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/EP2022/066453, filed 06/16/2022. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 00751/21, filed on 06/29/2021 in Switzerland.
Information Disclosure Statement
The information disclosure statement (IDS) filed 12/14/2023 is considered, initialed and is attached hereto.
Claim Objections
Claims 1-6, 10, 11 and 16 are objected to because of the following informalities:
Claims 1, 2, 4, 10, 11, 16 each recite abbreviations in the claims (for example, PSA, THBS1, CTSD, OLFM4, ICAM1). It is suggested that anywhere an abbreviation is presented, that it be accompanied at its first instance by the full terminology for the abbreviation in order to improve clarity of the record. For example, THBS1 should first be presented as “thrombospondin 1 (THBS1)” and PI-RADS as “Prostate Imaging Reporting and Data System (PI-RADS)”.
Dependent claims 2 and 3 recite “a method according to claim 1”, dependent claims 4-17 recite “Method according to claim 1”. It is suggested Applicant amend the dependent claims in order to recite “The method of claim 1” so that the claim clearly refers back to, and encompasses all, the limitations of independent claim 1. The amendment is suggested in order to improve clarity and consistency among the claims.
Claim 5 is objected to for grammatical reasons; it is suggested that “a first step being performed” be amended in order to recite “a first step performed by…” or “a first step of contacting”.
Claim 6 recites “determined beforehand”, and it appears to be Applicant’s intention that this means determined before calculation of the combined score value. As such, it is suggested that Applicant amend claim 6 in order to recite “as determined before performing the method of claim 1”.
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 1-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “A method…involving…”, the claim language is indefinite for reciting the language “involving”, and it is suggested that Applicant amend the claim to use typical transitional language “comprising” (i.e., A method…comprising quantitative detection”) in the interest of improving clarity of the record, particularly since the language “involving”, while does suggest the limitations following are necessary features of the claim, does not clearly communicate that the claim requires the active step of performing quantitative detection as claimed”. For example, “involving” is subject to conflicting interpretation, and may not be interpreted as requiring performance of quantitative detection, but rather could merely be using data obtained in a previously performed quantitative detection. The language is indefinite because it is not readily clear whether or not the instant method for collecting information requires the practitioner to perform an active step of quantitative detection of the concentration as claimed.
Claim 1 recites the limitation "the quantitative detection…of the concentration" in line 2. There is insufficient antecedent basis for this limitation in the claim. The claim language is indefinite because it suggests “the quantitative detection” as a limitation previously introduced to the claim, however this is the first instance. Consistent with the previous rejection above, it is suggested that applicant amend the claim in the interest of improving clarity to recite something such as, “A method of collecting information…comprising quantitative detection …of the concentration of THBS1”.
Claim 3 is indefinite for the language “further involves” and “a prostate volume parameter”, the language “further involves” is rejected for the same reasons as applied previously above, namely it is not readily clear what is or is not encompassed by “involves” in terms of what step/parameter is required.
Additionally, it is not readily clear if “a prostate volume parameter” refers to measurement of the volume of the prostate, or some other parameter not limited to the volume of the prostate. The language “a” and “parameter” suggests this could be something other than prostate volume itself.
Claim 4 is indefinite for the language “involving the quantitative detection….as well as”, the language “involving” is indefinite for the reasons above. It is suggested Applicant amend the claim in order to recite something such as, “The method of claim 1, wherein the method further comprises quantitative detection of at least one additional protein selected from the group consisting of cathepsin (CTSD), olfactomedin 4(OLFM4), and intracellular adhesion molecule 1 (ICAM1).”
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claims 5 and 13 each recites the broad recitation “at least one … affinity reagent(s)”, and the claim also recites “at least two” which is the narrower statement of the range/limitation.
Similarly, claim 9 recites the broad recitation “in the range of 15-32”, and the claim also recites “16.5-31.1” or “21-29” which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 5 and 13 also recite “using quantitative readout of the respective protein’s concentration… allowing the calculation of the respective concentration”, this language is indefinite because it is not readily clear if the recited language is implying the method involves a reader or some instrumentation that produces a readout as a display of data from a system, or encompasses merely an observable result that can be used to calculate concentration. The claims do not recite a particular structural component used in the method that is an instrument/reader.
Furthermore, the language is confusing because “a quantitative readout of the…concentration” suggests one is obtaining the concentration but then the claim also then additionally recites “allowing the calculation of the respective concentration”, which appears to contradict that the earlier “quantitative readout” is the concentration. The claim should be amended in order to clarify.
Claim 13 also recites “wherein after the second step in a third step the risk of a positive biopsy and/or prostate cancer of the subject”, the recited language is indefinite because it is confusing, for example, risk of a positive biopsy suggests a diagnosis of prostate cancer, and as a result the language “and/or” is indefinite because it appears both a positive biopsy and diagnosis of prostate cancer are the same outcome (i.e., you wouldn’t have one or the other, but rather only both).
Claims 6 and 14 recite “as x1 a risk score expressed in the range of 0-1”, however, it is not clear what is or is not encompassed by “a risk score”. In turning to the originally filed specification for understanding regarding the term “risk score”, the specification only refers to the prior art reference of a PCa risk score which is produced using a software algorithm to aid in the identification of a clinically significant PCa, however the claims are indefinite because there is no indication what this “risk score” represents or how it is determined such that one having ordinary skill could readily determine what is and is not encompassed by the recited language.
Additionally, the language “expressed in the range” does not clearly communicate whether the risk score is a value that is either 0 or 1, or if the risk score can be some value in between. As such, because the boundaries are unclear, the claim is indefinite.
Claims 6-8 and 14 each recites parenthesis in the claims, “the prostate volume (expressed in mL)” at claims 6 and 14, and “(-6)-(-3)”, “(-.0.03)-(0.01)” at claim 7, “(-5.83)-(-3.47)”, “(-0.027)-(-0.010)” claim 8 . The use of parenthesis in the claims raises question as to whether or not the limitations within the parenthesis are limiting, i.e., it is not clear if the limitations are considered to be limiting, or merely exemplary language. In the present case, claim 6 it is not clear if this language is limiting, i.e., if the volume must be in mL. For claims 7 and 8 it is not clear what purpose the parenthesis serves.
Claims 11 and also claim 16 recites “the…assay to the respective protein is one obtained by using recombinant proteins of human THBS1, CTSD, ICAM1 and OLFM4, respectively and mouse monoclonal antibodies generated through immunization of mice therewith” (claim 11, see claim 16, “obtained by using recombinant proteins…and mouse monoclonal antibodies generated through immunization of mice therewith”), the claim is indefinite because it is not clear how these limitations limit the claimed assay. Specifically, it is not understood what is meant by the assay is obtained “by using recombinant proteins”, for example, what role or how the is the method, particularly the assay step, being performed using the recombinant proteins, as it is the proteins which are being quantitatively determined. It is not clear if the recombinant proteins are being used as a reagent in the assay, or rather if the claim is referring to the monoclonal antibodies (i.e., the antibodies used in the assay to determine the proteins relies on monoclonal antibodies specific to the recombinant proteins).
Claim 12 also recites the language “the quantitative detection… involves the determination…relative to an external protein standard, involving the preparation of a reference standard curve by measuring defined concentrations of several protein standards…to be measured in the same set of measurements of the samples”, the claim language “involves” and “involving” is indefinite because it is not readily clear if the method comprises the actual active steps of preparing a reference standard, and measuring concentrations of several protein standards as part of the method claimed. The scope of what is and is not encompassed by the language “involve” and “involving” is not readily clear such that one can readily determine the boundaries of the claim.
Claims 12 and 17 recite the limitation "the same set of measurements" in the second to last line of the claim. There is insufficient antecedent basis for this limitation in the claim. The language is confusing, and it is unclear what limitation this language places on the claim, for example, it is not clear if this language means measuring the protein standards during the assay performed on the samples (“in the same set” as in at the same time), or rather if this means under the same assay conditions/using same steps as performed on the samples. Clarification is necessary.
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 5, 6-9, 12-14 and 17 rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas 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
Claim 5 recites “a second step of calculating, based on all the protein concentration as well as the free PSA proportion determined in the first step, a combined score value”.
Claims 6 and 14 each recite “wherein a combined score value is calculated using the following formula:
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where βi are regression coefficients as determined beforehand with an optimization using experimental data, β0 being the intercept (claim 6) or “wherein βi are regression coefficients as determined beforehand with a maximization of the AUC in ROC approach using experimental data, β0 being the intercept (claim 14), and wherein xi is as x1 a risk score expressed in the range of 0-1, as x2 the prostate volume (expressed in mL), and as x3 a PI-RADS score, expressed as integer in the range of 1-5” (claims 6 and 14, and see further claims 7 and 8, which recite further limitations imposed on the coefficients of claim 6).
Claim 9 recites “wherein for a greater than 90% sensitivity threshold value of the combined score value in the range of 15-32 or 16.5-31.1 is selected, or 21-29 is selected”.
Claim 12 recites “wherein the quantitative detection…involves the determination of the concentration of such biomarkers relative to an external protein standard, involving the preparation of a reference standard curve by measuring defined concentrations of several protein standards diluted in the same buffer as for the protein dilution to be measured in the same set of measurements of the samples”.
Claim 13 recites “a second step of calculating….a combined risk score value” and further “wherein after the second step is a third step of a positive biopsy and/or prostate cancer of the subject as based on the biomarkers is determined based on the combined score value as determined in the second step”.
Regarding claim 17, the claim recites “wherein the quantitative detection of the respective concentration…involves the determination of the concentration of such biomarkers relative to an external protein standard, involving the preparation of a reference standard curve by measuring defined concentrations of 5-7 proteins standards diluted in the same buffer as for the protein dilution to be measured in the same set of measurements of the sample”.
Calculating a combined score value as claimed is an abstract idea, see MPEP 2106.05 regarding groupings of abstract ideas, specifically calculating a combined score value is considered to amount to a mathematical concept (calculation), the claim further limited to recite a particular mathematical formula. Mathematical equations, which represent abstract ideas, are not themselves patentable. The recited coefficients/variables limited in terms of the claimed values (referring to claims 6-8 and 14) are also mathematical concepts/part of the mathematical calculations. While the specific values recited further narrow the judicial exception, they fail to make the limitations any less of an abstract idea(s).
Regarding claims 9, 12 and 17, these claims are directed to comparing steps, for example, although claim 9 does not explicitly state a comparing step, it is implied by the language recited which refers to particular threshold values relied upon to achieve 90% sensitivity. Additionally, claim 12, is directed to (i.e., recites “involving”) the determination “relative to” a reference standard curve produced using external reference standard dilutions of known concentration, which amounts to comparing test samples to known reference/control values presented as a standard curve.
Such comparing steps be categorized as abstract ideas, namely mental processes/ concepts performed in the human mind (such as a doctor simply thinking about the calculated risk score value in relation to threshold/reference data and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of identifying solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a control or target data (in this case, comparing a numerical level to a cutoff value to standard calibration curve/standard reference values) represents abstract ideas.
Additionally, the recited threshold values (claim 9) constitute abstract ideas, given that a threshold value is itself a mathematical concept. The particular range values narrow the abstract idea, but do not make the comparison/reference to the standards any less abstract, and as such is not sufficient to provide eligibility under 35 U.S.C. 101 on its own.
Step 2A, Prong 2
The above discussed limitations are insufficient to integrate the judicial exceptions into a practical application because steps corresponding to mathematical calculations and mental concepts are themselves insufficient to constitute a practical application (as these are the judicial exceptions, not a practical application thereof).
In addition to the claimed limitations directed to judicial exceptions, the claims also recite that the method is “involving the quantitative detection, in serum, plasma or blood of the subject, of the concentration of THBS1, as well as the proportion of free PSA… in combination with data obtained from multi-parametric prostate magnetic resonance imaging data”, such steps are also insufficient to integrate the judicial exceptions because the purpose is merely to obtain the data. These limitations do not go beyond insignificant presolution activity, i.e., mere data gathering steps necessary in order to use the judicial exceptions/necessary to the judicial exceptions (steps to obtain the input data), 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). Additionally, these steps (determining the concentrations, proportions and data) are recited a high level of generality.
The claims fail to recite additional (in addition to the judicial exceptions themselves) steps/elements that apply, rely on or use the judicial exception(s) in a manner that impose a meaningful limit on the judicial exception.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
It is also the case that the additional steps/elements fail to go beyond activity that was considered well-known, routine and conventional in the art at the time.
For example, see Steuber et al. cited in detail below, teaching a method comprising collecting information about the health status of a subject (health status related to prostate health, see abstract), the method comprising quantitative detection of THBS1 and free PSA, further the reference performing multi-parametric prostate magnetic resonance imaging (MPMRI) (see specifically using Proclarix, a blood based-test which combines THBS1, CTSD, total PSA and free PSA, as well as age, to generate a risk score (page 322, col. 1, para 3, see page 323, col 1, para 2 blood collected and the assay performed). In addition to the assay performed using Proclarix, see Steuber teach subjects undergoing MPMRI, specifically page 324, col. 1, first full paragraph refers to subjects who underwent both Proclarix and mpMRI. See also page 326, col. 1, para 3, Steuber teach clinical performance of Proclarix improved when mpMRI was used (also col. 2, last paragraph, and page 327, conclusions paragraph). Steuber is collecting, as one method, all the information about healthy consistent with the present claims.
Even further, while Steuber does teach considering together all the collected data as claimed, it also supports that each biomarker/measurement individually is recognized in the prior art as a known biomarker/indicator, see for example the reference acknowledges free PSA, mpMRI are recognized/known indicators in the art (referring to current guidelines recommended for use or risk calculators (page 322, col. 1, para 1), that THSB1, CTSD are already known/measured in relation to prostate health/risk determination (page 322, col. 1, para 3), further the prostate volume is a variable considered in the art when available.
See also the originally filed specification, e.g., page 1, acknowledging PSA is a measurement part of what is considered the “classical approach” in the prior art. Also, page 1, acknowledges mpMRI as a recent, prior improvement recognized in the art for detection (see reciting “The recent improvement of early detection of csPCa has come from multiparametric magnetic resonance imaging (mpMRI) and guided biopsies using MRI as a template”. See also page 2, regarding the state of the prior art, which also supports each of the claimed markers was known/available, relied upon in the art for prostate health considerations (fPSA, THBS1, CTSD, OLFM4, CAM1, mpMRI).
Regarding these limitations which are performed in order to gather the data, there is nothing to suggest or indicate that the data is obtained or collected in a non-routine or unconventional way.
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.
Claim(s) 1-4, 10, 11 and 15-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Steuber et al., PROPOSe: A Real-life Prosptective Study of Proclarix, a Novel Blood-based Test to Support Challenging Biopsy Decision-making in Prostate Cancer, European Urology Oncology, 5, (2022), p. 321-327 (first published and available online 01/06/2021, IDS entered 12/14/2023), as evidenced by Macagno et al., Analytical performance of thrombospondin-1 and cathepsin D immunoassays part of novel CE-IVD marked test as an aid in the diagnosis of prostate cancer, PLOS One, 15(5), (2020), 14 pages.
Steuber et al. teach a method comprising collecting information about the health status of a subject (health status related to prostate health, see abstract), the method comprising quantitative detection of THBS1 and free PSA, further the reference performing multi-parametric prostate magnetic resonance imaging (MPMRI) (see specifically using Proclarix, a blood based-test which combines THBS1, CTSD, total PSA and free PSA, as well as age, to generate a risk score (page 322, col. 1, para 3, see page 323, col 1, para 2 blood collected and the assay performed). In addition to the assay performed using Proclarix, see Steuber teach subjects undergoing mpMRI, specifically page 324, col. 1, first full paragraph refers to subjects who underwent both Proclarix and mpMRI. See also page 326, col. 1, para 3, Steuber teach clinical performance of Proclarix improved when mpMRI was used (also col. 2, last paragraph, and page 327, conclusions paragraph).
Steuber anticipates claim 1 because their methods, combining Proclarix and mpMRI amounts to a method of collecting prostate health status information, the collection of information comprising quantitative detection in blood as claimed, in combination with data obtained from mpMRI data.
Regarding claim 2, Steuber teach the mpMRI data is used in the form of PI-RADS evaluation (see page 323, col. 1, para 2, interpreted using Prostate Image Reporting and Data system (PI-RADS) v2 by radiologists).
Regarding claim 3, Steuber’s collection of information further included a prostate volume parameter (i.e., measurement, see page 322, col. 1, para 3 “if available, prostate volume can be considered to calculate Proclarix density”, also col. 2, para 4, under 2.1 to page 323, including subjects that had small prostate volume, further Steuber at page 323, col. 1, para 3 teaches Proclarix density was calculated according to PSA density by dividing the risk score by prostate volume). Further see page 326, col. 1, paras 1 and 4).
Regarding claim 4, see as cited above, Proclarix includes further assay for CTSD.
Regarding claim 15, Steuber teach collecting the information by performing a first step of contacting blood with affinity reagent for each protein, detecting binding, see e.g., page 323, col. 1, para 3, using Proclarix kit, further teaching detection of free PSA using the Roche Cobas immunoassay system. Steuber teach using the biomarker values determined to predict a subject’s outcome (using Proclarix in those with positive mpMRI). Steuber is obtaining a quantitative value (i.e., readout) representative of concentration (using a readout/measure to determine concentration).
Regarding claims 10, 11 and 16, the immunoassay as used in Steuber comprise quantitative sandwich ELISA (see Steuber reference at page 323, col. 1, para 3, Proclarix kit (Proteomedix) described as in reference 13, reference 3 refers to Macagno et al.). Macagno is evidence that the assay is sandwich ELISA for THBS1 and CTSD (see Macagno et al., page 5, paragraph 3). The assays comprise antibody which reads on that claimed, see as evidenced by Macagno, namely using purified recombinant protein, and mouse monoclonal antibodies to the proteins (the antibodies of Macagno appear to read on the claims, as the claims do not clearly recite/require a step of producing the used antibodies (as part of the method) by immunizing mice, the antibodies used in the assay of Steuber, as evidenced by Macagno, appear to be indistinct from those presently claimed).
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.
Claim(s) 5 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Steuber et al. in view of Wang et al., A multivariable logistic regression equation to evaluate prostate cancer, Journal of the Formosan Medican Association, (2011), 110, p. 695-700, Kwak et al., Prediction of sarcopenia using a combination of multiple serum markers, Scientific Reports, (2018), 8(8574), 7 pages and Moons et al., Transparent Reporting of a multivariable prediction model for Individual Prognosis of Diagnosis (TRIPOD): Explanation and Elaboration, Annals of Internal Medicine Research and Reporting Methods, 162(1), (2015), 73 pages, and as evidenced by Macagno et al. (cited previously above).
Steuber et al. teach a method substantially as claimed, which relies on collection of information regarding a subject’s health status respect to prostate cancer (see as cited above) and uses that information to make decisions regarding one’s healthy status related to prostate cancer/decide on whether a biopsy is necessary. See Steuber et al. teach a first and second step (as evidenced by Macagno, see Macagno cited above), and further performing assay on diluted samples (page 5, para 4) and performs a step of determining the risk of a positive biopsy and/or prostate cancer based on the combination score (see abstract conclusion, and also page 326, col. 1, paras 2-3, Steuber specifically teaches Proclarix can accurately predict csPCa and patients with nor or insignificant PCa can reliably be ruled out by biopsy, further teaching performance of Proclarix improved when mpMRI was used in the biopsy decision algorithm, page 327, conclusions
However, although Steuber collects information about a subject’s status, information including detection of concentration of THBS1, fPSA, and mpMRI imaging data and relies on the combination of information together in order to decide a need for biopsy/assess one’s risk of cancer, Steuber does not clearly teach combining all of these parameters into a combined risk score (claims 5, 13).
However, it was well-known in the clinical assay art at the time to use multiparameter approach, combining measurements of various variables into a single calculated risk score for predicting a patient’s risk/outcome related to cancer, particular prostate cancer.
See for example, Wang et al., teaching a multivariable logistic regression equation to evaluate prostate cancer (abstract, page 696, col. 1, para 1), specifically relying on variables known and recognized in the art as being related to prostate cancer, each having a good accuracy for predicting a possibility of prostate cancer (see page 699, end of col. 1, to col. 2). The equation (P = 1 /(1 - e- x), see abstract) received the input and calculates a final score that represents an estimation of likelihood of prostate cancer, that such a calculation can aid in follow-up and may allow patients to more willingly undergo guided biopsy (see page 699, col. 2, para 2).
See also Kwak et al., who also acknowledges combining different markers/indicators into a single risk score using regression analysis for multiple biomarkers is a technique known to those of ordinary skill in the assay art (see page 2, paragraph 1 and 6), generating logistic regression coefficients, calculating a risk score as a sum of the risk score for each marker.
Moons et al. teach it is known in the art that a multivariable prediction model is a mathematical equation that relates multiple predictors for a particular individual to the probability of risk for the presence of diagnosis or future outcome (prognosis) (that other names for such model are risk prediction model, predictive model, prognostic (or prediction) index or rule and risk score 9 see page 1, end of col. 2). Moon et al. acknowledge that various types of models are used in medical prediction research, that most models are derived using multivariate regression, that logistical regression model is most often applied for binary endpoints, such as presence or absence of disease.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Steuber et al. to combine the obtained information as indicated (the multiple variables including the mpMRI data) to generate a single risk score (for example using multivariable logistic regression as in Wang) representative as a convenient and accurate art recognized technique (Wang, Kwak, Moons) known to those of ordinary skill for predicting a subject’s disease and need for subsequently follow-up (e.g., such as biopsy, see Wang). One having ordinary skill would be particularly motivated with regard to prostate cancer, as in Steuber, because the prior art recognized a more accurate prediction would contribute to patient willingness regarding further needed biopsy.
The modification would have been considered an obvious matter of applying a known technique to a known method, in particularly considering Steuber teaching combining mpMRI data achieves improved results compared to Proclarix alone (Steuber considering each of mpMRI (as PI-RADS score), prostate volume, fPSA and quantitative measure of at least THBS1). The art recognized the technique of calculating a risk score as an accurate way to combine plural measurements, each of the plural measurements recognized as having utility toward a common diagnostic/prognostic result. One having ordinary skill would have recognized that applying the known technique of generating a risk score to the known method as taught by Steuber would yield the predictable result of a convenient and accurate way to assess one’s prostate diagnosis/need for biopsy.
There is a reasonable expectation of success because Steuber already teach consideration of multiple predictors for prostate cancer together, providing them together into a calculation to generate a risk would be expected to provide a convenient, accurate representation of the combination of data using techniques known to those of ordinary skill in the art.
Claims 12 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Steuber et al. in view of Harris et al., Quantitative Chemical Analyses, Sixth Edition. New York: W. H. Freeman; Company (2003), p. 5-6 and Deepachandi et al., Quantification of Soluble or Insoluble Fractions of Leishmania Parasite Proteins in Microvolume Applications: A Simplification to Standard Lowry Assay, Hindawi International Journal of Analytical Chemistry, Article ID 6129132, (2020), 8 pages, as evidenced by Macagno et al. (cited previously above).
Steuber et al. and the cited prior art teach a method substantially as claimed (see as cited above); however, fail to teach determination of the concentrations of biomarkers relative to an external protein standard, involving preparation of a reference standard curve by measuring defined concentration of several protein standards diluted in the same buffer as for the protein dilution to be measured in the same set of measurements of samples (claim 12), and fail to teach determination measuring 5-7 protein standards (claim 17).
It is known in the art that in general, analytes with equal concentrations give different detector responses, that as a result, the response must be measured for known concentrations of analyte, i.e., it is known to produce a calibration or standard curve, see for example Harris at page 5, last paragraph. Harris teach (end of page 5 to page 6) using standard protein preparations (external protein standards) of known concentrations to produce the curve.
See also Deepachandi as another example demonstrating technique for producing a standard curve using standard dilutions in order to determine an unknown concentration relative to the external protein standards, Deepachandi teach (e.g., page 2, col. 2, para 2, preparation of standards, preparing standards samples under the same conditions/with the same reagents as the unknown test samples, see further para 4, Deepachandi use, for example 6 protein standard dilutions to create their curve.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention when performing the assay of Steuber et al. and the cited art to determine the concentrations of biomarkers relative to an external protein standard(s), namely to prepare a reference standard curve using external protein standards (as in Harris and Deepachandi), standards diluted/prepared under the same conditions as the unknown samples (Deepachandi), namely using 6 standards as shown by the prior art (e.g., in Deepachandi), as an obvious matter of applying a known analytic technique for quantitative biomarker determination (known for determining concentration), one motivated to use this technique given that the prior art recognized as a result of different concentrations producing different instrument response that it was known necessary to use such a standard curve to determine the unknown concentrations in a test sample (Harris, and as supported by Deepachandi). One having ordinary skill in the art would have recognized that applying the known analytical technique of producing and comparing to a standard curve, one would predictably achieve the ability to determine the concentration of the unknown.
Further, one having ordinary skill in the art would have a reasonable expectation of success applying known analytical assay techniques recognized by those of skill in the art for their art recognized intended purpose of determining an unknown.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 11,320,435 B2
Claims 1-5, 10-13 and 15-17 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- of U.S. Patent No. 11,320,435 B2 in view of Steuber et al. (cited previously above).
Although the claims at issue are not identical, they are not patentably distinct from each other because ‘435 similarly a method for collecting information about the health status of a subject involving the quantitative detection, in serum, plasma or blood of the subject, the concentration of THBS1, and proportion of free PSA in combination (see ‘435, claim 1)
However, ‘435 fails to recite in combination with data obtained form multiparametric prostate magnetic resonance imaging data (claim 1).
However, see Steuber cited in detail previously above, Steuber teaches a method comprising collecting information about the health status of a subject (health status related to prostate health, see abstract), the method comprising quantitative detection of THBS1 and free PSA (similarly as ‘435), further the reference performing multi-parametric prostate magnetic resonance imaging (MPMRI) (see specifically using Proclarix, a blood based-test which combines THBS1, CTSD, total PSA and free PSA, as well as age, to generate a risk score (page 322, col. 1, para 3, see page 323, col 1, para 2 blood collected and the assay performed). In addition to the assay performed using Proclarix, see Steuber teach subjects undergoing MPMRI, specifically page 324, col. 1, first full paragraph refers to subjects who underwent both Proclarix and mpMRI. See also page 326, col. 1, para 3, Steuber teach clinical performance of Proclarix improved when mpMRI was used (also col. 2, last paragraph, and page 327, conclusions paragraph). Steuber is collecting, as one method, all the information about healthy consistent with the present claims.
It would have been prima facie obvious to one having ordinary skill to further include mpMRI as in Steuber in order to improve the clinical performance of the combination of markers for the purpose of assessing/collecting information pertaining to one’s health status with respect to prostate cancer. One having ordinary skill in the art would have a reasonable expectation of success given that Steuber’s combination similarly includes each of THBS1 and fPSA (as with ‘435).
Regarding claim 2, see Steuber, the data for mpMRI provided in the form of a PI-RADS evaluation.
Regarding claim 3, Steuber’s collection of information further included a prostate volume parameter (i.e., measurement, see page 322, col. 1, para 3 “if available, prostate volume can be considered to calculate Proclarix density”, also col. 2, para 4, under 2.1 to page 323, including subjects that had small prostate volume, further Steuber at page 323, col. 1, para 3 teaches Proclarix density was calculated according to PSA density by dividing the risk score by prostate volume). Further see page 326, col. 1, paras 1 and 4. It would have been further prima facie obvious to include a measure for prostate volume because the prior art further recognized this a parameter contributing to sensitivity; based on the combination of the cited art one having ordinary skill would have a reasonable expectation of success because the prior art establishes the combination of parameters as performing improved compared to limited combinations/induvial measures alone.
Regarding claim 4, see claim 1 of ‘435, similarly teach an additional marker that is CTSD.
Regarding claim 5, see ‘435 at claim 1.
Regarding claim 10, see ‘435 at claim 1.
Regarding claim 11, see ‘435 at claim 1(mouse monoclonal antibodies having been generated through immunization of mice with the respective recombinant human THBS1 or CTSD protein).
Regarding claim 12, see ‘435 at claim 8 (external protein standard, preparation of a reference standard curve, protein dilutions in same buffer dilutions as to be measured for the test samples).
Regarding claims 13, 15 and 16, see ‘435 at claim 17.
Regarding claim 17, see ‘436 at claim 18.
Correspondence
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
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