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 .
Applicants Amendment
Applicant’s amendment filed 1/23/2026 has been received and entered. Claims 1, 5, 9, 12, 13, 20, 21, 28, 29 and 34 have been amended.
Claims 1-34 are pending.
Election/Restriction
In prosecution, Applicant's election with traverse of Group I in the reply filed on 7/14/2022 was acknowledged. The restriction requirement was withdrawn because the search and art of record appears to demonstrate that test compounds administered in vivo versus in vitro can have different effects, but as broadly claimed do not appear to affect the analysis steps.
Claims 1-34, drawn to a method of evaluating genotoxicity of a test substance on the effect on DNA in a variety of cell sources are pending and currently under examination.
Priority
This application filed 2/7/2019 is a Continuation of PCT/JP2017/005700 filed 2/16/2017 in Japan.
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.
Claim 34 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subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention for a source of DNA that is from a virus is withdrawn.
The amendment to provide that it is derived from a cell has addressed the basis of the rejection.
Claims 1-33 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
The amendment to the independent claims to indicate ‘corresponding to the DNAs of the cell population’ has addressed the basis of the rejection.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 34 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn.
Amending the claim to indicate the viral DNA was derived from a cell has addressed the basis of the rejection.
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.
Claims 1- 34 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 for the limitation of ‘at least’ is withdrawn.
Applicants note support of the specification for ‘preferably 1,000 bp or more’ in [0047] and Examiner agrees while not ipsis verbis, provides adequate support for at least 1000 as amended.
Claims 1-34 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 is withdrawn.
Amendment to the claims to provide the relationship more clearly has addressed the basis of the rejection.
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 1-34 stand s 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 analysis
The claims have been amended and still are directed to evaluating genotoxicity of a test substance by analyzing sequence data after testing the compounds in cultured cells. More specifically the independent claims have been amended to indicate the reference being compared is ‘corresponding to the DNAs of the cell population’ and appears to be an embodiment previously considered. Broadly, each of the independent claims provide for DNA obtained from a different cell source and that the correlation of genotoxicity is based on the degree of increase in the mutation frequency observed in the reads and that an increase means it is a genotoxic compound and no increase means it is not genotoxic. As amended the claims provide that the read fragment data is at least 100 pb and that the reference to which it is compared is at least 1000bp in steps 1) and 3), and mismatches are obtained based on frequency among the read sequences in step 4).
The steps as additional elements that are performed in the method have been amended to indicate the source has an unknow or heterogeneous genome, and encompass several steps for obtaining DNA, sequencing fragments to produce read data, comparing read data to a reference, identifying variations between the two and classifying and providing frequency of the variations/mutations observed.
The cell sources are cell populations (claims 1, 5, 9), cancer cells (claims 12, 28), cultured cells (claim 21, 29), and newly added claim 34 provides for the sources comprised in claim 1 and set forth in other dependent claims. This limitation provides for possible sources for the observation of various types of possible mutations which may vary between cells, cell types and organisms where the alterations include possible insertions, deletions, and specific alterations of one nucleic acid to another. In view of the guidance of the specification and the art of record, it appears that certain substances provide an increased type of mutation that can be observed. Given the guidance of the specification, Matsuda et al. (in IDS) provide a comparison of AF-2 and DMSO effects on genomic DNA and quantitate the differences in frequency of mutations observed (see Table 1 and 2 for example). While specific types of alterations are provided as limitations in the claims, they appear as possible observable changes as they appear to be dependent on the cell source and substance tested generically claimed, not a necessary outcome of the method steps themselves.
Response to Applicant’s arguments
Applicants provide a summary of the basis of the invention no as comparing DNA fragments from a cell population, but rather a method for evaluation genotoxicity by determining whether the sites are mutation sites based on their observed frequency in the read data. Applicants argue that mutations can be low frequency and the instant method solves the problem by comparing each read to a reference without filtering for a consensus sequence, and is consistent with the fact pattern in McRo. Applicants argue that this is not a mental process, provided practical improvements for higher throughput and more sensitive detection and are too complex to practically performed in the human mind. Summarizing the analysis and basis of the rejection and request reconsideration that the claims are not directed to a judicial exception and is practically applied and more than application of mathematical process. Applicants argue that the claims provide an ordered combination and providing an analysis of the claim as a whole under each step applicants note the relevant guidance of MPEP 2106 as it applies to the independent claims.
In response, the amendments are acknowledged and discussed above. While the genome of a cell can be unknown or heterogeneous, all that is needed to be performed is comparing one sequence to another which examiner would contend can be done visually once aligned. The potential size or complexity of the whole of the data sets for a genome is recognized, however after obtaining the read and ref data, all that is required of the claim steps 3-4 is comparing 100bp reads to a 1000bp reference as a judicial exception. Presumably for the analysis to be informative, the 100bp and 1000bp have some relationship to each other and so once aligned it appears to be a simple comparison of the two sequences for similarities or differences between the two. If more than one read is provided for comparison, the various reads can be aligned and compared for a simple analysis and generic ‘classification’ based on what is observed. The final part of the claims set forth what the observations mean, here if more alterations are seen then the compound in culture altered the genome being analyzed and thus genotoxic. For analyzing the judicial exception of the claim, the analysis requires assessing the requirements of the claim, and here it is found that comparing two sequences for possible differences between them is not complex as asserted in arguments and can be performed visually using the human mind. Dependent claims do not appear to add complexity, and practically should limit the independent claim as to what is required. A step of ‘extracting’ appears to be drawn to assessing the read data generically, and as argued whether the data ‘reliability’ is an issue of the sequencing platform for example or truly an alteration as compared to a reference. Here again, as generically required of the claims, this is an assessment of a AGTC or possible an N if the device could not conclude a specific base, or alternatively though not required providing a PHRED score for each of the bases, however this is broadly provided in the claims and has no clear requirement given the guidance of the specification to provide for a complexity beyond human assessment of the read data that is provided. As discussed above, indicating that the counting of variations between a read sequence and a reference is considered an instruction and something that can be performed by observation and using one’s mind. The amendment not to consider the frequency of a difference among the reads was noted, however there is no requirement that the data would even require this. More generally with respect to evaluating a read as compared to a reference this appears to describe how the alignment and differences between two sequences are assessed, effectively indicating that every difference is considered a ‘mutation’ for the purposes of assessing and calculating differences between compounds that generate alterations in the cell and those that do not.
For Step 2A prong 2 Applicants argue that any possible judicial exception when viewed as a whole integrates it into a practical application and reflects an improvement to the function of the analysis of genetic mutations.
In response, the evidence of record does not appear to support any improvement. Moreover, in the assessment of the judicial exception an improvement in data analysis of the data itself is not sufficient for patent eligibility. When the claims are viewed as a whole, they appear to have two parts, obtaining read and reference data which is 100bp and 1000bp then taking the data and analyzing it for alterations between the two. The interpretation of the data is generic where the amendments in prosecution indicate that an increase in observations means or is correlated with the agent causing alterations which appears to only describe or explain the correlation or effect of the compound on the cell. In view of the art and affects associated with ‘genotoxic’, it would be well understood that genotoxic agents cause damage to the DNA in a cell, and that some of the damage will result in alterations that can be detected when the DNA from the cell is isolated and sequenced.
Applicants note the fact pattern of Ex Parte Desjardins, and note the claims provide a technological problem of missed data and the method provides a means to overcome the problem.
In response, the analysis appears to be applied after receiving data and does not follow the fact pattern of Desjardins. Wha tis required of the instant steps is simply comparing sequence reads to a reference and noting and quantifying any alteration that is observed.
Therefore, for the reasons above and of record the rejection is maintained.
As noted previously, one way to overcome a rejection for non-patent-eligible subject matter is to persuasively argue that the claimed subject matter is not directed to a judicial exception. Another way for the applicants to overcome the rejection is to persuasively argue that the claims contain elements in addition to the judicial exception that either individually or as an ordered combination are not well understood, routine, or conventional. Another way for the applicants to overcome the rejection is to persuasively argue that the claims as a whole result in an improvement to a technology. Persuasive evidence for an improvement to a technology could be a comparison of results of the claimed subject matter with results of the prior art, or arguments based on scientific reasoning that the claimed subject matter inherently results an improvement over the prior art. The applicants should show why the claims require the improvement in all embodiments.
Previous 101 Analysis of record
For step 1 of the 101 analysis, the claims are found to be directed to a statutory category of a process.
Generally, the claims provide a method of screening substances for the possible genotoxic properties on genomic DNA of a cell in culture by analyzing read data obtained from the treated cell.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of accessing sequence data for variations/mutations of the sequences. The step of aligning and comparing sequence to arrive at the identification of variations between a test DNA and control or reference sequence, as well as quantitating what is observed are instructional steps. The judicial exception is a set of instructions for analysis of sequence read data and appear to fall into the category of Mathematical Concepts, to the extent the claims require counting the number of observed variations and also into the category of Mental Processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion), where here comparing aligned fragments of reads to determine potential differences appears to be instructions one can perform in one’s mind. The breadth of “comparing”, “obtaining”, and “classifying” encompasses non-transformative visual assessment of the read data that is obtained in the first steps. This breadth does not impose a meaningful limit on the claim scope, such that all others are not precluded from using the natural principle. Although the claims recite specific alterations that might occur, the courts have also identified limitations that did not integrate a judicial exception into a practical application; for example, merely including instructions to implement an abstract idea on a computer, or merely using a computer as a tool to perform an abstract idea, as discussed in MPEP § 2106.05(f).
Recent guidance from the office requires that the judicial exception be evaluated under a second prong to determine whether the judicial exception is practically applied. In the instant case, the claims do not have an additional element to which the analysis is applied, and provide a conclusion or determination of what was observed in the analysis. This judicial exception requires steps recited at high level of generality, and is not found to be a practical application of the judicial exception as broadly set forth.
For step 2B of the 101 analysis, each of the independent claims recites additional elements and are found to be the steps of obtaining sequence data from different cell sources. A review of the art provides that treating cells with genotoxic agents and analysis of high through put sequence analysis was known and is considered a conventional means to obtain read data for further analysis. As such, the claims do not provide for any additional element to consider under step 2B which provides significantly more.
To the extent the analysis could be performed using a general purpose computer and known software programs, for example for alignment of a test and reference read fragment, it is noted that in explaining the Alice framework, the Court wrote that "[i]n cases involving software innovations, [the step one] inquiry often turns on whether the claims focus on the specific asserted improvement in computer capabilities or, instead, on a process that qualifies as an abstract idea for which computers are invoked merely as a tool." The Court further noted that "[s]ince Alice, we have found software inventions to be patent-eligible where they have made non-abstract improvements to existing technological processes and computer technology." Moreover, these improvements must be specific -- "[a]n improved result, without more stated in the claim, is not enough to confer eligibility to an otherwise abstract idea . . . [t]o be patent-eligible, the claims must recite a specific means or method that solves a problem in an existing technological process."
As indicated in the summary of the judicial exception above and in view of the teachings of the specification, the steps are drawn to analysis of sequence read data. While the instructions for the method and the data for the reads could be stored on a medium and could be implemented on a computer, together the steps do not appear to result in significantly more than a means to compare sequences. The judicial exception of the method as claimed can be performed by hand and in light of the previous claims to a computer medium and in light of the teaching of the specification on a computer. In review of the instant specification the methods do not appear to require a special type of processor and can be performed on a general purpose computer.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
The closest art of record has been Matsuda et al. 2013 provide for the physical steps of a mutation assay using high throughput DNA sequence reads, and Matsuda et al. 2015 provide a similar mutation assay using single-molecule real-time (SMART™) sequencing technology. With respect to different test compounds, Matsuda et al. provide a comparison of AF-2 and DMSO effects on genomic DNA and quantitate the differences in frequency of mutations observed (see for example data in Table 1 and 2). Similar to Matsuda et al. Matsumura et al. teach a genotoxicity method using a NGS that enables sensitive detection of frameshift mutations and uses the evaluation NGS reads for quantification of point mutations and frameshift mutations for mutagens like ENU, and indicate that the method provides qualitative and quantitative information about mutagens on cells genomic DNA. More generally, Mortelmans et al. provides an overview of an Ames mutagenicity assay, and evidence of expectations for suspected mutagens and their effect on genomic DNA. Gundry et al. is provided as further evidence for direct, genome-wide assessment of DNA mutations in single cells and for the use of cell populations from flies and cultured MEF cells treated with ENU. Finally, Maslov et al. (2015) is provided for the teaching of genotoxicity assays and protocols for using NGS to precisely characterize mutations that result for applications of test mutagens to a variety of cell types.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Joseph T Woitach whose telephone number is (571)272-0739. The examiner can normally be reached Mon-Fri; 8:00-4:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz R Skowronek can be reached at 571 272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Joseph Woitach/Primary Examiner, Art Unit 1687
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