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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 12-16 and 18-20, drawn to a method and system of determining an order of nucleotides of an RNA molecule using LC-MS data using anchor-based analysis, performing base calling and performing draft read strategies in the reply filed on 11/21/2024 was acknowledged in the office action mailed 03/18/2025.
Claims 1-11 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/21/2024.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/01/2026 has been entered.
Applicant Response
Applicant's response, filed 04/01/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 17 is canceled.
Claim 21 is new.
Claims 1-16 and 18-21 are pending.
Claims 1-11 are withdrawn pursuant to a restriction requirement.
Claims 12-16 and 18-21 are under examination herein.
Claim 12 is objected to.
Claims 12-16 and 18-21 are rejected.
Priority
The instant application is the National Stage entry of PCT/US2019/033895 , International Filing Date: 05/24/2019, which claims priority to US Provisional Application 62676754 , filed 05/25/2018. As such, the effective filing date assigned to each of claims 12-16 and 18-20 is 5/25/2018.
However, the limitation for fragmentation by controlled formic acid hydrolysis in claim 21 is not support by the instant disclosure or the priority documents, which only recite “acid degradation”. Therefore, the effective filing date assigned to claim 21 is 11/24/2020.
Drawings
The objections to the drawings are withdrawn in view of replacement drawings filed 04/01/2026.
Claim Objections
The objection to claim 14 is withdrawn in view of claim amendments file 04/01/2026.
Claim 12 is objected to because of the following informalities:
Steps (i)-((v) are not presented with line indentations. Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation. See MPEP 608.01(m).
The “performing base calling…” step should have a step number (i.e. (v)).
“(v) building..” should be “(vi) building…”.
The “and performing a draft read process and” step should also have a step number, and should be “(vii) ; and”
“(vi) performing an alignment/assembly…” should be “viii) performing an alignment/assembly…”.
Appropriate correction is required. This objection is newly recited.
Claim Rejections - 35 USC § 112
The rejection of claim 20 under 35 U.S.C. 112(b) are withdrawn in view of claim amendments filed 04/01/2020.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is newly recited and necessitated by claim amendments filed 04/01/2026.
The limitation for fragmentation by controlled formic acid hydrolysis in claim 21 is not support by the instant disclosure or the priority documents, which only recite “acid degradation”.
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 1-16 and 18-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: performing LC-MS, in claim 12. This rejection is newly recited and necessitated by claim amendments.
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 12-26 and 18-21 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea/law of nature/natural phenomenon without significantly more. Newly recited portions are necessitated by claim amendments.
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 12 recites performing anchor-based sub-setting on the LC- MS data, the anchor based sub-setting including selecting a data zone; performing base calling for each nucleotide in a RNA sequence by comparing mass differences of two adjacent ladder fragments to theoretical nucleotide unit masses in a database, calculated from chemical formula of all known ribonucleotides including those with base modifications on the subset of LC-MS data to generate a dataset of tuples; (v) building trajectories linking tuples in the dataset to generate a draft read from the RNA ladder fragments; and performing a draft read process and (vi) performing an alignment/assembly algorithm by overlapping bidirectional reads (one reading from 5'-> 3' direction and the other reading from 3'-> 5' direction) and short reads from both native RNA ladder fragments and non-native forms.
Claim 20 recites the method further including performing an alignment/assembly algorithm wherein alignment is based on the overlapping regions of the ladder fragments if the leading sequence of one ladder fragment aligns with the ending sequence of another ladder fragment thereby aligning the multiple ladder fragments leading to assembly of a complete RNA sequence..
These recitations equate to steps of collecting information, analyzing data and making observations, evaluations and judgements that can be carried out in the human mind. Specifically, performing anchor-based sub-setting on the LC-MS data, performing base calling by comparing mass differences for adjacent lagger fragments to generate a dataset of tuples, building trajectories linking tuples to generate a draft read, performing a draft read strategy and performing an alignment/assemble algorithm can be practically performing the human mind as claimed and are similar to the concepts of collecting and comparing known information in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011) and collecting information, analyzing it, and reporting certain results of the collection and analysis in Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016) that the courts have identified as concepts that can be practically performed in the human mind. Therefore, each of the above recited limitations fall under the “Mental Processes” grouping of abstract ideas. Furthermore, the steps as claimed for performing anchor-based sub-setting, building trajectories and determining PPM equate to organizing information and manipulating information through mathematical correlations and reciting a mathematical equation, similar to the concepts of taking existing information, manipulating the data using mathematical functions, and organizing this information into a new form in Digitech Image Techs., LLC v. Electronics for Imaging, Inc., 758 F.3d 1344, 1350, 111 USPQ2d 1717, 1721 (Fed. Cir. 2014). Therefore, these limitations fall under the “Mathematical Concepts” grouping of abstract ideas. Claims 13-16 and 17-19 further qualify the recited judicial exceptions. As such, claims 12-16 and 18-21 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exceptions are not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies or uses the recited judicial exception to affect a particular treatment for a condition. Rather, the instant claims recite additional elements that amount to mere data gathering and mere instructions to implement the abstract ideas in a generic computing environment. Specifically, the claims recite the following additional elements:
Claim 12 recites a computer, (i) biochemical labeling of the RNA sample; (ii) fragmentation of the RNA sample into RNA ladder fragments for mass-spectrometry (MS) sequencing; (iii) receiving liquid chromatography-mass-spectrometry (LC-MS) data of the RNA sample wherein biochemical labeling of the RNA sample has been performed and the RNA sample has been fragmented in RNA ladder fragments.
Claim 21 recites wherein the RNA fragmentation is performed by controlled formic acid hydrolysis.
Claim 12 recite limitations for gathering data and claim 21 recites further limitations on that data. The biochemical labeling, RNA fragmentation, receiving LC-MS data and accessing a database steps are performed to gather data to perform the mental steps and mathematical processes, and there is no indication that these steps are impacted by the recited the judicial exception, and therefore the recited judicial exception is not integrated into these additional elements. These limitations equate to mere data gathering, which the courts have found to be insignificant extra-solution activity (see MPEP 2106.05(g)).
Furthermore, claim 12 also recites using a generic computing systems and computer program products to carry out instructions to implement an abstract idea on a computer. The use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, there is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself. As such, claims 12-16 and 18-21 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). Further analyzing the additional elements under step 2B, the additional elements as described above do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims under the 2B analysis, the prior art to Turner et al. (Nucleic Acids Research 2011, Volume 39, Issue 21, Page e147) and Wetzel et al. (Analyst 2016, 141(1), 16-23) discloses biochemical labeling and fragmentation of RNA using acid hydrolysis is well-understood, routine and conventional in the art (Turner et al.: p 2, col 1, para 3- p 1, col 2, para 1; Wetzel et al.: section 2.1-2.3; fig 2). Furthermore, the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, the additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception, and the claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 12-16 and 18-21 are not patent eligible.
Response to applicant’s arguments
Applicant states the claims do not recite a mental process because the fragmentation of the one or RNA molecules in a sample results in thousands of RNA fragments which must be analyzed to determine the RNA sequence and the presence of RNA modifications within any given RNA sequence, and this analysis cannot be practically performed in the human mind (Applicant’s Arguments, p 12, para 3).
It is respectfully submitted that this is not persuasive. Under the broadest reasonable interpretation of the claim limitations, the data set size is not inherently large. Even if the data consisted of millions of data points, it is noted that such computations performed mentally, or with paper and pencil, may take considerable time and effort, but that is, of course, the singular purpose of computers and computer networks, to perform large numbers of calculations, via algorithms, rapidly, and without error (assuming no error in user input). Although a general-purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.), 687 F.3d 1266,1278 (Fed. Cir. 2012) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also See SiRF Tech., Inc. v. Int’l Trade Comm ’n, 601 F.3d 1319,1333 (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations). Therefore, the recited limitation fall under the “Mental Processes” grouping of abstract ideas.
Applicant further states, that even if the claims recite a mental process, said mental process is integrated into practical application because the claims provide a much needed addition to available addition to available RNA sequencing technology that permits both the identification of RNA sequences and the presence of RNA modification within an RNA sample which reflect a particular improvement to the RNA sequencing technology available at the time of the disclosure, by providing methods for simultaneously reading one or more RNA sequences with a single nucleotide resolution and for determining the presence, type, location and quantity of a wide spectrum of RNA modifications, , where LC-MS data contains data from multiple-cut RNAS fragments, and further states that h present claimed methods can address the long-standing challenge enabling unbiased sequencing of RNA modification and revealing the true sequence of an RNA that no other method can (Applicant’s Arguments, p 12, para 4-p 13, para 1).
It is respectfully submitted that this is not persuasive. It appears the improvements are solely provided by the steps for analyzing the fragments and are to those analysis steps themselves. As discussed in MPEP 2106.05(a), the judicial exception alone cannot provide the improvement and the improvement cannot be to the judicial exception itself. As discussed above, the additional elements of the claims amount to mere data gathering and mere instructions to implement the abstract ideas in a generic computing environment. Therefore, there is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself, and as such, claims 12-16 and 18-20 are directed to an abstract idea and the rejection is maintained.
It is noted that the claims still do not require the labeling of the RNA be performed prior to fragmentation or specify the RNA to be tRNA.
Claim Rejections - 35 USC § 102
The rejections of claims 12-13 and 16-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Björkbom et al. (IDS filed 03/02/2022, NPL reference 2; previously cited; hereafter referred to as Björkbom) is withdrawn in view of claim amendments filed 04/01/2026, as Björkbom does not appear to disclose of suggest performing the alignment/assembly algorithm by overlapping bidirectional reads and short reads from both native RNA ladder fragments and non-native forms as disclosed by instant claim 12.
Claim Rejections - 35 USC § 103
The rejection of claim 14 under 35 U.S.C. 103 as being unpatentable over Björkbom et al. (IDS filed 03/02/2022, NPL reference 2; previously cited; hereafter referred to as Björkbom), and further in view of Wang and Gu (Anal. Chem. 2010, 82, 17, 7055–7062; hereafter referred to as Wang) and Brenton and Godfrey (Journal of the American Society for Mass Spectrometry 2010, 21(11), pp.1821-1835; previously cited; hereafter referred to as Brenton) is withdrawn in view of claim amendments filed 04/01/2026, as none of Björkbom, Wang or Brenton appear to disclose of suggest performing the alignment/assembly algorithm by overlapping bidirectional reads and short reads from both native RNA ladder fragments and non-native forms as disclosed by instant claim 12, on which claim 14 depends.
The rejection of claims 15 under 35 U.S.C. 103 as being unpatentable over Björkbom et al. (IDS filed 03/02/2022, NPL reference 2; previously cited; hereafter referred to as Björkbom) as applied to claims 12 above, and further in view of Brenton and Godfrey (Journal of the American Society for Mass Spectrometry 2010, 21(11), pp.1821-1835; previously cited; hereafter referred to as Brenton) is withdrawn in view of claim amendments filed 04/01/2026, as neither Björkbom nor Brenton appear to disclose of suggest performing the alignment/assembly algorithm by overlapping bidirectional reads and short reads from both native RNA ladder fragments and non-native forms as disclosed by instant claim 12, on which claim 15 depends.
Prior Art
Claims 12-16 and 18-21 appear to be free from prior art, as the closest prior art to Björkbom et al. (IDS filed 03/02/2022, NPL reference 2; previously cited; hereafter referred to as Björkbom) does not appear to disclose of suggest performing the alignment/assembly algorithm by overlapping bidirectional reads and short reads from both native RNA ladder fragments and non-native forms as disclosed by instant claim 12.
Conclusion
No claims allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIDHI DHARITHREESAN whose telephone number is (571)272-5486. The examiner can normally be reached Monday - Friday 9:00 - 5:00.
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/N.D./ Examiner, Art Unit 1686
/LARRY D RIGGS II/ Supervisory Patent Examiner, Art Unit 1686