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 April 24, 2026. Currently, claims 1, 5-8, 10-12, 14, 16-22 are pending. Claims 11, 20-22 have been withdrawn as directed to non-elected subject matter.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
The 102 rejection over Jones has been withdrawn in view of the arguments that the samples were not amplified “using primers specific for NDRG4 and ARHGEF4”.
Election/Restrictions
Applicant's election of the combination of ARHGEF4 and PITX1 in the paper filed April 24, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Claims 11, 20, 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
PNG
media_image1.png
55
476
media_image1.png
Greyscale
Drawings
The drawings are acceptable.
Information Disclosure Statement
It is noted that Applicant subsequentially filed with this response another 2 IDS comprising another 10 pages of IDS. This is in additional to the already filed 18-page and 80-page Information Disclosure Statements (IDS). The IDS’s have been reviewed to the extent reasonably possible. Applicant is reminded that "burying" relevant references in a lengthy IDS is discouraged. See, e.g., Molins PLC v. Textron Inc., 48 F.3d 1172, 33 USPQ2d 1823, 1831 (Fed. Cir. 1995).
The court concluded that, by “burying” Wagenseil in a multitude of otherreferences, Hirsh and Smith intentionally withheld it from the PTO becausethis manner of disclosure was tantamount to a failure to disclose. Citing PennYan Boats, Inc. v. Sea Lark Boats, Inc., 359 F.Supp. 948, 175 USPQ 260(S.D. Fla. 1972), aff'd, 479 F.2d 1328, 178 USPQ 577 (5th Cir.), cert.denied, 414 U.S. 874 (1973), the court stated that Hirsh's and Smith's failureto highlight Wagenseil in light of their knowledge of Whitson's actions in theforeign prosecutions violated their duty of candor to the PTO. Citing ourprecedent, Textron asserts that Smith's and Hirsh's conduct is “inexcusable,fraudulent, and cannot operate to cure Whitson's inequitable conduct.” See
Rohm & Haas Co. v. Crystal Chem. Co., 722 F.2d 1556, 220 USPQ 289(Fed.Cir. 1983), cert. denied, 469 U.S. 851 (1984) (where intentionalmaterial misrepresentations have been made, a “cure” through voluntaryefforts during prosecution must be demonstrated by clear, unequivocal, andconvincing evidence).
Improper Markush Rejection
Claims 1, 5-8, 10, 12, 14, 16-19, 21 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 combination of markers listed in Claim 1. Applicant elected ARHGEF4 and PITX1.
The recited alternative species in the groups set forth here do not share a single structural similarity, as 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 methylation 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 colon 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 colon 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 7, 8, 16-17 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.
Claim 7 is directed to “a method for ..at least one DMR comprises an increased methylation percentage as compared to a control DNA or an increased hypermethylation ratio as compared to a control DNA sample”.
Claims 16-17 are directed to determining a methylation frequency and determining a methylation pattern.
The claims are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “determining a methylation profile”; “comparison to a control” or comparison to a ratio or “determining a methylation frequency” or “determining a methylation pattern”).
Herein, claims 16-17 involve the patent-ineligible concept of an abstract process as Claims 16-17 are directed to determining a methylation profile. Neither the specification nor the claims set forth a limiting definition for "determining" and the claims do not set forth how “determining” is accomplished. As broadly recited the determining step may be accomplished mentally by thinking about a subject’s methylation state and assessing whether the subject has a methylation profile. Thus, the determining step constitutes an abstract process idea.
Claims 7-8 further recites a comparison between a methylation percentage as compared to a control or an increased hypermethylation ratio as compared to 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)).
Even more, determining frequencies and ratios are deemed mathematical calculations. The determination of frequencies and ratios is an arithmetic calculation which is a “mathematical calculation” and so falls into the “mathematical concepts” grouping of abstract ideas.
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 treating the sample with a reagent that modifies DNA in a methylation specific manner, 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.
Accordingly, the claims are directed to judicial exceptions.
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 methylation and evaluating methylation profiles/status are 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 biomarkers of 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 methylation through whatever known processes they wish to use.
The step of determining the methylation was well known in the art at the time the invention was made. The prior art teaches that methylation 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 methylation analysis to determine the methylation 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 MS AP-PCR and MethylLight PCR analysis are known in the art methods for determining the methylation state of CPG dinucleotides (see page 28).
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 § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1, 5-8, 10, 12, 14, 16-19, 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “determining a methylation level of at least one DMR from each of NDRG4 and/or ARHGEF4” however, the elected invention is directed to ARHGEF4 and not NDRG4, therefore the use of “each” is unclear. Clarification is required.
Claim 1 is directed to amplifying ARHGEF4 and additional gene, namely PITX1, however the claim only requires determining the methylation level of ARHGEF4. It is unclear if the claim does not require determining the methylation of PITX1. Clarification is required.
Conclusion
The prior art does not teach or suggest analyzing the methylation pattern of the combination of ARHGEF4 and PITX1 in patients having or suspected of having esophageal cancer. The art also does not teach using primers comprising SEQ ID 35-36 for amplifying ARHGEF4. Thus, claims directed to the particular primers are allowable over the art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wang et al. PLos ONE, Vol. 11, No. 4, e0153125, April 25, 2016 teaches ARHGEF4 is differentially methylated in colon cancer specimens. This reference was published 10 days after the provisional filing date.
Xiao et al. (Oncology Letters, Vol. 9, pages 1383-1387, 2015) teaches NDRG4 gene is methylated as a biomarker for diagnosis of colorectal cancer.
US Patent 10,006,093 and US Patent 10,597,733 teaches ARHGEF4 and NDRG4 are optimal markers for detecting stomach cancer (col 8, lines 65-col. 9, lines 1- 5).
Jones et al. (US 2011/0318738, December 29, 2011) Jones teaches a method of bisulfite sequencing in adenoma samples from five different patients (page 43, lines 1-3). Jones teaches changes in methylation were seen in numerous genes including ARHGEF4 (page 45, col. 2; page 43, col. 1). Jones teaches the methylation from FAP adenoma tissues samples were analyzed (para 320-321). Jones teaches verification of methylation status was conducted by qPCR or MeDIP samples or bisulfite sequencing (para 317).
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
May 12, 2026
Prosecution Insights