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 .
Status of the Claims
Claims 1-11 and 18-20 were pending. Claims 1, 8, 10, and 18-20 are amended. Claim 11 is cancelled.
Claims 1-10 and 18-20 are examined herein.
Withdrawn Rejections
The objections to claims 1, 8 and 18-20 are withdrawn in view of claims amendments.
The rejections of claim 11 are withdrawn in view of claim cancellation.
The rejection of claims 1-9 under 35 U.S.C. §103 is withdrawn in view of claim 1 amendments. However, upon further consideration, a new ground(s) of rejection is made in view of a new prior art reference of Li et al. (Diabetes Care. 2010 Jul;33(7):1618-24).
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 1-10 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 “an QA-value reflecting the length of the female's menstrual cycle”. There is insufficient antecedent basis for “the length”. It is also unclear the length of which cycle from the entire life of the female is included in the data set.
Claim 1 recites twice “a sample obtained from the female” (step a)). It is unclear if the claim is referring to two samples obtained from the female, or only one sample.
Claim 10 recites “a sample obtained from the female”. Parent claim 1 already recites “in a sample obtained from the female”. It is unclear if the claim is referring to an additional sample or the sample already recited in claim 1.
Claim 10 recites “the method further includes determining one or more values of the data set provided in step a) by measuring the amount or concentration of one or more hormones.” It is unclear what one or more values of the data set provided in step a) are further determined. All values recited in parent claim 1 are already determined there according to the current amendments. It is also unclear what one or more hormones are measured beyond those already recited and measured in claim 1. The claim is indefinite because the metes and bounds of the claim are unclear.
Claims 2-10 are rejected because they depend from rejected claim 1.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS. —Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 recites the method of claim 1, wherein the method further includes determining one or more values of the data set provided in step a) by measuring the amount or concentration of one or more hormones.
Parent claim 1 recites measuring the amount or concentration of free testosterone (FT) or total testosterone (TT) and sex hormone-binding globulin (SHBG); and AMH. As such, all hormones are already measured in claim 1; therefore, claim 10 does not recite a further limitation.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring correlation, without significantly more.
Claim 1 recites a method of assessing a female's risk of having polycystic ovary syndrome. The claim recites at least one step of assessing the patient’s risk for a medical condition. Thus, the claim is a process, which is a statutory category of invention.
The claim recites establishing a relationship between certain physiological and biomarker data and female's risk of having polycystic ovary syndrome. This relationship is categorized as a naturally occurring correlation, and therefore it is a judicial exception.
The claim recites the steps of providing a data set, processing the data set, comparing the combined value, and indication of the risk via an indication unit. These additional steps are an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
The claim recites that the HA- and AMH-values are determined by measuring the amount or concentration of free testosterone (FT) or the amount or concentration of total testosterone (TT) and sex hormone-binding globulin (SHBG), and AMH in a sample obtained from the female using an immunoassay and/or mass spectrometry. These additional measuring steps are an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
Additionally, the broadest reasonable interpretation of processing the data set limitation requires a mathematical calculation. Hence, the limitation recites a “mathematical calculation” and so falls into the “mathematical concepts” grouping of abstract ideas.
The limitation of comparing the combined value requires comparing a female’s score against a reference population. The limitation falls into the “mental process” grouping of abstract ideas because the comparing can be practically performed in the human mind.
The final limitation of the claim is indicating the female's risk of having PCOS via an indication unit. Based on the plain meaning of the words “indicating” and “indication unit”, the broadest reasonable interpretation of this limitation is showing calculation results on a computer display or its functional equivalent. Therefore, indicating the female's risk of having PCOS via an indication unit is a final step of the mathematical calculation discussed above.
The claim does not recite any additional steps that would make the claim as a whole to integrate the recited judicial exception into a practical application of the exception, such as a treatment procedure or a medication.
The additional elements of providing a data set, processing the data set, comparing the combined value, indicating the risk via an indication unit, and measuring steps are an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
The measuring steps for determining the amounts or concentrations of the recited biomarkers are recited at a high level of generality as immunoassay and/or mass spectrometry and constitute a well-understood, routine, and conventional activity known in the prior art: Li et al. (Diabetes Care. 2010 Jul;33(7):1618-24) teach measuring serum concentrations of total testosterone and SHBG using competitive electrochemiluminescence immunoassays on the Elecsys 2010 autoanalyzer (pg. 1619, col. 1, par. 2). Casadei et al. (Arch Gynecol Obstet. 2018 Jul;298(1):207-215) teach measuring AMH blood levels using the enzyme immunoassay AMH-EIA from Immunotech, Beckman Coulter company (pg. 208, col. 2, par. 2) The use of commercial analyzers for all three analytes provides sufficient evidence that measuring concentrations of total testosterone, SHBG, and AMH is well-understood, routine, and conventional activity known in the prior art.
As such, there are no additional elements, or combinations of additional elements, recited in the claim adding to inventive concepts of the claim.
Claims dependent from claim 1:
Claim 2 recites providing additional value of weight to the data set without any additional steps. The step of providing additional value of weight to the data set is an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
Claim 3 recites how the HA-value is determined or calculated. The limitation recites a “mathematical calculation” and so falls into the “mathematical concepts” grouping of abstract ideas.
Claim 4 recites the combined value is a weighted combined value obtained by weighted calculation of the values. The limitation recites a “mathematical calculation” and so falls into the “mathematical concepts” grouping of abstract ideas.
Claim 5 recites assigning a risk factor based on the combined value and threshold values. The limitation is a step of comparing the combined value to the three threshold values. The limitation falls into the “mental process” grouping of abstract ideas because the comparing can be practically performed in the human mind.
Claim 6 recites retrieved from a database one or more values of the reference population and/or the combined value of the reference population. Retrieving values from a database is an insignificant extra-solution activity that relates to data gathering necessary to apply the judicial exception and the calculation steps. The reference values have to be stored in one form or another and retrieved for comparison or calculation purposes.
Claim 7 recites the data set further includes a PHE-value. This additional value is just another parameter for establishing a relationship between certain physiological and biomarker data and female's risk of having polycystic ovary syndrome.
Claim 8 recites the sample is a blood sample selected from the group consisting of serum, plasma, and whole blood; and claim 9 recites the female is a human. Using serum, plasma, or whole blood samples is well-understood, routine, and conventional activity known in the art of diagnostics.
Claim 10 is very confusing and fails to recite limitations sufficient to make the subject matter eligible under 35 U.S.C. 101 (see 112(b) and 112(d) rejections for details).
Therefore, claims 2-10 are not eligible under 35 U.S.C. 101 for the same reasons as parent claim 1.
For these reasons, claims 1-10 are ineligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5-9, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Khuraseva et al. (RU 2629720) in view of Karakas (Clin Chim Acta. 2017 Aug; 471:248-253), Li et al. (Diabetes Care. 2010 Jul;33(7):1618-24), and Casadei et al. (Arch Gynecol Obstet. 2018 Jul;298(1):207-215), and as evidenced by Han et al. (Hum Reprod. 2014 May; 29(5):1042-8), SHBG Roche (2024), and Testosterone Roche (2025).
Regarding claim 1, Khuraseva teaches a method for predicting risk levels of polycystic ovary syndrome (PCOS) ([0002]) comprising clinical signs corresponding to an OA-value reflecting the length of the female's menstrual cycle and/or the number of the female's menstrual cycles per year as menstrual cycle disorders such as oligo-/amenorrhea ([0024]); and laboratory signs corresponding to an HA-value reflecting the female's androgen status as increased levels of total testosterone ([0044]) and androstenedione level above normal ([0045]) (both testosterone and androstenedione are androgens); and an AMH-value corresponding to the amount or concentration of anti-Mullerian hormone (AMH) as an increase in the AMH level above the age norm ([0048]).
Regarding the limitation of processing the data set by combining values of the data set into one combined value, the reference teaches assigning to each data parameter a value (menstrual cycle disorder - 3 points; increased levels of total testosterone - 2 points; androstenedione level above normal - 2 points; and an increase in the AMH level above the age norm - 1 point) and calculating the sum of the points ([0055]). The total score is compared to a set of reference values to estimate a risk of developing polycystic ovary syndrome: a score of 1-15 indicates a low risk; a score of 16-31 indicates an average risk; and a score of 32-62 corresponds to a high risk of developing polycystic ovary syndrome ([0056]-[0058]).
Khuraseva teaches the HA-value reflecting the female's androgen status as increased levels of total testosterone ([0044]), but does not specifically teach measuring the amount or concentration of free testosterone (FT) or the amount or concentration of total testosterone (TT) and sex hormone-binding globulin (SHBG) in a sample obtained from the female using an immunoassay and/or mass spectrometry and measuring the amount or concentration of AMH in a sample obtained from the female using an immunoassay and/or mass spectrometry.
Regarding claim 1, Karakas teaches new biomarkers for diagnosis and management of polycystic ovary syndrome (Title). Karakas also teaches measuring total testosterone (TT) and sex hormone-binding globulin.
Specifically, the reference teaches that insulin resistance or use of contraceptives can elevate total testosterone and “it is very important not to rely on total testosterone concentrations for PCOS diagnosis but to order a panel which includes total testosterone, SHBG, bioavailable and free-testosterone measurements” (pg. 250, col. 1, par. 1) meeting the limitation reciting measuring the amount or concentration of total testosterone (TT) and sex hormone-binding globulin (SHBG).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva, by employing total testosterone and SHBG measurements as taught by Karakas, in order to provide a more reliable method than using only total testosterone for diagnosis of polycystic ovary syndrome (Karakas, pg. 250, col. 1, par. 1). One having ordinary skill in the art would have been motivated to make such a change because more reliable method for diagnosis leads to better healthcare. The use of such combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Khuraseva and Karakas as similarly drawn to detection of an androgen level in female samples. Measuring SHBG levels is a separate assay from the TT assay, therefore, both assays cannot interfere with each other.
Khuraseva and Karakas do not specifically teach measuring the amount or concentration of TT and SHBG using an immunoassay and/or mass spectrometry; processing the data set with a processing unit and indicating the female's risk of having PCOS via an indication unit; and measuring the amount or concentration of AMH in a sample obtained from the female using an immunoassay and/or mass spectrometry.
Regarding claim 1, Li teaches “Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men” (Title). Li also teaches measuring serum concentrations of total testosterone and SHBG using competitive electrochemiluminescence immunoassays on the Elecsys 2010 autoanalyzer (pg. 1619, col. 1, par. 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva and Karakas, by employing the immunoassay methods as taught by Li, in order to measure total testosterone and SHBG levels, as an obvious matter of applying a known technique of immunoassay to a known method for diagnosis of polycystic ovary syndrome to yield predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Li teaches the immunoassay of total testosterone and SHBG in serum and Khuraseva and Karakas are generic on specific measurement methods.
Khuraseva, Karakas, and Li do not specifically teach measuring the amount or concentration of AMH in a sample obtained from the female using an immunoassay and/or mass spectrometry; and processing the data set with a processing unit and indicating the female's risk of having PCOS via an indication unit.
Regarding claim 1, Casadei teaches “The diagnosis of PCOS in young infertile women according to different diagnostic criteria: the role of serum anti-Mullerian hormone” (Title). Casadei also teaches AMH blood levels were measured using the enzyme immunoassay AMH-EIA from Immunotech, Beckman Coulter company (pg. 208, col. 2, par. 2).
Additionally, Casadei teaches that statistical analysis was performed by SPSS software (pg. 209, col. 1, par. 2). The reference teaches that a computer (the processing unit) and a computer display (the indication unit) were necessarily used in data processing because SPSS software has been developed for use on general purpose computers having displays.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva, Karakas, and Li, by employing the immunoassay method as taught by Casadei, in order to measure AMH levels, as an obvious matter of applying a known technique of immunoassay to a known method for diagnosis of polycystic ovary syndrome to yield predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Casadei teaches the immunoassay of AMH in blood and Khuraseva, Karakas, and Li are generic on specific measurement methods.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva, Karakas, and Li, by employing a computer with a display as taught by Casadei, in order to perform calculations of the combined value, as an obvious matter of applying a known device (a computer with a display) to a known method (diagnosis of polycystic ovary syndrome) to yield predictable results.
One having ordinary skill in the art would have found it obvious to use a computer and indicate the final result on the computer display because computers are widely used for calculations and data processing in diagnostics, and they provide more reliable results than manual calculations.
Regarding claim 2, Khuraseva teaches including current body weight of a patient in the calculation of the total score ([0027]).
Regarding claim 5, Khuraseva teaches that the total score is compared to a set of reference values to estimate a risk of developing polycystic ovary syndrome: a score of 1-15 indicates a low risk; a score of 16-31 indicates an average risk; and a score of 32-62 corresponds to a high risk of developing polycystic ovary syndrome ([0056]-[0058]). Therefore, the score of 32 corresponds to thresholdhigh and the score 16 corresponds to thresholdmoderate of instant invention.
Regarding claim 6, Khuraseva teaches that the total score is compared to a set of reference values to estimate a risk of developing polycystic ovary syndrome: a score of 1-15 indicates a low risk; a score of 16-31 indicates an average risk; and a score of 32-62 corresponds to a high risk of developing polycystic ovary syndrome ([0056]-[0058]). Khuraseva does not explicitly teach that the reference values are retrieved from a database. However, the score values indicating the ranges of the risk categories must be stored in an electronic or printed form to prevent their loss (the database of instant invention) and retrieved from the database when actual patient’s data are analyzed. One having ordinary skill in the art would have found it obvious to store the score values in an electronic or printed form to preserve them for future use and retrieve them from this storage when needed. It is a common practice of dealing with any reference data.
Regarding claim 7, Khuraseva teaches ovarian volume of more than 10 cm3 as one of the indicators in predicting the degree of risk of developing PCOS ([0051]). Ovarian volume of more than 10 cm3 is a characteristic of polycystic ovarian morphology.
Regarding claim 8, Khuraseva teaches determining the level of hormones in the blood ([0004]), meeting the limitation of claim 8 reciting whole blood.
Regarding claim 9, Khuraseva teaches diagnosing PCOS in adolescent girls ([0004]), meeting the limitation of claim 9 reciting the female is human.
Regarding claims 18-20, Khuraseva and Karakas teach a method of assessing a female's risk of having polycystic ovary syndrome comprising measuring the amount or concentration of total testosterone (TT), sex hormone-binding globulin (SHBG), and anti-Mullerian hormone (AMH). Li and Casadei teach immunoassay methods that teach the limitation of claims 18-20 - providing a serum sample for measuring serum concentrations of total testosterone and SHBG (Li; pg. 1619, col. 1, par. 2) and providing a blood sample for measuring AMH blood levels (Casadei; pg. 208, col. 2, par. 2).
The immunoassays methods of Li and Casadei do not explicitly teach contacting the sample with a binding agent for AMH, a binding agent for TT, and a binding agent for SHBG, and detecting the binding between AMH and the AMH binding agent, binding between TT and the binding agent for TT, and binding between SHBG and the binding agent for SHBG. However, any immunoassay necessarily comprises contacting a sample with a binding agent for an analyte and detecting the binding between the analyte and the analyte binding agent. These steps are inherent to the immunoassays.
Additionally, Han provides evidence that the Beckman Coulter AMH immunoassay taught by Casadei (pg. 208, col. 2, par. 2) comprised antibodies as binding agents for AMH “two antibodies used in the assay are directed against epitopes in the mature and the pro-region of the molecule (pg. 1043, col. 1, par. 1). Roche Diagnostics provides evidence that both SHBG and testosterone immunoassays taught by Li (pg. 1619, col. 1, par. 2) comprised antibodies as binding agents: (a) “a biotinylated monoclonal SHBG-specific antibody, and a monoclonal SHBG-specific antibody labeled with a ruthenium complex form a sandwich complex” (SHBG Roche; pg. 1, col. 2, section “Test principle”, 1st incubation step) and (b) “Anti-testosterone-Ab~biotin” and “Biotinylated monoclonal anti-testosterone antibody” (Testosterone Roche; pg. 1, col. 2, section Reagents – working solutions, R1).
Therefore, the immunoassays of Li and Casadei, as evidenced by Han and Roche Diagnostics teach contacting the sample with a binding agent for AMH, a binding agent for TT, and a binding agent for SHBG, and detecting the binding between AMH and the AMH binding agent, binding between TT and the binding agent for TT, and binding between SHBG and the binding agent for SHBG.
The immunoassays for TT, SHBG, and AMH are quantitative assays, therefore, they detect both the presence (claim 18) and the amount or concentration of TT, SHBG, and AMH (claim 19).
Together, TT, SHBG, and AMH biomarkers constitute a panel of biomarkers. Therefore, measuring all three biomarkers necessarily meets the limitation of claim 20, reciting determining a measurement for the panel of biomarkers in the sample, wherein the panel comprises the biomarkers anti-Mullerian hormone (AMH) and total testosterone (TT) and sex hormone-binding globulin (SHBG), wherein the measurement comprises determining a level of each of the biomarkers in the panel.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Khuraseva, Karakas, Li, and Casadei as applied to claim 1 above, in view of Rosner et al. (J Clin Endocrinol Metab. 2007 Feb;92(2):405-13).
The teachings of Khuraseva, Karakas, Li, and Casadei have been set forth above.
Khuraseva, Karakas, Li, and Casadei do not teach the ratio of the amount or concentration of total testosterone (TT) and the amount or concentration of sex hormone-binding globulin (SHBG) in a sample obtained from the female (TT/SHBG).
Regarding claim 3, Rosner teaches “Utility, Limitations, and Pitfalls in Measuring Testosterone: An Endocrine Society Position Statement” (Title). Rosner also teaches the TT/SHBG ratio.
Specifically, the reference teaches that the ratio TT/SHBG has a reasonable correlation with free testosterone, particularly in women (pg. 410, col. 1, last par.). Additionally, Rosner teaches that free testosterone often correlates better with the androgenic state of the patient than does TT (pg. 408, col. 2, par. 3). Therefore, the TT/SHBG ratio can be used interchangeably with the concentration of free testosterone.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva, Karakas, Li, and Casadei, by employing the TT/SHBG ratio as taught by Rosner, in order to provide a biomarker with a better correlation with the androgenic state of the patient than does TT (Rosner, pg. 408, col. 2, par. 3). One having ordinary skill in the art would have been motivated to make such a change because measuring concentration of free testosterone is a more difficult task than measuring the concentrations of TT and SHBG, and calculating the TT/SHBG ratio. The use of such combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Khuraseva, Karakas, Li, and Casadei and Rosner are similarly drawn to detection of testosterone levels. Rosner teaches TT/SHBG ratio as a biomarker with a better correlation with the androgenic state of the patient.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Khuraseva, Karakas, Li, and Casadei as applied to claim 1 above, in view of Chajka et al. (RU 2134061).
The teachings of Khuraseva, Karakas, Li, and Casadei have been set forth above.
Regarding claim 4, Khuraseva, Karakas, Li, and Casadei teach combining values of the data set into one combined value based on points assigned to each data parameter, but do not explicitly teach the combined value is a weighted combined value obtained by weighted calculation of the values.
Regarding claim 4, Chajka teaches a method for diagnosis of polycystic ovary syndrome in adolescent girls (Title). Chajka also teaches the combined value is a weighted combined value obtained by weighted calculation of the values.
Specifically, Chajka teaches calculating the risk for developing PCOS from individual biomarker values using the formula: y = 0.02012•p1 + 040292•In(t) + 0.07243•p - 1.12114•p(tm) -0.04008•b + 0.07146•gir + 0.07565•yami + 3.74045 ([0005]), wherein the coefficients for each biomarker concentration are weights of the biomarker contribution to the total combined value of the risk.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva, Karakas, Li, and Casadei, by replacing approximate weight points for each biomarker with more precise weights as taught by Chajka, as an obvious matter of simple substitution of one known element for another to obtain predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because an approximate calculation scheme of Khuraseva is replaced by more precise calculation scheme of Chajka without changing the principle of the calculation.
Response to Arguments
Applicant's arguments filed May 26, 2026 have been fully considered.
Claim 1 reciting ““an QA-value reflecting the length of the female's menstrual cycle”. There is insufficient antecedent basis for “the length”. It is also unclear the length of which cycle from the entire life of the female is included in the data set” was rejected under 112(b) (pg. 3, par. 3).
Applicant argues that “Read in light of the specification, the phrase "the length" in the recitation "an QA-value reflecting the length of the female's menstrual cycle" plainly refers to the length of "the female's menstrual cycle" recited in the same limitation. The specification expressly defines that "the length of the female's menstrual cycle may be determined" by reference to the first day of menstruation as the first day of the cycle and the last day before the next menstruation as the end of the cycle. Specification, para. [0041]. The specification further confirms that oligomenorrhea is assumed if the menstrual cycle length is reported as "repeatedly >35 days." Specification, paras. [0044], [0058]” (pg. 9, par. 1).
The argument is not persuasive because a PHOSITA is not expected to search the specification for essential information/limitations not presented in the claims. The relevant passage from the specification must be recited in the claim. Claims 2-10 stay rejected because they depend from rejected claim 1 (pg. 10, last par.).
Claim 10 reciting “wherein the method further includes determining one or more values of the data set provided in step a)” was rejected under 112(b). Applicant amends claim 10; therefore, the previous rejection is withdrawn. However, the amended claim is still rejected under 112(b) because parent claim 1 already recites “a sample obtained from the female”, and it is unclear what one or more values of the data set provided in step a) are further determined. All values recited in parent claim 1 are already determined there according to the current amendments. It is also unclear what one or more hormones are measured beyond those already recited in claim 1. The claim is indefinite because the metes and bounds of the claim are unclear. Additionally, a new rejection under 112(d) is added because claim 1 already recites measuring the amount or concentration of free testosterone (FT) or total testosterone (TT) and sex hormone-binding globulin (SHBG); and AMH. As such, all hormones are already measured in claim 1; therefore, claim 10 does not recite a further limitation.
Cancellation of claim 11 renders the § 112(b) rejection of claim 11 moot (pg. 10, par. 6).
Claims 1-10 are rejected under 35 U.S.C. § 101 as being directed to a naturally
occurring correlation without significantly more (Remarks, section V).
Applicant argues legal standard for a rejection under § 101 (pg. 11-12, section A.). Specifically, that “The 2019 Guidance specifically excludes consideration of whether additional elements are well-understood, routine, or conventional at Step 2A, Prong Two; that analysis is reserved for Step 2B” (pg. 12, par. 2). Additionally, Applicant argues that “The Office must expressly support any finding of well-understood, routine, or conventional activity with one of the four types of factual evidence identified in the USPTO's Berkheimer Memorandum” (pg. 12, par. 3).
The argument is not persuasive because well-understood, routine, or conventional analysis performed in Step 2B recites two prior art reference of Li and Casadei which teach that immunoassay methods used for biomarker concentration measurements were performed using commercially available immunoassay instruments. One of these instruments is manufactured by Applicant and is sold all over the world, which conveys that the instrument is well-understood, routine and conventional.
Finally, Applicant is advised to provide a copy of the USPTO's Berkheimer Memorandum and a proper reference to specific pages in it for consideration by the Office.
Applicant states that amended claim 1 and dependent claims 2-10 “as a whole integrate any such exception into a practical application under Step 2A, Prong Two, and are therefore not "directed to" a judicial exception” (pg. 12, section B, par. 1).
Specifically, Applicant argues that: (a) claim 1 recites measuring the amount or concentration of the hormones using an immunoassay and/or mass spectrometry (pg. 12, last par.) and these methods are concrete laboratory techniques that inherently require physical instrumentation, reagents, and a biological sample that cannot be performed in the human mind.
The arguments are not persuasive because the recited methods of measuring the amount or concentration of the hormones are considered an insignificant extra-solution activity that amounts to mere data gathering incidental to the recited limitation (Subject Matter Eligibility 2024, example 49, pg. 33, par. 1) and Applicant’s statement that these methods cannot be performed in the human mind (pg. 13, section 1) fails to overcome §101 rejection of claim 1 because the methods by themselves are insufficient to make claim 1 eligible under §101.
Applicant further argues that amended claim 1 recites “a specific multi-step laboratory methods and computational workflows that goes well beyond merely observing a naturally occurring correlation” (pg. 13, section 1, par. 2). The argument is not persuasive because Applicant fails to provide evidence how the “multi-step laboratory methods and computational workflows” make claim 1 eligible under §101”.
Applicant argues that “The Amended Claims Are Directed to a Specific Technological Solution to a Documented Unmet Need” (pg. 13, section 2 – pg. 14, par. 1-2). The argument is not persuasive because Applicant fails to provide evidence for an unmet need, but Applicant's arguments cannot take place of evidence. Moreover, Applicant provides evidence for known PCOS diagnostic methods “existing diagnostic methods for PCOS based on the Rotterdam Criteria” (pg. 13, section 2, par. 1).
In section 4 on page 15 Applicant argues again that “The Office Failed to Provide Adequate Evidentiary Support for Its Step 2B Analysis”. Applicant states “The Office's reliance on Khuraseva (RU 2629720) and Chajka (RU 2134061) to establish that the combined value calculation is WURC is misplaced.
The argument is moot because the rejection was revised and it no longer relies on Khuraseva (RU 2629720) and Chajka (RU 2134061). Instead, it relies on two prior art reference of Li and Casadei (see details above in Remarks).
Another Applicant’s argument is “The Office's Differential Treatment of Claims 18-20 Confirms the Patent Eligibility of Amended Claim 1” stating that “Applicant notes that claims 18-20, which recite the physical steps of detecting AMH and (i) FT, or (ii) TT and SHBG using binding agents in a sample, did not receive a §101 rejection” (pg. 16, par. 1).
The argument is not persuasive because claims 18-20 do not recite any diagnostic decisions or naturally occurring correlations, instead they recite steps of detecting the levels of the recited hormones in a sample, which is an eligible subject matter. For claim 20, the risk of developing polycystic ovary syndrome is in the preamble, so it is interpreted as an intended use of the method.
Applicant argues that “Dependent Claims 2-10 Are Patent Eligible for the Reasons Set Forth Above and Add Further Specific Limitations” (pg. 16, section C). Applicant recites specific limitations of the dependent claims and concludes that “The dependent claims further integrate any alleged judicial exception into a practical application of PCOS risk assessment” (section C, par. 2) without providing any argument how the recited limitation overcome the §101 rejection. For example, how can claim 9 overcome the rejection by reciting that the female is a human? The argument is not persuasive.
Additionally, claim 10 is free of the prior art because it is unclear what is actually claimed and how claim 10 further limits parent claim 1. Claim 10 being free of the prior art does not help to overcome the §101 rejection for the other claims.
Claim Rejections Under 35 U.S.C. § 103 – Obviousness (pg. 17, Section VI).
Applicant argues about rejection of claims 1-2 and 5-9 are rejected under 35 U.S.C. § 103. Specifically, that claim 1 is amended “to incorporate specific limitations regarding the determination of the HA-value and AMH-value. Specifically, amended claim 1 now requires that: (1) the HA-value is determined by measuring the amount or concentration of free testosterone (FT) or the amount or concentration of total testosterone (TT) and sex hormone-binding globulin (SHBG) in a sample obtained from the female using an immunoassay and/or mass spectrometry; and (2) the AMH-value is determined by measuring the amount or concentration of AMH in a sample obtained from the female using an immunoassay and/or mass spectrometry” (pg. 17, last par.).
The argument is persuasive and the rejections of claims 1-9 under 35 U.S.C. §103 are withdrawn in view of claim 1 amendments. However, upon further consideration, a new ground(s) of rejection is made in view of claim 1 amendments in view of a new prior art reference of Li.
Briefly, Li teaches measuring serum concentrations of total testosterone and SHBG using competitive electrochemiluminescence immunoassays on the Elecsys 2010 autoanalyzer (pg. 1619, col. 1, par. 2) and Casadei teaches measuring AMH blood levels using the enzyme immunoassay AMH-EIA from Immunotech, Beckman Coulter company (pg. 208, col. 2, par. 2).
Applicant argues that “Khuraseva' s Binary Point-Scoring System Is Fundamentally Different from the Claimed Method” (pg. 18, section B.1). Specifically, Applicant states that “The Office maps Khuraseva's binary clinical and laboratory indicators to the claimed OA-, HA-, and AMH-values. Office Action, pp. 7-9. This mapping is incorrect because it conflates Khuraseva' s binary present/absent assessments with the claimed continuous quantitative measurements” (pg. 19, last par. and the entire pg. 20) and that “The Office Has Not Articulated a Sufficient Motivation to Modify Khuraseva” (pg. 21, section 3).
The argument is not persuasive because Applicant is arguing limitations which are not claimed. In response to applicant’s argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., continuous quantitative measurements vs. binary indicators) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The argument that “separate scoring inputs in Khuraseva does not constitute a teaching to combine these inputs (and no others) in the specific manner recited in the amended claims” (pg. 22, par. 1) as also not persuasive because Applicant fails to provide evidence how “the specific manner” recited in claims is different from the formular taught by Chajka ([0005]), wherein the coefficients for each biomarker concentration are weights of the biomarker contribution to the total combined value of the risk.
Applicant argues that “The Proposed Modification Would Require a Substantial Reconstruction and Change in the Basic Principles of Khuraseva” (pg. 22, section 4) and “The proposed modification of Khuraseva to arrive at the claimed method would require a substantial reconstruction and redesign of Khuraseva and would destroy the basic principles under which Khuraseva was designed to operate” (pg. 22, par. 2).
The argument is not persuasive because:
(a) the statement that “Khuraseva expressly criticizes its own prototype, Chajka (RU 2134061), precisely because "the authors do not take into account the anamnestic data, the genetic predisposition, the risk factors for the development of PCOS, but only consider a small part of the clinical and laboratory data, and this amount of research is currently insufficient."” is not a teaching away situation, but a normal improvement of a diagnostic method achieved by including more clinical and laboratory indicators into the prediction model;
(b) for the purposes of the Office Action, Khuraseva is cited of its teaching of “a method for predicting risk levels of polycystic ovary syndrome (PCOS) ([0002]) comprising clinical signs corresponding to an OA-value reflecting the length of the female's menstrual cycle and/or the number of the female's menstrual cycles per year as menstrual cycle disorders such as oligo-/amenorrhea ([0024]); and laboratory signs corresponding to an HA-value reflecting the female's androgen status as increased levels of total testosterone ([0044]) and androstenedione level above normal ([0045]) (both testosterone and androstenedione are androgens); and an AMH-value corresponding to the amount or concentration of anti-Mullerian hormone (AMH) as an increase in the AMH level above the age norm ([0048])” (pg. 7, last par. – pg. 8, par. 1); the other factors Applicant recites “anamnestic data, the genetic predisposition, the risk factors for the development of PCOS” were not used in the rejection;
(c) Applicant fails to provide evidence of the substantial reconstruction and redesign of Khuraseva teachings as presented in the OA (see (b) above) and what basic principles this reconstruction and redesign would destroy.
Applicant argues that “The Claimed Combination Produces Unexpectedly Superior Diagnostic Performance That Constitutes Objective Evidence of Non-Obviousness” (pg. 22, section 5). The argument is not persuasive because Applicant is arguing limitations which are not claimed. In response to applicant’s argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Superior Diagnostic Performance, “AUC, sensitivity, specificity, or any other standardized diagnostic performance metric” (pg. 23, par. 2)) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that “The Combination of Khuraseva and Karakas Does Not Render Claim 3 Obvious” (pg. 23, section C). Specifically, Applicant argues again about not claimed continuous quantitative measurements vs Khuraseva's binary point-scoring system (pg. 23, last par.). The argument is not persuasive as it has been addressed above.
Applicant argues that “The Office Has Not Articulated Why FT Specifically Would Be Selected” and “The Office has not articulated any specific reason why a PHOSITA would select FT specifically from among the four measurements recommended by Karakas. Nor has the Office addressed why a PHOSITA, having selected an androgen measurement from Karakas, would substitute it into Khuraseva' s binary point-scoring system rather than into a different diagnostic framework. The Office's combination is conclusory and does not satisfy the articulated reasoning requirement of KSR” (pg. 24, section 2).
The argument is moot because the rejection has been revised and no longer includes free testosterone. However, the argument is still not persuasive because the OA stated “Karakas also teaches measuring free testosterone as a biomarker of PCOS. Specifically, the reference teaches that insulin resistance or use of contraceptives can elevate total testosterone and “it is very important not to rely on total testosterone concentrations for PCOS diagnosis but to order a panel which includes total testosterone, SHBG, bioavailable and free-testosterone measurements” (pg. 250, col. 1, par. 1). It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva, by employing free-testosterone measurements as taught by Karakas, in order to provide a more reliable method for diagnosis of polycystic ovary syndrome (Karakas, pg. 250, col. 1, par. 1). One having ordinary skill in the art would have been motivated to make such a change because more reliable method for diagnosis leads to better healthcare” (pg. 9, rejection of claim 3). The OA clearly identified the benefit of measuring free testosterone. Additionally, Karakas does teach measuring free testosterone and does not have to “single out free testosterone as the preferred androgen measurement for PCOS diagnosis”.
Applicant argues that “The Combination of Khuraseva and Chajka Does Not Render Claim 4 Obvious” (pg. 24, section D).
Specifically, “Chajka discloses a formula for diagnosing PCOS that uses seven input variables: prolactin (pl), serum testosterone (entered as ln(t)), serum progesterone (p), uterus thickness (tm), testosterone-estradiol binding globulin (b), hirsutism degree (gir), and ovarian-uterine index (yami). Chajka, para. [0005]. None of these variables corresponds to the OA-value (menstrual cycle length or number), the FAI-based or FT-based HA-value, or the AMH-value recited in the amended claims. Chajka does not measure or use AMH at all, and does not measure menstrual cycle length or number as continuous variables” (pg. 24, last par. – pg. 25, par. 1), and “Such a substitution would replace not only the computational approach (additive point scoring with regression-based formula) but also the entire set of input parameters (Khuraseva' s OA, total testosterone, AMH, and others with Chajka's seven different variables). This is a fundamental redesign of both references, not a simple substitution” (pg. 25, par. 2).
The argument is not persuasive because Applicant is arguing limitations which are not claimed. In response to applicant’s argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., seven input variables of Chajka) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The values OA, HA, and AMH recited in the claims are taught by Khuraseva: “a method for predicting risk levels of polycystic ovary syndrome (PCOS) ([0002]) comprising clinical signs corresponding to an OA-value reflecting the length of the female's menstrual cycle and/or the number of the female's menstrual cycles per year as menstrual cycle disorders such as oligo-/amenorrhea ([0024]); and laboratory signs corresponding to an HA-value reflecting the female's androgen status as increased levels of total testosterone ([0044]) and androstenedione level above normal ([0045]) (both testosterone and androstenedione are androgens); and an AMH-value corresponding to the amount or concentration of anti-Mullerian hormone (AMH) as an increase in the AMH level above the age norm ([0048])” (OA, pg. 7, last par. – pg. 8, par. 1). Therefore, the fundamental redesign of both references is not supported by any evidence presented by Applicant.
Applicant’s argument “Even Combining Khuraseva and Chajka Would Not Arrive at the Claimed Method” (pg. 25, section 2) is not persuasive and has been addressed right above.
Applicant argues that “Khuraseva's Criticism of Chajka Undermines the Office's Motivation to Combine” (pg. 25, section 2) and “Khuraseva expressly identifies Chajka (RU 2134061) as its prototype and criticizes Chajka because "the authors do not take into account the anamnestic data, the genetic predisposition, the risk factors for the development of PCOS, but only consider a small part of the clinical and laboratory data, and this amount of research is currently insufficient." Khuraseva, para. [0005]” (pg. 25, last par.).
The argument is not persuasive because “the anamnestic data, the genetic predisposition, the risk factors for the development of PCOS” cited by Applicant were not used in the rejection. As has already been presented above, the values OA, HA, and AMH recited in the claims are taught by Khuraseva. The OA does present any motivation to combine the teachings of Khuraseva and Chajka. Instead, it states “It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Khuraseva, by replacing approximate weight points for each biomarker with more precise weights as taught by Chajka, as an obvious matter of simple substitution of one known element for another to obtain predictable results” (OA, pg. 11, 2nd par. from the bottom). This is a valid obviousness rejection (see KSR).
Applicant argues that “The Combination of Khuraseva, Karakas, and Casadei Does Not Render Claims 18-20 Obvious” (pg. 26, section E).
The rejection of claims 1-9 under 35 U.S.C. §103 is withdrawn in view of claim 1 amendments. However, upon further consideration, a new ground(s) of rejection is made in view of claim 1 amendments in view of a new prior art reference of Li et al. (Diabetes Care. 2010 Jul;33(7):1618-24). Claims 18-20 are now rejected under 35 U.S.C. 103 as being unpatentable over Khuraseva in view of Karakas, Li, and Casadei. (see details in §103 rejection above).
Briefly, the immunoassays methods of Li and Casadei teach the limitation of claims 18-20 - providing a serum sample for measuring serum concentrations of total testosterone and SHBG (Li; pg. 1619, col. 1, par. 2) and providing a blood sample for measuring AMH blood levels (Casadei; pg. 208, col. 2, par. 2).
Any immunoassay necessarily comprises contacting a sample with a binding agent for an analyte and detecting the binding between the analyte and the analyte binding agent. These steps are inherent to the immunoassays. Therefore, the immunoassays taught by Li and Casadei, and evidenced by Han and Roche Diagnostics teach contacting the sample with a binding agent for AMH, a binding agent for TT, and a binding agent for SHBG, and detecting the binding between AMH and the AMH binding agent, binding between TT and the binding agent for TT, and binding between SHBG and the binding agent for SHBG.
Subject Matter Free of the Prior Art
Claim 10 reciting the method further includes determining one or more values of the data set provided in step a) by measuring the amount or concentration of one or more hormones in a sample obtained from the female is free of the prior art, because it is unclear what is actually claimed and how claim 10 further limits parent claim 1. Please, see 112(b) and 112(d) rejections above for details.
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 date of this final action.
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/ALEXANDER ALEXANDROVIC VOLKOV/Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677
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