DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed November 25, 2025. Currently, claims 1-3, 7-8, 11-13, 17-19, 21-24, 27-30 are pending. Claims 7, 21-24, 27-30 have been withdrawn as drawn to non-elected subject matter.
Election/Restrictions
Applicant's election without traverse of Group I and the combination of PTGS2 and S100A4, claims 1-3, 8, 11-13, 17-19 in the paper filed November 25, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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Drawings
The drawings are acceptable.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The specification on page 24-25 contains a list of references.
Improper Markush Rejection
Claims 1-3, 8, 11-13, 17-19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent. See MPEP § 2117.
Here each species is considered to each of the combinations of colorectal cancer biomarker genes listed in Claim 1.
The recited alternative species in the groups set forth here do not share a single structural similarity, as the expression of each different gene that could be detected is itself located in a separate region of the genome and has its own structure. The genes recited in the instant claims, do not share a single structural similarity since each consists of a different nucleotide sequences with different expression patterns. The only structural similarity present is that all detected positions are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with colorectal cancer. Accordingly, while the different markers are asserted to have the property of being expressed in colorectal cancer, they do not share a single structural similarity.
MPEP 2117 (II)(A) provides the following guidance as to what constitutes a physical, chemical, or art recognized class:
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”
The recited genes do not belong to a recognized chemical class because there is no expectation from the knowledge in the art that the genes will behave in the same manner and can be substituted for one another with the same intended result achieved. In other words, there is no expectation from the knowledge in the art that each of the recited genes would function in the same way in the claimed method; it is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention. Further there is no evidence of record to establish that it is clear from their very nature that each of the recited genes possess the common property of being associated with colorectal cancer.
MPEP 2117 (II) further states the following:
Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the compounds do not appear to be members of a recognized physical or chemical class or members of an art-recognized class, the members are considered to share a "single structural similarity" and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The recited alternative species do not share a substantial common structure just because they all have a sugar phosphate backbone. The sugar phosphate backbone of a nucleic acid chain is not considered to be a substantial common structural feature to the group of genes being claimed because it is shared by ALL nucleic acids. Further, the fact that the genes all have a sugar phosphate backbone does not support a conclusion that they have a common single structural similarity because the structure of comprising a sugar phosphate backbone alone is not essential to the asserted common use of being associated with colorectal cancer.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 8, 11-13, 17-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
Claim 1 is directed to “a method of stratifying the risk of a subject of having an advanced colorectal adenoma or a colorectal cancer” by analyzing mRNA expression of elected PTGS2 and S100A4 and comparing the expression profile to control to make a determination has an increased risk of advanced colorectal adenoma if expression is increased.
Claim 1 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “stratifying subjects” “comparing profiles to controls”) and a law of nature/natural phenomenon (i.e. the natural correlation between the mRNA expression of elected PTGS2 and S100A4 and colorectal cancer).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Herein, claim 1 involves the patent-ineligible concept of an abstract process. Claim 1 requires performing the step of “stratifying the risk of a subject”. Neither the specification nor the claims set forth a limiting definition for "stratifying the risk of a subject " and the claims do not set forth how “stratifying” is accomplished. As broadly recited the determining step may be accomplished mentally by thinking about a subject’s mRNA expression profile and mentally putting the subject in a “group”. Thus, the stratifying step constitutes an abstract process idea. It is noted that the stratifying step is conditional and only required “if” the subject’s expression is increased with respect to the control.
Claim 1 further recites a comparison between the expression level and a control that is deemed an abstract idea (see MPEP 2106.04(a)(2)(III)(A); • claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)).
A correlation that preexists in the human is an unpatentable phenomenon. The association the mRNA expression of elected PTGS2 and S100A4 and risk of colorectal cancer is a law of nature/natural phenomenon. The wherein clause which tells users of the process to predict colorectal cancer in the sample, amounts to no more than an "instruction to apply the natural law". This wherein clause is no more than a mental step. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The wherein clause does not require the process user to do anything in light of the correlation. The wherein step fails to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Claim 13 is directed to “associated with a predisposition to a colorectal cancer in the colorectal epithelial cell of the subject”. This is a law of nature/natural phenomenon.
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claim recites obtaining a stool sample and determining the mRNA expression level, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Claim 18 recites submitting the subject having been stratified as being at increased risk of developing the colorectal cancer to chemotherapy, radiotherapy and/or surgery. This treatment step is general and not particular to the judicial exception. As provided in MPEP 2106.04(d)(2) the limitation is generic and merely is a “apply it’ type limitation.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The measuring expression is mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the expression of the mRNA expression of elected PTGS2 and S100A4 in a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the markers through whatever known processes they wish to use.
The step of determining the expression levels was well known in the art at the time the invention was made. The prior art teaches that expression analysis using commercially available biochips and arrays that comprise the claimed genes. The steps are recited at a high level of generality. The claim merely instructs a scientist to use any expression analysis assay to determine the expression status. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements were well known. Specifically, the specification teaches RNA isolation, reverse transcription was performed using known TaqMan PreAmp Master kit and commercially available TaqMan primer and probe mixtures (page 19, lines 15-25).
Further it is noted that the courts have recognized the following 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.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim(s) 1-3, 19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ishii et al. (US 20090011413, January 8, 2009).
Ishii teaches a method for screening colon cancer cells for examination of colon cancer. Ishii teaching providing stool samples from colon cancer patients and stool samples from healthy subjects (para 169). Ishii teaches determining RNA expression using the human U133 oligonucleotide probe array which comprises probes for the elected PTGS2 and S100A4 genes. Ishii teaches analyzing gene expression from the healthy and cancer cells. Thus, Ishii teaches all of the required limitations of the instant claims.
With respect to Claims 2-3, Ishii teaches epithelial cells may be separated from stool by MACS (para 77).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 8, 11-12, 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bankaitis-Davis et al. (US 2010/0196889, August 5, 2010) in view of DeMaio et al. (World J. Gastroenterol, Vol. 20, No. 4, pages 957-967, January 28, 2014).
Bankaitis-Davis teaches gene expression profiling for identification, monitoring and treatment of colorectal cancer. Bankaitis-Davis teaches the genes are selected to distinguish i.e. classify or stratify between a normal and colon cancer diagnosed subject with accuracy (para 36). Bankaitis-Davis teaches determining risk and colon cancer profiling for characterizing a subject with colon cancer by measuring expression of mRNA panels of genes (para 23). Bankaitis-Davis teaches measurements for each assay were analyzed for quantitation of target mRNA using an internal control (para 149). Bankaitis-Davis identifies PTGS2 in Table 2 and S100A4 in Table 3 as genes that are differentially expressed in colon cancer.
With regard to Claim 8, the mRNA expression levels may be determined by quantitative PCR (para 113) or RT-PCR (para 55).
With regard to Claim 11-12, Bankaitis-Davis teaches fecal occult blood test (FOBT) or fecal immunochemical test (FIT) are known methods for screening for possible disease (para 15).
With regard to Claim 17, the methods would be appropriate for screening for subjects suitable for colonoscopy. The claim does not require performing a colonoscopy but rather defines a patient population.
With respect to Claim 18, Bankaitis-Davis teaches the methods may monitor progression of colon cancer in a subject and take samples prior to the subject receiving treatment (such as chemotherapy, radiation, surgery) and after the treatment is administered (para 22). Thus, the subject was submitted or administered the treatment.
Bankaitis-Davis does not teach analysis of mRNA in a stool sample.
However, De Maio teaches analysis of circulating DNA from blood and stool is a relatively simple and non-invasive procedure for detecting genetic changes and to monitor disease progression. De Maio teaches a correlation between blood and stool biomarkers could also help to enhance currently available diagnostic approaches. De Maio teaches non-invasive, no bowel preparation and the sampling design are some of the main advantages of molecular stool analysis.
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have modified the RT-PCR detection method of Bankaitis-Davis for PTGS2 and S100A4 analysis in blood of colon cancer patients with the method of DeMaio that teaches sampling mRNA from stool samples. DeMario teaches sampling stool samples for nucleic acid analysis is an alternative successful method in analyzing nucleic acids that is relatively simple and non-invasive. Thus, the ordinary artisan would have been motivated to have samples using non-invasive samples that may be collected at home.
Claims 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bankaitis-Davis et al. (US 2010/0196889, August 5, 2010) in view of DeMaio et al. (World J. Gastroenterol, Vol. 20, No. 4, pages 957-967, January 28, 2014) in view of Claims 1, 8, 11-12, 17 above and further in view of Vecchione (Cell, Vol. 165, pages 317-330, April 7, 2016).
Neither Bankatitis-Davis nor DeMaio teach analyzing BRAF gene mutations with the expression analysis.
However, Vecchione teaches the presence of BRAF mutation in about 20% of colon cancers. Vecchione teaches BRAF (V600E) is the most common point mutation if the BRAF gene and is present in approximately 8-10% of CRC patients (abstract). The BRAF mutation has consistently shown the negative impact of BRAF (V600E) mutation on CRC prognosis, especially in the metastatic setting (abstract).
Therefore, it would have bene prima facie obvious prior to the effective filing date of the claimed invention to have performed the mRNA expression analysis of Bankatitis-Davis in view of DeMaio and further have added analysis of the BRAF mutation, as taught by Vecchione. Vecchione teaches the mutation is predictive of colon cancer and prognosis. Combining two methods with the same purpose would provide further confidence and information about the risk and prognosis of colon cancer for the subject.
Conclusion
No claims allowable over the art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Herring et al. (Multitarget stool mRNA test for detecting colorectal cancer lesions including advanced adenomas, 2021) is Applicant’s post-filing date paper that illustrates the over expression of PTGS2 and S100A4.
Gongoll et al. (Gasteroenterology, Vol. 123, pages 1478-1484, 2002) teaches prognostic significance of calcium binding protein S100A4 in colorectal cancer. Gongoll uses immunohistochemical S100A4 expression in colorectal cancer.
Ogino et al. (Clinc Cancer Research, Vol. 14, No. 24, pages 8221-8227, December 2008) teaches COX-2, also known as PTGS2) is considered to play an important role in colorectal carcinogenesis and upregulated in colon cancers. Ogino teaches immunohistochemistry analysis of COX-2/PTGS2.
Wilson et al (Prostaglandins Leukot Essent Fatty Acids, Vol. 139, pages 14-19, December 2018) teaches the PTGS2 expression is generally low in normal colon.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
January 4, 2026