DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Response to Amendment
The amendment filed November 19th, 2025 is acknowledged. Regarding the Office Action mailed May 19th, 2025:
The objections to the claims are withdrawn in view of the amendments.
Maintained or modified rejections are set forth below. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claim 1 has been amended. Claims 2-5 and 8 have been canceled. Claims 1, 6-7, and 9-10 are pending. Claims 1, 6-7, and 9-10 are under examination and discussed in this Office action.
Claim Objections – New – Necessitated by Amendment
Claim 1 is objected to because of the following informalities: the recitation of “…wherein the threshold level is an NMT2 level greater than an NMT2 level measured in as sample from a control patient who does not have colorectal cancer…” is awkwardly placed with respect to where other details of the threshold are discussed. It would be clearer to have this phrase appear earlier in the claim. For example, it could appear following the recitation of “…wherein NMT2 levels above a threshold level indicates that the individual is a candidate for CRC diagnosis…”. Another option would be after the recitation of “…examining the individual with NMT2 levels above the threshold level by colonoscopy or sigmoidoscopy for CRC…”. Appropriate correction is required.
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, 6-7, and 9-10 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and breadth of claims
Claims 1, 6-7, and 9-10 are broadly drawn to a method identifying a candidate for further colorectal cancer (CRC) screening comprising: measuring N-myristoylatransferase 2 (NMT2) levels in a sample in an individual selected from a patient at risk of developing colorectal cancer, a patient suspected of having colorectal cancer or a patient having colorectal cancer with an antibody specific for NMT2, wherein NMT2 levels above a threshold level indicates that the individual is a candidate for CRC diagnosis, said sample selected from the group consisting of: peripheral blood monocyte cells, T-cells and CD8+ cells; examining the individual with NMT2 levels above the threshold level by colonoscopy or sigmoidoscopy for CRC, wherein the threshold level is an NMT2 level greater than an NMT2 level measured in a sample from a control patient who does not have colorectal cancer; during the colonoscopy or sigmoidoscopy, removing a tissue sample from the patient at risk; preforming a biopsy on the tissue sample; and diagnosing colorectal cancer in the individual based on the biopsy of the tissue sample. However, as will be further discussed, there is no support in the specification and prior art for the claimed method commensurate fully in scope.
The invention is 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).
Working Examples
The specification has a working example in which peripheral blood mononuclear cell samples and either CD4+ or CD8+ T cells of four controls, four CRC patients and three patients with high NMT2 expression with no CRC (n=11) were examined for the presence of NMT2 protein using polyclonal antibodies. The results were presented as H-scores, which is a product of intensity of staining and penetrance in the sample. Therefore, high intensity in a small sample area or low intensity over most of the sample would result in a similar H-score. As can be seen from Tables 2 and 3, for CD4+ T cells in the control group, the H-score ranged from 5-40, with a mean of 13.75; in the CRC group it ranged from 30-120 (low penetrance, high intensity), with a mean of 75; in the no CRC group the score was between 20 and 180 (low penetrance, high intensity) with a mean of 127. For CD8+ T cells the H-score values were: in controls from 5-40, with a mean of 17.5; in CRC patients between 60 and 180 (low penetrance) with a mean of 127.5 and for no CRC group between 120 and 180, with a mean of 153. Therefore, it is quite clear from these results that staining with anti-NMT2 antibodies in either CD4+ or CD8+ cells cannot distinguish patients with CRC from patients with resected CRC, polyps or diverticulitis. Also, Applicant does not show how a single disease-free individual would be an appropriate guide for a threshold value as claimed. Applicant instead uses at least 4 control subjects in their working examples, as shown in Table 2 and 3.
Guidance in the Specification
The specification provides no evidence that the claimed method can be used to categorize patients as having or not having a risk of developing CRC. The number of subjects used by Applicant was very small, therefore it is not clear how statistically significant these results are in terms of large populations. While Applicant has claimed that the threshold level is an NMT2 level greater than an NMT2 level measured in a sample from a control patient without colorectal cancer, Applicant does not provide guidance of how to establish the context of “greater than” to determine whether a patient should or should not qualify for CRC diagnosis. The specification and claims state that a threshold value may be an NMT2 level that is greater than for example statistically significantly greater than the NMT2 level of a sample from a control patient who does not have colorectal cancer (see spec last paragraph on page 9 to first paragraph on page 10). The specification does not provide any specific confidence interval when dealing with the totality of the data, only a statement of a p-value Pa = 0.05 in the table 1 for a particular set of the data produced through the method described on page 12 of the specification. Furthermore, the specification and claims state that the threshold is determined based on a single control patient (see spec last paragraph on page 9 to first paragraph on page 10). Statistical significance is generally based on the data of large groups. Using a single control individual does not guarantee a reasonable level for a threshold of normal NMT2 level, much less a statistically significant level for the threshold.
The unpredictability of the art and the state of the prior art
There are no publications, either pre- or post-filing of the instant application dealing with detection of NMT2 protein in the claimed cells.
As can be seen in a general teaching from MBL Life Science (Various non-specific reactions of antibodies [online]. MBL Life Sciences, [2017] [retrieved on December 19th, 2025]. Retrieved from: https://www.mblbio.com/bio/g/support/method/nonspecific-reaction.html), there are known issues of non-specific reactions of antibodies. This can vary from interaction with Fc receptors, cross-reaction of secondary antibodies, and interference of heterophilic antibodies (Page 1). Therefore, it would be unpredictable if the antibody is binding to NMT2 or non-specifically binding, causing false positive results.
Quantity of Experimentation
The quantity of experimentation in this area is extremely large since there is significant number of parameters which would have to be studied to apply this method to diagnose patients as having CRC or being at risk to develop CRC. First, studies of NMT2 expression using antibodies would need to be performed on all potential subjects who are at risk of developing CRC and these subjects would need to be followed up to determine if they indeed developed CRC. Considering that there is a large number of factors which might predispose a subject to CRC, this study would involve years of work. For example, large numbers of subjects over 55 would need to be studied to determine how many develop CRC if their NMT2 levels are above threshold, which would need to be determined for each of the NMT2 level detection methods. This would require years of inventive effort, with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the succeeding steps.
Conclusion
In the instant case, as discussed above, in a highly unpredictable art where the level of protein in a cell depends on a multitude of factors, one of which is the detection method used (antibody-based detection), the factor of unpredictability weighs heavily in favor of undue experimentation. Further, the prior art and the specification provides insufficient guidance to overcome the art recognized problems non-specific interactions of antibodies. Thus, given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables and the lack of guidance provided in the specification balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Response to Arguments
Applicant's arguments filed November 19th, 2025 have been fully considered but they are not persuasive. The Applicant’s only argument directed towards the enablement rejection states that given the amendment to claim 1 to delete reference to primer and probe, the “objection” is overcome (Page 4 of the Remarks filed November 19th, 2025). This is not found persuasive given the above identified issues when the claims are directed to just an antibody. Therefore, the rejection is modified as necessitated by amendment and maintained.
In addition, it is noted that the claims were rejected, not objected to.
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, 6-7, and 9-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claims recite the natural correlation between changes in levels of NMT2 and colorectal cancer. Such correlation is a natural phenomenon because it describes a consequence of natural processes in the human body (e.g. a change in NMT2 levels due to disease). The claims also recite an abstract idea in that the determined levels are compared to each other, which can be a mental process.
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: the natural correlation between changes in levels of NMT2 and colorectal cancer. The claims also recite a mental process of comparing.
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 (c) and (e) 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 measuring NMT2 levels using an antibody and using the levels being greater than a threshold as compared to a control patient who does not have colorectal cancer to identify individuals for further screening, performing that screening with a colonoscopy or sigmoidoscopy to remove a tissue sample, performing a biopsy on the tissue sample, and diagnosing colorectal cancer in the individual based on the biopsy, the claims do not improve upon methods of measuring levels of a protein or comparing control values to test values. The claims as written could use any well-known method for detecting protein levels 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 measuring NMT2 levels using an antibody and using the levels being greater than a threshold as compared to a control patient who does not have colorectal cancer to identify individuals for further screening, performing that screening with a colonoscopy or sigmoidoscopy to remove a tissue sample, performing a biopsy on the tissue sample, and diagnosing colorectal cancer in the individual based on the biopsy, no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, such as an imaging device to detect the NMT2 antibody in samples, 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, measuring NMT2 levels does not transform the measured NMT2 into something else.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between changes in levels of NMT2 and colorectal cancer and the mental process of comparing in the instant case have to do with measuring NMT2 levels in peripheral blood monocyte cells, T-cells, or CD8+ cells via an antibody in an individual and comparing to a threshold, the individual identified for screening being human, that individual being over 55 or having a familial history of colorectal cancer, further determining a threshold by comparing to a positive NMT2 control from an individual with colorectal cancer, and the threshold level being a level statistically significantly greater than a control level. 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.” As has been discussed, the additional limitations 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 exception is the natural correlation between changes in levels of NMT2 and colorectal cancer and the mental process of comparing. The additional elements recited in the claims (i.e. measuring NMT2 levels in peripheral blood monocyte cells, T-cells, or CD8+ cells via an antibody in an individual and comparing to a threshold, the individual identified for screening being human, that individual being over 55 or having a familial history of colorectal cancer, further determining a threshold by comparing to a positive NMT2 control from an individual with colorectal cancer, and the threshold level being a level statistically significantly greater than a control level) does amount to mere instructions to apply the correlation, since the individuals coming from particular risk groups and using further controls to define the threshold level serve as mere conventional steps taken for the purpose of gathering data related to if an individual should receive further screening, which any practical use of the natural correlation 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, detecting NMT2 in those samples via an antibody, and comparing the detected levels to a threshold from a control individual.
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 identify individuals for further screening of colorectal cancer 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.
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception. The judicial exception is the natural correlation between the fragmentation profile of cfDNA and disease and the mental process of comparing. In view of the foregoing, claims 1, 6-7, and 9-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
Response to Arguments
Applicant's arguments filed November 19th, 2025 have been fully considered but they are not persuasive. The Applicant’s only argument directed to the 101 rejection states that given the amendments to claim 1, the objection is overcome as the claim is not directed to the diagnosis of the individual (Page 4 of the Remarks filed November 19th, 2025). This is not found persuasive because claim 1 is ultimately directed to diagnosis of an individual with no integration into a practical application. Therefore, the rejection is modified as necessitated by amendment, but otherwise maintained.
Conclusion
All claims are 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
/Robert T. Crow/ Primary Examiner, Art Unit 1683