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 .
Response to Amendment
The amendment filed March 23rd, 2026 is acknowledged. Regarding the Office Action mailed December 23rd, 2025:
Maintained or modified rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claim 1 has been amended. Claims 3, 17, 19, and 22-23 have been canceled. Claims 1-2, 4-16, 18, and 20-21 are pending. Claims 1-2, 4-16, 18, and 20-21 are under examination and discussed in this Office action.
Claim Rejections - 35 USC § 112(a) – Modified – Necessitated by Amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4-15, 18, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. This is a scope of enablement rejection because the specification, while being enabling for a method for determining a subject's gene expression inflammatory age (GE iAge), comprising the steps of: (a) obtaining a sample from a subject; (b) measuring the expression of fifteen genes in a cell in the sample from the subject to obtain a mean gene expression signal consisting of a GBP5, a MMP9, a SIGLEC5, a S100P, an OLFM1, a CISH, a MT1A, a CHURC1, an IGLL1, a RPLP0, a SLC16A10, a FCER1A, a CD248, a DDX3Y, and a MAN1A1; (c) normalizing the mean gene expression signal by multiplying it by a regression coefficient for each gene; and (d) adding the resultant number to calculate the subject's GE iAge, wherein the subject’s GE iAge is used to classify the subject as being capable of having a clinical response to an immunotherapy or as being a non-responder, this does not reasonably provide enablement for a method for determining a subject's gene expression inflammatory age (GE iAge), comprising the steps of: (a) obtaining a sample from a subject; (b) measuring the expression of three or more genes in a cell in the sample from the subject to obtain a mean gene expression signal wherein three or more genes are selected from a group consisting of a GBP5, a MMP9, a SIGLEC5, a S100P, an OLFM1, a CISH, a MT1A, a CHURC1, an IGLL1, a RPLP0, a SLC16A10, a FCER1A, a CD248, a DDX3Y, and a MAN1A1; (c) normalizing the mean gene expression signal by multiplying it by a regression coefficient for each gene; and (d) adding the resultant number to calculate the subject's GE iAge, wherein the subject’s GE iAge is used to classify the subject as being capable of having a clinical response to an immunotherapy or as being a non-responder as embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 1 as currently drafted encompasses a method for determining a subject’s gene expression inflammatory age (GE iAge) comprising obtaining a sample, measuring gene expression of 3 or more genes from the 15 listed in claim 1, normalizing the mean expression by multiplying it by a regression coefficient for each gene, adding the resultant number to calculate the subject’s GE iAge, and classifying a subject’s response to immunotherapy based on this value. The claim is overly broad because it requires only three of fifteen biomarkers, which results in thousands of different combinations of markers, none of which appear to have support for determining a GE iAge. Consequently, the breadth of the claim is expansive. Claims 2, 4-15, 18, and 21 encompass the same breadth as claim 1 since they do not limit the measured genes to all 15 in the list of claim 1, and in fact claims 6-15 and 21 make the number of combinations increase by requiring progressively more genes.
(B) The nature of the invention: The invention is in the field of determining a gene expression inflammatory age via the expression of biomarkers.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Mayeux (Biomarkers: potential uses and limitations, NeuroRX, April 2004, 2, 182-188; previously cited) teaches that while biomarkers provide a dynamic and powerful approach to understanding a spectrum of diseases, variability is a major concern in biomarkers (Summary). Biomarkers are subject to critical timing regarding sample collection, storage conditions, and adequate laboratory handling (Table 2). Further, normal ranges are often difficult to establish, given interindividual variability, tissue localization, reliability of the biomarker measurements, and persistence of the biomarker (Pages 187-188). This would make comparison to establish disease or select treatment highly unpredictable.
This is especially true in inflammaging, which was only identified as a body process two decades ago (see Fulop, Immunology of Aging: the Birth of Inflammaging, Clinical Reviews in Allergy and Immunology, September 2021, 64, 109-122; see abstract; previously cited). According to Fulop, there are many different definitions of aging, and none of them capture its complexity since they do not use the integration of complex systems (Page 109). Even the current definition of the hallmarks of aging seems to be a sort of catalogue of pathways without really defining the basic interactions between these hallmarks and how they interact, which would influence the whole complex process (Page 109).
According to Liu (Biomarkers of chronic inflammation in disease development and prevention: challenges and opportunities, Nature Immunology, October 2017, 18, 1175-1180; previously cited), reports of inconsistent results from biomarker-discovery research have been due in part to the lack of robust biomarker validation, lack of quality control and insufficient causal evidence linking chronic inflammation biomarkers to disease development (Page 1179). Many population-based studies have provided data on the association of inflammatory markers with diseases (population studies mentioned during the workshop are in Box 2; Page 1179). However, as with biomarker identification in other research areas, such studies are hampered by the lack of reliable assays, scarce biospecimens and limited longitudinal data from the same subject (Page 1179). These challenges make the translation of biomarker discovery to the clinic difficult (Page 1179).
Given this unpredictability in the field, one of skill in the art would not be able to engage in routine experimentation to determine which biomarker combinations to use out of the thousands of possible combinations presented in the claims for determining GE iAge. In fact, it would take an enormous amount of undue experimentation to test the combinations presented by the claims.
In addition to the unpredictably of biomarker combinations, the art also teaches that coefficients in multiple regression will change as variables are added to the regression. de Nooy (Statistical Inference [online]. GitHub, [2025] [retrieved on December 18th, 2025]. Retrieved from: https://shklinkenberg.github.io/Statistical-Inference/; previously cited) teaches that the effect (e.g. regression coefficient) of a predictor (e.g. independent variable) on a dependent variable is adjusted for the effects of other predictors as additional predictors are added to the regression (Page 1). de Nooy further teaches that a predictor only predicts the part of the dependent variable that cannot be predicted by other predictors (Page 1). When a new predictor is added, some of the effect of the existing predictors is reassigned to the effect of the new predictor as a result of some amount of correlation between predictors (Page 1; Page 11). This is due to correlation between predictors (Page 1; Page 11), which ultimately causes regression coefficients to change. Therefore, predictors would need to be fully independent from each other to not change the effect of existing predictors. Altogether, these teachings indicate that dependent variable prediction is very much related to the number of predictors and correlation between them.
In addition, it cannot readily be said that the claimed genes are independent from each other. Tang (The IRF1/GBP5 axis promotes osteoarthritis progression by activating chondrocyte pyroptosis, Journal of Orthopaedic Translation, December 2023, 44, 47-59; previously cited) teaches that at least GBP5 and MMP9 have related expression in the inflammatory disease osteoarthritis, where expression of GBP5 results in increased expression of MMP9 (Abstract).
Given this information regarding regression coefficients and the general knowledge of correlation between at least some of the genes that are claimed, it is highly unpredictable that using three or more of the claimed genes will ultimately have equivalent ability to calculate a subject’s GE iAge as using all 15 genes.
Overall, based on the unpredictability of biomarkers, and the unpredictability of different predictors having equivalent ability to calculate a subject’s GE iAge, methods for determining GE iAge comprising subcombinations of the claimed genes other than all 15 as described in the specification is highly unpredictable.
The invention is drawn to biological molecules, and is therefore in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The level of skill in the art is therefore deemed to be high.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The Applicant has provided one description directed towards using all the genes of claim 1. As presented in the specification, “To derive gene expression inflammatory age (GE iAge), the mean gene expression signal can be normalized and used for multiple regression analysis, which is computed using the following regression coefficients: GBP5: 1.3452, MMP9: 0.6083, SIGLEC5: 0.5419, S100P: 0.4408, OLFM1: 0.4155, CISH: 0.2270, MT1A: 0.1978, CHURC1: -0.1308, IGLL1: -0.2250, RPLP0: -0.2861, SLC16A10: -0.4742, FCER1A: -0.6154, CD248: -0.6580, DDX3Y: -0.6937, MAN1A1: -0.7070. The gene expression signal can be multiplied by the regression coefficient for the gene, and these numbers can be all added together to give the GE iAge of the subject.” (Page 18, paragraph [074]). This implies that the expression of all 15 genes would be needed. The following paragraph, [075], which includes Table 2, simply states that one or more of the genes in Table 2 can be used for GE iAge. However, given the information in the art regarding regression coefficients, this paragraph does not demonstrate that any particular subcombination of the cited genes, besides the 15 cited together in paragraph [074], can be used to calculate GE iAge. There is no evidence as to how these coefficients were generated, and also no evidence that a subcombination of the 15 genes listed in claim 1 will provide the same GE iAge for a subject as a different subcombination of the 15 genes. The working example provided later in the disclosure, while titled “Gene Expression iAge”, does not appear to relate to GE iAge, but instead another metric called iAge (Page 77, paragraphs [0235]-[0236]).
Therefore, the applicants have not provided direction or examples comprising using between 3 and 14 of the claimed genes to determine GE iAge, as covered in claims 1, 6-15, and 21.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high unpredictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that using 15 specific genes for determining a GE iAge is distinct from using any three or more genes from a selected list for determining a GE iAge. A skilled artisan would know that using any three or more genes from a selected list would require multiple experiments for each possible group of three or more, using large cohorts of all possible “subjects” as claimed, which include a variety of species (human, dog, cat, bird, etc.). Thus, applicability of the claimed method to any 3 or more genes up to 14 as embraced by the claim remains unpredictable, requiring undue experimentation.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1, 2, 4-15, 18, and 21, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the full scope of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 1, 2, 4-15, 18, and 21 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed invention to the full scope embraced by the claims. However, claim 16 appears to claim measuring expression of all 15 genes and is enabled based on the specification.
Response to Arguments
Applicant's arguments filed March 23rd, 2026 have been fully considered but they are not persuasive.
The Applicant first acknowledges the Examiner’s previous rejection, as well as a summary of case law related to objective enablement and what is considered a permissible amount of experimentation (Page 6 of the Remarks filed March 23rd, 2026). The Applicant disagrees with the Examiner’s rejection, arguing that the specification provides reasonable description of the method steps involved and provides a list of genes along with their regression coefficients (Page 6 of the Remarks filed March 23rd, 2026). The Applicant argues that the listed genes are not an all-inclusive, mandatory list of genes to be used in the claimed method, and that the disclosure enables the skilled artisan to use selected genes from the list (Page 6 of the Remarks filed March 23rd, 2026). The Applicant also argues that the inventors have demonstrated possession of the claimed invention given the provisional application (Page 6 of the Remarks filed March 23rd, 2026).
In response to these arguments, it is first noted that while the Applicant may state that the listed genes are not in all-inclusive, mandatory listed of genes to be used, the language of paragraph [074] can reasonably be interpreted to mean that the genes associated with the coefficients listed are a mandatory list. Any arguments related to this interpretation can reasonably be considered an argument of counsel as there is no clear evidence stating that 3-14 of the claimed genes may be used in the claimed method. Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, Applicant should not merely rely upon counsel's arguments in the place of evidence in the record.
It is further noted that while the Applicant may state that there is adequate description of the method steps involved as it relates to what may be a considerable amount of permissible experimentation, there is no explicit indication from paragraph [074] that a subcombination of less than 15 of the claimed genes is adequate for calculating GE iAge. Even though paragraph [075] further states that one or more of the genes in Table 2 may be used for GE iAge, there is no subsequent calculation of GE iAge to show that any particular subcombination of the 15 genes listed in claim 1 is capable of producing an equivalent value to any other particular subcombination of those genes. This is further complicated by the coefficient values of paragraph [074] being different from those listed for the same genes in Table 2. There is no evidence indicative of how regression coefficients were determined, and therefore there is no clear description for a skilled artisan to follow to complete the method as claimed. As has been indicated above in the art, regression coefficients will change if there is correlation between independent variables, and there is no evidence provided that every gene listed is independent from the rest.
While the Applicant may argue that the selection of three or more genes is not undue experimentation in view of the case law on objective enablement and permissible amounts of experimentation, there is no guidance on how GE iAge experiments should proceed beyond that presented in paragraphs [074] and [075], which are already noted as inadequate for making and using the method as claimed. Ultimately, this means there is no guarantee that any less than all 15 genes in claim 1 can be used to calculate GE iAge. Therefore, there is still a considerable amount of experimentation required to use the method as claimed because what is described is not merely routine and there is not a reasonable amount of guidance with respect to the direction in which experimentation should proceed. The arguments are not found persuasive.
Written Description
Claims 1, 2, 4-15, 18, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). See MPEP § 2163.
Claim 1 recites the limitation “A method for determining a subject's gene expression inflammatory age (GE iAge), comprising the steps of: (a) obtaining a sample from a subject; (b) measuring the expression of three or more genes in a cell in the sample from the subject to obtain a mean gene expression signal wherein three or more genes are selected from a group consisting of a GBP5, a MMP9, a SIGLEC5, a S100P, an OLFM1, a CISH, a MT1A, a CHURC1, an IGLL1, a RPLP0, a SLC16A10, a FCER1A, a CD248, a DDX3Y, and a MAN1A1; (c) normalizing the mean gene expression signal by multiplying it by a regression coefficient for each gene; and (d) adding the resultant number to calculate the subject's GE iAge, wherein the subject’s GE iAge is used to classify the subject as being capable of having a clinical response to an immunotherapy or as being a non-responder.” The claim as written embraces a method wherein the gene expression signal of three or more genes is used to determine a GE iAge, and further classifying a subject as a responder to immunotherapy or a non-responder.
However, the specification does not provide a method by which to determine this GE iAge using expression of just three of the claimed genes. In fact, the specification does not appear to provide a method by which to determine GE iAge with any less than all 15 of the claimed list of genes. As presented in the specification, “To derive gene expression inflammatory age (GE iAge), the mean gene expression signal can be normalized and used for multiple regression analysis, which is computed using the following regression coefficients: GBP5: 1.3452, MMP9: 0.6083, SIGLEC5: 0.5419, S100P: 0.4408, OLFM1: 0.4155, CISH: 0.2270, MT1A: 0.1978, CHURC1: -0.1308, IGLL1: -0.2250, RPLP0: -0.2861, SLC16A10: -0.4742, FCER1A: -0.6154, CD248: -0.6580, DDX3Y: -0.6937, MAN1A1: -0.7070. The gene expression signal can be multiplied by the regression coefficient for the gene, and these numbers can be all added together to give the GE iAge of the subject.” (Page 18, paragraph [074]). This does not appear to provide support for using less than all 15 of the described genes for the claimed calculations and instead implies that the expression of all 15 genes would be needed. While the following paragraph [075] then introduces Table 2 and that one or more of the genes listed can be used for GE iAge, there is no further description or working example explaining how to choose which genes to use or how a particular subcombination of the 15 genes listed in claim 1 will produce an equivalent GE iAge value to a different particular subcombination of those genes. This is further complicated by the described regression coefficients being different between paragraph [074] and Table 2 for the same genes. This indicates that there is some discrepancy of how regression coefficients are determined which is also not further explained.
de Nooy (Statistical Inference [online]. GitHub, [2025] [retrieved on December 18th, 2025]. Retrieved from: https://shklinkenberg.github.io/Statistical-Inference/; previously cited) teaches that the effect (e.g. regression coefficient) of a predictor (e.g. independent variable) on a dependent variable is adjusted for the effects of other predictors as additional predictors are added to the regression (Page 1). de Nooy further teaches that a predictor only predicts the part of the dependent variable that cannot be predicted by other predictors (Page 1). When a new predictor is added, some of the effect of the existing predictors is reassigned to the effect of the new predictor as a result of some amount of correlation between predictors (Page 1; Page 11). This is due to correlation between predictors (Page 1; Page 11), which ultimately causes regression coefficients to change. Therefore, predictors would need to be fully independent from each other to not change the effect of existing predictors. Altogether, these teachings indicate that dependent variable prediction is related to the number of predictors and correlation between them. There is no description in the specification that the claimed genes are independent from each other such that any three or more genes claimed in claim 1 could be used together to calculate GE iAge. At best, paragraph [074] supports using all 15 of the genes in claim 1 based on the provided language. The working example provided later in the disclosure, while titled “Gene Expression iAge”, does not appear to relate to GE iAge, but instead another metric called iAge (Page 77, paragraphs [0235]-[0236]).
Based on the specification, the Applicant does not have possession of the method as claimed. Claims 2, 4-15, 18, and 21 do not further present possession of the method as claimed in claim 1 and are also rejected here. It is also noted that claims 6-15 and 21 suffer from the same issue of claiming less than 15 of the claimed genes, but claim 16 appears to claim measuring expression of all 15 genes, which does have support based on the specification.
Response to Arguments
Applicant's arguments filed March 23rd, 2026 have been fully considered but they are not persuasive.
The Applicant first acknowledges the Examiner’s previous rejection, as well as a summary of case law related to the written description requirement (Page 7 of the Remarks filed March 23rd, 2026). The Applicant argues that the subject application provides sufficient written description to satisfy this requirement Page 7 of the Remarks filed March 23rd, 2026). The Applicant states that paragraph [074] provides a first list of 15 genes along with regression coefficients and paragraph [075] provides a second list of other gene expression signals with regression coefficients (Page 7 of the Remarks filed March 23rd, 2026). The Applicant argues the specification describes how a gene expression signal can be multiplied by the regression coefficient of that gene and the numbers can be added together to give a GE iAge of a subject, with one or more of the regression coefficients being used (Page 7 of the Remarks filed March 23rd, 2026). The Applicant finishes by arguing that a skilled person would be able to envision and practice the claimed method using the information in the specification, namely paragraphs [074] and [075] (Page 7 of the Remarks filed March 23rd, 2026).
In response, the Examiner does agree with the Applicant that the mathematics of calculating GE iAge are adequately described in the specification. It is clear from the provided description that a gene expression signal can be multiplied by a regression coefficient and further the resultant numbers added together. However, the simple statement that “one or more” of the regression coefficients, and therefore the associated genes, can be used for GE iAge does not provide adequate support for any less than all 15 genes in claim 1 given that there is no further description of how this works. As explained in the above rejection, there is no further description or working example explaining how to choose which genes to use or how a particular subcombination of the 15 genes listed in claim 1 will produce an equivalent GE iAge value to a different particular subcombination of those genes. Without any more evidence besides one sentence, it cannot be said that the Applicant has possession of the method as claimed unless all 15 genes are used. Furthermore, while the Applicant may posit that a skilled person with knowledge in the art and familiar with the instant specification would be able to envision and practice the claimed method, that is not what is in question regarding written description. It is if the Applicant had possession of the method as claimed, not if the method can actually be done. That has been addressed above in the scope of enablement rejection.
Claim Rejections - 35 USC § 101 – Modified – Necessitated by Amendment
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 2, 4-16, 18, and 20-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and abstract ideas without significantly more. While the claim(s) is/are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claim(s) recite the natural correlation between gene expression and gene expression inflammatory age, the mathematical concepts of multiplication and addition, and the mental process of classifying subjects. The natural correlation between gene expression and gene expression inflammatory age is a natural phenomenon because it describes a consequence of natural processes in the human body (e.g. a change in gene expression during the process of aging). The mathematical concepts are abstract ideas as set forth in MPEP 2106.04(a). The mental process is an abstract idea as set forth in MPEP 2106.04(a)
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe a natural phenomenon and abstract ideas: the natural correlation between gene expression and gene expression inflammatory age, the mathematical concepts of multiplication and addition, and the mental process of classifying subjects.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of determining a gene expression inflammatory age (GE iAge) by samples, which can be blood or serum; measuring expression of 3 or more of a list of 15 genes, with later steps encompassing measuring from between 4 to 15 genes; normalizing the mean gene expression; measuring via a multiplex assay and PCR; and measuring cholesterol, gender, or BMI, the claims do not improve upon techniques for measuring gene expression or PCR. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps of determining a gene expression inflammatory age (GE iAge) by samples, which can be blood or serum; measuring expression of 3 or more of a list of 15 genes, with later steps encompassing measuring from between 4 to 15 genes; normalizing the mean gene expression; measuring via a multiplex assay and PCR; and measuring cholesterol, gender, or BMI, no particular machines are required by the claim. Even if some conventional machine were recited in the claims, like a specific brand of PCR machine, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, measurement of expression of a gene does not turn that gene into something else.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between gene expression and gene expression inflammatory age, mathematical concepts of multiplication and addition, and the mental process of classifying subjects in the instant case have to do with specifically collecting blood or serum samples, measuring expression of progressively more genes, measuring cholesterol, gender or BMI, and measuring expression via a multiplex assay or PCR. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” However, as will be discussed below, these limitations do not arrive at an inventive concept. In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exceptions are the natural correlation between gene expression and gene expression inflammatory age, the mathematical concepts of multiplication and addition and the mental process of classifying subjects. The additional elements recited in the claims (i.e. specifically collecting blood or serum samples, measuring expression of progressively more genes, measuring cholesterol, gender or BMI, and measuring expression via a multiplex assay or PCR) does amount to mere instructions to apply the correlation, since the collection of particular biological samples, measuring gene expression of more genes, and measuring other parameters of the subjects serve as mere conventional steps taken for the purpose of gathering data about gene expression of the claimed genes, which any practical use of the natural correlation and mathematical concepts would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to gathering samples, measuring gene expression, and calculating a GE iAge.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method being used to determine a subject’s GE iAge is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
Finally, in regards to MPEP 2106.5(d), claims that focus on the use of judicial exceptions must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the judicial exceptions themselves. See Mayo 101 USPQ2d at 1966. Adding steps to a judicial exception that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966, 1970. The claims identify blood cell types for testing, subjects to be tested, and assays for determining gene expression levels. The identification of sample types and subjects from which the samples are to be collected is routine in the art of medical testing. As stated in MPEP 2106.05(d), the courts have recognized certain laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. One of these techniques is determining the level of a biomarker in blood by any means (see Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)). Regarding the assays to detect gene expression, the assays claimed are routine in the art for measuring gene expression. Regarding the calculations, the claimed calculations are routine in the art for normalizing multiple regression data to determine a dependent variable. Regarding the mental process, it is routine in the art to compare test values and control values to determine an outcome. The claims use conventional means to observe all these judicial exceptions and therefore the steps of the claimed methods are not sufficient to transform unpatentable judicial exceptions into patentable applications of those regularities. This is also supported by the findings of in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 115 USPQ2d 1152 (Fed. Cir. 2015), wherein the Federal Circuit held that claims that measure biological substances using methods that are routine and conventional do not amount to more than reliance on a correlation that is a law of nature for patentability.
In summary, claims 1, 2, 4-16, 18, and 20-21 are rejected under 35 U.S.C. 101 for being directed to judicial exceptions without significantly more. It is noted here, however, that paragraph [014] of the specification has treatment options that would be sufficient to overcome this rejection.
Response to Arguments
Applicant's arguments filed December 8th, 2025 have been fully considered but they are not persuasive.
The Applicant first provides a summary sentence of the Examiner’s previous rejection (Page 9 of the Remarks filed December 8th, 2025). The Applicant then presents arguments separated into the steps of the patent eligibility determination (Page 9 of the Remarks filed December 8th, 2025).
With regards to Step 1, the Applicant acknowledges the Examiner’s assessment that the invention relates to a process (Page 8 of the Remarks filed March 23rd, 2026). The Examiner has reiterated the consideration that the invention is a process above.
With regards to Step 2A, Prong 1, the Applicant argues that amended claim 1 recites acts that cannot be practically performed in the human mind, and that the skilled artisan would understand that the processes as claimed add meaningful limits to the claimed method (Page 8 of the Remarks filed March 23rd, 2026).
In response to these arguments, it is noted that the cited steps of “obtaining a sample from a subject” and “measuring gene expression of genes in a cell from a sample” are acknowledged as not capable of being performed in the human mind. However, as has been addressed above, these steps can reasonably be considered data gathering for the recited judicial exceptions. Furthermore, these steps are also considered well-known, routine, and conventional in the art. Given these considerations, these steps are not considered meaningful limitations of the claimed method and cannot serve to overcome the judicial exceptions.
With regards to Step 2A, Prong 2, the Applicant argues that the claimed method is integrated into a practical application because of the claims recite an improvement to a technology, i.e. determining a GE iAge of a subject that may be used to classify the subject as capable of having a clinical response to an immunotherapy or as being a non-responder (Page 8 of the Remarks filed March 23rd, 2026). The Applicant states that this provides the ability to improve clinical and immune responses to a therapeutic treatment given the growing need to identify biomarkers that will improve the selection of patients who will respond to therapy (Page 8 of the Remarks filed March 23rd, 2026).
In response to these arguments, it is noted that the amendment used to show integration into a practical application, using GE iAge to classify a subject as being capable of having a clinical response to an immunotherapy or as being a non-responder, has itself been identified as a judicial exception in the above rejection. It is noted that it is an abstract idea because it represents a mental process that can reasonably be performed in the human mind. A skilled artisan would simply need to look at GE iAge and call a subject a responder or a non-responder. As stated in MPEP 2106.04(II)(A)(2), “…if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377.” Because the amended claim element is itself a judicial exception, it is not sufficient to integrate the other judicial exceptions into a practical application and cannot serve to overcome the rejection.
With regards to Step 2B, the Applicant provides a short summary of the determining criteria of the step (Page 8 of the Remarks filed March 23rd, 2026). The Applicant argues that the amended claim 1 provides for improved methods for diagnosing and treating subjects based on their GE iAge level given that the method is directed to classifying the subject as capable of having a clinical response to an immunotherapy or as being a non-responder based on GE iAge (Pages 8 and 9 of the Remarks filed March 23rd, 2026).
In response to these arguments, it is again noted from MPEP 2106.04(II)(A)(2), “…if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377.” Because the amended claim element is itself a judicial exception, it is not sufficient to integrate the other judicial exceptions into a practical application. It also cannot be used to amount to significantly more than the other judicial exceptions. As has already been discussed above, all other limitations have been addressed as well-understood, routine, and conventional or as other judicial exceptions, and therefore cannot serve to overcome the rejection.
Given the above considerations, the arguments are not considered persuasive.
Conclusion
All claims stand rejected.
THIS ACTION IS MADE FINAL. 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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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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