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 .
Office Action Overview
Claim Status
Canceled:
1, 2, 7-11, 13-15
Pending:
3-6, 12, and 16-27
Withdrawn:
none
Examined:
3-6, 12, and 16-27
Independent:
19, 22
Amended:
3-6, 12, 16-19, 20
New:
23-27
Allowable:
none
Objected to:
19, 25, and 26
Rejections applied
Abbreviations
X
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
X
102, 103
JE
Judicial Exception
X
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed in the 06/06/2025 filing receipt, this application is a CON of PCT/US2023/081160 filed 11/27/2023, which claims priority to U.S provisional application 63/385,194 filed 11/28/2022.
Overview of Withdrawal/Revision of Objections/Rejections
In view of the amendment and remarks received 11/22/2025:
The objection is withdrawn; claim 1 has been canceled. New objections to claim 19, 25, and 26 are asserted.
The 112(b) rejections are withdrawn; claims 10, 11, 14, and 15 are canceled; claims 19 and 20 has been amended to recite "timeframes" instead of "prediction periods." New 112(b) rejections have been asserted below for claim 19.
The 112(d) rejection is withdrawn; claim 7 has been canceled.
The 101 rejection is withdrawn for claim 19 and 20.
The 101 rejection is maintained/asserted for claims 3-6, 12, and 16-27.
The 103 rejection is maintained with revision.
Claim Objections
Claims 19, 25, and 26 are objected to because of the following informalities (emphasis added):
Line 2 of the "transmitting" step of Claim 19 repeats the term "the" in reciting: "response comprising the the probability that…" The extra "the" should be deleted.
Line 3-4 of the "wherein the training data" step of claim 19 repeat the term "age" in reciting: "the variables of the training data comprise age, free light chain (FLC) ratio, M-spike level, age, creatinine level, or hemoglobin level…" The extra "age" should be deleted. (Note, there is a 112(b) asserted below for a somewhat related issue involving "age," but in different steps of claim 19.)
Claim 25 recites "time-vary marker", which should be corrected to "time-varying marker."
Claim 26 should recite "further comprising" instead of "wherein".
Claim 26 recites the terms "resulted" and "comprised" twice each. The instances of these terms should be respectively corrected to "resulting" and "comprising".
Appropriate correction is required.
Claim Interpretation
Claim 21 recites "the multiple myeloma precursor disease progression request further comprises bone marrow plasma cell percent (BMPC%) as a variable and the variables of the training data comprise BMPC%", in which it is interpreted:
• that, for the multiple myeloma precursor disease progression request, BMPC% is included in the list of variables which may be selected from; and
• that the variables of the training data comprise age, free light chain (FLC) ratio, M-spike level, age, creatinine level, hemoglobin level, or BMPC%.
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 19-21 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. Claims depending from rejected claims are rejected similarly, unless otherwise noted, and any amendments in response to the following rejections should be applied throughout the claims, as appropriate.
Line 2-4 of the receiving step of claim 19 recites "…comprising age and three or more variables selected from free light chain (FLC) ratio, M-spike level, age, creatinine level, and hemoglobin level,…" (emphasis added).
Because the request comprises "age", and "age" is also recited in the list of variables to select from, it is not clear if age is supposed to be in the group of variables to select from or not. Further, it is not clear if the request should comprise a total of four variables (age being one of them) or if it could comprise a total of three variables (age being one of them). For examination purposes, the claim will be interpreted as including an embodiment where age plus two other variables (two besides age) are selected from "…free light chain (FLC) ratio, M-spike level, age, creatinine level, and hemoglobin level." Possibly amending by deleting "age" from the list of three or more variables to select from might help get over the rejection.
In a related issue, line 3 of the "determining" step of claim 19 recites "models based at least in part on the age and the three or more variables", while line 2-3 of the "utilizing" step of claim 19 only recites " …model to ingest the three or more variables", without reciting "age."
This issue regarding age, and if age is to be included in variables selected from, should be addressed throughout the claim(s).
(Note, in a related issue involving "age", line 3-4 of the "wherein the training data" step of claim 19 have received an objection (above) for repeating "age" in reciting: "the variables of the training data comprise age, free light chain (FLC) ratio, M-spike level, age, creatinine level, or hemoglobin level.)
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 3-6, 12, 16-18, and 21-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP § 2106 details the following framework for subject matter eligibility analysis:
• Step 1: Are the claims directed to a category of statutory subject matter (a process, machine, manufacture, or composition of matter)? (see MPEP § 2106.03)
• Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. an abstract idea, a law of nature, or a natural phenomenon? (see MPEP § 2106.04) Note, the MPEP at 2106.04(a)(2) & 2106.04(b) explains that abstract ideas and laws of nature are defined as:
• mathematical concepts, (mathematical formulas or equations, mathematical
relationships and mathematical calculations);
• certain methods of organizing human activity (fundamental economic practices
or principles, managing personal behavior or relationships or interactions between people); and/or
• mental processes (procedures for observing, evaluating, analyzing/ judging and
organizing information; this includes performance in the human mind, or by a
human using a pen and paper);
• laws of nature and natural phenomena are naturally occurring principles/ relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
• Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application? (see MPEP § 2106.04(d))
• Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? (see MPEP § 2106.05)
Regarding Step 1:
Step 1: Yes, the claims are directed to related methods, and therefore to a category of statutory subject matter. (See MPEP § 2106.03).
Regarding Step 2A, Prong One:
The claims recite judicial exceptions in the form of abstract ideas and a law of nature as follows:
Independent claim 22 recites abstract ideas in the form of mental processes and/or mathematical concepts in:
• The model is a multivariate Cox proportional hazards model.
• Determining via the trained model a numeric probability that a patient with a multiple
myeloma (MM) precursor disease will progress to MM.
Regarding claims 3, 4, 5, 6, 12, (which ultimately depend from independent claim 22), mental processes and/or mathematical concepts are recited as follows: Claim 3 further limits the time varying markers. Claim 4 further limits the MM precursor disease as being monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). Claim 5 and 6 recite determining a numeric probability the precursor disease will progress. via the trained model. Claim 12 further limits the clinical variables.
Regarding claims 16-18, (which depend from independent claim 22): Claims 16-18 respectively further limit the data for analysis to include an indicator of whether the patient has been detected to have at least one genetic marker; a genetic marker selected from the group consisting of 17 deletion, l 7p deletion, 13 deletion, 13q deletion, and lq gain; or the patient is found to have a 17 deletion, l 7p deletion, 13 deletion, 13q deletion, and/or lq gain.
Regarding claim 21, (which depends from independent claim 19): Claims 21 further limits the data that the disease request comprises.
Regarding claims 23-27, (which depend from independent claim 22): Claim 23-27 further limit the clinical values received. Claim 25 additional recites abstract ideas of determining time trajectory value.
Additionally, dependent claims 16-18 recite a law of nature in the naturally occurring correlation between the genotype of the patient and the risk of MM precursor disease progressing into MM.
Step 2A Prong One Summary:, the claims recite abstract ideas and a law of nature. The limitations for analyzing data, determining/using a model, generating a numeric value, determining a model, rendering a plot, etc., recite mental processes because one could mentally perform the steps, as the limitations are claimed at a high level of generality such that they could be performed in the human mind or with pen and paper [see MPEP§ 2106.04(a)(2)(III)]. The limitations involving the trained model, for determining and/or using a model trained to evaluate risk of an MM precursor disease progressing into MM, also recite mathematical concepts, because when considering the broadest reasonable interpretation in light of the Specification, these limitations encompass mathematical concepts such as those disclosed at least at Specification p.12-13 [see Figs.2-27]; p.55; p.63-64; etc. [see MPEP§ 2106.04(a)(2)(I)]. Further, regarding using a computer to perform the abstract idea: When considering the such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea. Finally, the law of nature correlates naturally occurring genotype of the patient and the risk of MM precursor disease progressing into MM. Therefore, the claims recite elements that constitute a judicial exception in the form of an abstract idea and law of nature. (Step 2A, Prong One: Yes.)
Regarding Step 2A, Prong Two:
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs). Here at Step 2A, Prong Two, any remaining steps and/or elements not identified as JEs are therefore in addition to the identified JE(s), and are considered additional elements. Because the claims have been interpreted as being directed to judicial exceptions, abstract ideas in this instance, then Step 2A, Prong Two provides that the claims be examined further to determine whether the judicial exception is integrated into a practical application [see MPEP § 2106.04(d)]. A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
MPEP § 2106.04(d)(I) lists the following example considerations for evaluating whether a judicial exception is integrated into a practical application:
(1) An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
(2) Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
(3) Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
(4) Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
(5) Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
Additional elements of data gathering/outputting steps: Claims 12, 16, 18, 22-24, 26, and 27 recite steps for receiving data and/or outputting data. These limitations represent data gathering and outputting steps, and are additional elements which perform functions of inputting, collecting, and the outputting data needed to carry out the abstract idea. These steps are considered insignificant extra-solution activity, and are not sufficient to integrate an abstract idea into a practical application as they do not impose any meaningful limitation on the abstract idea or how it is performed, nor do they provide an improvement to technology [see MPEP § 2106.04(d)(I)].
Additional elements of computer components: Claim 21 recites an additional element of a computer. The claim requires only generic computer components, which do not improve computer technology, and do not integrate the recited judicial exception into a practical application (see MPEP § 2106.04(d)(1) and MPEP § 2106.05(f)).
Step 2A Prong Two summary: The claims have been further analyzed with respect to Step 2A, Prong Two, and no additional elements have been found, alone or in combination, that would integrate the judicial exception into a practical application. (Step 2A, Prong Two: No).
Regarding Step 2B:
Because the additional claim elements do not integrate JE (in this case, the abstract ideas) into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept. An inventive concept is furnished by an element or combination of elements that is recited in the claim in addition to the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself (see MPEP § 2106.05).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are well-understood, routine, and conventional. Those additional elements are as follows:
Additional elements of data gathering/ outputting steps: The additional elements of receiving data and/or outputting data in claims 12, 16, 18, 22-24, 26, and 27 do not cause the claims to rise to the level of significantly more than the judicial exception. The courts have recognized receiving or transmitting data over a network; storing and retrieving information in memory; determining the level of a biomarker in blood by any means; using polymerase chain reaction to amplify and detect DNA; detecting DNA or enzymes in a sample; analyzing DNA to provide sequence information or detect allelic variants; and amplifying and sequencing nucleic acid sequences, [see MPEP§2106.05(d)(II)], as well-understood, routine, conventional activity when they are claimed in a merely generic manner (e.g., at a high level of generality) or as extra-solution activity. As such, the additional elements of data gathering are shown to be routine, well-understood, and conventional in the art, and do not provide an inventive concept needed to amount to significantly more than the judicial exception.
Additional elements of computer components: The additional elements of a computer in claim 21, does not cause the claims to rise to the level of significantly more than the judicial exception; this is a conventional computer component, which does not provide an inventive concept.
Further regarding the conventionality of additional elements, the MPEP at 2106.05(b) and 2106.05(d) presents several points relevant to conventional computers and data gathering steps in regard to Step 2A Prong 2 and Step 2B, including:
• A general purpose computer that applies a judicial exception, such as an abstract idea, by use of conventional computer functions, does not qualify as a particular machine (see 2106.05(b)(I)), as in the case of claim 21, which is interpreted to recite conventional computer components.
• Integral use of a machine to achieve performance of a method may integrate the recited judicial exception into a practical application or provide significantly more, in contrast to where the machine is merely an object on which the method operates, which does not integrate the exception into a practical application or provide significantly more [see 2106.05(b)(II)]. In the instant claims, the recited processor, computer, and server and memory are used in assessing risk, receive and transmit data, and utilize and determine models; in this way the processor, computer, and server act only as tools to perform the steps of assessing risk, and do not integrate the exception into a practical application or provide significantly more.
• Use of a machine that contributes only nominally or insignificantly to the execution of the claimed method (e.g., in a data gathering step or in a field-of-use limitation) would not integrate a judicial exception or provide significantly more (see 2106.05(b)(III). The computer of claim 21 used in performing assessing of risk do not impose meaningful limitations on the claims.
• The courts have recognized "receiving or transmitting data over a network", "performing repetitive calculations", and "storing and retrieving information in memory", as well-understood, routine, and conventional functions when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)). The receiving, ingesting, and transmitting of data is recited in a generic manner.
All limitations of claims 3-6, 12, 16-18, and 21-27 have been analyzed with respect to Step 2B, and none provides a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception, and thus do not transform the judicial exception into a patent eligible application of the exceptions. Step2B: NO. Therefore, the claims 3-6, 12, 16-18, and 21-27, when the limitations are considered individually and as a whole, are rejected under 35 U.S.C. § 101 as being directed to non-statutory subject matter.
Response to Applicant Arguments - 35 USC § 101:
Applicant's arguments filed 11/22/2025 regarding the 101 rejection (remarks, p.19-28) have been fully considered. They are persuasive with regard to claims 19 and 20, however, they are not persuasive with regard to claims 3-6, 12, 16-18, and 21-27.
Regarding Step 2A Prong One:
Applicant asserts the claims not practically performable in the human mind (p.20, ¶ 3).
The argument is not persuasive, as the claims recite JEs which include mental processes as interpreted in the 101 rejection above.
Regarding Step 2A Prong Two:
Applicant asserts arguments (at p.22-23) for showing an improvement to technology at Step 2A prong Two of the 101 analysis, making the following points:
Applicant asserts "the 20/2/20 system of assessing a patient's risk of disease progression is not individualized…In contrast, the claimed methods use machine learning models to individualize a patient's risk assessment" (p.22, ¶ 4).
Applicant asserts "The 20/2/20 system requires a painful and costly bone marrow biopsy to obtain BMPC%... In contrast, the method of independent claims 19 and 22 do not require patient input values obtained by bone marrow biopsies" (p.22, ¶ 5).
Applicant asserts "The 20/2/20 system is limited by reliance on the binary yes/no of patient values compared to fixed threshold values…In contrast, the claimed methods include patient non-binary values" (p.22, ¶ 6). Applicant further asserts "the inventors have recognized and appreciated that informative markers for MM risk do not have levels that remain consistent, but instead naturally vary up and down over time" (p.23, ¶ 1).
Applicant asserts "at least in FIGS. 8A (reproduced below), FIG. 8B (reproduced below), Table 2, and Table 3, the PANGEA model yielded C-statistic increases, with minimal changes in corresponding confidence intervals, compared to both the 20/2/20 and rolling 20/2/20 systems" (remarks, p.23, ¶ 3). Applicant further asserts "The PANGEA no BM model showed a 30% increase and an average of a 22% increase in C-statistic relative to the 20/2/20 system and the rolling 20/2/20 system, respectively" (p.25, ¶ 1).
Applicant asserts "Additionally, Example 3 showed that bone marrow biopsy variables are not necessary to accurately assess progression risk when other factors are considered... in Validation Cohort 1, both PANGEA models (BM and no BM) outperformed the 20/2/20 and rolling 20/2/20 systems…In Validation Cohort 2, the PANGEA no BM model outperformed the PANGEA BM model" (remarks, bridging p.25-26).
With respect to claims 19 and 20, the Step 2A Prong Two arguments are persuasive, in all respects, of points A) through E), for the individualized assessment of patient risk using the PANGEA model (no BM), which includes data of non-binary values, not requiring bone marrow biopsies, while at the same time showing an improved C-statistic, and outperforming in the validation cohort, over the conventional 20/2/20 model. As such, an improvement to technology is shown which result in integration of the JEs into a practical application at Step 2A Prong Two of the 101 analysis.
With respect to claims 3-6, 12, 16-18, and 21-27, the Step 2A Prong Two arguments are persuasive with regard to points A) and C), but are not persuasive with regard to points B), D), and E):
Consideration was given to all points A) through E) of the Step 2A Prong 2 improvement arguments, and the conclusion was made that the aspect of not requiring a bone marrow biopsy is key to the overall persuasiveness of Applicant's arguments for showing a real world technological improvement.
With respect to points A) and C), for the individualized assessment of patient risk which includes data of non-binary values, the arguments are persuasive.
However, regarding point B), the claim of an improvement by not requiring a bone marrow biopsy is not persuasive, because there are embodiments of claims 3-6, 12, 16-18, and 21-27 which inherently include a bone marrow biopsy by reciting "BMPC%" (bone marrow plasma cell percent). The Specification at 15:28 states: "… BMPC%, which can only be determined by obtaining a bone marrow biopsy." Consideration was given to all aspects of the Step 2A Prong 2 improvement arguments, and the conclusion was made that the aspect of not requiring a bone marrow biopsy is key to the overall persuasiveness of Applicant's arguments for showing a real world technological improvement. Amending to remove the embodiments which include BMPC% would likely be a step to overcoming the 101.
Regarding points D) and E), for the PANGEA model showing both an increased C-statistic and an increased performance in the validation cohort over the 20/2/20 model, the arguments are not persuasive. Because points D) and E) are directed to showing improvement using data from use of the PANGEA model, and claims 3-6, 12, 16-18, and 21-27 do not recite "PANGEA," these arguments are not persuasive, as there are embodiments in which the PANGEA model is not the model used in claims 3-6, 12, 16-18, and 21-27.
Regarding Step 2B:
No arguments were received for Step 2B.
Summary of response to 101 arguments:
Applicant's arguments (points A) through E)) for claim 19 and 20 are persuasive, as there is an improvement to technology for the individualized assessment of patient risk using the PANGEA model (no BM), which includes data of non-binary values, not requiring bone marrow biopsies, while at the same time showing an improved C-statistic, and outperforming in the validation cohort study; this integrates the JEs into a practical application at Step 2A Prong Two of the 101 analysis.
Applicant's arguments for claims 3-6, 12, 16-18, and 21-27 are not persuasive, as there are embodiments of claims 3-6, 12, 16-18, and 21-27 that inherently include a bone marrow biopsy in reciting BMPC%. Additionally, it is noted claims 3-6, 12, 16-18, and 21-27 do not recite "PANGEA."
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 3-6, 12, and 16-27 are rejected under 35 U.S.C. 103 as being unpatentable over Visram, (Blood cancer journal, vol. 11(11):186, pp. 1-8 (2021); cited on the 07/29/2025 form PTO-892), in view of Farswan, (Translational oncology, vol. 14(9):101157, pages 1-9 (2021); cited on the 07/29/2025 form PTO-892), in view of Wu, (Blood Advances, vol. 2(12), pages 1470-1479 (2018); cited on the 07/29/2025 form PTO-892).
Note about dependency:
• Dependent claims 3-6, 12, 16-18, and new dependent claims 23-27 ultimately depend from new independent claim 22.
• Dependent claim 20 and new dependent claim 21 depend from independent claim 19.
Regarding the steps for:
• "Receiving, by at least one server from a computing device via a network, a multiple myeloma precursor disease progression request comprising: age and three or more variables selected from free light chain (FLC) ratio, M-spike level, age, creatinine level, and hemoglobin level, wherein each variable represents a marker measurement associated with a subject" of independent claim 19.
• "Receiving the age of the patient and a plurality of numeric values into a model trained to evaluate risk of an MM precursor disease progressing into MM, wherein the plurality of numeric values corresponds to time-varying markers of the patient, the time-varying markers comprising at least 3 clinical variables selected from creatinine, hemoglobin, M-spike, serum free light chain (FLC) ratio, and bone marrow plasma cell percent (BMPC%)" of independent claim 22.
• Determining, a …model based on age and the three or more variables; …for a particular combination of variables based at least in part on training data; wherein the …data comprises historical marker measurements for the particular combination of variables paired with known trajectories of the particular combination of variables and wherein the variables of the …data comprise age, free light chain (FLC) ratio, M-spike level, age, creatinine level, or hemoglobin level; utilizing, by the at least one server, the…model to ingest the three or more variables and produce a predicted risk calculate the probability that a patient with a multiple myeloma (MM) precursor disease will progress to MM within a plurality of timeframes of independent claim 19.
• Transmitting the response comprising a probability of progression from MM precursor disease to MM of independent claim 19.
• Bone marrow plasma cell percent (BMPC%) of claim 21.
• The model is a multivariate Cox model of claim 22.
• The MM precursor disease is monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) of claim 4.
• The bone marrow biopsy of claim 26.
Visram presents a study on assessing whether Mayo 2018 and IMWG 2020 (stratification method models) scores could be used dynamically to risk-stratify smoldering multiple myeloma (SMM) patients post-diagnosis, and whether they could identify SMM patients with evolving disease (p.2, col.1). Visram shows a study based on assessing risk using stratification scores in progression of SMM (p.1, and entire document). Visram shows using electronic medical records to obtain SMM patient characteristics and clinical values, i.e., age, serum MCP (monoclonal protein, i.e. M-spike), serum FLCr (free light chain ratio), and BM PC% (bone marrow plasma cell %). Additionally, serial FLC, MCP, and BM PC data (when available) were collected for SMM patients. Bone marrow biopsy for plasma cell quantification was performed. Cox proportional hazards analyses were used to provide a hazard ratio of the time-to-progression (TTP) based on the SMM risk score at pre-specified timepoints. (p.2, col.1, col.2, and table 1). Visram shows risk scores in a summary of risk progression at 2 yrs and at 5 yrs., (p.4, table 1). The assessment of and display of data inherently shows transmitting data.
Regarding the steps for:
• The clinical variables further comprise one or more of total protein, IgA, IgM, IgG, kappa free light chain (FLC), lambda FLC, calcium, albumin, LDH, beta-2 microglobulin, and weight of claim 3.
Visram shows serial serum FLCr (free light chain ratio) and percentage of k and λ chains (free light chains) (p.2, col.1 and table 1).
Wu also shows involved and uninvolved FLC, involved k concentration, and involved λ concentration when compared with the FLCr (free light chain ratio, i.e., a ratio involving k and λ chain concentrations (bridging pp.1472-1473). Wu shows evolving changes in FLCr (p.1476, fig.2).
Regarding the steps for:
• wherein the method further comprises determining …a numeric probability that a patient with a multiple myeloma (MM) precursor disease will progress to MM within a timeframe or each of the plurality of timeframes respectively of claim 5 and 6.
• determining a numeric probability (and graphical plot in claim 19; and outputting the numeric probability of claim 22) that a patient with an MM precursor disease will progress to MM of claims 19, 22, and 26.
Visram shows the change in risk score (i.e., a numeric probability of progression from SMM to MM) over time, using baseline Mayo 2018 SMM risk score, every year for five years (p.5, fig.2); and time to progression stratification of SMM Mayo 2018 migration of risk category (p.5, fig.3) and IMWG 2020 risk stratification (p.6, fig.4) (i.e., graphs showing plot of numerical probability).
Regarding the steps for:
• Receiving further includes an indicator of whether the patient has been detected to have at least one genetic marker; the marker is selected from the group consisting of 17 deletion, l7p deletion, 13 deletion, 13q deletion, and lq gain; and whether a patient has been found to have a 17 deletion, l7p deletion, 13 deletion, 13q deletion, and/or lq gain, respectively of claims 16, 17, and 18.
Visram shows analyzing high risk markers t (4;14), t (14;16), gain 1q, or del[13q]/monosomy was done by FISH analysis, and discusses calculating risk scores after a secondary cytogenetic abnormality (gain 1q or del13q/monosomy 13) was detected, patients were assumed to be positive for that abnormality for the remainder of their SMM follow up (p.2, col.1, and table 1).
Visram does not show a trained model and/or training data of claims 5, 6, 19, 21, 22, 26.
Visram, while including "age" among the list of clinical information, does not specifically include age as a value in their baseline study, so is not considered to show analyzing age of claims 19, 20, 22.
Visram does not explicitly show trajectories of claims 12, 19, 23-25.
Visram does not show creatinine or hemoglobin, and/or increase/decrease of trajectory of hemoglobin, of claims 12, 19, 20, 22, 27.
Regarding the steps for:
• The clinical variables comprise: a free light chain (FLC) ratio, M-spike, creatinine, and
hemoglobin of claims 12 and 20.
• Wherein the time trajectory value indicates whether an amount of hemoglobin increased or decreased of claim 12 .
• The clinical variable hemoglobin of claims 12, 19, 20, 22, 27
• Receiving a time-trajectory value describing a change over time of one of the received time-varying markers of claim 23.
• Receiving three or more values of the time-trajectory value collected at different times of claim 24.
• The time-trajectory value is determined from serial values of the received time-vary marker of claim 25.
• Receiving only 3 clinical variables selected from creatinine, hemoglobin, M-spike, and
serum free light chain (FLC) ratio of claim 27.
Wu presents a method for risk stratification of SMM (smoldering multiple myeloma) using group-based trajectory modeling (GBTM) to compare evolving biomarkers (p.1471, col.1, and entire doc.) Wu shows distinctive trajectories of biomarkers (i.e., first, second, and third time-varying markers) were derived by modeling the change of hemoglobin (Hb) and percent change of m-protein (i.e., M-spike) and FLC, from baseline, as a function of time since SMM diagnosis. Quadratic curves were used to model trends in Hb and FLC over time and cubic curves were used to model trends in m-protein over time (p.1471, col.2). Wu shows identification of evolving Hb, MP, and FLC as significant predictors of 2-year disease progression (p.1475, col.1); while evolving changes in hemoglobin, m-protein, free light chain ratio over one year after SMM diagnosis, with trajectories of the high risk group based trajectory modeling markers (i.e., serial values of time varying markers) collected at different times are shown on p.1476, fig.2; and specifically at p.1476, fig.2A, the trajectories of Hb are shown as increasing or decreasing.
The clinical variable creatinine is shown below by Farswan.
Regarding the steps for:
• The machine learning model of claim 19.
• The trained model and/or training data of claims 5, 6, 19, 21, 22, 26.
• The clinical variable creatinine of claims 12, 19, 20, 22, 27.
Farswan shows a machine learning method for a risk stratification system, Modified Risk Staging (MRS) for MM using six easy-to-acquire laboratory parameters: albumin, ß2M, calcium, eGFR (calculated from serum creatinine), hemoglobin along with age. The model was developed on a training dataset of patients with newly diagnosed multiple myeloma (NDMM) and validated on two test datasets (p.2, col.1; p.6-7, fig.3-4; and entire document). (Showing the trained model and/or training data of claims 5, 6, 19, 21, 22, 26; clinical values of creatinine and hemoglobin of claims 12, 19, 20, 22, 27).
Regarding the limitation for:
• Generating a value for the not received clinical variable to be used in the determining step that is based on at least one of the plurality of values that were received, or
using a default value in the determining step for the clinical variable not received of claim 27.
Farswan shows patients (n=1070) in MMIn (Multiple Myeloma Indian cohort) were randomly split in the ratio of 67:33 as training (n=716) and test cohorts (n=354). The test cohort did not have any missing value. In the training cohort, 41 patients (5.7% of 716 patients) had one or two missing values that were imputed with the median value of the parameters… No missing imputation was applied on the test cohort or the MMRF (MM Research Foundation) dataset (p.2, end of col.1). While no determination of a variable not received was performed for test data, it would be obvious to use the same method for imputing a missing clinical variable as was used for imputation in the training data.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the methods used in Visram for assessing progression risk across time periods of SMM using serial M-spike, FLCr, BM PC% values, and the genetic indicator markers; with the trained model, including analysis of age and creatinine, as in Farswan, with the trajectories of time-varying markers, including hemoglobin, of Wu, to result in a method for determining risk of progression from smoldering multiple myeloma (SMM) to multiple myeloma using a trained model for analyze age and time-varying markers. This is because Visram shows that both the Mayo 2018 and IMWG 2020 risk scores reproducibly stratified patients based on the risk of progression of SMM (Visram, p.6, col.1); while Farswan provides motivation to combine by disclosing their reliable and inexpensive staging system, MRS, utilizes easily acquirable laboratory parameters (Farswan, p.9, col.1). Wu adds further motivation to combine by using trajectory modeling to compare evolving biomarkers in risk stratification of SMM, and identifying evolving Hb, MP, and FLC as significant predictors of 2-year PD (progression of disease) (Wu, p.1475, col.1). One of ordinary skill would have had a reasonable expectation of success, as Visram, Farswan, and Wu are generally drawn to related teaching, and one of ordinary skill in the art would have understood how to and would have been motivated to combine the teachings of Visram, Farswan, and Wu, and as such, the combination would have been obvious.
Response to Applicant Arguments - 35 USC § 103:
Applicant's arguments filed 11/22/2025 regarding the 103 rejection over Visram in view of Farswan in view of Wu (remarks, p.28-30) have been fully considered but they are not persuasive.
Regarding Visram in view of Wu, (p.29, emphasis added):
• Applicant asserts "First, a person of ordinary skill in the art would not be motivated to combine components of Visram and Wu because Visram explicitly calls out the limitations of Wu…" (remarks, p.29, ¶ 2).
• Applicant asserts "Specifically, page 6, column 2 of Visram states: …While this model may better represent the biological evolution of tumor markers, the lack of clear cutoffs to define high versus low-risk biomarkers makes it difficult to implement in clinical practice. …defined SMM using the 2003 IMWG definition, and therefore may have incorporated patients with SLiM criteria who would now be treated for MM… Furthermore, neither study has been externally validated which limits applicability of these models" (p.29, ¶ 2-3).
• Applicant asserts "Because Visram explicitly outlines potential issues with the model of Wu, a person of ordinary skill in the art would not be motivated to combine the teachings of Visram and Wu" (p.29, ¶ 4).
The arguments regarding Visram in view of Wu are not persuasive. While Visram (at page 6, column 2) does disclose "the lack of clear cutoffs to define high versus low-risk biomarkers makes it difficult to implement in clinical practice; (Larrea and) Wu studies defined SMM using the 2003 IMWG definition, and therefore may have incorporated patients with SLiM criteria who would now be treated for MM; …furthermore, neither study has been externally validated," Visram nonetheless first discloses "this model (Visram here is referring to Wu's model) may better represent the biological evolution of tumor markers," providing motivation to combine the aspect of trajectories of markers, which Wu was relied upon for teaching in the 103 rejection.
Regarding Visram and/or Wu with elements of Farswan, (p.29, emphasis added):
• Applicant asserts "…Second, a person of ordinary skill in the art would not be motivated to combine components of Visram and/or Wu with elements of Farswan because Visram and Wu are directed at a different disease state than Farswan" (p.29, ¶ 5).
• Applicant asserts "Visram and Wu are directed at models for the risk stratification of patients having smoldering multiple myeloma, a precursor to multiple myeloma…In contrast, the model of Farswan is concerned with cancer prognostication for patients already diagnosed with multiple myeloma….Because smoldering multiple myeloma and multiple myeloma are different disease states, a person of ordinary skill in the art would not be motivated to combine the teachings of Visram and/or Wu with the teachings of Farswan" (p.29, ¶ 5).
The arguments regarding Visram and/or Wu with elements of Farswan are not persuasive. Smoldering multiple myeloma (SMM) is a precursor disease that may progress to multiple myeloma (MM). A person of ordinary skill in the art would find modeling risk for progression and prognosis of SMM and/or MM involves analysis of similar biomarkers, such that modeling one disease state may naturally inform the other disease state. Additionally, Visram, Wu, and Farswan all disclose methods for "risk stratification"; specifically either involving risk stratification of SMM and MM (Visram and Wu), or involving risk stratification of MM alone (Farswan).
Conclusion
No claims are allowed.
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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/M.A.V./Examiner, Art Unit 1687
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686