and 80% of individuals with prostate cancer have a value of PSA, as measured by utPSA and/or ufPSA below the respective threshold value” does not impart any active step of the method of detecting prostate cancer. In fact, it is a screening result of the claimed method in a study population, thus it is not patentable weight.
Gen Hospital Corp doesn’t teach measuring prostate specific antigen (PSA) in the urine sample for diagnosing the individual for performance of a prostate biopsy for prostate cancer.
Bolduc evaluates the usefulness of urinary prostate specific antigen (uPSA) in the differential diagnosis of benign prostatic hyperplasia (BPH) and prostate cancer, so the number of unnecessary prostatic biopsies can be decreased (see Abstract).
The evaluation comprises a/ providing a urine sample of the individual; b/ quantitative determination of the uPSA (see Abstract: disclosing that uPSA from prostate cancer, BPH patients, and age-matched control subjects are measured);
c/ comparing the quantified value of uPSA with a respective threshold value, the respective threshold value being a quantified value of the respective one of uPSA in healthy individuals (see page 378 col.2 par.2: teaching that age-matched control subjects have no clinical symptoms of BPH, which encompasses healthy individuals, see Table 1: showing a comparison of uPSA among prostate cancer, BPH, and control groups);
d/ the quantified value of uPSA is lower than the threshold value from the control group (see Table 1: showing uPSA in prostate cancer group 52.9 ng/ml, uPSA in control group 105 ng/ml);
diagnosing the individual for performance of a prostate biopsy for prostate cancer only when the uPSA is lower than the respective threshold value (see page 380 col.1 par.2: “patients with a serum PSA between 2.5 ng/mL and 10 ng/mL will often undergo TRUS with prostate biopsies to rule out prostate cancer. Only 20%–30% of these men will have positive biopsies, meaning that the majority of men undergo these invasive investigations with little benefit.”
Bolduc teaches that uPSA could be a tool to differentiate the prostate cancer from BPH, to reduce the number of negative TRUS biopsies especially in the gray zone of serum PSA (2.5–10 ng/mL). Bolduc suggests that a urinary PSA threshold of > 150 ng/mL might be used to decrease the number of prostatic biopsies (see page 380 col.2 par.3). This teaching encompasses performing the prostate biopsy for prostate cancer on the diagnosed patient.
Prior provides a concept of improving detection of prostate cancer (PCa) by analyzing a combination of multi-markers in bodily fluid from patients with tumor and controls without tumor (see Abstract). Prior emphasizes that the repeated biopsies when patients continue to exhibit suspicious clinical signs may cause psychological stress to both patients and doctors, with attendant pain, inconvenience, financial costs, and risk of infection (see page 682 col.1 par.2). Prior teaches no single biomarker is likely to achieve the desired level of diagnostic and prognostic accuracy for PCa because this disease is multifocal and genetically heterogeneous (See page 682 col.1 par.4). Prior demonstrates that analysis of combinations of biomarkers may greatly improve diagnosis of PCa (see Abstract, page 685 col.2 par.2).
Prior suggests future diagnostic tests should probably rely on panels of markers (even new candidate markers) in serum and/or urine for optimal screening and risk assessment to achieve the accuracy of prostate cancer detection tests (see page 682 col.2, page 685 col.2 par.3). This would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies (see page 682, and page 685 col.2 par.3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by Gen Hospital Corp with the method taught by Bolduc, analyzing the combination of multi-markers, e.g., urinary Zinc and PSA for prostate cancer diagnosis because Gen Hospital Corp and Bolduc teach using urinary Zinc and PSA, in respectively, as prostate biomarkers because the concentrations of zinc and PSA in urine sample are prostate cancer clinically relevant (see Gen Hospital Corp par.(s).8-9, see Bolduc Tables 1-2 and page 380), and Prior teaches the combined analysis of multi-markers would improve the accuracy of PCa (see Prior Abstract, page 685 col.2 par.2). The improvement in PCa detection would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies to balance the risk and benefit of biopsy test for the PCa suspected patients (see Gen Hospital Corp par.68, Bolduc page 380, and Prior page 682).
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Bolduc and Prior because they are directed to the methods of diagnosing prostate cancer by detecting biomarker(s) in urine sample. While Gen Hospital Corp and Bolduc teach using a single marker for PCa diagnosis, Prior demonstrates that analysis of combinations of biomarkers may greatly improve diagnosis of PCa.
Regarding claim 11, Gen Hospital Corp, Bolduc and Prior teach method according to claim 1, wherein the quantification of the zinc is performed by means of colorimetric test. (Gen Hospital Corp further teaches a method of determining the level of zinc in a sample using optical detection of a signal in a colorimetric (see par.50)).
Regarding claim 12, Gen Hospital Corp, Bolduc and Prior teach method according to claim 1, wherein the quantification of the total PSA (utPSA) and/or of the free PSA (ufPSA) is performed by means of immunoassay (see Bolduc in page 378 col.1 par.4: teaching that Urinary PSA was expressed in ng/mL and an enzyme-linked immunosorbent assay method).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Gen Hospital Corp in view of Bolduc and Prior, as applied in claim 1 above, and further in view of Chinnaiyan et al (US 20110151497).
Regarding claim 3, Gen Hospital Corp, Bolduc and Prior teach method according to claim 1. They do not teach wherein in step b) spermine is also quantified and in step c) the quantified value of spermine is compared with a threshold value, the threshold value being a quantified value of spermine in healthy individuals.
Chinnaiyan teaches a method of diagnosing prostate cancer comprising: detecting one or more cancer specific markers (e.g., spermine) in a sample (e.g., urine) from a subject (see par.10). Chinnaiyan teaches that the advent of prostate specific antigen (PSA) screening has led to earlier detection of PCA and significantly reduced PCA-associated fatalities. However, coincident with increased serum PSA testing, there has been a dramatic increase in the number of prostate needle biopsies performed. Thus, developing additional biomarkers to supplement PSA screening is needed to reduce the equivocal biopsies. See paragraphs 8, 10 and 107.
Chinnaiyan teaches that a panel of markers is useful in diagnostic, prognostic, screening or therapeutic applications (see par.85).
Chinnaiyan teaches that the spermine is also quantified and the quantified value of spermine is compared with a reference value (see par.42, Fig.23: showing the difference of spermine levels between positive prostate cancer patients and biopsy-negative controls). The control or reference values are from biopsy-negative controls or benign controls (see par.179-180). The teaching encompasses that the reference values are from healthy individuals.
See the discussion of Gen Hospital Corp, Bolduc, and Prior in claim 1 above about the combination of biomarkers for accurate disease diagnosis and unnecessary biopsy reduction.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the methods taught by Gen Hospital Corp and Bolduc with the method taught by Chinnaiyan because Chinnaiyan suggests that spermine is an additional prostate cancer marker supplemented to PSA in prostate cancer screening to reduce the equivocal prostate biopsy results (see par.8-10, 17 and 107). Moreover, Chinnaiyan and Prior teach the combined analysis of multi-markers would improve the accuracy of PCa (see Chinnaiyan par.85 and see Prior Abstract, page 685 col.2 par.2). The improvement in PCa detection would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies to balance the risk and benefit of biopsy test for the PCa suspected patients (see Gen Hospital Corp par.68, Bolduc page 380, Prior page 682, and Chinnaiyan par.8).
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Bolduc, Prior and Chinnaiyan because they are directed to the methods of diagnosing prostate cancer by detecting biomarker(s) in urine sample. While Gen Hospital Corp and Bolduc teach using a single marker for PCa diagnosis, Prior and Chinnaiyan demonstrate that analysis of combinations of biomarkers may greatly improve diagnosis of PCa.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Gen Hospital Corp in view of Bolduc and Prior, as applied in claim 1 above, and further in view of Casero et al (Casero RA, Pegg AE. Polyamine catabolism and disease. Biochem J. 2009 Jul 15;421(3):323-38., IDS dated 01/26/2021) and Chinnaiyan et al (US 20110151497).
Regarding claims 4-5, Gen Hospital Corp, Bolduc and Prior teach method according to claim 1. They do not teach that in spermine oxidase (SMOX) is also quantified and the quantified value of spermine is compared with a reference value (according to instant claim 4); and the total PSA (prostate specific antigen) (utPSA), the zinc and the spermine oxidase (SMOX) are quantified and in step c) the quantified values of total PSA (prostate specific antigen) (utPSA), zinc and spermine oxidase (SMOX) are compared with a respective threshold value, the respective threshold value being the quantified value of the respective one of total PSA, zinc, and spermine oxidase in health individuals (according to instant claim 5).
Casero teaches throughout the document the relationship between catabolism of polyamines such as spermine through activity of spermine oxidase (SMOX or SMO) and diseases such as cancer (Abstract, and Fig.1 shows spermine oxidase as a compound that is related to spermine and is involved with its metabolic pathway.).
Casero further teaches spermine oxidase is expressed at higher levels in prostate cancer tissue compared to normal prostate tissue (Fig. 6 and page 334, col. 1, par.1, lines 1-9: teaching that expression of SMOX was uniformly higher in all of the tissues of the prostate cancer patients than in the normal prostate tissues).
Chinnaiyan teaches a method of diagnosing prostate cancer comprising: detecting one or more cancer specific markers (e.g., spermine) in a sample (e.g., urine) from a subject (see par.10). Chinnaiyan suggests that spermine is an additional prostate cancer marker supplemented to PSA in prostate cancer screening to reduce the equivocal prostate biopsy results (see par.8-10, 17 and 107). Additionally, the level(s) of the one or more metabolites may be measured indirectly, for example, by using an assay that measures the level of a compound (or compounds) that correlates with the level of the biomarker(s) that are desired to be measured (see par.93).
Since Casero teaches that there is a relationship between catabolism of polyamines such as spermine through activity of spermine oxidase (SMOX or SMO) and diseases such as prostate cancer as discussed above, SMOX can be used as an alternative marker for spermine to detect prostate cancer as taught by Chinnaiyan.
At the same time, Gen Hospital Corp further teaches that the expressed prostate secretion fluids were obtained following gentle prostate massage during digital rectal examination prior to biopsy (see par.213). Chinnaiyan further teaches that digital rectal examination causes prostate cells to shed into the urinary tract (see par.88). Therefore, there is a reasonable expectation that SMOX can be detected in urine sample. Accordingly, the value of SMOX in urine of the prostate cancer patient is expected to be higher in the patient with prostate cancer than that in healthy control as taught by Casero.
See the discussion of Gen Hospital Corp, Bolduc, and Prior in claim 1 above about the combination of biomarkers for accurate disease diagnosis and unnecessary biopsy reduction.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by Gen Hospital Corp, Bolduc and Casero, quantifying the amount of the three biomarkers (e.g., zinc, PSA, and spermine oxidase) for the purpose of performing a prostate biopsy for prostate cancer detection because Gen Hospital Corp and Bolduc teach that the decrease in the amount of zinc and PSA, respectively, indicates the subject being at risk of having or developing prostate cancer, and the combination teaching of Gen Hospital Corp, Chinnaiyan and Casero suggests that SMO can be an alternative biomarker for prostate cancer instead of using spermine as discussed above. Moreover, Chinnaiyan and Prior teach the combined analysis of multi-markers would improve the accuracy of PCa (see Chinnaiyan par.85 and see Prior Abstract, page 685 col.2 par.2). The improvement in PCa detection would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies to balance the risk and benefit of biopsy test for the PCa suspected patients (see Gen Hospital Corp par.68, Bolduc page 380, Prior page 682, and Chinnaiyan par.8).
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Bolduc, Prior, Casero and Chinnaiyan because they are directed to the methods of diagnosing prostate cancer by detecting biomarker(s) in biological samples. While Gen Hospital Corp, Bolduc, Casero and Chinnaiyan teach using a single marker for PCa diagnosis, Prior and Chinnaiyan demonstrate that analysis of combinations of biomarkers may greatly improve diagnosis of PCa.
Claims 6 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Gen Hospital Corp in view of Bolduc and Prior, as applied in claim 1 above, and further in view of Gaines et al. (Effect of creatinine and specific gravity normalization on urinary biomarker1,6-hexamethylene diamine, J. Environ. Monit., 2010, 12, 591–599, PTO 892 06/06/2025).
Regarding claim 6, Gen Hospital Corp, Bolduc and Prior teach method according to claim 1. The method of claim 1 differs from the method of claim 6 in step d/ and e/, normalizing the quantified value of zinc and the quantified value of PSA with the quantified value of a molecule having molecular formula C4H7N30 (creatinine); and comparing the normalized value of zinc and the normalized value of PSA with a respective threshold value, the respective threshold value being a normalized value with the molecule having molecular formula C4H7N30 (creatinine) of the respective one of zinc and PSA in healthy individuals.
Gen Hospital Corp, in par(s).8-10, discloses that the zinc score is determined by precise quantitative determination of the zinc content in a prostate secretion urine sample obtained from the subject followed by normalizing the zinc content in the sample to a control substance, provides a clinically relevant quantitative measure of the likelihood of a subject having prostate cancer (see par.8), wherein the control substance comprises creatinine (see par.10). This teaching encompasses the step d/ and e/ of claim 6.
While Bolduc does not teach normalizing the value of uPSA with the value of creatinine, Bolduc adjusts the value of uPSA with the prostate volume before comparing the value of uPSA among individuals (see page 379 col.1 par.1, Table 2). The teaching of Bolduc is also a way to normalize the value of uPSA, so that the value of uPSA among individuals can be compared to each other.
In addition, Gaines provides that urinary biomarker levels in urine can vary due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample. Therefore, urinary biomarker levels are generally normalized with urinary creatinine concentration, specific gravity, or urine volume. Creatinine has been frequently used to normalize urinary biomarker levels to allow comparison between individuals, thus excluding variations in hydration levels. See Introduction page 591.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the normalization method of Gaines in the method taught by Bolduc because the normalization methods of Gaines and Bolduc are functionally equivalent. The motivation of normalizing the value of biomarkers comes from the teaching of Gaines, which urinary biomarker levels in urine can vary from person to person due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample. Thus, the normalized concentrations of biomarkers relatively with creatinine as taught by Gaines or with the prostate volume as taught by Bolduc would allow comparison between individuals. Therefore, the normalization of urinary biomarkers is another way to improve the accuracy of the prostate cancer detection.
One having ordinary skill in the art would have had a reasonable expectation of success in substituting the normalization method of Gaines in the method taught by Bolduc because Gen Hospital Corp supports for the successfulness of normalizing the value of biomarker in urine sample with the creatinine value in urine.
Regarding claim 15, Gen Hospital Corp, Bolduc, Prior, and Gaines teach method according to claim 6, wherein the quantification of the total PSA (utPSA) and/or of the free PSA (ufPSA) is performed by means of immunoassay (see Bolduc in page 378 col.1 par.4: teaching that Urinary PSA was expressed in ng/mL and an enzyme-linked immunosorbent assay method).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Gen Hospital Corp in view of Bolduc, Prior, and Gaines as applied in claim 6 above, and further in view of Chinnaiyan et al (US 20110151497).
Regarding claim 8, Gen Hospital Corp, Bolduc, Prior and Gaines teach method according to claim 6. They do not teach wherein in step b') spermine is quantified, in step d') the quantified value of spermine is normalized with the quantified value of a molecule having molecular formula C4H7N30 (creatinine), and in step e') the normalized value of spermine is compared with a threshold value, the threshold value being a normalized value with the molecule having molecular formula C4H7N30 (creatinine) of spermine in healthy individuals.
Chinnaiyan teaches a method of diagnosing prostate cancer comprising: detecting one or more cancer specific markers (e.g., spermine) in a sample (e.g., urine) from a subject (see par.10). Chinnaiyan teaches that the advent of prostate specific antigen (PSA) screening has led to earlier detection of PCA and significantly reduced PCA-associated fatalities. However, coincident with increased serum PSA testing, there has been a dramatic increase in the number of prostate needle biopsies performed. Thus, developing additional biomarkers to supplement PSA screening is needed to reduce the equivocal biopsies. See paragraphs 8, 10 and 107.
Chinnaiyan teaches that a panel of markers is useful in diagnostic, prognostic, screening or therapeutic applications (see par.85).
Chinnaiyan teaches that the spermine is also quantified and the quantified value of spermine is compared with a reference value (see par.42, Fig.23: showing the difference of spermine levels between positive prostate cancer patients and biopsy-negative controls). The control or reference value is from biopsy-negative controls or benign controls (see par.179-180), thus encompasses the reference value is from healthy individuals. Data is also normalized according to creatinine levels in the samples (see par.176).
Gaines teaches that the normalized concentrations of biomarkers relatively with creatinine would allow comparison between individuals. See Introduction page 591
See the discussion of Gen Hospital Corp, Bolduc, Prior in claim 1 above about the combination of biomarkers for accurate disease diagnosis and unnecessary biopsy reduction.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the methods taught by Gen Hospital Corp and Bolduc with the method taught by Chinnaiyan because Chinnaiyan suggests that spermine is an additional prostate cancer marker supplemented to PSA in prostate cancer screening to reduce the equivocal prostate biopsy results (see par.8-10, 17 and 107). Moreover, Chinnaiyan and Prior teach the combined analysis of multi-markers would improve the accuracy of PCa (see Chinnaiyan par.85 and see Prior Abstract, page 685 col.2 par.2). The improvement in PCa detection would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies to balance the risk and benefit of biopsy test for the PCa suspected patients (see Gen Hospital Corp par.68, Bolduc page 380, Prior page 682, and Chinnaiyan par.8).
Since urinary biomarker levels in urine can vary from person to person due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample, the normalized concentrations of biomarkers relatively with creatinine as taught by Gaines would allow comparison between individuals. Therefore, the normalization of urinary biomarkers with creatinine is another way to improve the accuracy of the prostate cancer detection.
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Bolduc, Prior and Chinnaiyan because they are directed to the methods of diagnosing prostate cancer by detecting biomarker(s) in urine sample. While Gen Hospital Corp and Bolduc teach using a single marker for PCa diagnosis, Prior and Chinnaiyan demonstrate that analysis of combinations of biomarkers may greatly improve diagnosis of PCa.
One having ordinary skill in the art would have had a reasonable expectation of success in substituting the normalization method of Gaines in the method taught by Bolduc and Chinnaiyan because Gen Hospital Corp supports for the successfulness of normalizing the value of biomarker in urine sample with the creatinine value in urine.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Gen Hospital Corp in view of Bolduc, Prior and Gaines, as applied in claim 6 above, and further in view of Casero et al (Casero RA, Pegg AE. Polyamine catabolism and disease. Biochem J. 2009 Jul 15;421(3):323-38., IDS dated 01/26/2021) and Chinnaiyan et al (US 20110151497).
Regarding claims 9-10, Gen Hospital Corp, Bolduc and Prior teach method according to claim 6. See the discussion of Gen Hospital Corp, Bolduc, and Prior in claim 1 above about the combination of biomarkers for accurate disease diagnosis and unnecessary biopsy reduction.
They do not teach that in spermine oxidase (SMOX) is also quantified and the quantified value of spermine is compared with a reference value (according to instant claim 9); and the total PSA (prostate specific antigen) (utPSA), the zinc and the spermine oxidase (SMOX) are quantified and in step c) the quantified values of total PSA (prostate specific antigen) (utPSA), zinc and spermine oxidase (SMOX) are compared with a respective threshold value, the respective threshold value being the quantified value of the respective one of total PSA, zinc, and spermine oxidase in health individuals (according to instant claim 10).
Casero teaches throughout the document the relationship between catabolism of polyamines such as spermine through activity of spermine oxidase (SMOX or SMO) and diseases such as cancer (Abstract, and Fig.1 shows spermine oxidase as a compound that is related to spermine and is involved with its metabolic pathway.).
Casero further teaches spermine oxidase is expressed at higher levels in prostate cancer tissue compared to normal prostate tissue (Fig. 6 and page 334, col. 1, par.1, lines 1-9: teaching that expression of SMOX was uniformly higher in all of the tissues of the prostate cancer patients than in the normal prostate tissues).
Chinnaiyan teaches a method of diagnosing prostate cancer comprising: detecting one or more cancer specific markers (e.g., spermine) in a sample (e.g., urine) from a subject (see par.10). Chinnaiyan suggests that spermine is an additional prostate cancer marker supplemented to PSA in prostate cancer screening to reduce the equivocal prostate biopsy results (see par.8-10, 17 and 107). Additionally, the level(s) of the one or more metabolites may be measured indirectly, for example, by using an assay that measures the level of a compound (or compounds) that correlates with the level of the biomarker(s) that are desired to be measured (see par.93).
Since Casero teaches that there is a relationship between catabolism of polyamines such as spermine through activity of spermine oxidase (SMOX or SMO) and diseases such as prostate cancer as discussed above, SMOX can be used as an alternative marker for spermine to detect prostate cancer as taught by Chinnaiyan.
At the same time, Gen Hospital Corp further teaches that the expressed prostate secretion fluids were obtained following gentle prostate massage during digital rectal examination prior to biopsy (see par.213). Chinnaiyan further teaches that digital rectal examination causes prostate cells to shed into the urinary tract (see par.88). Therefore, there is a reasonable expectation that SMOX can be detected in urine sample. Accordingly, the value of SMOX in urine of the prostate cancer patient is expected to be higher in the patient with prostate cancer than that in healthy control as taught by Casero.
In addition, Gaines provides that urinary biomarker levels in urine can vary due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample. Therefore, urinary biomarker levels are generally normalized with urinary creatinine concentration, specific gravity, or urine volume. Creatinine has been frequently used to normalize urinary biomarker levels to allow comparison between individuals, thus excluding variations in hydration levels. See Introduction page 591.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by Gen Hospital Corp, Bolduc and Casero, quantifying the amount of the three biomarkers (e.g., zinc, PSA, and spermine oxidase) for the purpose of performing a prostate biopsy for prostate cancer detection because Gen Hospital Corp and Bolduc teach that the decrease in the amount of zinc and PSA, respectively, indicates the subject being at risk of having or developing prostate cancer, and the combination teaching of Gen Hospital Corp, Chinnaiyan and Casero suggests that SMO can be an alternative biomarker for prostate cancer instead of using spermine as discussed above. Moreover, Chinnaiyan and Prior teach the combined analysis of multi-markers would improve the accuracy of PCa (see Chinnaiyan par.85 and see Prior Abstract, page 685 col.2 par.2). The improvement in PCa detection would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies to balance the risk and benefit of biopsy test for the PCa suspected patients (see Gen Hospital Corp par.68, Bolduc page 380, Prior page 682, and Chinnaiyan par.8).
Since urinary biomarker levels in urine can vary from person to person due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample, the concentrations of biomarker spermine oxidase in urine should be normalized with creatinine because Gaines teaches the normalization would allow comparison between individuals. Therefore, the normalization of urinary biomarkers with creatinine is another way to improve the accuracy of the prostate cancer detection.
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Bolduc, Prior, Casero and Chinnaiyan because they are directed to the methods of diagnosing prostate cancer by detecting biomarker(s) in biological samples. While Gen Hospital Corp, Bolduc, Casero and Chinnaiyan teach using a single marker for PCa diagnosis, Prior and Chinnaiyan demonstrate that analysis of combinations of biomarkers may greatly improve diagnosis of PCa.
One having ordinary skill in the art would have had a reasonable expectation of success in substituting the normalization method of Gaines in the method taught by Bolduc and Chinnaiyan because Gen Hospital Corp supports for the successfulness of normalizing the value of biomarker in urine sample with the creatinine value in urine.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Gen Hospital Corp (US20150004711 as WO 2013/126501 as cited on the IDS dated 01/26/2021) in view of Yoon et al. (US20120252040, PTO-892 11/27/2024), Gaines et al. (Effect of creatinine and specific gravity normalization on urinary biomarker1,6-hexamethylene diamine, J. Environ. Monit., 2010, 12, 591–599, PTO 892 06/06/2025), Buechler et al. (WO2004059293, PTO-892 11/27/2024), and Vartsky et al. (Prostatic Zinc and Prostate Specific Antigen: An Experimental Evaluation of Their Combined Diagnostic Value, Journal of Urology 2003, PTO 892 06/06/2025).
Regarding claim 18, Gen Hospital Corp teaches method of detecting prostate cancer in an individual, the method comprising: a/ providing a urine sample of the individual (see Abstract and par(s).8-10); b/ quantifying zinc in the urine sample using a colorimetric test (see Abstract and par(s).8-10 and 50); d/ normalizing the quantified zinc to normalized values with respect to a value of creatinine in the urine sample (see Abstract and par(s).8-10); e/ detecting prostate cancer when a normalized value of zinc is lower than a threshold value, wherein the threshold value is a normalized value with respect to a value of creatinine of zinc in healthy individuals (see Abstract and par(s).8-10, and 16). See discussion of Gen Hospital Corp in claims 1, 6 and 11 above.
The limitation “80% of individuals with prostate cancer have a zinc value below the respective threshold and 80% of individuals with prostate cancer have a value of PSA, as measured by utPSA and/or ufPSA below the respective threshold value” does not impart any active step of the method of detecting prostate cancer. In fact, it is a screening result of the claimed method in a study population, thus it is not patentable weight.
Gen Hospital Corp doesn’t teach measuring prostate specific antigen (PSA) in the urine sample for detecting a prostate cancer.
Yoon discloses a method for diagnosing prostate cancer, which uses an antibody to prostate-specific antigen (PSA) to detect PSA in human urine. See Abstract. The method comprises a/ obtaining a urine sample from a subject; c/ determining the amount of PSA by immunoassay; c/ comparing the amount of PSA in a subject with a reference amount, wherein the reference amount is from healthy individuals. See paragraphs 12-13, 20, 25 and 28.
(See par.20: teaching that the reference is obtained from a normal subject who has no prostate cancer. See par.12, Yoon determines that a subject has prostate cancer when the amount of PSA detected in the human urine of a subject by a PSA-specific antigen is smaller than that in normal persons. The normal person taught by Yoon encompasses healthy individuals recited in the claims. See par.25 and 28, Yoon also teaches that PSA in a urine sample is measured by immunoassay.)
Yoon generally teaches detecting the levels of PSA in the urine sample, thus encompassing the detection of total PSA or free PSA in the urine sample. From the teaching, the amount of total and/or free PSA in a patient is lower than that in a healthy control.
However, Yoon does not teach normalizing PSA levels with the creatinine levels.
In addition, Gaines provides that urinary biomarker levels in urine can vary due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample. Therefore, urinary biomarker levels are generally normalized with urinary creatinine concentration, specific gravity, or urine volume. Creatinine has been frequently used to normalize urinary biomarker levels to allow comparison between individuals, thus excluding variations in hydration levels. See Introduction page 591.
Furthermore, Buechler teaches methods for the identification and use of diagnostic markers for differential diagnosis of diseases and/or conditions (Abstract). To identify subjects at risk for an underlying disease, i.e. prostate cancer, the concentration of biomarker(s) in a sample is compared to a threshold amount (see in par.12-13). Buechler provides that the advantage of using a panel of markers over a single marker is to increase the effectiveness of the test (see in par.282, 303).
In addition, Vartsky suggests the possibility of using prostatic zinc combined with prostate specific antigen (PSA) as a novel tool for the reliable diagnosis of prostate cancer. A combination of these parameters represents a significant improvement on the diagnostic value of each of them separately and provides a powerful tool for more accurate diagnosis. See page 2. Although Vartsky detects the biomarkers in serum sample, Vartsky also proves the advantage of using a panel of markers over a single marker in increasing the effectiveness of the diagnosis test.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by Gen Hospital Corp with the method taught by Yoon, quantifying the amount of the two biomarkers (e.g., zinc and PSA) for prostate cancer detection because Gen Hospital Corp and Yoon teach that the decrease in the amount of zinc and PSA, respectively, indicates the subject being at risk of having or developing prostate cancer.
A person of ordinary skill in the art would have been motivated to combine these teachings because the probability of having a disease would have been defined effectively and accurately (see at least in Buechler par.35 last sentence and Vartsky page 2). As discussed above, Buechler is generic to suggest the advantage of analyzing a panel of biomarkers for diseases diagnosis (Buechler: Abstract). Additionally, Vartsky is specific for prostate cancer detection based on the combination of zinc and PSA levels.
Since urinary biomarker levels in urine can vary due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample, one skilled in the art would have been aware that the diagnosis can be based on the normalized concentrations of biomarkers relatively with creatinine as taught by Gaines because it allows comparison between individuals. Therefore, the normalization of urinary biomarkers with creatinine is another way to improve the accuracy of the prostate cancer detection.
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Yoon, Gaines, Buechler and Vartsky because: Gen Hospital Corp and Yoon are drawn to methods of using a single urinary biomarker to diagnose a prostate cancer, Gaines provides a method of analyzing urinary biomarker levels so that the adjusted values of biomarkers can be compared between subjects, and Buechler and Vartsky provides a more accurate and effective method for disease diagnosis, e.g., prostate cancer, by using a panel of biomarker analysis.
Response to Arguments
Applicant's arguments in the Remarks and the Affidavit filed 11/06/2025 have been fully considered.
In the Remarks, Applicant requests a reconsideration of the rejections under section 101. The rejection of claims 1, 3-6, 8-12, 15-16 under USC 101 is withdrawn in view of the amendment of the claims. The rejection of claim 18 under USC 101 is maintained.
In the Remarks, Applicant argues that none of the applied references discloses or suggests the combined use of zinc and PSA in detecting prostate cancer only when both values are less than the respective threshold as in claim 18.
This argument is not persuasive because the combined teaching of Gen Hospital Corp, Yoon, Gaines, Buechler and Vartsky encompasses the limitations of the claim. Gen Hospital Corp and Yoon are drawn to methods of using a single urinary biomarker to diagnose a prostate cancer. Gen Hospital Corp teaches quantifying the amount of zinc in urine for prostate cancer detection. Yoon teaches quantifying the amount of PSA in urine for prostate cancer detection. Gen Hospital Corp and Yoon teach that the decrease in the amount of zinc and PSA, respectively, indicates the subject being at risk of having or developing prostate cancer.
Buechler is generic to suggest the advantage of analyzing a panel of biomarkers for diseases diagnosis (Buechler: Abstract). Vartsky is specific for prostate cancer detection based on the combination of zinc and PSA levels. Varsky supports the advantage of analyzing a panel of biomarkers for prostate cancer detection. A person of ordinary skill in the art would have been motivated to combine Gen Hospital Corp and Yoon because the probability of having a disease would have been defined effectively and accurately when using a panel of markers (see at least in Buechler par.35 last sentence and Vartsky page 2). Therefore, the combination of Gen Hospital Corp and Yoon would have been obvious to improve the accuracy of the prostate cancer detection.
In addition, since urinary biomarker levels in urine can vary due to the person’s hydration level that in turn is reflected in the water content of the collected urine sample, normalized concentrations of biomarkers relatively with creatinine allows comparison between individuals (see discussion of Gaines). Therefore, the normalization of urinary biomarkers with creatinine is another way to improve the accuracy of the prostate cancer detection.
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Yoon, Gaines, Buechler and Vartsky because: Gen Hospital Corp and Yoon are drawn to methods of using a single urinary biomarker to diagnose a prostate cancer, Gaines provides a method of analyzing urinary biomarker levels so that the adjusted values of biomarkers can be compared between subjects, and Buechler and Vartsky support a more accurate and effective method for disease diagnosis, e.g., prostate cancer, by using a panel of biomarker analysis.
In the Remarks and the Affidavit, Applicant argues that none of the applied references discloses or suggests the combined use of zinc and PSA in performing prostatic biopsy only when both values are less than the respective threshold as in claims 1 and 6.
Applicant stated that the Applicant’s invention related to an improved method for diagnosing prostate cancer and/or the aggressiveness of prostate cancer in an individual using quantification of zinc and prostate specific antigen (PSA) in a urine sample. The invention has shown that when both PSA and Zinc levels in an individual are simultaneously low in urine in relatively with levels typically found in healthy individuals, it is highly indicative of the presence of prostate cancer in the individual. The finding at section 12 and 13 of the declaration highlights the unique value of the PSA-Zinc urinary combination as a biomarker capable of identifying clinically significant prostate cancers, those that are progressing and therefore require biopsy and clinical intervention. The ability to detect such cases is significant advance for improving patient outcomes and avoiding unnecessary procedures in men with indolent or non-progressive disease. Therefore, the combined assessment of these two biomarkers provides a reliable method to identify men who should undergo prostate biopsy.
Applicant argued that none of the references that were applied in the action suggest using levels of both PSA and zinc in urine to improved diagnostics or how to treat testing data. Rather, individual use of either zinc levels or PSA levels is disclosed. In such instances, given that the references teach each individually as diagnostically relevant, the skilled person would perform the biopsy when only one threshold is met.
These arguments are not persuasive, and the rejections are updated in view of the amendment of the claims. The amended limitations are taught by references Gen Hospital Corp, Bolduc, Prior, Gaines, Chinnaiyan and Casero.
Briefly, Gen Hospital Corp teaches that a subject is at risk of prostate cancer if the level of zinc in a urine sample is lower than that in the healthy group. Gen Hospital Corp teaches performing the prostate biopsy for prostate cancer on the subject if the urinary zinc score is less than 85% of the average urinary zinc score for a population of healthy adult males. See discussion of Gen Hospital Corp in claim 1 above.
Bolduc evaluates the usefulness of urinary prostate specific antigen (uPSA) in the differential diagnosis of benign prostatic hyperplasia (BPH) and prostate cancer, so the number of unnecessary prostatic biopsies can be decreased (see Abstract). The quantified value of uPSA is lower than the threshold value from the control group. Bolduc teaches that uPSA could be a tool to differentiate the prostate cancer from BPH, to reduce the number of negative TRUS biopsies especially in the gray zone of serum PSA (2.5–10 ng/mL). Bolduc suggests that a urinary PSA threshold of > 150 ng/mL might be used to decrease the number of prostatic biopsies (see page 380 col.2 par.3). See discussion of Bolduc in claim 1 above.
Prior emphasizes that the repeated biopsies when patients continue to exhibit suspicious clinical signs may cause psychological stress to both patients and doctors, with attendant pain, inconvenience, financial costs, and risk of infection (see page 682 col.1 par.2). Prior demonstrates that analysis of combinations of biomarkers may greatly improve diagnosis of PCa (see Abstract, page 685 col.2 par.2). Prior suggests future diagnostic tests should probably rely on panels of markers (e.g., new candidate markers) in serum and/or urine for optimal screening and risk assessment to achieve the accuracy of prostate cancer detection tests (see page 682 col.2, page 685 col.2 par.3). This would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies (see page 682, and page 685 col.2 par.3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by Gen Hospital Corp with the method taught by Bolduc, analyzing the combination of multi-markers, e.g., urinary Zinc and PSA for prostate cancer diagnosis because Gen Hospital Corp and Bolduc teach using urinary Zinc and PSA, in respectively, as prostate biomarkers because the concentrations of zinc and PSA in urine sample are prostate cancer clinically relevant (see Gen Hospital Corp par.(s).8-9, see Bolduc Tables 1-2 and page 380), and Prior teaches that the combined analysis of multi-markers would improve the accuracy of PCa (see Prior Abstract, page 685 col.2 par.2). The improvement in PCa detection would aid making a decision on management of PCa, e.g., reducing unnecessary biopsies to balance the risk and benefit of biopsy test for the PCa suspected patients (see Gen Hospital Corp par.68, Bolduc page 380, and Prior page 682).
One having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Bolduc and Prior because they are directed to the methods of diagnosing prostate cancer by detecting biomarker(s) in urine sample. While Gen Hospital Corp and Bolduc teach using a single marker for PCa diagnosis, Prior demonstrates that analysis of combinations of biomarkers may greatly improve diagnosis of PCa.
In the Affidavit, Applicant argued that while Vartsky speculates the potential value of using prostatic zinc combined with prostate specific antigen for diagnosis, Vartsky does not teach how to actually use evaluation of zinc and PSA in making such diagnosis, e.g., performing a biopsy when zinc and PSA levels are below their respective thresholds. Moreover, Vartsky would not give the skilled person any expectation that the relationship found between zinc concentration in prostate tissue and serum PSA would correlate to a relationship between zinc concentration and PSA levels in urine, or even serum.
This argument is not persuasive. First, while Vartsky does not teach how to actually use evaluation of zinc and PSA in making such diagnosis, e.g., performing a biopsy when zinc and PSA levels are below their respective thresholds, the argument is moot because the rejections of independent claims 1 and 6, which comprise performing the biopsy for prostate cancer, are updated in view of the amendment of the claims. The amended limitations are taught by references Gen Hospital Corp, Bolduc, Prior. See a brief discussion above.
Second, the rejection of claim 18 is not based on Vartsky alone. The combined teaching of Gen Hospital Corp, Yoon, Buechler and Vartsky would give the skilled person an expectation that using a panel of biomarkers, e.g., zinc and PSA, would improve the disease diagnosis.
Gen Hospital Corp and Yoon are drawn to methods of using a single urinary biomarker to diagnose a prostate cancer. Gen Hospital Corp teaches quantifying the amount of zinc in urine for prostate cancer detection. Yoon teaches quantifying the amount of PSA in urine for prostate cancer detection. Gen Hospital Corp and Yoon teach that the decrease in the amount of zinc and PSA, respectively, indicates the subject being at risk of having or developing prostate cancer. Buechler is generic to suggest the advantage of analyzing a panel of biomarkers for diseases diagnosis (Buechler: Abstract). Based on the teaching of Gen Hospital Corp, Yoon, and Buechler, a person of ordinary skill in the art would have been motivated to combine Gen Hospital Corp and Yoon because the probability of having a disease would have been defined effectively and accurately when using a panel of markers as taught by Buechler.
On the other hand, Vartsky supports the advantage of using a panel of markers over a single marker in increasing the effectiveness of the diagnosis test. Even though the biomarkers are derived from different sources, Vartsky teaches that the combination of these parameters, e.g, zinc and PSA, represents a significant improvement on the diagnostic value of each of them separately and provides a powerful tool for more accurate diagnosis (see Vartsky in Conclusions).
Therefore, one having ordinary skill in the art would have had a reasonable expectation of success in combining Gen Hospital Corp, Yoon, Buechler and Vartsky to improve the prostate cancer diagnosis by measuring both zinc and PSA in urine.
Conclusion
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.
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/CHAU N.B. TRAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 January 10, 2026
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