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 .
Herein, “the previous Office action” refers to the Non-Final Rejection filed on 4/24/2025.
Amendments Received
Amendments to the claims were received on 9/18/2025.
Priority
As detailed on the Filing Receipt filed 5/18/2020, the instant application claims priority to as early as 7/7/2017. At this point in prosecution, all claims are accorded the earliest claimed priority date.
Information Disclosure Statement
The Information Disclosure Statement filed on 12/12/2025 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of the IDS is included with this Office Action.
Claim Status
Claims 1-19, 21 and 23-24 are canceled.
Claims 20, 22 and 25-29 are pending.
Claims 27-28 stand withdrawn pursuant to 37 CFR 1.142(b) as being directed to a nonelected invention, there being no currently allowable generic or linking claim. Election without traverse was made in the reply filed 7/11/2023.
Claims 20, 22, 25-26 and 29 are examined herein. Please note that claims are examined in accordance with the species elections made in the reply filed 7/11/2023.
Withdrawn Rejections
The rejection of claims 21 and 23-24 under 35 USC § 101, as being directed to nonstatutory subject matter, is hereby withdrawn in view of Applicant’s cancellation of the claims.
The rejections of claims 20, 22-23, 25-26 and 29 under 35 USC § 103, as being unpatentable over combined teachings of Brahmbhatt, Parati, McDonald, Mann and/or Fisher, is hereby withdrawn in view of Applicant’s amendment of the claims; persuasive argument that none of the applied references teach or suggest administering treatment suitable to treat a recited disease, or analyzing mean platelet volume and free thyroxine T4 (Remarks filed 9/18/2025 at pg. 9, para. 4 - pg. 10, para. 1); and cancelation of claim 23.
The rejection of claims 21 and 24 under 35 USC § 103, as being unpatentable over Brahmbhatt, in view of Parati, McDonald, Mann and O’Leary is hereby withdrawn in view of Applicant’s cancellation of the claims.
Claim Objections
Claim 20 is objected to because of the following informalities:
The semicolon should be removed from the recited “parameter X; from said value” (lines 41-42) to render “parameter X from said value”. Lines 42-45 describe the values whose statistical relationships are the basis for the step of identifying, therefore lines 42-45 should not be formatted as a clause independent from lines 40-41.
Appropriate correction is required.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art (MPEP 2111). This section documents the Examiner’s interpretation of certain claim elements under this standard.
Claim 20 recites the following optional limitation:
“c’’) optionally, providing at least two values of at least one serum biological parameter measured at different spaced-apart times for each subject in said sub-group defined at c') and removing from the sub-group those subjects in whom this serum biological parameter shows drift or potential drift, to define a second sub-group of subjects which does not comprise the removed subjects”.
Language that suggests or makes a step optional (but does not require that step) does not limit the scope of a claim under the broadest reasonable interpretation (MPEP 2111.04 § I and 2143.03). The cited limitation is therefore not considered to further limit the claimed subject matter.
Claim 29 recites the term “A computer-readable recording medium on which a computer program is recorded… comprising program code instructions to execute [steps] of the method”.
The specification reads, in relevant part, “A further subject of the invention is a computer programme comprising programme code instructions to execute one or more steps of one of the methods such as defined above, when said programme is executed on a computer” (pg. 35, lines 16-18). In light of the specification, the recited term is interpreted as a physical recording medium capable of interface with a computer.
Claim Rejections - 35 USC § 101
35 USC § 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 20, 22, 25-26 and 29 are rejected under 35 USC § 101 because the claimed invention is directed to non-statutory subject matter. This rejection is maintained from the previous Office action, and has been revised to address the amended claims (filed 9/18/2025).
"Claims directed to nothing more than abstract ideas, natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts (including formulas, equations and calculations), and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)).
The claims as a whole, considering all claim elements both individually and in combination, do not amount to significantly more than an abstract idea.
Step 1: The Four Categories of Statutory Subject Matter (MPEP 2106.03)
The claims are directed to methods (claims 20, 22 and 25-26) and a physical computer-readable recording medium (claim 29, see ‘Claim Interpretation’ section) which fall under categories of statutory subject matter.
‘Mathematical concepts’ are relationships between variables and numbers, numerical formulas or equations, or acts of calculation, which need not be expressed in mathematical symbols (MPEP 2106.04(a)(2) § I). The claims recite acts of calculation, including the following:
“determining that said values provided… do not fluctuate around a mean reference value… and thus the mean of said values provided… is not equal or equivalent to said mean reference value” (claim 20), i.e., calculating a mean and comparing numbers;
“identifying… biological parameter(s) statistically related to the quantitative biological parameter X… from said value of the quantitative biological parameter X and/or from the mean of said at least two values of the quantitative biological parameter X, and from said values of said at least one other quantitative biological parameter or the mean of said values of said at least one other biological parameter” (claim 20), i.e., evaluating statistical relationships; and
“defining the mean of the biological parameter X in the sub-group” (claim 20), i.e., calculating a mean.
The recited acts of calculation constitute mathematical concepts.
‘Mental processes’ are processes that can be performed in the human mind at least with use of a physical aid, e.g., a slide rule or pen and paper (MPEP 2106.04(a)(2) § III). The claims recite steps of evaluating information (including acts of calculation) that are practicably performable in the human mind, including the following:
“concluding therefrom that said…biological parameter shows drift or potential drift” (claim 20) i.e., making an inference based on numeric information; and
“for each biological parameter identified… removing from the group those subjects in whom this biological parameter shows drift or potential drift, to define a sub-group of subjects which does not comprise the removed subjects” (claim 20), i.e., organizing a dataset based on numeric information.
The recited steps encompass processes of manipulating information that are practicably performable in the human mind. For example, the human mind is capable of evaluating measured values and concluding that they indicate drift of the measured parameter. Therefore, recited steps encompass mental processes.
The following claim element delimits claimed embodiments of the mental processes, but does not alter their characterization as such:
“said at least one quantitative parameter showing drift has the following characteristics… the absolute value of the difference between (i) the mean of said values and (ii) the mean reference value is higher than or equal to 1 reference standard deviation” (claim 25).
Hence, the claims recite elements that constitute an abstract idea. The claims must therefore be examined further to determine whether they integrate this abstract idea into a practical application (MPEP 2106.04(d)).
Step 2A, Prong Two: Whether the Claims Contain Additional Elements that Integrate the Judicial Exception(s) into a Practical Application (MPEP 2106.04 § II.A.2)
The claims recite the following additional elements, which gather data required for performance of the claimed method:
“providing said values of at least one first quantitative biological parameter measured at least at two different spaced-apart times… to obtain at least two values v1 and v2” (claim 20);
“providing values of at least one other biological parameter statistically related to said first biological parameter… being measured at least at two different spaced-apart times… to obtain at least two values v1’ and v2’” (claim 20);
“providing (i) a value of… quantitative biological parameter X, measured at a given time or at least two values of the quantitative biological parameter X measured at different spaced-apart times and (ii) at least two values of at least one other quantitative biological parameter measured at different spaced-apart times, for each subject in a group of at least 50 subjects” (claim 20);
“providing the value of at least one other biological parameter statistically related to the biological parameter showing drift” (claim 22); and
“measuring the value of said quantitative biological parameter at another time” (claim 26).
Necessary data gathering is considered insignificant pre-solution activity, which is insufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g).
Further claim elements delimit the nature of the gathered data, but do not alter characterization of the data gathering steps as such:
“measured at least at two different spaced-apart times” (claim 20);
“[a] disease is associated with said biological parameter showing drift” (claim 20);
“said at least one first quantitative biological parameter is mean platelet volume” (claim 20); and
“said one other biological parameter statistically related to said first biological parameter… is free thyroxine T4” (claim 20).
The claims further recite the following additional element:
“administering an early treatment suitable for treating the disease to halt or slow the drifting of said biological parameters, wherein said disease is hypothyroidism… a Graves-Basedow disease and/or Hashimoto’s thyroiditis” (claim 20).
The recited step does not effect a particular treatment for a disease or medical condition, and is therefore considered generic. See discussion regarding particularity of “administering a suitable medication” in MPEP 2106.04(d)(2). Generic treatment steps amount to insignificant post-solutional activity, which is insufficient to integrate the abstract idea into a practical application (MPEP 2106.05(g)).
The claims further recite additional elements that require performance of claimed functions on a computer, including:
“A computer-readable recording medium on which a computer program is recorded, said computer program comprising program code instructions to execute [steps] of the method” (claim 29).
The claims do not describe any specific computational steps by which a computer executes functions drawn to the abstract idea, nor do they provide any details of how specific structures of a computer are used to implement these functions. The claims state nothing more than that a generic computer executes functions drawn to the abstract idea, and are therefore mere instructions to apply the abstract idea using a computer. As such, the claims do not integrate the abstract idea into a practical application (see MPEP 2106.04(d) § I and 2106.05(f)).
No further additional elements are recited.
When the claims are considered as a whole: they do not improve the functioning of a computer, other technology, or technical field (MPEP 2106.04(d)(1) and 2106.05(a)); they do not apply the abstract idea to effect a particular treatment or prophylaxis for a disease or medical condition (MPEP 2106.04(d)(2)); they do not implement the abstract idea with, or in conjunction with, a particular machine (MPEP 2106.05(b)); they do not effect a transformation or reduction of a particular article to a different state or thing (MPEP 2106.05(c)); and they do not apply or use the abstract idea in some other meaningful way beyond linking the use of the abstract idea to particular technological environments and/or fields of use (e.g., diagnosis and treatment of disease; MPEP 2106.05(e) and 2106.05(h)).
Therefore, the claims do not integrate the abstract idea into a practical application. See MPEP 2106.04(d) § I.
Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are directed to the abstract idea. Claims that are directed to an abstract idea must be examined further to determine whether the additional elements besides the abstract idea render the claims significantly more than the abstract idea. Additional elements besides the abstract idea may constitute inventive concepts that are sufficient to render the claims significantly more (MPEP 2106.05).
Step 2B: Whether the Claims Contain Additional Elements that Amount to an Inventive Concept (MPEP 2106.05)
As noted above, several recited additional elements amount to insignificant extra-solution activity. Mere addition of insignificant extra-solution activity does not amount to an inventive concept that would render the claims significantly more than the recited judicial exceptions, particularly when the activities are well-understood or conventional (MPEP 2106.05(g)). The conventionality of recited additional elements that amount to insignificant extra-solution activity must be further considered.
Recited additional elements amounting to insignificant extra-solution activity encompass generic steps of providing biological parameter values through measurement of subject samples. Generic steps of measuring biomarker levels in subject blood samples have been recognized by the courts as well-understood, routine, and conventional activity. See Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 79 (2012) and Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362 (Fed. Cir. 2017).
Additionally, administering treatment suitable for treating hypothyroidism, a Graves-Basedow disease and/or Hashimoto’s thyroiditis is indicated as well-understood, routine and conventional activity by relevant prior art. The cited article by Weetman (Autoimmunity 37(4): 337-340; published 7/7/2009) reviews autoimmune thyroid diseases and describes suitable treatments. Weetman states that autoimmune hypothyroidism can result from Hashimoto’s thyroiditis, while in cases of suspected neonatal hypothyroidism it is mandatory to preventatively treat the neonate with thyroxine (pg. 337, l. column; pg. 339, l. column). Weetman also states that first line treatment for Graves’ disease is usually with antithyroid drugs (pg. 339, l. column). In this way, Weetman indicates that suitable treatments for the recited thyroid diseases are well-known in the art.
Hence, the claims encompass well-understood, routine and conventional activity. Well-understood, routine and conventional activity is insufficient to constitute an inventive concept that would render the claims significantly more than the abstract idea (MPEP 2106.05(d)).
Mere instructions to implement an abstract idea using a computer are, when considered individually, similarly insufficient to constitute an inventive concept that would render the claims significantly more than the abstract idea (MPEP 2106.05(f)).
When the claims are considered as a whole: they do not improve the functioning of a computer, other technology, or technical field (MPEP 2106.04(d)(1) and 2106.05(a)); they do not implement the abstract idea with, or in conjunction with, a particular machine (MPEP 2106.05(b)); they do not effect a transformation or reduction of a particular article to a different state or thing (MPEP 2106.05(c)); they do not add specific limitations or steps, other than what is well-understood, routine and conventional activity in the field, that confine the claims to a particular useful application (MPEP 2106.05(d)); and they do not provide meaningful limitations beyond linking the use of the abstract idea to particular technological environments and/or fields of use (e.g., diagnosis and treatment of disease; MPEP 2106.05(e) and 2106.05(h)).
Therefore, the claims do not provide an inventive concept and/or significantly more than the abstract idea itself. See MPEP 2106.05.
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole, are directed to judicial exceptions and lack an inventive concept. Hence, the claimed invention does not constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Response to Arguments - Claim Rejections Under 35 USC § 101
In the remarks filed 9/18/2025, Applicant traverses the rejection under 35 USC § 101 and presents supporting arguments.
Applicant points to the USPTO Memorandum dated June 7, 2018 (hereafter, “the Memorandum”), concerning the Court decision of Vanda Pharma. Inc. v. West-Ward Pharma. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018, hereafter “Vanda”), and analogizes the instant claims to exemplary treatment claims which the Memorandum indicates as eligible in light of Vanda (pg. 7, para. 6 – pg. 8, para. 3).
As noted in the Memorandum, Vanda established that claimed treatment steps need not be unconventional for consideration as integrating natural phenomena into a practical application. Vanda did not supplant requirements regarding consideration of treatment limitations as directed to a ‘particular treatment or prophylaxis’ sufficient to integrate a judicial exception into a practical application. See description of these requirements in MPEP 2106.04(d)(2).
Unlike the claims considered in Vanda or exemplified in the Memorandum, the instant claims do not recite steps that effect a particular treatment for a disease or medical condition and thereby integrate the abstract idea into a practical application. The instant claims recite a step of “administering an early treatment suitable for treating… hypothyroidism and/or a Graves-Basedow disease and/or Hashimoto’s thyroiditis” (claim 20). Although this step administers a treatment for a specific disease or medical condition, the step is not limited to any particular manner or type of treatment according to the abstract steps previously performed. There are no meaningful constraints on the treatment step such that the ‘particular treatment or prophylaxis’ consideration would apply, thus the argument is found unpersuasive.
Applicant notes that the amended claims require treatment of a specific disease or medical condition, and points to Example 43 from the October 2019 Update to the 2019 Revised Patent Subject Matter Eligibility Guidance (hereafter “October 2019 Guidance”) in support of consideration of the instant treatment as sufficiently particular (pg. 8, para. 4).
Claim 1 of Example 43 recites a method step of “administering a treatment to the patient having a non-responder phenotype”, while the exemplary claim 2 requires that “the treatment is a non-steroidal agent capable of treating NAS-3” (October 2019 Guidance, pg. 2, emphasis added), nephritic autoimmune syndrome type 3. A careful reading of analysis presented therein reveals the critical nature of the limitation to a non-steroidal agent. The analysis reads, in relevant part: “the abstract idea is used to identify the patient as being nonresponsive to glucocorticoids, and the patient is then administered a treatment that is particular to that identified phenotype (i.e., a drug that is not a glucocorticoid or other steroid)” (October 2019 Guidance, pg. 5, emphasis added).
The mere fact that the exemplified step involves administration of treatment capable of treating of a specific disease or medical condition (NAS-3) is not sufficient for its consideration as a particular treatment. Rather, this consideration hinges on the limitation of the treatment to non-steroidal drugs based on determination, via abstract steps, that the patient is nonresponsive to glucocorticoids. The instant treatment step includes no such structural limitation according to prior abstract steps.
The requirements for consideration as a ‘particular treatment or prophylaxis’, as detailed in MPEP 2106.05(d)(2), are not satisfied by the instant treatment. Thus, the argument of integration via the amended treatment step is found unpersuasive. See Example 49 of the July 2024 Update on Patent Subject Matter Eligibility, which is relevant to the instant fact pattern.
Applicant submits that combined elements of the claimed invention allow for earlier detection of abnormal values of a biological parameter and administration of early treatment, thus integrating any abstract ideas into the practical application of preventing or delaying onset of a disease. In support, Applicant cites paras. 0009-10 of the specification and points to recited step g (“administration an early treatment suitable for treating the disease”) of claim 20 (pg. 8, para. 5 – pg. 9, para. 2).
Integration of a judicial exception into a practical application may demonstrated by incorporation of additional elements that provide an improvement to technology and/or a technical field (MPEP 2106.04(d)). Applicant has not elaborated how technical aspects of the claimed invention, recited in the claims as additional elements, allow for earlier diagnosis and/or achieve prevention or delayed onset of a recited disease as compared to prior technology employed in the field. Thus, the argument is found unpersuasive.
For the above reasons. the arguments are found unpersuasive and the rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 USC §§ 102 and 103 (or as subject to pre-AIA 35 USC §§ 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 USC § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 USC § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 USC § 102(b)(2)(C) for any potential 35 USC § 102(a)(2) prior art against the later invention.
Claims 20, 22, 26 and 29 are rejected under 35 USC § 103 as being unpatentable over Brahmbhatt et al (US 2015/0011019; published 1/8/2015; on IDS filed 1/7/2020; previously cited), in view of Parati et al (Diabetes Care 36(Supp. 2), pp. 312-324; published August 2013; previously cited), McDonald (Handbook of Biological Statistics, Sparky House Publishing; published 2008; previously cited), and Mann (Emergency Medicine Journal 20: 54-60; published 1/1/2003; previously cited), Sit et al (Acta Medica Mediterranea 30: 1263-1266; published 2014), and Weetman (Autoimmunity 37(4): 337-340; published 7/7/2009). The new grounds of rejection presented herein were necessitated by Applicant’s incorporation of new claim limitations by amendment (filed 9/18/2025).
Claim 20 recites a method for preventing or delaying the onset of a disease by analyzing metabolic drift of quantitative biological parameter(s) in a subject, comprising:
a) providing the values of at least one first quantitative biological parameter measured at least at two different times t1 and t2, wherein:
1. said first parameter(s) is mean platelet volume;
b) determining that the values provided in a) do not fluctuate around a mean reference value for said parameter(s), i.e., that the mean of said values is not equal or equivalent to said mean reference value, wherein:
1. the mean reference value is defined according to a method comprising:
I) providing, for each subject in a group of at least 50 subjects:
i. a value of a quantitative biological parameter X measured at a given time or at least two values of the parameter(s) measured at different times, and
ii. at least two values of at least one other quantitative biological parameter measured at different times,
II) identifying statistically related quantitative biological parameter(s) from the values, or means of the values, of each of parameter X and the other parameter(s);
III) removing from the group those subjects for whom any of the statistically related parameter(s) show drift or potential drift, to define a sub-group of subjects which does not comprise the removed subjects, and
IV) defining the mean of the parameter X in the sub-group;
c) concluding that said parameter(s) shows drift or potential drift;
d) providing values of at least one other biological parameter statistically related to said first biological parameter measured at least at two different times t1’ and t2’, wherein:
1. said other parameter(s) is free thyroxine T4;
e) determining that the values provided in d) do not fluctuate around a mean reference value for said other parameter(s), i.e., that the mean of said values is not equal or equivalent to said mean reference value;
f) concluding that said other parameter(s) shows drift or potential drift; and
g) administering an early treatment suitable for treating the disease to halt or slow the drifting of said biological parameters, wherein said disease:
1. is hypothyroidism, a Graves-Basedow disease and/or Hashimoto’s thyroiditis, and
2. is associated with said biological parameter showing drift or potential drift.
With respect to claim 20, Brahmbhatt discloses a “method for predicting the risk of acquiring… inflammation for a subject” (Abstract), comprising:
a) “providing a biological sample from a subject… [and] determining in said sample the level of at least one biomarker” (pg. 1, para. 0011-0012), wherein “samples may be provided which have been obtained at other time points” (pg. 4, para. 0078) such as “before a treatment… [and] after a treatment” (pg. 1, paras. 0022-0023), i.e., providing the values of at least one quantitative biological parameter measured at least at two different times;
b) “comparing the level of at least one biomarker to a reference value… [and] determining whether… the level of biomarker(s) deviate significantly from”, i.e., are not equal or equivalent to, “the respective reference level” (pg. 2, paras. 0037-38), wherein “[a] reference level… could be established using… mean plus or minus standard deviation(s)… In one embodiment, the reference level is an average value of a non-inflamed group of subjects” (pg. 3, paras. 0053-54 and 0059);
c) “said subject is likely to be at risk… when the level of biomarker(s) deviate significantly from the respective reference level” (pg. 2, para. 0038);
d-f) “it may be advantageous to determine the level of more than one biomarker… [e.g.,] at least two biomarkers” (pg. 2, para. 0050);
g) “treatments may be initiated to lower the risk of acquiring an age-related low-grade inflammation” (pg. 4, para. 0074), i.e., administering early treatment, wherein:
2. “the determined risk is also the risk of acquiring one or more conditions defined by a low-grade inflammation…selected from… type 2 diabetes… and Parkinson’s disease” (pp. 3-4, para. 0071), i.e., assessed parameter deviation is associated with a specific disease.
Brahmbhatt does not disclose determining if parameter values fluctuate based on whether the mean of said values is equal or equivalent to a mean reference value; filtering a group of subjects, based on quantitative parameter values, to define sub-groups for statistical analysis; or analyzing 50 subjects.
Parati presents a “review [of] the available evidence on the prognostic importance of BP”, blood pressure, “mean values and… variability” (pg. 312, m. column), and teaches that “BP is characterized by marked short-term fluctuations within the 24 h… [and] over more prolonged periods of time (i.e., between days, weeks, months, and seasons and even years)… the result of complex interactions between extrinsic environmental and behavioral factors with intrinsic CV”, cardiovascular, “regulatory mechanisms… not yet completely understood” (pg. 313, r. column). Accordingly, Parati presents study findings that “average”, i.e., mean, “BP measured… may be an even better predictor of CV outcomes than isolated… readings… [and [] the extent of fluctuations of BP over time may provide additional, independent prognostic information compared with… isolated office readings” (pg. 312, l. column).
More specifically, Parati teaches that “both cross-sectional and longitudinal studies have shown a superior prognostic value for 24-h, daytime, and nighttime average ABP”, ambulatory blood pressure, “values compared with OBP”, office blood pressure (i.e., isolated readings), wherein “ABP values were… more effective in predicting the development of CV events as well as CV and non-CV mortality both in a general population and in hypertensive patients” (pg. 313, l. column), i.e., when compared to corresponding reference values.
In this way Parati teaches that, for the considered quantitative biological parameter (blood pressure), evaluating the fluctuation and mean of multiple values measured at different time points with respect to reference values has greater prognostic utility regarding abnormal clinical conditions than evaluating single measured values. The teachings of Parati thereby teaches determining whether measured quantitative parameter values fluctuate over time, and statistically evaluating the mean of measured parameter values. The combined teachings of Brahmbhatt and Parati are viewed as teaching determining if parameter values fluctuate based on whether the mean of said values is equal or equivalent to a mean reference value.
Parati also mentions parameter correlation, teaching that “some studies in the diabetic population have shown norepinephrine levels to be directly correlated to nighttime systolic BPV” (pg. 314, r. column). However, Parati does not teach identifying statistically related parameters; filtering a group of subjects, based on quantitative parameter values, to define sub-groups for statistical analysis; or analyzing 50 subjects.
McDonald discusses “how to choose the appropriate statistical test for a particular experiment, then apply that test and interpret the results” (pg. 1) and exemplifies “survey[ing] genotypes… of the apolipoprotein B signal peptide… [and] coronary artery disease” (pg. 53). McDonald further exemplifies “a sample size of 50 individuals” (pg. 31), i.e., analyzing 50 subjects.
McDonald mentions “compar[ing] the means of certain subsets of the groups you have chosen” (pg. 116), but does not explicitly teach filtering a group of subjects, based on quantitative parameter values, to define sub-groups for statistical analysis.
Mann discusses “observational studies… practicable method[s] of studying various problems… compar[ing] groups… and are useful for studying rare diseases or outcomes” (pg. 54, Abstract), such as “case-control studies… [wherein] the researcher determines… the presence of a variable in each of the study groups” (pg. 57, r. column). Mann teaches that “Each variable studied must be accurately measured… for example… weight” (pg. 56, l. column), i.e., a quantitative biological parameter, and exemplifies a case wherein “the relevant observation is… a laboratory test or radiograph” (pg. 58, l. column). Mann defines a control group as “A group of people without the condition of interest” (pg. 60, l. column), e.g., an internal reference, and exemplifies a case-control study design wherein a population of study individuals is divided into subsets of “Selected cases” and “Selected controls” (pg. 57, Fig. 3). Mann thereby teaches filtering a group of subjects, based on quantitative parameter values, to define sub-groups for statistical analysis.
The combination of Brahmbhatt, Parati, McDonald and Mann does not teach analysis of the recited biological parameters (mean platelet volume and free thyroxine T4); or administration of an early treatment suitable to treat hypothyroidism, a Graves-Basedow disease and/or Hashimoto’s thyroiditis.
Sit discusses clinical characterization of Hashimoto’s thyroiditis (pg. 1263, Abstract), and presents study findings that mean platelet volume and free thyroxine levels (FT4) are both significantly associated with Hashimoto’s thyroiditis (pg. 1264, l. column and Table 1). Sit does not teach administering an early treatment suitable for treating Hashimoto’s thyroiditis (or treating hypothyroidism and/or a Graves-Basedow disease).
Weetman reviews autoimmune thyroid diseases and teaches that Hashimoto’s thyroiditis can cause hypothyroidism, while in cases of suspected neonatal hypothyroidism it is mandatory to preventatively treat the neonate with thyroxine (pg. 337, l. column; pg. 339, l. column). Weetman also states that first line treatment for Graves’ disease is usually with antithyroid drugs (pg. 339, l. column). In this way, Weetman discusses administering an early treatment suitable for treating hypothyroidism, a Graves-Basedow disease and/or Hashimoto’s thyroiditis.
Weetman further discusses the utility of measuring particular autoantibody levels as predictors of future autoimmune hypothyroidism, and of treatment outcomes for subjects with Graves’ disease (pg. 339, l. column – pg. 340, l. column).
With respect to claim 22, McDonald teaches performance of “correlation analysis… to see whether two variables covary” (pg. 190), and that “Often, a significant correlation suggests further experiments to test for a cause and effect relationship” (pg. 191). In this way, McDonald teaches identifying statistically related parameters.
With respect to claim 26, Brahmbhatt discloses that “samples may be provided which have been obtained at other time points” (pg. 4, para. 0078).
With respect to claim 29, Brahmbhatt discloses that the discussed statistical methodologies “can be performed on the commercially available computer program statistical package Statistical Analysis system… or other statistical software packages… known to those skilled in the art” (pg. 3, para. 0045). Storage on a computer readable recording medium is an obvious-to-try implementation of the disclosed computer software.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have considered fluctuation of measured values and evaluating the mean of measured values with respect to a mean reference value, within the biological parameter analysis method of Brahmbhatt, because Brahmbhatt teaches evaluation of measured values with respect to mean reference values and Parati teaches that evaluation of the fluctuation over time and mean of measured values has greater prognostic utility (for at least the considered quantitative biological parameter) than evaluating single measured values (pg. 312, l. column). Said practitioner would have had a reasonable expectation of success because both Brahmbhatt and Parati discuss statistical analysis of quantitative biological parameter values measured at different time points.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented analysis of covariance, as taught by McDonald, to assess statistical relation between biological parameters within the biological parameter analysis method of Brahmbhatt, because McDonald teaches that identification of statistically related parameters can guide further investigation of cause (pp. 190-191). Said practitioner would have had a reasonable expectation of success because both Brahmbhatt and McDonald discuss statistical analysis of quantitative biological parameters and disease occurrence.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have filtered a group of subjects according to biological parameter values to define sub-groups, as taught by Mann, within the biological parameter analysis method of Brahmbhatt, because Mann teaches that doing so establishes a useful framework (case-control) for statistical analysis of diseases and outcomes (pg. 54, Abstract; pg. 57, r. column). Said practitioner would have had a reasonable expectation of success because both Brahmbhatt and Mann discuss statistical analysis of quantitative biological parameters and disease occurrence.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have employed the biological parameter analysis method of Brahmbhatt to analyze mean platelet volume and free thyroxine levels, because Sit teaches that these parameters are significantly associated with incidence of Hashimoto’s thyroiditis (pg. 1264, l. column and Table 1). The teachings of Sit thus indicate that analysis of these biological parameters would extend the clinical utility of the method of Brahmbhatt to assessment of Hashimoto’s thyroiditis. Said practitioner would have had a reasonable expectation of success because both Brahmbhatt and Sit discuss statistical analysis of quantitative biological parameters and disease occurrence.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have administered a suitable treatment for the recited thyroid disease(s), because Weetman teaches that suitable treatments for said diseases are known in the art (pg. 337, l. column; pg. 339, l. column). The teachings of Weetman indicate that assessment and early treatment of Hashimoto’s thyroiditis / hypothyroidism is an enabled clinical application of the method of Brahmbhatt. Said practitioner would have had a reasonable expectation of success because both Brahmbhatt and Weetman discuss statistical analysis of quantitative biological parameters and disease occurrence.
In this way the disclosure of Brahmbhatt, in view of Parati, McDonald, Mann, Sit and Weetman, makes obvious the limitations of instant claims 20, 22, 26 and 29. Thus, the invention is prima facie obvious.
Claim 25 is rejected under 35 USC § 103 as being unpatentable over Brahmbhatt, in view of Parati, McDonald, Mann, Sit and Weetman, as applied to claim 20 above, and further in view of Fisher (Metron 5: 90-104; published 1925; previously cited). The new grounds of rejection presented herein were necessitated by Applicant’s incorporation of new claim limitations by amendment (filed 9/18/2025).
With respect to claim 25, Brahmbhatt discloses that “the usual method for evaluating whether two or more levels are different or equal involves statistics… Commonly used statistical tests.. include [the] t-test… Using such a test or method enables a conclusion of whether two or more samples are significantly different or significantly equal” (pg. 3, paras. 0056-0057). Brahmbhatt does not discuss statistical conditions as claimed.
Parati presents study findings that “average”, i.e., mean, “BP measured… may be an even better predictor of CV outcomes than isolated… readings… [and [] the extent of fluctuations of BP over time may provide additional, independent prognostic information compared with… isolated office readings” (pg. 312, l. column). Parati does not discuss statistical conditions as claimed.
McDonald teaches “[using] Student's t-test when you have one nominal variable and one measurement variable, and you want to compare the mean values of the measurement variable… The statistical null hypothesis is that the means of the measurement variable are equal for the two categories” (pg. 110). McDonald does not directly discuss statistical conditions as claimed.
Mann teaches that “Case controlled studies compare groups” (pg. 54, Abstract) and “Where two cohorts are compared one will have been exposed to the agent of interest and one will not” (pg. 55, r. column). Mann does not discuss statistical conditions as claimed.
Sit exemplifies calculation of means and standard deviations of measured biological parameters for a group of subjects with Hashimoto’s thyroiditis (HT) and a control group (pg. 1264, l. column and Table 1), but does not directly discuss statistical conditions as claimed.
Weetman discusses measurement of thyroid autoantibodies as predictors of future autoimmune hypothyroidism, and of treatment outcomes for patients with Graves’ disease (pg. 339, l. column – pg. 340, l. column). Weetman does not discuss statistical conditions as claimed.
Fisher discusses applications of “testing significance… [by] calculat[ing] t” (pg. 91), i.e., performing a t-test, specifically “the comparison of two mean values”, and states that “If x and x are the means… and we wish to test if the two means are sufficiently alike… or… significantly different, we may suppose the hypothetical population to have a standard deviation, σ” (pg. 45).
To illustrate, Fisher presents “an example of the application of this method in experimental work”, wherein “The difference between the means is [calculated]… [and] The value of t”, i.e., the calculated criterion, “is the ratio of the difference to [the] estimated standard deviation” (pg. 46). In other words, the difference between the sample mean and population mean is divided by a standard deviation. Fisher thus teaches comparison of a mean of sample values and a mean reference value by means of a t-test, and provides evidence that such application is mathematically equivalent to evaluation of statistical conditions recited in claim 25 (i.e., whether the difference between the mean of the measured values and the mean reference value is higher than, equal to, or lower than a given multiple of reference standard deviation(s)).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have considered the difference between the mean of the measured values and the mean reference value with respect to the reference standard deviation, as taught by Fisher, within the biological parameter analysis method of Brahmbhatt, in view of Parati, McDonald, Mann, Sit and Weetman, because the combined teachings of Brahmbhatt and Parati suggest application of a t-test to compare mean sample values to mean reference values and Fisher provides evidence that that such application of a t-test is mathematically equivalent to consideration of the claimed statistical condition. Said practitioner would have had a reasonable expectation of success because both Brahmbhatt and Fisher discuss statistical analysis of sample values with respect to reference values.
In this way the disclosure of Brahmbhatt, in view of Parati, McDonald, Mann, Sit, Weetman and Fisher, makes obvious the limitations of instant claim 25. Thus, the invention is prima facie obvious.
Response to Arguments - Claim Rejections Under 35 USC § 103
In the remarks filed 9/18/2025, Applicant traverses the rejections under 35 USC § 103 and submits that none of the cited references teach or suggest: suitable treatment of hypothyroidism, a Graves-Basedow disease and/or Hashimoto’s thyroiditis; or analysis of mean platelet volume as a first quantitative biological parameter and free thyroxine T4 as a second, statistically-related biological parameter (pg. 9, para. 4 - pg. 10, para. 1).
This argument is found persuasive, and the rejection has been withdrawn. However, upon further consideration, new grounds of rejection are made in view of newly found prior art. The newly-cited articles by Sit et al and Weetman are considered to remedy the deficiency of the previously-cited art with respect to the referenced features. See rejections for full details.
Conclusion
At this point in prosecution, no claim is allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Dodds et al (US 2011/0093298; published 4/21/2011) discusses assessment of animal health and thyroid function, including presence of autoimmune thyroiditis (paras. 0033, 0071-2), based on comparison to predetermined levels of measured values for diagnostic panels of parameters including free T4 level and mean platelet volume (paras. 0034-7, 0081-5 and 0106).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/T.C.S./Examiner, Art Unit 1685
/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 December 15, 2025