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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 9th, 2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Response to Amendment
The amendment filed February 9th, 2026 is acknowledged. Regarding the Office Action mailed September 8th, 2025:
The rejection set forth under 35 U.S.C. 112(b) is withdrawn in view of the cancellation of claims 8-10 and amendments to claim 12.
The rejection of claim 10 set forth under 35 U.S.C. 112(a) is withdrawn in view of the cancellation of the claim.
The rejection set forth under 35 U.S.C. 102 is withdrawn in view of the amendments.
Maintained, modified, and/or new rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claim 12 has been amended. Claims 1-11 have been canceled. Claims 13-16 have been added. Claims 12-16 are pending. Claims 12-16 are under examination and discussed in this Office action.
Claim Interpretation
Claim 12 recites the limitation “specifically and differentially diagnosing the subject as having the colon cancer, rectal cancer, or colorectal adenoma if the level of methylation at the CpG site is increased relative to the control”. The phrase “specifically and differentially” is not given a definition in the instant disclosure. For the purpose of examination, this phrase is being interpreted to mean specifically and differentially diagnosing the subject as having one of the claimed cancers as opposed to other cancers or conditions.
Claim Rejections - 35 USC § 112(b) - New - Necessitated by Amendment
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 12-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites the limitation "CpG sites", and later the limitation “the CpG site”. There is insufficient antecedent basis for “the CpG site” in the claim given the earlier introduction of “CpG sites”. It is further unclear if there are intended to be multiple CpG sites or just one CpG site analyzed given these recitations. Claim 14 also recites “the CpG site”, and therefore also lacks antecedent basis as described above. Therefore, claims 12 and 14 are found indefinite. Claims 13-16 are further rejected here for their dependence on claim 12 and not further clarifying the identified issue.
Claim 15 recites the limitation “the gene CpG site”. There is insufficient antecedent basis for this limitation in the claim. Claim 12, from which claim 15 depends, introduces “CpG sites”, not “a gene CpG site”. Therefore, claim 15 is found indefinite.
Given the similar issues noted for claims 12, 14, and 15, for the purpose of compact prosecution, all instances referring to “CpG sites”, “the CpG site”, and “the gene CpG site” will be interpreted to mean a single CpG site.
Claim Rejections - 35 USC § 112(a) - New - 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.
Scope of Enablement
Claims 12-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a sample type of tissues, cells, or plasma, does not reasonably provide enablement for a sample type of blood, serum, feces, or urine as embraced by the claim. 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 this claim.
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 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 12 as currently drafted encompasses a method wherein methylation level of CpG sites of the gene GLRB can be determined in samples from the group: tissues, cells, blood, plasma, serum, feces, and urine. This group of samples does not limit the sample type in question to tissues, cells, or plasma as described in the specification. Consequently, the breadth of the claim is expansive. Claims 13-16 encompass the same breadth as claim 12 since they do not limit the sample type to tissues, cells, or plasma.
(B) The nature of the invention: The invention is in the field of providing information for diagnosing colon cancer, rectal cancer, or colorectal adenoma via methylation levels of GLRB.
(C), (D), (E) With respect to the state of the art, the level of one of ordinary skill and predictability of the art: Laugsand (DNA methylation markers detected in blood, stool, urine, and tissue in colorectal cancer: a systematic review of paired samples; International Journal of Colorectal Disease, October 2020, 36, 239-251; previously cited) reviews studies that evaluate methylation as it relates to colorectal cancer in matched samples (Page 240, column 1, paragraph 2). These matched samples comprise tissue, plasma, stool, and urine (Page 240, column 1, paragraph 2 to column 2, paragraph 1), which represent four of the claimed options. Laugsand teaches that while sensitivity to CRC is 75% or above for some methylation markers in different sample types from the same patient, the sample types that are the same are not universal for each methylation marker (Table 1). For instance, BMP3 is sensitive for colorectal cancer in plasma and tissue, while ITGA4 is sensitive for colorectal cancer in tissue and stool (Table 1). There is no general consensus on all four examined sample types being sensitive for colorectal cancer for each methylation marker that was considered (Table 1). Laugsand further teaches that methylation markers that have been separately examined in different sample types do not consistently show reproducibility of methylation status between different sample types (Page 241, column 1, paragraph 3 to column 2, paragraph 1). Overall, Laugsand’s teachings show inconsistency between tissue samples and liquid samples in many cases, which is noted as confusing and would need to be further addressed (Page 246, column 1, paragraph 2).
The art does not support all the sample types claimed as being interchangeable for each other. Methods comprising sample types of blood, serum, feces, and urine in the instant case are therefore 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 working examples directed to detecting methylation levels of CpG sites of GLRB in tumor tissues and non-tumor tissues (Example 1, Example 5, Example 6, Example 7), cell lines (Example 3), and plasma (Example 8).
The Applicant has not provided working examples comprising detecting methylation levels of CpG sites of GLRB in blood, serum, feces, or urine.
(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 predictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that detection of methylation in sample types tissues, cells, and plasma is distinct from detection of methylation in sample types blood, serum, feces, and urine and thus applicability of the claimed method to blood, serum, feces, and urine as embraced by the claim remains unpredictable, requiring undue experimentation.
For example, to determine if methylation levels of CpG sites of the GLRB gene is relevant to colon cancer, rectal cancer, or colorectal adenoma in a sample type like urine, one of skill in the art would be required to collect urine samples from a statistically significant number of those affected by the claimed cancers, isolate DNA from all of these samples, and perform methylation analysis for the CpG sites of the GLRB gene to determine the statistical significance of the difference in methylation measured in affected urine samples as compared to control samples. This would all be required to determine if urine is a viable sample type for determining the occurrence of colon cancer, rectal cancer, or colorectal adenoma. A similar method would need to be performed for each of blood, serum, and feces as well. This is a large amount of experimentation with unpredictable results. Furthermore, it is noted that while the Applicant states in the instant specification that examination of GLRB gene CpG site methylation in plasma means this is an effective means for diagnosing colon cancer, rectal cancer, or colorectal adenoma in blood (Page 29), whole blood contains many more elements than just the plasma that was tested. Whole blood samples would still need to be examined to determine if they are a viable sample type for determining the occurrence of colon cancer, rectal cancer, or colorectal adenoma. The same is true of serum, which is a different component of blood that would need to be separately examined.
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 12-16, 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 12-16 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 it the full scope embraced by the claims.
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 12-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and an abstract idea 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 GLRB gene CpG site methylation levels and colorectal cancer, as well as the mental process of identifying increased levels of methylation relative to controls, and diagnosing the occurrence of colorectal cancer based on this comparison. The natural correlation is a natural phenomenon because it describes a consequence of the human body (e.g. a change in GLRB gene CpG site methylation due to disease). The mental process is an abstract idea because it can reasonably be performed in the human mind (e.g. visually looking at one methylation level compared to another on a computer screen and determining they are different values to diagnose cancer).
It is specifically noted that while claim 12 has been amended to recite “administering a treatment for the colon cancer, rectal cancer, or colorectal adenoma to the subject”, the treatment is so unspecific as to not integrate the judicial exceptions into a practical application. As stated in MPEP 2106.04(d)(2)(a), “The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s).” This section also includes the example: “Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.” The current recitation of step d) of claim 12 closely aligns with this example, and thus it does not serve to integrate the judicial exceptions into a practical application.
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 GLRB gene CpG site methylation levels and colorectal cancer) and an abstract idea (the mental process of identifying increased levels of methylation relative to controls, and diagnosing the occurrence of colorectal cancer based on this comparison).
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 obtaining a sample from a human subject; measuring methylation level of CpG sites of a GLRB gene from the sample suspected of having colon cancer, rectal cancer, or colorectal adenoma, wherein the sample is selected from the group consisting of tissues, cells, blood, plasma, serum, and feces; identifying the subject as having an increased level of methylation at the CpG site relative to a control, and specifically and differentially diagnosing the subject as having the colon cancer, rectal cancer, or colorectal adenoma if the level of methylation at the CpG site is increased relative to the control; administering a treatment for the colon cancer, rectal cancer, or colorectal adenoma to the subject; measuring methylation by one of a variety of bisulfite-free, PCR, and sequencing methods; the CpG site being located at between a transcription start site of the gene and +/- 2000 bases therefrom; the step of measuring the methylation level of the gene CpG site is conducted by at least a substance selected from the group consisting of a compound that modifies an unmethylated cytosine or methylated cytosine base, a primer specific to a methylated sequence of the CpG sites of the GLRB gene, and a primer specific to an unmethylated sequence; and wherein the compound of modifying the unmethylated cytosine base is bisulfite or a salt thereof and the compound of modifying the methylated cytosine base is a TET protein, the claims do not improve upon any methods claimed. 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. That the above steps were known in the prior art will be shown below.
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 obtaining a sample from a human subject; measuring methylation level of CpG sites of a GLRB gene from the sample suspected of having colon cancer, rectal cancer, or colorectal adenoma, wherein the sample is selected from the group consisting of tissues, cells, blood, plasma, serum, and feces; identifying the subject as having an increased level of methylation at the CpG site relative to a control, and specifically and differentially diagnosing the subject as having the colon cancer, rectal cancer, or colorectal adenoma if the level of methylation at the CpG site is increased relative to the control; administering a treatment for the colon cancer, rectal cancer, or colorectal adenoma to the subject; measuring methylation by one of a variety of bisulfite-free, PCR, and sequencing methods; the CpG site being located at between a transcription start site of the gene and +/- 2000 bases therefrom; the step of measuring the methylation level of the gene CpG site is conducted by at least a substance selected from the group consisting of a compound that modifies an unmethylated cytosine or methylated cytosine base, a primer specific to a methylated sequence of the CpG sites of the GLRB gene, and a primer specific to an unmethylated sequence; and wherein the compound of modifying the unmethylated cytosine base is bisulfite or a salt thereof and the compound of modifying the methylated cytosine base is a TET protein, no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a specific kind 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, performing a bisulfite based technique on DNA does not fundamentally transform that DNA into something else.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between GLRB gene CpG site methylation levels and colorectal cancer and the mental process of identifying increased levels of methylation relative to controls, and diagnosing the occurrence of colorectal cancer based on this comparison in the instant case have to do with obtaining a sample from a human subject; measuring methylation level of CpG sites of a GLRB gene from the sample suspected of having colon cancer, rectal cancer, or colorectal adenoma, wherein the sample is selected from the group consisting of tissues, cells, blood, plasma, serum, and feces; administering a treatment for the colon cancer, rectal cancer, or colorectal adenoma to the subject; measuring methylation by one of a variety of bisulfite-free, PCR, and sequencing methods; the CpG site being located at between a transcription start site of the gene and +/- 2000 bases therefrom; the step of measuring the methylation level of the gene CpG site is conducted by at least a substance selected from the group consisting of a compound that modifies an unmethylated cytosine or methylated cytosine base, a primer specific to a methylated sequence of the CpG sites of the GLRB gene, and a primer specific to an unmethylated sequence; and wherein the compound of modifying the unmethylated cytosine base is bisulfite or a salt thereof and the compound of modifying the methylated cytosine base is a TET protein. 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 GLRB gene methylation levels and colorectal cancer and the mental process of identifying increased levels of methylation relative to controls, and diagnosing the occurrence of colorectal cancer based on this comparison. The additional elements recited in the claims (i.e. obtaining a sample from a human subject; measuring methylation level of CpG sites of a GLRB gene from the sample suspected of having colon cancer, rectal cancer, or colorectal adenoma, wherein the sample is selected from the group consisting of tissues, cells, blood, plasma, serum, and feces; administering a treatment for the colon cancer, rectal cancer, or colorectal adenoma to the subject; measuring methylation by one of a variety of bisulfite-free, PCR, and sequencing methods; the CpG site being located at between a transcription start site of the gene and +/- 2000 bases therefrom; the step of measuring the methylation level of the gene CpG site is conducted by at least a substance selected from the group consisting of a compound that modifies an unmethylated cytosine or methylated cytosine base, a primer specific to a methylated sequence of the CpG sites of the GLRB gene, and a primer specific to an unmethylated sequence; and wherein the compound of modifying the unmethylated cytosine base is bisulfite or a salt thereof and the compound of modifying the methylated cytosine base is a TET protein) does amount to mere instructions to apply the correlation, since the collection of particular biological samples from particular subjects and measuring a methylation level at CpG sites of GLRB in those samples with known analysis techniques serve as mere conventional steps taken for the purpose of gathering data about the methylation level of GLRB CpG sites in a subject, which any practical use of the natural correlation and mental process 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 obtaining a sample from a human subject; measuring methylation level of CpG sites of a GLRB gene from the sample suspected of having colon cancer, rectal cancer, or colorectal adenoma, wherein the sample is selected from the group consisting of tissues, cells, blood, plasma, serum, and feces; administering a treatment for the colon cancer, rectal cancer, or colorectal adenoma to the subject; measuring methylation by one of a variety of bisulfite-free, PCR, and sequencing methods; the CpG site being located at between a transcription start site of the gene and +/- 2000 bases therefrom; the step of measuring the methylation level of the gene CpG site is conducted by at least a substance selected from the group consisting of a compound that modifies an unmethylated cytosine or methylated cytosine base, a primer specific to a methylated sequence of the CpG sites of the GLRB gene, and a primer specific to an unmethylated sequence; and wherein the compound of modifying the unmethylated cytosine base is bisulfite or a salt thereof and the compound of modifying the methylated cytosine base is a TET protein.
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 provide information for diagnosing colon cancer, rectal cancer, or colorectal adenoma by measuring methylation levels of CpG sites in GLRB 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.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was known in the prior art to ascertain methylation levels in CpG sites of GLRB as it relates to diagnosing colorectal cancer. Zavattari (IT 201700072650 A1, published December 28th, 2018; cited on the IDS filed September 11th, 2024, English translation provided; previously cited) teaches a method for treating colon cancer, rectal cancer, or colorectal adenoma comprising the steps of: a) obtaining a sample from a human subject suspected of having the colon cancer, rectal cancer, or colorectal adenoma (Page 11, paragraph 2 to Page 12, whole page), wherein the sample is selected from the group consisting of tissues (Page 21, first paragraph); b) measuring the methylation level of CpG sites of a GLRB gene from the sample (Page 11, paragraph 2 to Page 12, whole page); and c) identifying the subject as having an increased level of methylation at the CpG site relative to a control, and specifically and differentially diagnosing the subject as having the colon cancer, rectal cancer, or colorectal adenoma if the level of methylation at the CpG site is increased relative to the control (Page 13, lines 25-30 to Page 14, lines 1-4: SEQ ID NO:23 corresponds to a CpG site in GLRB, as shown on Page 41, SEQ ID 23 is taught to under hypermethylation). Zavattari teaches wherein the step of measuring the methylation level is conducted by real time methylation-specific polymerase chain reaction (Page 83, lines 22-27). Zavattari teaches wherein the CpG site is located at between a transcription start site of the gene and +/- 2000 bases therefrom (Page 41, SEQ ID NO:23: CpG site coordinates chr4:157997166-157997686). As evidenced by the UCSC Genome Browser (UCSC Genome Browser on Human (GRCh37/hg19) [online]. UCSC Genome Browser, [2026] [retrieved on May 5th, 2026]. Retrieved from: https://genome.ucsc.edu/), and represented in the image found in the 103 rejection, the CpG site in the GLRB gene taught by Zavattari falls within +/- 2000 bases of the transcription start site of every identified GLRB transcription start site on the hg19 genome assembly on Genome Browser. Zavattari teaches wherein the step of measuring the methylation level of the gene CpG site is conducted by at least a substance selected from the group consisting of a compound that modifies an unmethylated cytosine (Page 14, lines 8-9). Zavattari teaches wherein the compound of modifying the unmethylated cytosine base is bisulfite (Page 14, lines 8-9).
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), as well as the prior art of Zavattari, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exceptions into a practical application of those exceptions in such a way as to provide meaningful limits on the use of the judicial exceptions. Therefore, claims 12-16 are rejected here under 35 U.S.C. 101.
Response to Arguments
Applicant's arguments filed February 9th, 2026 have been fully considered but they are not persuasive.
The Applicant first argues that the claims as amended are not directed to a judicial exception, and furthermore, even if they were, they recite significantly more than any alleged natural phenomenon (Page 4 of the Remarks filed February 9th, 2026). The Applicant argues that claim 12, as amended, is directed to a method of treating colon cancer, rectal cancer, or colorectal adenoma, and the claims as a whole are focused on a concrete medical treatment protocol that applies information from the methylation of GLRB in a meaningful and practical way (Pages 4-5 of the Remarks filed February 9th, 2026). The Applicant argues that the inclusion of an affirmative treatment step distinguishes the amended claims from claims that merely observe or report a natural correlation (Page 5 of the Remarks filed February 9th, 2026). The Applicant cites case law that allegedly recognizes that method-of-treatment claims that apply biological relationships to achieve a therapeutic outcome are not direct to a judicial exception (Page 5 of the Remarks filed February 9th, 2026).
In response to these arguments, it is noted that the main argument the Applicant relies upon, the addition of the administration of treatment step, does not serve to integrate the judicial exceptions into a practical application. As noted at the beginning of the rejection, and restated here, MPEP 2106.04(d)(2)(a) states, “The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s).” This section also includes the example: “Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.” The current recitation of step d) of claim 12 closely aligns with this example, and thus it does not serve to integrate the judicial exceptions into a practical application. A particular treatment is required to fully integrate the judicial exceptions, and therefore, the arguments are not found persuasive.
The Applicant further argues that the claims require active human intervention and concrete technical steps (Pages 5-6 of the Remarks filed February 9th, 2026). The Applicant argues that the steps claimed to beyond merely recognizing or observing a natural law, and instead require laboratory manipulation of biological material, as well as specific reagents (Page 6 of the Remarks filed February 9th, 2026). The Applicant argues that claims 13-16 further limit the method to specific technological implementations that represent meaningful limitations and reflect technological solutions in molecular diagnostics and treatment planning (Page 6 of the Remarks filed February 9th, 2026). The Applicant further argues that the claims are distinguishable from Mayo and similar cases because of the specific diagnostic techniques, specific identification of disease, and actual administration of treatment (Page of the Remarks filed February 9th, 2026).
Applicant’s arguments directed towards “active human intervention and concrete technical steps”, “specific technological implementations”, and “claims distinguishable from Mayo and similar cases” are not persuasive because while the steps as claimed may require specific laboratory manipulation, as well as specific reagents and methods, there is no evidence provided that these aspects of the invention represent anything more than either insignificant extra-solution activity or mere data-gathering. This has been addressed in the above rejection. Furthermore, given the prior art of Zavattari, the methods and reagents that are additional to the judicial exceptions were known and well-understood for the purpose of measuring methylation in samples, particularly measuring methylation of the GLRB gene from human subjects suspected of having colorectal cancer. It cannot be said, as is argued on Page 5 of the Remarks filed February 9th, 2026, that the claimed methods are non-conventional. Therefore, these arguments are not persuasive.
Claim Rejections - 35 USC § 103 - New - Necessitated by Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Zavattari (IT 201700072650 A1, published December 28th, 2018; cited on the IDS filed September 11th, 2024, English translation provided; previously cited), in view of Sapienza (WO 2015021263 A2).
Regarding instant claim 12, Zavattari teaches a method for treating colon cancer, rectal cancer, or colorectal adenoma comprising the steps of: a) obtaining a sample from a human subject suspected of having the colon cancer, rectal cancer, or colorectal adenoma (Page 11, paragraph 2 to Page 12, whole page), wherein the sample is tissues (Page 21, first paragraph); b) measuring the methylation level of CpG sites of a GLRB gene from the sample (Page 11, paragraph 2 to Page 12, whole page); and c) identifying the subject as having an increased level of methylation at the CpG site relative to a control, and specifically and differentially diagnosing the subject as having the colon cancer, rectal cancer, or colorectal adenoma if the level of methylation at the CpG site is increased relative to the control (Page 13, lines 25-30 to Page 14, lines 1-4: SEQ ID NO:23 corresponds to a CpG site in GLRB, as shown on Page 41, SEQ ID 23 is taught to under hypermethylation; Page 97, lines 26-30 and Figure 3 for specificity to colorectal cancer).
Zavattari does not teach administering a treatment for the colon cancer, rectal cancer, or colorectal adenoma to the subject.
Sapienza, in the same field of endeavor, teaches on a method of treating a subject diagnosed with colorectal cancer with an anti-cancer therapy (Page 3, lines 24-26). Sapienza teaches that the diagnosing comprises determining the level of methylation of a biomarker in a biological sample of the subject, compare to a control, and diagnose when the level of methylation of the biomarker is altered in a statistically significant amount compared to the control (Page 3, lines 27-32).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Zavattari with the treatment step of Sapienza. Since both Zavattari and Sapienza are in the same field of endeavor (e.g. diagnosis of colorectal cancer based on methylation), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because administering to the subject a therapeutically effective amount of a therapeutic agent treats a subject having or at risk for having a proliferative disease (Sapienza, Page 33, lines 21-28).
Regarding instant claim 13, Zavattari, in view of Sapienza, teaches the method of claim 12. Zavattari further teaches wherein the step of measuring the methylation level is conducted by real time methylation-specific polymerase chain reaction (Page 83, lines 22-27).
Regarding instant claim 14, Zavattari, in view of Sapienza, teaches the method of claim 12. Zavattari teaches wherein the CpG site is located at between a transcription start site of the gene and +/- 2000 bases therefrom (Page 41, SEQ ID NO:23: CpG site coordinates chr4:157997166-157997686). As evidenced by the UCSC Genome Browser (UCSC Genome Browser on Human (GRCh37/hg19) [online]. UCSC Genome Browser, [2026] [retrieved on May 5th, 2026]. Retrieved from: https://genome.ucsc.edu/), and represented in the below image, the CpG site in the GLRB gene taught by Zavattari falls within +/- 2000 bases of the transcription start site of every identified GLRB transcription start site on the hg19 genome assembly on Genome Browser.
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Regarding instant claim 15, Zavattari, in view of Sapienza, teaches the method of claim 12. Zavattari further teaches wherein the step of measuring the methylation level of the gene CpG site is conducted by at least a substance selected from the group consisting of a compound that modifies an unmethylated cytosine (Page 14, lines 8-9).
With respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Regarding instant claim 16, Zavattari, in view of Sapienza, teaches the method of claim 15. Zavattari further teaches wherein the compound of modifying the unmethylated cytosine base is bisulfite (Page 14, lines 8-9). It is noted that claim 15, from which claim 16 depends, requires either a compound that modifies an unmethylated cytosine or a compound that modifies a methylated cytosine, not both. Claim 16 only serves to further limit the options for these compounds. Therefore, the teaching of the compound of modifying the unmethylated cytosine base being bisulfite is considered to fully teach claim 16.
Response to Arguments
Applicant's arguments filed February 9th, 2026 have been fully considered but they are not persuasive.
The Applicant first argues that Zavattari fails to disclose the amended method of claim 12 given that Zavattari does not anticipate every limitation of the claim (Page 7 of the Remarks filed February 9th, 2026).
In response to this argument, it is noted that it is not relevant to the new rejection as analyzed given that Zavattari is no longer anticipating the claims as amended, but instead makes the claims obvious in view of Sapienza.
The Applicant argues that Zavattari does not disclose specific and differential diagnosis using GLRB (Page 7 of the Remarks filed February 9th, 2026). Instead, the Applicant argues that Zavattari broadly discloses a panel of up to 74 genes that may be evaluated for CpG methylation in connection with colorectal cancer, with no teaching of GLRB having a unique capability to specifically and differentially diagnose the claimed cancers (Page 7 of the Remarks filed February 9th, 2026). The Applicant further argues that Zavattari does not identify GLRB as a discriminator between the claimed cancers, disclose threshold methylation levels of GLRB that are diagnostic of the claimed cancers, or teach that GLRB methylation can distinguish the claimed cancers from other conditions (Page 7 of the Remarks filed February 9th, 2026). The Applicant further argues that Zavattari is generic and non-enabling with respect to GLRB because the taught gene list represents a speculative screening approach with no disclosure of a particular gene’s diagnostic relevance (Page 8 of the Remarks filed February 9th, 2026). The Applicant argues that many of the genes listed in Zavattari have been reported in the literature as being associated with other cancers or disease states, not colorectal cancer, and Zavattari provides no guidance for selecting GLRB for any particular diagnostic purpose (Page 8 of the Remarks filed February 9th, 2026).
In response to these arguments, it is first noted that while Zavattari teaches on a panel of biomarkers, it is clearly taught that one CpG island in one gene from their panel can be used to detect colorectal cancer (see Page 12 of Zavattari). Furthermore, the claim 12 currently recites the open claim language “[a] method for treating colon cancer, rectal cancer, or colorectal adenoma comprising the steps of”, which may encompass aspects of the panel as taught by Zavattari. Therefore, this argument is not persuasive.
In response to the Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., discriminator between colorectal cancers, threshold levels, distinguishing from other conditions) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The current claim language does not indicate that levels of methylation are associated with particularly distinguishing colon cancer, rectal cancer, and colorectal cancer from each other. Instead, the claim language indicates that the level of methylation measured can specifically and differentially diagnose colon cancer, rectal cancer, or colorectal adenoma. In other words, the level of methylation can serve to diagnose a cancer selected from this list, not differentiate between the three cancers. Furthermore, the claims do not require a threshold level, only that methylation is increased relative to a control. Finally, the claims do not require GLRB to distinguish the claims cancers from other conditions. Therefore, these arguments are not persuasive.
Finally, with respect to the argument about the reports in the literature of the genes of Zavattari being associated with other cancers and diseases does not have corresponding references to support this statement. The 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, the Applicant should not merely rely upon counsel’s arguments in place of evidence in the record.
The Applicant argues that Zavattari does not disclose a method of treatment (Page 8 of the Remarks filed February 9th, 2026).
In response to this argument, it is noted that it is not relevant to the new rejection as analyzed given the introduction of Sapienza to teach a treatment step.
The Applicant argues that claims 13-16 are not further anticipated by Zavattari given the inclusion of additional limitations that are absent from Zavattari (Page 8 of the Remarks filed February 9th, 2026).
In response to this argument, it is noted that it is not relevant to the new rejection as analyzed given that all the newly added claims are taught by Zavattari.
Finally, the Applicant argues that impermissible hindsight is required to arrive at the claimed invention given what is required by the amended claims, and therefore Zavattari does not anticipate the claims as currently amended (Pages 8-9 of the Remarks filed February 9th, 2026).
In response to this argument, it is noted that it is not relevant to the new rejection as analyzed given that Zavattari is no longer anticipating the claims as amended, but instead makes the claims obvious in view of Sapienza.
Conclusion
All claims stand rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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