DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/25/2025 has been entered.
Status of the Claims
Claims 1, 18-20, and 23 have been amended. Claims 11, 13, 16, and 24-28 have been withdrawn previously, and claims 1-4 and 18-23 are examined herein.
Status of the Rejection
New grounds of claim objection are necessitated by the amendment.
All 35 U.S.C. § 112(b) and 35 U.S.C. § 103 rejections from the previous office action are withdrawn in view of the Applicant’s amendment.
New grounds of rejection under 35 U.S.C. § 112(b), 35 U.S.C. § 101, and 35 U.S.C. § 103 are outlined below.
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.
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.
Claims 1-4 and 18-23 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 “referring to a result of analysis” in line 7. It is unclear what steps are intended by “referring to a result” (e.g., displaying and reading the mass spectrometry results, comparing the tunneling current to the mass spectrometry results via a computer, etc.), such that the claim is indefinite. It is also not clear what result is being analyzed. Claim 18 also recites a similar limitation of “referring to accumulated data” in lines 2-3 that renders the claim indefinite. Claims 2-4 and 18-23 are further rejected by virtue of their dependence upon and because they fail to cure the deficiencies of indefinite claim 1.
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 1-4 and 18-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claim 1 recites the steps “(C) analyzing the modification state based on the tunneling current, (D) referring to a result of analysis of the microRNA by a mass spectrometer to associate the modification state with a pattern obtained by the tunneling current, and (E) analyzing a condition of the subject based on the results of steps (C) and (D),” which can be performed as mental processes. The additional positively recited steps such as passing microRNA between an electrode pair and detecting a generated tunneling current are well-known and conventional in the pertinent industry (see Kawai et al. [US 20140055150 A1], Taniguchi et al. [“Big Data Produced by Single-Molecule Electrical Sequencing of DNA,” The 30th Annual Conference of the Japanese Society for Artificial Intelligence, 2016], Astier [US 20170342480 A1], para. [0039] and Figs. 1- 2 designated as prior art in Gumbrecht et al. [US 20160186254 A1], and paras. [0023-0025] in Lee [KR 20130127293 A, referencing furnished machine translation] stating “the method for sequencing nucleic acids using tunneling current is well known in the technical field of the present invention.” See also MPEP 2106.05(d)(II)) that serve to obtain the measured values of the tunneling current that are then processed by implementing the abstract idea (via mental processes).
Claim 1 is ineligible due to the following analysis:
Step 1 (Statutory Category): Claim 1 is directed to a method of analyzing a modification state of a microRNA derived from a subject. Therefore, it is directed to a statutory category, i.e., a process (Step 1: YES).
Step 2A, Prong 1 (the claim is evaluated to determine whether it is directed to a judicial-exception/abstract-idea): Claim 1 recites the steps “(C) analyzing the modification state based on the tunneling current, (D) referring to a result of analysis of the microRNA by a mass spectrometer to associate the modification state with a pattern obtained by the tunneling current, and (E) analyzing a condition of the subject based on the results of steps (C) and (D),” which is an abstract idea since the steps are mental steps. Therefore, claim 1 is directed to a judicial exception/abstract idea (Step 2A, Prong 1: YES).
Step 2A, Prong 2 (the claim is evaluated to determine whether the judicial exception/abstract idea is integrated into a Practical Application): the abstract ideas related to “(C) analyzing the modification state based on the tunneling current, (D) referring to a result of analysis of the microRNA by a mass spectrometer to associate the modification state with a pattern obtained by the tunneling current, and (E) analyzing a condition of the subject based on the results of steps (C) and (D),” are not integrated into a practical application, and do not belong to a particular technological environment, industry or field since no further step is performed after the mental step. None of the dependent claims implement the analyzed condition into a practical application (e.g., by administering a non-generic treatment to the subject based on the results of the analysis). Consequently, the aforesaid abstract ideas are not integrated into a practical application and/or applied, relied upon, and/or used with an additional element or elements in a manner that imposes a meaningful limit, thus, monopolizing the steps (Step 2A, Prong 2: NO, because there is no integration of the abstract idea into a practical application).
Step 2B (the claim is evaluated to determine whether recites additional elements that amount to an inventive concept, or also, the additional elements are significantly more than the recited the judicial-exception/abstract-idea): Claim 1 recites the additional elements: “(A) passing the microRNA between an electrode pair; (B) detecting a tunneling current that is generated when the microRNA passes between the electrode pair,” which are well-known and conventional steps previously known to the pertinent industry (see Kawai, Taniguchi, Astier, para. [0039] and Figs. 1- 2 designated as prior art in Gumbrecht, and paras. [0023-0025] in Lee stating “the method for sequencing nucleic acids using tunneling current is well known in the technical field of the present invention.” See also MPEP 2106.05(d)(II)) that serve to obtain the measured values of tunneling current, which are processed by the mental processes in steps (C)-(E). Therefore, the claims do not include additional elements that are significantly more, and/or do not amount to more than the judicial exception/abstract idea itself and the claim is not patent eligible (Step 2B: NO).
Regarding claims 2-4 and 18-23, claims 2-4 and 18-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claims 2-4 and 18-23 depend on the independent claim 1, therefore, have the abstract idea of claim 1 and also have the well-known and conventional steps of claim 1 listed above. The elements added in the dependent claims 2-4 and 18-23 are further directed to abstract ideas. Claims 2-4 and 18-23 recite mental processes or further modify the mental processes in claim 1 without amounting to an inventive concept or practical application. Therefore, claims 2-4 and 18-23 do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
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.
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.
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 1-4, 18-20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Kawai et al. (US 20140055150 A1) in view of Schmittgen et al. (US 20100286232 A1), Taniguchi et al. (“Big Data Produced by Single-Molecule Electrical Sequencing of DNA,” The 30th Annual Conference of the Japanese Society for Artificial Intelligence, 2016), Yuan (“Chapter 3 - Liquid Chromatography-Mass Spectrometry for Analysis of RNA Adenosine Methylation,” 2017, In: Lusser, A. (eds) RNA Methylation, Methods in Molecular Biology, vol 1562, pgs. 33-42), and Kullolli et al. (“Intact MicroRNA Analysis Using High Resolution Mass Spectrometry,” 2014, Journal of The American Society for Mass Spectrometry, vol. 25, pgs. 80-87).
Regarding claim 1, Kawai teaches a method of analyzing a modification state of a microRNA (polynucleotide base sequence determination method that identifies chemically modified ribonucleotides [0034, 0046], wherein the polynucleotide comprises microRNA [miRNA] [0300]), comprising:
(A) passing the microRNA between an electrode pair (a first process passes a polynucleotide between an electrode pair in Fig. 1 [0036]);
(B) detecting a tunneling current that is generated when the microRNA passes between the electrode pair (a second process of detecting pulses of tunnel current as the polynucleotide passes between the electrode pair [0037]); and
(C) analyzing the modification state based on the tunneling current (a third process of generating primary base sequence data by comparing measured tunneling currents to reference current values [0038], wherein modified nucleotides are also identified [0021, 0099, 0101]).
Kawai is silent to the microRNA being derived from a subject, and the method further comprising (D) referring to a result of analysis of the microRNA by a mass spectrometer to associate the modification state with a pattern obtained by the tunneling current, and (E) analyzing a condition of the subject based on the results of steps (C) and (D).
Schmittgen teaches a method of analyzing a condition of a subject based on a microRNA sample, wherein the microRNA is derived from the subject (method includes measuring the level of at least one microRNA gene product derived from the subject's pancreas and comparing that level to a control sample to diagnose pancreatic cancer [0008]). Using microRNA derived from a subject enables individualized cancer diagnostics [0006].
Taniguchi teaches that a condition can be identified based on the modification state of RNA, wherein the base sequence of microRNA (short RNA [pg. 4, para. 2]) is identified (chemically modified base molecules are known biomarkers for cancer when identified within larger a base sequence [pg. 4, para. 2; pg. 9, para. 1; pg. 10, para. 1]).
Kawai, Schmittgen, and Taniguchi are considered analogous to the claimed invention because they are in the same field of microRNA analysis. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of analyzing a modification state of a microRNA in Kawai by (1) using a microRNA sample derived from a subject, as taught in Schmittgen, and (2) analyzing a condition of the subject based on the RNA modification state of the microRNA sample, as taught in Taniguchi, since this would identify cancer biomarkers for individualized diagnostics ([pg. 4, para. 2] in Taniguchi and [0006] in Schmittgen). Furthermore, Taniguchi and Schmittgen teach the claimed improvements as known techniques that are applicable to the base method in Kawai. One skilled in the art could have applied (1) the subject-derived microRNA sample in Schmittgen and (2) the analysis of a condition based on the modification state of an RNA sample in Taniguchi in the same way to the base method in Kawai, yielding predictable results (MPEP 2143(I)(D)).
Yuan teaches a method of analyzing microRNA (the modified RNA used as the sample is 15 nucleotides long [pg. 35, para. 2]) by mass spectrometry to identify a modification state of the RNA [pg. 33, Abstract].
Kullolli teaches that analyzing microRNA by mass spectrometry can identify modified microRNA [pg. 81, col. 1, para. 1; pg. 81, col. 1, para. 4], and further teaches that mass spectrometry analysis results can substantiate information obtained from other microRNA analysis methods [pg. 86, col. 1, para. 2-pg. 86, col. 2, para. 1].
Examiner notes that performing mass spectrometry is not a positively recited step in claim 1. Rather, a generic step of referring to results of mass spectrometry and associating said results with a tunneling current pattern is recited in steps (D) and (E). It would have been obvious to one of ordinary skill in the art to correlate the analyzed modification state based on tunneling current from step (C) with results from other modified microRNA analysis methods, including mass spectrometry results as taught in Yuan, to complement the tunneling current results [pg. 86, col. 1, para. 2-pg. 86, col. 2, para. 1 in Kullolli].
Regarding claim 2, modified Kawai teaches the method of claim 1, and Kawai further teaches wherein a modified position on a base sequence of the microRNA is identified (the generated sequence data would include the sequence position of modified nucleotides [0038, 0046]).
Regarding claim 3, modified Kawai teaches the method of claim 1, and Kawai further teaches wherein the modification state comprises methylation (nucleotides may be subjected to methylation [0099]).
Regarding claim 4, modified Kawai teaches the method of claim 1, and Kawai further teaches wherein a base sequence of the microRNA is at least partially identified (miRNA fragment sequences are assembled to identify a larger base sequence in Fig. 4(e) [0310]).
Regarding claim 18, modified Kawai teaches the method of claim 1, and further teaches wherein the condition of the subject from whom the microRNA has been obtained is analyzed by referring to accumulated data on a combination of the modification state and a pattern of the tunneling current to analyze the modification state of the microRNA based on the detected pattern of the tunneling current (to analyze the microRNA molecule, the measured tunneling current is compared to the accumulated tunneling current data in Tables 1 and 2 in Kawai to sequence unmodified and modified base molecules [0098, 0101 in Kawai]. The identified modified base molecules could then be used to analyze the condition of the subject [pg. 4, para. 2; pg. 9, para. 1 in Taniguchi]).
Regarding claim 19, modified Kawai teaches the method of claim 1, but is silent to the limitation wherein a result of analyzing the condition of the subject from whom the microRNA has been obtained is shown in 15 minutes or less from a time the sample obtained by the subject was subjected to tunneling current measurement.
Kawai teaches that a tunneling current measurement duration of 10-60 minutes is appropriate to determine the full-length sequence of a polynucleotide, with shorter polynucleotides requiring less time [0075]. Tunneling current measurement is the most time-intensive step of the method in modified Kawai, as the miRNA sequencing step and the subject condition determination step are performed automatically by a CPU with a stored program [0209 in Kawai] and a pre-trained algorithm [0181, 0188 in Schmittgen], respectively. Thus, a result of analyzing the condition of the subject from whom the microRNA has been obtained is shown in 10-60 minutes from a time the sample was subjected to tunneling current measurement. This time range overlaps with the claimed range of 15 minutes or less.
It would have been obvious to have selected and utilized a tunneling current measurement duration, such that the time from when the sample is subjected to tunneling current measurement to when a result of analyzing the condition of the subject from whom the microRNA has been obtained is within the disclosed range, as taught by Kawai, including those amounts that overlap within the claimed range, since one of ordinary skill in the art would reasonably expect any value within the taught range to be suitable given that Kawai specifically teaches that the range is appropriate to determine the full-length sequence of a polynucleotide [0075]. It has been held that obviousness exists where the claimed ranges overlap or lie inside ranges disclosed by the prior art. See MPEP 2144.05 (I).
Regarding claim 20, modified Kawai teaches the method of claim 1, and further teaches wherein the condition of the subject includes cancer (as stated in the rejection of claim 1 above, the miRNA modification state is a cancer biomarker [pg. 4, para. 2 in Taniguchi]).
Regarding claim 23, modified Kawai teaches the method of claim 1, and further teaches the method comprising analyzing the base sequence based on the tunneling current (the third process of generates primary base sequence data by comparing measured tunneling currents to reference current values [0038 in Kawai]) and analyzing the condition of the subject based on the modification state and a base sequence of the microRNA (as stated in the rejection of claim 1 above, analysis of the subject’s condition requires identification of the modification state within the context of a base sequence determined by tunneling current [pg. 9, para. 1; pg. 10, para. 1 in Taniguchi]).
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Kawai in view of Schmittgen, Taniguchi, Yuan, and Kullolli, as applied to claim 20 above, and further in view of Yi et al. (“Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer,” 2013, Clinical Cancer Research, vol. 19, pgs. 6544-6555).
Regarding claim 21, modified Kawai teaches the method of claim 20, but is silent to the limitation wherein the condition of the subject includes the stage of the cancer.
Yi teaches that the modification state of polynucleotides is associated with the different stages of pancreatic cancer, such that analyzing the modification state of target polynucleotides allows for identification of a stage of cancer (DNA methylation levels change with the stages of cancer progression in Table 3 [pg. 6553, col. 2, para. 1]). Further, using the modified state of polynucleotides as a biomarker can detect very early stages of pancreatic cancer non-invasively [pg. 6553, col. 2, para. 2; pg. 6554, col. 1, para. 3].
Modified Kawai and Yi are both considered analogous to the claimed invention because they are in the same field of polynucleotide-based cancer diagnostics. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the analysis of the subject’s condition in modified Kawai by determining the stage of the cancer based on the modification state of a polynucleotide, as taught in Yi, since this would detect very early stages of pancreatic cancer non-invasively ([pg. 6553, col. 2, para. 2; pg. 6554, col. 1, para. 3] in Yi). Furthermore, Yi teaches the claimed improvement as a known technique that is applicable to the base method in modified Kawai. One skilled in the art could have applied the method of determining a stage of pancreatic cancer based on a modification state of a polynucleotide in Yi in the same way to the base method in modified Kawai, yielding predictable results (MPEP 2143(I)(D)).
Regarding claim 22, modified Kawai teaches the method of claim 21, wherein the cancer is pancreatic cancer (as stated in the rejection of claim 21 above, the cancer being determined is pancreatic cancer [pg. 6555, col. 1, para. 3 in Yi]).
Response to Arguments
Applicant's arguments, see Remarks Pgs. 6-8, filed 7/25/2025, with respect to the 35 U.S.C. § 103 rejections have been fully considered but are not persuasive.
Applicant’s Argument #1:
Applicant argues on pg. 6 that Kawai in view of Taniguchi, Schmittgen, and Kullolli do not disclose all the features of amended claim 1.
Examiner’s Response #1:
Applicant’s arguments have been fully considered, but are moot in view of the new grounds of rejection.
Applicant’s Argument #2:
Applicant argues on pgs. 7-8 that because claims 2-4 and 18-23 depend on independent claim 1, if independent claim 1 is allowable, dependent claims 2-4 and 18-23 are likewise allowable.
Examiner’s Response #2:
Based on the above response #1, applicant’s arguments regarding the amended claim 1 are moot in view of the new grounds of rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAYLEE Y TSENG whose telephone number is (703)756-5542. The examiner can normally be reached Mon - Fri 9-6 PT.
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/K.T./Examiner, Art Unit 1795
/LUAN V VAN/Supervisory Patent Examiner, Art Unit 1795