CTNF 18/565,383 CTNF 77002 DETAILED CORRESPONDENCE Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 1-7, 9-11 are pending. Claims 6-7 have been withdrawn as drawn to non-elected subject matter. Election/Restrictions Applicant's election without traverse of Group I and ARF1, Claims 1-5, 9-11 in the paper filed April 24, 2026 is acknowledged. The requirement is still deemed proper and is therefore made FINAL. Priority This application is a 371 of PCT /JP2022/022187, filed May 31, 2022 and claims priority to JAPAN 2021-091505, filed May 31, 2021. It is noted that a translation of the foreign document has not been received. Applicant cannot rely upon the certified copy of the foreign priority application to overcome any rejection set forth in this Office Action because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. Improper Markush Rejection Claims 1-5, 9-11 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 internal reference gene in Tables 1-3. 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 an internal reference gene. 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 internal reference genes. 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 internal reference genes. 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 07-04-01 AIA 07-04 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, 3-5, 11 are rejected under 35 U.S.C. 101 because the claimed invention fails to recite a claim within one of the statutory classes and is thus directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because Claim 1 provides for the use of the genes but fails to provide any recited steps. MPEP 2173.05(q) provides that “ use” claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 101 because a “use” is not among the categories of patentable inventions specified in 101. Claims 2, 9, 10 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. Claims 2, 9-10 are directed to “a method for measuring an expression level of a target gene” comprising correcting an amount of an amplification product of the target gene with an amount of an amplification product of the internal reference gene to calculate the expression level of the target gene. Claims 2, 9-10 are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “correcting an amount of amplification product…..to calculate the expression level of the target gene). 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, claims 2, 9-10 involves the patent-ineligible concept of an abstract process . Claims 2, 9-10 requires performing the step of “correction an amount of amplification product”. The specification states that “correction” is typically made by dividing an expression level of the target gene by an expression level of the internal reference gene. This is a mathematical calculation. Thus, the determining step constitutes an abstract process idea. 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 sample and genotyping, 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 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 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 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. 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. 07-34-01 AIA Claim s 1-5, 9-11 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 1, 3-5, are indefinite because they attempt to claim a process without setting forth any steps involved in the process. See MPEP 2173.05(q). Claim 1 is merely directed to “using at least one gene from the group of genes….” As an internal reference gene in PCR. This is not any active method steps. Correction is required. The claim refers to tables. MPEP 2173.05(s) states: Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). Claim 1 recites Tables 1-3. The tables are provided after the period of the claim and thus are not part of the claim. Appropriate correction is required. Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1-5, 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over PBI (Pressure Biosciences Inc. (PBI) Application Note, Detection of Propionibacterium acnes 16S rRNA and Lipase genes from Sebu Samples October 4, 2009) in view of Trumpp et al. (WO2018/141796, August 2018) and Shak et al. (US 2013/0196321, August 2013) . PBI teaches detection of bacteria from sebum samples collected on lipid-specific adhesive skin strips. PBI teaches collecting sebum samples from human skin. PBI teaches performing RT-PCR to detecting the 16S rRNA gene and the lipase gene of P. acnes. B-actin primers were used as a control. PBI does not teach using ARF1 as a control for expression analysis. However, Trumpp teaches methods for analyzing cancer for increased expression of genes and normalizing the genes using ARF1 for AML cancer. Further, Shak et al. (US 2013/0196321, August 2013) teaches gene expression profile analysis for prostate cancer and using ARF1 as an internal reference control. Therefore, it would have been prima facie obvious at the time the invention was made to have performed the method of PBI and substituted ARF1 as the reference gene, as taught by Trumpp and Shak for b-actin. The ordinary artisan would have been motivated to use ARF1 gene to analyze RNA from skin samples. It would have been obvious to try additional reference genes for gene expression analysis normalization that were known to be work in multiple samples . 07-21-aia AIA Claim s 1-5, 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Uehara et al. (US 2023/0197195, June 22, 2023; foreign priority May 14, 2020) in view of Trumpp et al. (WO2018/141796, August 2018) and Shak et al. (US 2013/0196321, August 2013) . Uehara teaches a method for processing RNA information to perform effective normalization in the case of RNA information obtained from a secretion derived from a subject. Uehara teaches nucleic acids of a biological origin can be extracted from skin surface lipids (SSL) and analyzed (para 2). Uehara teaches effective correction of RNA expression values approximated to a normal distribution is possible by normalization the total extracted expression information (para 44). Uehara does not teach using ARF1 as a control for expression analysis. However, Trumpp teaches methods for analyzing cancer for increased expression of genes and normalizing the genes using ARF1 for AML cancer. Further, Shak et al. (US 2013/0196321, August 2013) teaches gene expression profile analysis for prostate cancer and using ARF1 as an internal reference control. Therefore, it would have been prima facie obvious at the time the invention was made to have performed the method of Uehara and substituted ARF1 as the reference gene, as taught by Trumpp and Shak. Uehara teaches skin surface lipids allow detection of RNA in secretion samples and the prior art teaches ARF1 may be used as an internal reference gene in many different samples. The ordinary artisan would have been motivated to use ARF1 gene to analyze RNA from skin samples. It would have been obvious to try additional reference genes for gene expression analysis normalization that were known to be work in multiple samples . Double Patenting 15-24-06 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b). Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b). Conclusion No claims allowable. 07-96 AIA The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Inoue et al. (US 11,913,061, February 2024) teaches a method for preparing nucleic acid sample from skin surface lipid specimens for analysis of RNA. Inoue does not teach using internal reference genes. 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 27, 2026 Application/Control Number: 18/565,383 Page 2 Art Unit: 1682 Application/Control Number: 18/565,383 Page 3 Art Unit: 1682 Application/Control Number: 18/565,383 Page 4 Art Unit: 1682 Application/Control Number: 18/565,383 Page 5 Art Unit: 1682 Application/Control Number: 18/565,383 Page 7 Art Unit: 1682 Application/Control Number: 18/565,383 Page 8 Art Unit: 1682 Application/Control Number: 18/565,383 Page 9 Art Unit: 1682 Application/Control Number: 18/565,383 Page 10 Art Unit: 1682 Application/Control Number: 18/565,383 Page 11 Art Unit: 1682 Application/Control Number: 18/565,383 Page 12 Art Unit: 1682 Application/Control Number: 18/565,383 Page 13 Art Unit: 1682 Application/Control Number: 18/565,383 Page 14 Art Unit: 1682
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