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 30, 2026. Currently, claims 2, 5-10, 14, 16-20 are pending.
Election/Restrictions
Applicant's election of Group II, has-miR-1273f in the paper filed April 30, 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)).
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application is a 371 of PCT/JP2020/024027, filed June 18, 2020 and claims priority to JAPAN 2019-139247, filed July 29, 2019.
It is noted that a translation of the foreign document has not been received.
Drawings
The drawings are acceptable.
Improper Markush Rejection
Claims 2, 5-10, 14, 20 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 esophageal cancer miRNA biomarkers, namely miR-619-5p, has-miR-1273f and miR-4327. Each of the miRNA have different sequences (see Table 2, for example).
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 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 esophageal 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 esophageal 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 esophageal 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 2, 5-10, 14, 20 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 2 is directed to “a method for examining esophageal cancer” comprising using an expression level of has-miR-1273f in urine.
Claim 2 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “examining esophageal cancer” “using an expression level”) and a law of nature/natural phenomenon (i.e. the natural correlation between the expression level of miR-1273f and esophageal 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 2 involves the patent-ineligible concept of an abstract process. Claim 2 requires performing the step of “using an expression level” and “examining esophageal cancer”. Neither the specification nor the claims set forth a limiting definition for "using” or “examining” and the claims do not set forth how "using” or “examining” is accomplished. As broadly recited the "using” or “examining” step may be accomplished mentally by thinking about a subject’s expression levels and assessing whether the subject has esophageal cancer. Thus, the "using” or “examining” constitutes an abstract process idea.
Claim 8 and 17 further recites a comparison between the expression level and a normal 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)).
Finally, a correlation that preexists in the human is an unpatentable phenomenon. The association between expression level of miR-1273f and esophageal cancer is a law of nature/natural phenomenon. The claim does not provide any step which tells users of the process to predict esophageal cancer in the sample or amounts to no more than an "instruction to apply the natural law". Even if the claims required a step for diagnosing or determining cancer, this 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 steps do not require the process user to do anything in light of the correlation. The claims fail 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.”
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. 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 expression of miRNA 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 markers through whatever known processes they wish to use.
The step of using 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 miRNA. 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.
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- Second Paragraph
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 2, 5-10, 14, 16-20 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 pre-AIA the applicant regards as the invention.
Claims 16-19 are indefinite as being both incomplete, by its dependence on a cancelled claim 15; and for lack of antecedent basis for its limitation (“The method …”) which is not present in cancelled base claim 15. Amending claim 16-20 to refer to a claim which recites the method, or deleting the claim, would obviate the rejection. Claims 16-19 have not been further treated as depending on a cancelled claim.
Claims 2, 5-10, 14, 20 are directed to the use of an expression level is indefinite because it merely recites a use without any active positive steps delimiting how this use is actually practiced. See MPEP 2173.05(q).
Claims 2, 5-10, 14, 20 are further indefinite because it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of Claim 2 is directed to a method for examining esophageal cancer. However, the claim only provides for using an expression level of a biomarker. Thus, it is not clear if applicant intends to cover any method for using an expression level of a biomarker, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If the claim requires something more, it is unclear what additional active process step the method requires and it appears that the claims are incomplete. The claims fail to provide any active steps that clearly accomplish the goal set for the by the preamble of the claims. Claims 5-10, 14, 20 are similarly indefinite.
Claims 2, 5-10, 14, 20 are indefinite over the limitation “in urine” because it is unclear whether the claim is directed to the hsa-miR-1273f found in urine or the claim requires determining expression level of has-miR-1273f in urine for analysis. The claim does not require any particular method steps.
The term “early-stage” in claim 5 is a relative term which renders the claim indefinite. The term “early” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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) 2, 5-9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sudo et al. (Development and Validation of an Esophageal Squamous Cell Carcinoma Detection Model by Large-Scale MicroRNA Profiling. JAMA Netw Open 2019 May 3;2(5):e194573 and GSE122497).
Sudo teaches microRNA profiling of miRNAs, including has-miR-1273f for analysis of esophageal squamous cell carcinoma detection. Sudo teaches analysis of patients with ESCC for expression of miRNAs. As illustrated below, MIMAT0020601, namely has-miR-1273f was analyzed in esophageal cancer and non-cancer patients. The first values were cancer patients and the remainder were non-cancer patients.
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With respect to Claim 2, as noted in the 112b rejection above, it is not clear, the claim requires anything other than analysis of miR-1273f. The statement of “in urine” has been broadly interpreted to mean the same miR-1273f that is found in urine.
With respect to Claim 5, as noted in the 112b rejection, early stage esophageal cancer is a relative term. The cancer patients analyzed are deemed early stage. Even more, Sudo teaches the EC index showed high sensitivity not only in patients with advanced disease but also in those with early ESCC (page 8, para 1).
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Okuda et al. “Urinary microRNA biomarkers for detecting the presence of esophageal cancer, https://doi.org/10.21203/rs.3.rs-103726/v1, posted November 11, 2020, Version 1) teaches analysis of miR-1273f in urinary samples of subjects with esophageal cancer. This is published after the June 18, 2020 priority date.
Ivashchenko et al. (BioMed Research International, Vol. 2014, Article ID 620530, 2014) teaches binding sties of miR-1273 family including miR-1273f.
WO2015/194627 cited in the international search report teaches analysis of miR-619-5p in urine for esophageal cancer detection.
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.
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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
May 20, 2026
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