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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2022/086491, filed 12/16/2022. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. EP21215742.4, filed on 12/17/2021 in Europe.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 6/17/2024 and the information disclosure statement filed 8/29/2025 are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in page 32 line 6 and page 38 line 11. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
Claims 3 and are objected to because of the following informalities:
In claim 3 Table 4, Applicant uses biomarker abbreviations. It is recommended that abbreviations be accompanied by their full meaning (as in claim 1) at least at the first instance that the abbreviation is used in order to improve clarity of the record and avoid confusion.
Claim 3 lacks a period “.”. All claims must end with a period (MPEP 608.01(m)).
In claim 8 lines 12-18, “CD99 i. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 j. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP k. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP and LYVE1” appears to be a typographical error, namely it is suggested that “CD99 i. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 j. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP k. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP and LYVE1” read as “CD99 or i. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 or j. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP or k. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP and LYVE1” (annotations added) as per the specification page 13 lines 3-9.
In claim 8 last line, there is a missing period “.”. All claims must end with a period (MPEP 608.01(m)).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims: 4 (line 2), 10 (lines 4, 8 and 11), 11 (lines 3-10), 12 (line 7), 13 (lines 3-10), 14 (line 7), 15 (line 7), 16 (line 7), 17 (line 7), 18 (line 7), 19 (line 7), 20 (line 7) and 21 (line 7), the phrase "particularly" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. In other words, it is not clear whether the limitations following the phrase are optional or merely exemplary. See MPEP § 2173.05(d). A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 10 recites “wherein the concentration of the biomarkers is used to calculate a score value particularly wherein the score value is calculated by the following formula:…"x" values are the measured concentrations of the respective proteins in urine samples or the value of clinical data, particularly age and/or PI-RADS score…”.
However, “the measured concentrations of the respective proteins in urine samples” (lines 10-11) lacks sufficient antecedent basis. It is not clear what is meant by “the measured concentrations of the respective proteins in urine samples” because a measurement of the concentration of proteins in urine samples is not recited in claims 1 or 10. Although claim 1 recites “the quantitative detection, in a sample obtained from the subject, of the concentration
of a biomarker selected from the following Table”, it is not clear that the “urine sample” of claim 10 refers to the “sample” of claim 1.
Furthermore, it is not clear how the concentration of the biomarkers is used to calculate a score value because the formula appears to not require the concentration of the biomarkers. Note that the “x” values are drawn to what appears to be other “proteins in urine” or “clinical data”. Because of this apparent contradiction, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 11 recites “The method according to claim 11, wherein the biomarker concentration is determined via mass spectrometry, and – β0…– β1…– β2…– βn…– Score…”.
However, it is not clear how claim 11 can be dependent from claim 11. Is claim 11 an independent claim or a dependent claim? Furthermore, it is not clear what is meant by β0, β1, β2, βn, and Score. These terms appear to lack antecedent basis. A person having ordinary skill in the art would be confused by the language of claim 11, the terms β0, β1, β2, βn, and Score. Because of these reasons, there is a question regarding the metes and bounds of the claim.
Claims 12-22 are included in this rejection because they depend from rejected claim 11 but fail to clarify the scope of patent protection sought.
Claim 22 recites the limitation "the calculation of the score value" in line 2. There is insufficient antecedent basis for this limitation in the claim. It is not clear what is meant by “the calculation” because a calculation step is not recited in claims 11 or 22.
Claim 23 recites “…wherein collecting information about the health status comprises determining whether the subject…”. However, it is not clear what is meant by “wherein collecting information about the health status comprises” because claim 1 fails to recite a step of collecting information about the health status. This claim appears to lack antecedent basis. Because of this, a person having ordinary skill in the art would not recognize the metes and bounds 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 1-4 and 8-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Prong One asks does the claim recite an abstract idea, law of nature, or natural phenomenon? In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims "set forth" an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words "intermediated" or "settlement." See MPEP 2106.04 (II)(A)(1).
The claims recite “A method for determining whether a subject has prostate cancer, said method comprising the quantitative detection, in a sample obtained from the subject, of the concentration of a biomarker selected from the following Table (Table 5 .1 ):… establishing the statistical significance of the concentration of the biomarker”.
The natural relationship to which the claims are directed (i.e., the relationship between biomarker(s) from Table 5.1 and prostate cancer) 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 myeloperoxidase 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 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 levels of a biomarker from Table 5.1 and the presence of prostate cancer.
The correlation between the biomarker and prostate cancer 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 Table 5.1 biomarker levels are elevated to different extents in prostate cancer vs. in other diseases.
Additionally, the claims also recite “establishing the statistical significance of the concentration of the biomarker”. This limitation is reasonably interpreted as a mathematical calculation, which is an abstract idea, i.e. a judicial exception.
Dependent claim 2 recites “wherein the concentration of more than one biomarker is determined, and optionally combined with clinical data of the human subject” . This claim is also directed to a natural correlation, i.e. a judicial exception. Specifically, this claim recites the natural correlation between more than one biomarker and clinical data with prostate cancer.
Dependent claim 3 recites “wherein a biomarker of at least one, two or of each column of the following Table (Table 4) is determined:…”. This claim is also directed to a natural correlation, i.e. a judicial exception. Specifically, this claim recites the natural correlation between a biomarker of at least one, two or of each column of Table 4 and prostate cancer.
Dependent claim 4 recites “wherein the sample is a urine or blood sample, particularly wherein the sample is a urine sample”. This claim merely limits the type of sample used in the natural correlation. Therefore, this claim is also directed to at least one judicial exception.
Dependent claim 8 recites “wherein the concentration of the following biomarkers is determined: a….b….c….d….k….”. This claim is also directed to a natural correlation, i.e. a judicial exception. Specifically, this claim recites the natural correlation between biomarkers a-k and prostate cancer.
Dependent claim 9 recites “wherein the biomarker is PEDF”. This limitation merely limits the biomarker used in the natural correlation. Therefore, this claim is also directed to at least one judicial exception. Claim 9 further recites “and an intensity threshold score to detect men who should perform a prostate biopsy is below 100,000”. This limitation is reasonably interpreted as an abstract idea, namely the mental step (mathematical calculation) of setting a threshold value for detecting men who should perform a prostate biopsy. The recited cutoff values are reasonably interpreted as mathematical concepts.
Dependent claim 10 recites “wherein the concentration of the biomarkers is used to calculate a score value, particularly wherein the score value is calculated by the following formula:
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wherein
- Score is indicative for the probability of the subject to have prostate cancer,
particularly high-grade prostate cancer and/or a PI-RADS score of 3-5;
- “β” values are the regression coefficients,
- "x" values are the measured concentrations of the respective proteins in urine
samples or the value of clinical data, particularly age and/or PI-RADS score.
- β0 is the intercept,
- index "n" represents the number of variables used”.
This claim recites a mathematical calculation, which is an abstract idea, i.e. a judicial exception.
Regarding claims 11 and 13, although claim 11 is indefinite (see 112b rejection above), in the interest of compact prosecution, the “β0”, “β1”, “β2”, “βn”, and “Score” recited are interpreted to be referring to the terms of the equation of claim 10. Therefore, these limitations are interpreted to be directed to a mathematical calculation, which is an abstract idea, i.e. a judicial exception.
Claims 12 and 14-21 recite “…the score value is calculated by the following formula:…”. These limitations are interpreted to be directed to a mathematical calculation, which is an abstract idea, i.e. a judicial exception.
Claim 22 recites “wherein the age and/or PIRADS of the subject contributes to the calculation of the score value”. This claim is also directed to at least one judicial exception. The claim recites the use of age and/or PIRADS of the subject for the “calculation”, which is a mathematical step, an abstract idea, not patent eligible.
Claim 23 recites “wherein collecting information about the health status comprises determining whether the subject a. has, or is at risk of developing prostate cancer; and/or b. has, or is at risk of having a high-grade prostate cancer; and/or c. has, or is at risk of biochemical recurrence; and/or d. has, or is at risk of relapsing; and/or e. is likely to benefit from a biopsy; and/or f. is likely to benefit from active treatment; and/or g. is likely to benefit from active surveillance; and/or h. is likely to benefit from prostatectomy; and/or i. is likely to benefit from chemotherapy or radiotherapy or hormone depletion treatment”. The claim describes natural correlations, namely the correlation between the health status of the subject and prostate cancer, high-grade prostate cancer, biochemical recurrence, relapse and treatment response.
Step 2A, Prong 2
Claim 9 recites the additional limitation “a concentration of PEDF is determined by mass spectrometry”.
Claims 11-12 recite the additional limitation “wherein the biomarker concentration is determined via mass spectrometry”.
Claims 13-21 recite the additional limitation “wherein the biomarker concentration is determined via ELISA”.
Such steps of measuring the concentration of biomarker using mass spectrometry or ELISA are insufficient to integrate the judicial exception(s) because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of measuring the biomarkers are recited at a high level of generality and are not tied, for example, to any particular machine or apparatus.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, measuring the concentration of the biomarker using mass spectrometry or ELISA, do not add significantly more to the judicial exception(s). The step of measuring the biomarker is recited at a high level of generality.
In this case, it was well-understood, routine and conventional to determine the concentration of PEDF in blood samples using mass spectrometry or ELISA.
See for example, Qingyl et al. Cancer Investigation, 27:794-801, 2009 DOI: 10.l 080/07357900802175617 -Cite No. 2 of IDS 6/17/2024 (“Qingyl”).
Qingyl teaches “Two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry (MS) is a high-throughput method in identifying differences of protein expression…With the help of this technique, we compared the differences between the serum of prostate cancer and HGPIN patients and found a protein of pigment epithelium-derived factor (PEDF) with highly expressed in 2D protein profiles from the serum of the patients with HGPIN, which was significantly decreased in the serum of the patients with prostate cancer. The immunohistochemical and ELISA studies also confirmed it and found that PEDF expression was nearly absent in human prostate cancer patients as PEDF is one of the most potent inhibitors of angiogenesis” (page 798 col. 2 para. 2). See table 2 of Qingyl.
Furthermore, determining the concentration of PEDF and PTGS in blood or urine samples using mass spectrometry or ELISA appears to be well-understood, routine and conventional in the art. See Ross et al. (WO 2015/131177 Al) (“Ross”).
Ross teaches “a method for identifying a subject as having high grade prostate cancer comprises the steps of (a) obtaining a biological sample from the subject; (b) performing an assay on the sample obtained from the subject to measure the levels of one or more of…PTGDS,…SERPINF1…and (c) identifying the subject as having high grade prostate cancer based on a comparison of the measured levels of one or more protein biomarkers to one or more
reference controls… the assay of step (b) is an enzyme linked immunosorbent assay (ELISA)” (page 3 lines 16-24 and 30-31). Ross further teaches “the biological sample can
comprise blood, plasma, serum, urine or stool” (page 4 lines 1-2). Ross further teaches that “[i]n one aspect, the biomarkers of the present invention may be detected by mass spectrometry” (page 31 lines 2-3).
See also Byrne et al. Journal of Proteome Research 2009, 8, 942–957-Cite No. 3 of IDS 6/17/2024 (“Byrne”).
Byrne teaches that “pigment epithelium-derived factor (PEDF) and zinc-R2-glycoprotein (ZAG), have undergone extensive validation in serum and tissue samples from the original cohort and also from a larger independent cohort of patients. These results have indicated that PEDF is a more accurate predictor of early stage prostate cancer” (Abstract). Byrne further teaches “All samples were run on a Finnigan LTQ mass spectrometer connected to a Surveyor chromatography system incorporating an autosampler” (page 945 col. 1 para. 4). Byrne further teaches “ELISA based validation experiments were carried out using depleted serum from the original pilot cohort and also from an independent serum series. Each sample was assayed in duplicate. To compare the immunoreactivity of PEDF in depleted sera samples from the original pilot study cohort, the commercially available ChemiKine PEDF Sandwich ELISA kit (Chemicon International) was used” (page 946 col. 1 para. 2).
In view of the above evidence, the claimed steps of determining the concentration of biomarker using mass spectrometry or ELISA in blood or urine samples do not add any feature that is more than well-understood, purely 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 amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4 and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Qingyl et al. Cancer Investigation, 27:794-801, 2009 DOI: 10.l 080/07357900802175617 -Cite No. 2 of IDS 6/17/2024 (“Qingyl”).
Regarding claim 1, Qingyl teaches a method for determining whether a subject has prostate cancer, said method comprising the quantitative detection, in a sample obtained from the subject, of the concentration of a biomarker selected from SERPINF1 (PEDF) and AMBP (“Two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry (MS) is a high-throughput method in identifying differences of protein expression…With the help of this technique, we compared the differences between the serum of prostate cancer and HGPIN patients and found a protein of pigment epithelium-derived factor (PEDF) with highly expressed in 2D protein profiles from the serum of the patients with HGPIN, which was significantly decreased in the serum of the patients with prostate cancer. The immunohistochemical and ELISA studies also confirmed it and found that PEDF expression was nearly absent in human prostate cancer patients as PEDF is one of the most potent inhibitors of angiogenesis” page 798 col. 2 para. 2, see Table 2 showing the quantitative detection results of the concentration of AMBP and PEDF) establishing the statistical significance of the concentration of the biomarker (“Student's t-test was used to compare means on all cross-sectional analyses of these continuous data” page 796 col. 1 para. 4, “Analysis of spot intensities showed significant differences in 23 analyzed spots; however, only 15 were chosen for MS analysis (Fig, 3, p < 0.05). Then, database searches with Protein Prospector software were performed, and the result had high confidence if the protein was ranked as the best hit with a significant score. From the 15 spots, 12 proteins were identified. Table 2 shows the total list of proteins identified” page 796 col. 2 para. 2, Table 2, “significantly decreased serum PEDF was presented when compared to those patients with confirmed HGPIN (1.22 ±0.61 vs. 11 .07 ± 8.98 ng/mL, p < 0.05)” page 708 col. 1 para. 1).
Regarding claim 2, Qingyl teaches wherein the concentration of more than one biomarker is determined (“Both free and total PSA levels were measured using commercial1y available kits” page 795 col. 2 para. 4) and optionally combined with clinical data of the human subject (“Their clinical characteristics were described in Table 1. All patients were diagnosed with isolated PIN or prostate cancer (PCa) by transrectal ultrasonography (TRUS)-guided needle biopsy of the prostate at our Department of Urology” page 795 col. 1 para. 2)
Regarding claim 3, Qingyl further teaches wherein AMBP is determined (“1421 AMBP protein precursor P02760” Table 2 page 796).
Regarding claim 4, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the limitations following “particularly” are interpreted as being optional, and not required in order to address the claim over the art.
Qingyl teaches wherein the sample is a blood sample (“serum” page 798 col. 2 para. 2).
Regarding claim 23, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the limitation “wherein collecting information about the health status” is interpreted to be directed to the detection of the biomarker in claim 1.
Qingyl teaches wherein collecting information about the health status comprises determining whether the subject a. has, or is at risk of developing prostate cancer (“PEDF in HGPIN as a significant predictor of subsequent cancer, suggesting that PEDF implies in prostatic tumorigenesis and may be used to identify the patients with isolated HGPIN who are at high risk for cancer onset in the disease process” Abstract).
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 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Qingyl et al. Cancer Investigation, 27:794-801, 2009 DOI: 10.l 080/07357900802175617 -Cite No. 2 of IDS 6/17/2024 (“Qingyl”) in view of Di Vizio et al. (US 20200408766 A1) (“Di”).
Regarding claim 8, Qingyl teaches the method of claim 1 as discussed above.
Qingyl teaches wherein the sample is a serum sample (“serum” page 798 col. 2 para. 2) and wherein a concentration of PEDF is determined by mass spectrometry or ELISA (“Eleven HGPIN patients were enrolled, their serum protein patterns (2D-electrophoresis and mass spectroscopy) were compared with fifteen prostate cancer patients…confirmed by ELISA” Abstract). Qingyl further teaches that “Prostate cancer is currently the most common cancer and the second leading cause of cancer death in men throughout the world” (page 794 col. 1 para. 1).
Qingyl fails to teach wherein the concentration of the following biomarkers is determined: a. PEDF and FCER2; or b. PEDF and CANX; or c. HPX and KRT13; or d. PEDF and FCER2 and CANX; or e. PEDF and FCER2 and CANX and KRT13; or f. PEDF and FCER2 and CANX and KRT13 and HPX; or g. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR; or h. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 i. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 j. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP k. PEDF and FCER2 and CANX and KRT13 and HPX and HRNR and CD99 and SPARCL1 and AMBP and LYVE1.
Di teaches “Palmitoyl Protein Biomarkers In Purified Extracellular Vesicles For Early Identification Of Clinically Significant Prostate Cancer” (Title). Di further teaches “obtaining a biological sample from a subject having prostate cancer or suspected of having prostate cancer; …assaying the large EVs for at least 10 palmitoyl proteins selected from the group consisting of GNAQ, CD9, TLN1, STX11, ITGB3, LYN, SLC4A1, CANX, FLOT2, FLOT1, ABHD16A, MYADM, ATP2A3, TMX1, RAP2B, ATP2A2, SLC2A3, RTN4, LTBP1, and ABCC4; and detecting the one or more palmitoyl proteins selected from the group consisting of …CANX” (para. 10, emphasis added). Di further suggests determining the concentration of CANX using mass spectrometry or ELISA (“assaying for at least 10 palmitoyl proteins can comprise using mass spectrometry to detect the at least one palmitoyl proteins” para. 14, “[f]urther examples for detecting one or more of these palmitoyl proteins include but are not limited to flow cytometry, ELISA” para. 77). Di further teaches wherein the biological sample is serum (“the biological sample is whole blood or blood serum” para. 72). Di further suggest that determining the concentration of CANX enables the identification of patients with the highest risk of dying, a current need in the field (“Prostate cancer is frequently an indolent disease, and most of the patients die with prostate cancer but not of prostate cancer. Clinically significant prostate cancer are cases that can progress to lethal disease and kill the patients. These are the type of prostate cancer that needs therapeutic intervention and identifying them is important for treatment” para. 60). Di further shows results of the protein abundance of CANX in serum samples (Figure 19).
Di teaches determining the concentration of CANX from a list of 20 proteins. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have tried picking CANX from the list of 20 proteins because Di suggests CANX aids the identification of patients with the highest risk of dying from prostate cancer, a need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because Di shows results of the protein abundance of CANX in serum of prostate cancer patients.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Qingyl to include determining the concentration of CANX taught by Di because Di suggests CANX enables the identification of patients with the highest risk of dying and Qingyl is concerned with the high rate of prostate cancer deaths of men in the world. One would have been motivated to make such a modification in order to help reduce the rate of prostate cancer deaths in men and address the current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because both references teach determining the concentration of a prostate cancer biomarker from a blood sample using mass spectrometry or ELISA for diagnosing prostate cancer.
Regarding claim 9, Qingyl in view of Di teach the method of claim 8 as discussed above.
Qingyl in view of Di further suggests wherein the biomarker is PEDF, and a concentration of PEDF is determined by mass spectrometry (Abstract of Qingyl). Qingyl further suggests that an intensity threshold score to detect men who should perform a prostate biopsy is below 100,000 (“(PEDF) was found to be significantly down-regulated in prostate cancer patients” Abstract, “However, although previous studies suggested that there was strong association between HGPIN and prostatic carcinoma, the clinical management of patients diagnosed with HGPIN on prostate biopsy is also problematic (8). In clinical practice, some of patients with HGPIN didn't develop prostate cancer even after long-terms follow-up. Therefore, to stratify and find out those HGPIN patients who and when will they develop to the malicious form of prostate cancer seems to be especially important. In this study, we used two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) to identify differential expressed protein in serum of those patients with HGPIN and prostatic carcinoma in order to find out protein biomarkers related to the disease and to identify the patients with isolated HGPTN who are at high risk for cancer onset in the disease process” page 795 col. 1 para. 2, see change in mass spectrometry intensity of PEDF being “7.17” in Table 2 of Qingyl, page 796, “nowadays, what we can do was to repeat biopsy again and again in order to find out the prostate cancer early. The process was tiresome, and the results were disappointed. As mentioned above, PEDF play an important role in regulating the normal prostate, and loss of which in prostate tumors could contribute to tumor progression. Based on these results, we may suppose that the HGPIN patients with weak expression of PEDF were prone to develop into prostate cancer” page 798 col. 2 para. 3 of Qingyl). Note that although Qingyl fails to use the language “intensity threshold score to detect men who should perform a prostate biopsy is below 100,000” the teachings that PEDF may enable the detection of men who should perform a prostate biopsy and the teaching that PEDF intensity score of 7.17 was identified as a biomarker of prostate cancer together inherently provides the intensity threshold score to detect men who should perform a prostate biopsy.
Claims 10-11, 13 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Qingyl et al. Cancer Investigation, 27:794-801, 2009 DOI: 10.l 080/07357900802175617 -Cite No. 2 of IDS 6/17/2024 (“Qingyl”) in view of Linder et al. (US 11761962 B2) ("Linder").
Regarding claim 10, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the limitations following “particularly” are interpreted to be optional, except for the first “particularly” (line 4). Furthermore, the score formula is interpreted to be drawn to clinical data only.
Qingyl teaches the method of claim 1 as discussed above.
Qingyl further teaches wherein the concentration of the biomarkers is used to calculate a score value (“Analysis of spot intensities showed significant differences in 23 analyzed spots; however, only 15 were chosen for MS analysis (Fig, 3, p < 0.05). Then, database searches with Protein Prospector software were performed, and the result had high confidence if the protein was ranked as the best hit with a sign incant score. From the 15 spots, 12 proteins were identified. Table 2 shows the total list of proteins identified” page 796 col. 2 para. 2) Qingyl further teaches that “[a]ll patients were diagnosed with isolated PIN or prostate cancer (PCa) by transrectal ultrasonography (TRUS)-guided needle biopsy of the prostate at our Department of Urology” (page 795 col. 1 para. 2). Qingyl further teaches that “nowadays, what we can do was to repeat biopsy again and again in order to find out the prostate cancer early. The process was tiresome, and the results were disappointed.” (page 798 col. 2 para. 3).
Qingyl fails to teach particularly wherein the score value is calculated by the following formula:
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wherein
- Score is indicative for the probability of the subject to have prostate cancer,
particularly high-grade prostate cancer and/or a PI-RADS score of 3-5;
- “β” values are the regression coefficients,
- "x" values are the measured concentrations of the respective proteins in urine
samples or the value of clinical data, particularly age and/or PI-RADS score.
- β0 is the intercept,
- index "n" represents the number of variables used.
Linder teaches “[i]mproved methods disclosed herein are useful for predicting whether or not an invasive prostate tissue biopsy is merited for purposes of determining whether the subject has prostate cancer, particularly a prostate cancer of high grade (e.g., Gleason score of greater than or equal to 7.0))” (col. 1 lines 48-52). Linder further suggests wherein the score value is calculated by the following formula:
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wherein - Score is indicative for the probability of the subject to have prostate cancer, particularly high-grade prostate cancer; - “β” values are the regression coefficients, - "x" values are the value of clinical data, particularly age - β0 is the intercept, - index "n" represents the number of variables used (“the probability of the prostate cancer is determined in accordance with equation (1), reproduced below:
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where the logit (L) is determined using any of a plurality of logistic regression models. Non-limiting examples of different types of logistic regression models that may be used in accordance with the techniques described herein include:…
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”(col. 14 lines 46-60). Note that the logistic regression equation taught by Linder is the same as the score formular recited in claim 10. Linder further teaches that “[i]n the equations above "priorbx" is a binary value indicate of whether a subject had a prior biopsy to detect prostate cancer. A value of 1 indicates that a prior biopsy occurred and a value of 0 indicates that the prior biopsy did not occur” (col. 15 lines 64-67). Therefore, the priorbx, tPSA (total PSA), and age terms taught by Linder are reasonably interpreted as “clinical data” because these are typical clinical patient details (see for example Qingyl Table 1 “Clinical characters of HGPIN and prostate cancer patients” page 795 showing the PSA level of patients). Linder further teaches that “methods disclosed herein are advantageous because they produce results that are informative of the likelihood that invasive and relatively risky diagnostic procedures, such as prostate tissue biopsies, will be informative and worthwhile to perform. Accordingly, the methods are useful because they enable healthcare providers to make more informed decisions regarding the care of subjects” (col. 1 lines 53-59).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Qingyl to include the formula taught by Linder because Linder teaches that this enables the prediction of whether a prostate tissue biopsy obtained from the subject will contain high grade prostate cancer and Qingyl is interested in detecting prostate cancer and teaches that biopsies are routine in the clinic. One would be motivated to make such a modification because Linder suggests that this formula allows better care for the patients, minimizing the need for repetitive and invasive biopsies, which are tiresome and disappointing according to Qingyl. A person having ordinary skill in the art would have had a reasonable expectation of success because both Qingyl and Linder are drawn to methods for diagnosing prostate cancer comprising a prostate biopsy.
Regarding claims 11, 13 and 22, although claim 11 is indefinite (see 112b rejection above), in the interest of compact prosecution, the limitations following “particularly” are interpreted to be optional; also, the claims are interpreted to be drawn to the score formula of claim 10.
Qingyl further teaches wherein the biomarker concentration is determined via mass spectrometry (Abstract, page 796 col. 2 para. 2). Qingyl further teaches wherein the biomarker concentration is determined via ELISA ( “confirmed by ELISA” Abstract).
Qingyl fails to teach “– β0 is in the range of -10,000 to 10,000, particularly β0 is in the range of -10 to 10, more particularly β0 is in the range of 4 to 6, and/or– β1 is in the range of -10,000 to 10,000, particularly β1 is in the range of -10 to 10, particularly β1 is in the range of -1 to 1, and/or – β2 is in the range of -10,000 to 10,000, particularly β2 is in the range of -10 to 10, particularly β2 is in the range of -1 to 1, and/or– βn is in the range of -10,000 to 10,000, particularly βn is in the range of -10 to 10, particularly βn is in the range of -1 to 1, and/or– Score is in the range of -100 to 1000, wherein the age and/or PIRADS of the subject contributes to the calculation of the score value”.
Linder suggests “– β0 is in the range of -10,000 to 10,000, particularly β0 is in the range of -10 to 10, and/or– β1 is in the range of -10,000 to 10,000, particularly β1 is in the range of -10 to 10, particularly β1 is in the range of -1 to 1, and/or – β2 is in the range of -10,000 to 10,000, particularly β2 is in the range of -10 to 10, particularly β2 is in the range of -1 to 1, and/or– βn is in the range of -10,000 to 10,000, particularly βn is in the range of -10 to 10, particularly βn is in the range of -1 to 1, and/or– Score is in the range of -100 to 1000” (“(a) when determining the probability that a prostate tissue biopsy for the identified subject of (i) would contain any detectable prostate cancer, the values for β0- β12 are as follows: β0 is greater than or equal to - 2.86E+00 and less than or equal to -1.97E+00; β1 is greater than or equal to 2.88E-01 and less than or equal to 4.03E--01 ; β2 is greater than or equal to 3.76E-01 and less than or equal to 4.72E—01” claim 7). Note that although Linder fails to use the language “Score is in the range of -100 to 1000”, the teaching that the formula determines the “probability” inherently provides a score of at least 0 to at most 100 because a probability can only be between 0 to 100%. Linder further teaches wherein the age of the subject contributes to the calculation of the score value (“
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”col. 14 lines 46-60).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Qingyl to include the coefficients, age term and the score values taught by Linder for the same reasons as stated above. In short, Linder suggests these values enable the prediction of whether a prostate biopsy would contain prostate cancer, which would minimize the need for routine biopsy, a current need in the field, and Qingyl is interested in diagnosing prostate cancer and is concerned with the burden of multiple biopsies. A person having ordinary skill in the art would have had a reasonable expectation of success in view of the cumulative disclosures of these prior art references.
Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
For example, Canesin et l. Cell Rep. 2020 September 22; 32(12): 108181. doi:10.1016/j.celrep.2020.108181 (“Canesin”).
Canesin teaches “Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases” (Title). Canesin further teaches that “Hemopexin (Hx)…levels are inversely correlated in the plasma of patients with prostate cancer (PCa)” (Summary page 2).
See also Liu et al. PLoS ONE 11(10): e0163232. doi:10.1371/journal.pone.0163232 (“Liu”).
Liu teaches “Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone” (Title). Liu further teaches that “KRT13 expression is associated with poor prognosis at multiple stages of disease progression and may represent an important biomarker of adverse outcome in patients with prostate cancer” (Conclusions page 2).
However, although Canesin suggests HPX is a biomarker of prostate cancer, and although Liu suggests that KRT13 is a biomarker of prostate cancer, there is not enough motivation to combine Canesin or Liu with Qingyl and Linder.
The subject matter of claims 12 and 14-21 appears to be free of the prior art. There are no references found that teach the specific combination of biomarkers and coefficients recited in the score formulas.
Conclusion
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/Fernando Ivich/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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