CTNF 18/494,008 CTNF 101344 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. Election/Restrictions 08-25-01 AIA Applicant’s election without traverse of Invention I (claims 1-8) in the reply filed on 3 April 2026 is acknowledged. 08-06 AIA Claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3 April 2026 . Information Disclosure Statement The information disclosure statement(s) (IDS) filed 6 July 2024, 3 March 2025, 17 June 2025, and 21 October 2025 are considered, initialed, and attached hereto. Foreign Patent Documents Cite No 4 in the IDS filed 6 July 2024 (JP 2014-215173) is lined through and was not considered because no English language translation or explanation of relevance was provided. Claim Status Claims 1-8 are pending and under examination. Claim 9 is withdrawn. Specification 06-16 AIA Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided. The abstract of the disclosure filed 2 January 2024 is objected to because it contains phrases in square brackets '[]' that are not in narrative form and contains multiple line breaks splitting the abstract into 3 paragraphs. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b). The use of the terms such as McDry, MALDImini, and Shimadzu, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Claim Rejections - 35 USC § 112(b) - Indefiniteness 07-30-02 AIA 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. 07-34-01 Claims 4-7 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. Claims 4-7 recite various components and steps that are not part of claim 1 and are not clearly linked to any recited component or step of claim 1. The only shared recitation with claim 1 is the recitation “the matrix-assisted laser desorption/ionization mass spectrometer” (MALDI/MS), which is present in claim 1, but in claims 4-7 a mixture is subjected to a measurement by the MALDI/MS whereas in claim 1 an RNA contained in a sample is analyzed by the MALDI/MS. It is therefore unclear whether the components in claims 4-7 (a matrix solution containing DHAP or THAP, sample/mixed-matrix mixture, a sample solution containing an RNA, etc.) are distinct from the similar components of claim 1 (a mixed matrix, a matrix to analyze an RNA contained in a sample) or are intended to describe steps that either prepare or use the components recited in claim 1. For example, if the limitations in claims 4-7 are interpreted as distinct from those of claim 1, then claim 4 would be interpreted as claiming a method for analyzing RNA that includes both using a mixed matrix containing DHAP and THAP to analyze an RNA contained in a sample by MALDI/MS as well as mixing together a sample, DHAP, and THAP to make a mixture solution, dropping the solution onto a plate and drying it, and subjecting the dried mixture solution to a measurement by MALDI/MS. In contrast, if the limitations in claims 4-7 are interpreted as further limiting the preparation and use of components of claim 1, then claim 4 would be interpreted as claiming a method for analyzing RNA by mixing together a sample, DHAP, and THAP to make the mixed matrix of claim 1 containing the RNA contained in the sample of claim 1, dropping this mixed matrix onto a plate and drying it, and doing the analysis of claim 1 by subjecting it to a measurement by MALDI/MS. This lack of clarity makes the claims indefinite, so claims 4-7 are rejected. 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. 07-23-aia AIA 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. Claims 1-8 are rejected under 35 U.S.C. 103 as being obvious over Fukuyama and Shichi (US 2025/0299940, effectively filed 31 May 2022), herein Fukuyama. 07-15-02-aia The applied reference has a common applicant and inventor with the instant application, but it names another inventor. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP §717.02. Regarding claim 1 , Fukuyama teaches a method for analyzing nucleic acids, wherein a mixed matrix containing 2,4-dihydroxyacetophenone (DHAP) and 2,4,6-trihydrixyacetophenone monohydrate (THAP) (“a mixed matrix prepared by mixing […] 2,4-DHAP and THAP is preferable” [0071]) is used as a matrix to analyze a nucleic acid contained in a sample (“a nucleic-acid-containing sample” [0070]) by a matrix-assisted laser desorption/ionization mass spectrometer (“a structural analysis of a sample molecule with an ion trap (IT) mass spectrometer having a MALDI ion source” [0042]). While Fukuyama does not explicitly state that the nucleic acid target may be an RNA, it is commonly known in the art that RNA is a nucleic acid that may be analyzed with methods using MALDI, so it would be obvious to one of ordinary skill in the art to simply substitute RNA for the recited general nucleic acid in the method of Fukuyama. One of ordinary skill in the art would have a reasonable expectation of success in the simple substitution of RNA for the recited general nucleic acid in the method of Fukuyama because RNA is a nucleic acid analyzed with methods using MALDI, such as the method of Fukuyama. Regarding claim 2 , Fukuyama teaches the method for analyzing an RNA according to claim 1 (see 35 U.S.C. 103 rejection of claim 1 over Fukuyama above). The mixture ratio of DHAP and THAP in the mixed matrix being within a range from 30:1 to 10:1 is obvious. MPEP §2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. […] Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results)”. As the claimed ratios would be reached by one of ordinary skill in the art performing routine optimization by comparing various ratios of the mixture to identify a ratio most optimal for detection of their nucleic acid, the claimed ratios are obvious. Regarding claim 3 , Fukuyama teaches the method for analyzing an RNA according to claim 1 (see 35 U.S.C. 103 rejection of claim 1 over Fukuyama above), wherein diammonium hydrogen citrate is used as a matrix additive to the mixed matrix to analyze the RNA contained in the sample (“The sample for analysis may further contain a matrix additive. Ammonium citrate dibasic (ACD) can be used as the matrix additive” [0072], it is noted that ammonium citrate dibasic is another name for diammonium hydrogen citrate). Regarding claims 4-7 , Fukuyama teaches the method for analyzing an RNA according to claim 1 (see 35 U.S.C. 103 rejection of claim 1 over Fukuyama above), wherein the mixed matrix containing an RNA contained in a sample is prepared by either dropping a mixed solution (RNA and matrix substance) onto a plate and drying it or by mixing the components of the mixed solution on the plate and drying it (“The sample for analysis is prepared by drying a mixed solution, which is a mixture of a nucleic-acid-containing sample and a matrix substance, dropped onto a sample plate. For this task, a mixed solution prepared beforehand may be dropped onto and dried on the sample plate, or alternatively, the mixed solution may be prepared on the sample plate and then dried on the same plate” [0070]). It would be obvious to apply this flexibility in order of mixing taught by Fukuyama to the combination of DHAP and THAP matrix substances as well. Furthermore, changing the order of mixing ingredients and performing steps is obvious. See MPEP §2144.04(IV)(C): “ In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of 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) (Selection of any order of mixing ingredients is prima facie obvious.)”. Therefore, claims 4-7 are obvious in view of the teachings of Fukuyama. Regarding claim 8 , Fukuyama further teaches a method for analyzing nucleic acids wherein the matrix-assisted laser desorption/ionization mass spectrometer is a digital ion trap type (“a MALDI digital ion trap mass spectrometer” [0086]). Therefore, the invention as a whole of claims 1-8 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention. 07-21-aia AIA Claim s 1-2 and 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sze and Hua (U.S. Patent Application Publications Cite No 6 in IDS filed 6 July 2024)(US 2006/0261267, published 23 November 2006, effectively filed 20 May 2005), herein Sze . Regarding claim 1 , Sze teaches a method for analyzing RNA by a matrix-assisted laser desorption/ionization mass spectrometer (“a method for providing an analyte ion, which is suitable for analysis by MALDI mass spectrometry” [0088]; “The method of the invention may be applied to any desired analyte from which ions can be derived. Examples of such analytes include, but are not limited to, nucleotides, polynucleotides, nucleic acids” [0091]; “MALDI mass spectrometry is used in a variety of applications. A field of extensive use are life sciences, where it is for instance applied to […] DNA/RNA sequencing” [0002]) wherein a matrix containing at least one of 2,4-dihydroxyacetophenone (DHAP) and 2,4,6-trihydroxyacetophenone monohydrate (THAP) is used (“The method includes providing a composite matrix material comprising at least one MALDI matrix forming compound” [0088]; “The at least one MALDI matrix forming compound of the composite matrix material may be any suitable compound that is able to form a MALDI matrix” [0048]; “Examples of such compounds include […] 2,4,6-trihydroxyacetophenone […] 2,4-dihydroxyacetophe-none” [0049]). Regarding claim 1 , while Sze teaches a matrix comprising at least one MALDI matrix forming compound, DHAP and THAP are listed among other possible compounds such that one of ordinary skill in the art would not immediately envisage the species of a mixed matrix containing DHAP and THAP, and therefore the method Sze does not anticipate claim 1. However, in view of Sze’s teaching of at least one MALDI matrix forming compound, which provides an explicit suggestion to combine multiple MALDI matrix forming compounds, and Sze’s identification of DHAP and THAP as exemplary MALDI matrix forming compounds, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use a mixed matrix containing DHAP and THAP in the method of Sze. One of ordinary skill in the art would have a reasonable expectation of success in this combination because both DHAP and THAP are taught as compounds useful for forming MALDI matrices. Regarding claim 2 , Sze teaches the method for analyzing an RNA according to claim 1 (see 35 U.S.C. 103 rejection of claim 1 over Sze above). The mixture ratio of DHAP and THAP in the mixed matrix being within a range from 30:1 to 10:1 is obvious. MPEP §2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. […] Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results)”. As the claimed ratios would be reached by one of ordinary skill in the art performing routine optimization by comparing various ratios of the mixture taught by Sze to identify a ratio most optimal for detection of their desired analyte, the claimed ratios are obvious. Regarding claim 7 , Sze teaches the method for analyzing an RNA according to claim 1 (see 35 U.S.C. 103 rejection of claim 1 over Sze above), wherein a matrix solution and a sample solution are separately dropped onto a sample plate and dried to prepare the dried sample/matrix mixture for analyses by MALDI (“For conventional MALDI analysis, […] matrix […] was deposited on a stainless steel sample plate, followed by […] analytes and dried in air” [0110]). Regarding claims 4-6 , these claims differ from claim 7 only in the order of steps (whether DHAP and THAP are mixed before mixing with a sample solution containing RNA and whether the mixing of solution occurs before they are dropped onto a sample plate). Changing the order of mixing ingredients and performing steps is obvious. See MPEP §2144.04(IV)(C): “ In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of 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) (Selection of any order of mixing ingredients is prima facie obvious.)”. Therefore, claims 4-6 are obvious in view of the teachings of Sze. Therefore, the invention as a whole of claims 1-2 and 4-7 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention . 07-21-aia AIA Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Sze and Hua (U.S. Patent Application Publications Cite No 6 in IDS filed 6 July 2024)(US 2006/0261267, published 23 November 2006, effectively filed 20 May 2005), herein Sze, as applied to claims 1-2 and 4-7 above, and in view of Pieles et al. (“Matrix-assisted laser desorption ionization time-of-flight mass spectrometry: a powerful tool for the mass and sequence analysis of natural and modified oligonucleotides” Nucleic Acids Res 21(14), pages 3191-3196 (1993)), herein Pieles . Regarding claim 3 , Sze teaches the method for analyzing an RNA according to claim 1 (see 35 U.S.C. 103 rejection of claim 1 over Sze above). However, Sze does not teach the method wherein diammonium hydrogen citrate is used as a matrix additive to the mixed matrix to analyze the RNA contained in the sample. This deficiency is made up for in the teachings of Pieles. Regarding claim 3 , Pieles teaches that MALDI analysis of nucleic acids using a THAP matrix is improved by using diammonium hydrogen citrate as a matrix additive, which improves the signal intensity and resolution (“The oligonucleotides […] were analyzed after HPLC-purification and lyophilization by MALDI-TOF MS using 2,4,6-trihydroxy acetophenone as a matrix […] The addition of a large excess of diammonium hydrogen citrate to the samples suppressed the alkali-ion adducts almost completely and resulted in an increase of signal intensity and resolution” page 3192, left column, paragraph 5). In view of the advantages taught by Pieles, one of ordinary skill in the art prior to the effective filing date of the claimed invention would be motivated to combine the method of Sze with the addition of diammonium hydrogen citrate as taught by Pieles in order to improve the signal intensity and resolution of the method of Sze. One of ordinary skill in the art would have a reasonable expectation of success in this combination because Pieles teaches using diammonium hydrogen citrate with a THAP matrix, which is similar to the mixed DHAP and THAP matrix of Sze, and because both the methods of Pieles and Sze teach using their respective matrices for analysis of nucleic acids by MALDI. Therefore, the invention as a whole of claim 3 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention . 07-21-aia AIA Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Sze and Hua (U.S. Patent Application Publications Cite No 6 in IDS filed 6 July 2024)(US 2006/0261267, published 23 November 2006, effectively filed 20 May 2005), herein Sze, as applied to claims 1-2 and 4-7 above, and in view of Ding et al. (“A digital ion trap mass spectrometer coupled with atmospheric pressure ion sources” J Mass Spectrom 39(5), pages 471-484 (2004)), herein Ding . Regarding claim 8 , Sze teaches the method for analyzing an RNA according to claim 1 (see 35 U.S.C. 103 rejection of claim 1 over Sze above). However, Sze does not teach the method wherein the matrix-assisted laser desorption/ionization mass spectrometer is a digital ion trap type. This deficiency is made up for in the teachings of Ding. Regarding claim 8 , Ding teaches MALDI analysis with a digital ion trap mass spectrometer improves upon conventional techniques by providing a wider mass range of analysis (“In a digital ion trap (DIT), the quadrupole trapping and excitation waveforms are generated by the rapid switching between discrete d.c. voltage levels. As the timing of the switch can be controlled precisely by digital circuitry, the approach provides an opportunity to generate mass spectra by means of a frequency scan in contrast to the conventional voltage scan, thus providing a wider mass range of analysis […] The ion trap was coupled with electrospray ionization (ESI) and atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI) sources to demonstrate the capability of the digital method” Abstract). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the digital ion trap mass spectrometer taught by Ding for the generic mass spectrometer in the method of Sze (MPEP §2143 I. B.). One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because the substitution of a specific type of mass spectrometer for a more generic recitation of a mass spectrometer would not be expected to negatively impact the function of the method taught by Sze. Additionally, one of ordinary skill in the art would be motivated to perform this substitution because Ding teaches that the digital ion trap mass spectrometer has the advantage of a wider mass range of analysis, which would improve the method of Sze. Therefore, the invention as a whole of claim 8 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention. Conclusion Claims 1-8 are rejected. Claim 9 is withdrawn. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jeffrey Lawrence Bellah whose telephone number is (571)272-1024. The examiner can normally be reached M-Th, 7:30-5 ET. 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, Anne Gussow can be reached at (571)272-6047. 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. /JEFFREY BELLAH/Examiner, Art Unit 1683 /ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683 Application/Control Number: 18/494,008 Page 2 Art Unit: 1683 Application/Control Number: 18/494,008 Page 3 Art Unit: 1683 Application/Control Number: 18/494,008 Page 4 Art Unit: 1683 Application/Control Number: 18/494,008 Page 5 Art Unit: 1683 Application/Control Number: 18/494,008 Page 6 Art Unit: 1683 Application/Control Number: 18/494,008 Page 7 Art Unit: 1683 Application/Control Number: 18/494,008 Page 8 Art Unit: 1683 Application/Control Number: 18/494,008 Page 9 Art Unit: 1683 Application/Control Number: 18/494,008 Page 10 Art Unit: 1683 Application/Control Number: 18/494,008 Page 11 Art Unit: 1683 Application/Control Number: 18/494,008 Page 12 Art Unit: 1683 Application/Control Number: 18/494,008 Page 13 Art Unit: 1683 Application/Control Number: 18/494,008 Page 14 Art Unit: 1683
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