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 .
Applicant’s amendment
Applicant’s amendment filed 8/7/2025 has been received and entered. Claims 10, 11, 19, 20, 22 and 59 has been amended and claims 1-9, 12, 14-18, 21, 23-58 have been cancelled.
Claims 10, 11, 19-20, 22 and 59 are pending.
Election/Restriction
Applicant’s election without traverse of the species of frequency of genetic variants from claim 10 and blood samples from claim 22 in the reply filed on 2/1/2021 was acknowledged. In prosecution, the initial search and review of the guidance of the specification suggested that it would not be an undue burden to examine all the species recited in the claims and the restriction requirement was withdrawn.
Claims 10, 11, 19-20, 22 and 59 are pending and currently under examination.
Priority
This application filed 10/27/2017 is a Continuation of PCT/US2016/030301 filed 4/29/2016, which claims benefit to US provisional application 62/155755 filed 5/1/2015.
No comments have been made by Applicants instant response.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/7/2025 and 11/3/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Two cited references are Office. It is noted that for review of these, the pending claims that were reviewed in these actions were not provided, but for completeness and clarity of the record the cited references when provided in this prosecution were not considered in light of the instant claims.
Claim Rejections - 35 USC § 112
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 10, 11, 19-20, 22 and 59 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.
The limitation of ‘an at least bi-partite encoded sequence read’ and for the terms ‘decode’ and ‘encode’ which did not appear to support sequence reads, rather with operations of a computer for example in [00219] have been deleted from the claims.
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 10, 11, 19-20, 22 and 59 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 limitation of ‘an at least bi-partite encoded sequence read’ and for the terms ‘decode’ and ‘encode’ have been deleted from the claims.
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 10, 11, 19-20, 22 and 59 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 analysis
Claim 59 has been amended and still is generally directed to a method of analyzing a disease state of a subject by analyzing sequence reads in two different sequence runs, where when a variant/mutation seen in both runs indicates that the variant/mutation is associated with a disease as provided by the use of diagnostic confidence factors in the comparison as a form of the outputted data. Specifically, claim 59 has been amended to delete the use of a barcode and requires now generating with a sequencing instrument two sequencing runs from a sample and identifying candidate variants which exist in both runs to corroborate the presence of the variant and as an increased diagnostic confidence as a true variant, based also in part by other ‘co-variate’ sequences that might be informative in evaluating the read data.
Given the guidance of the specification for interpreting the claim requirements, DNA molecule reads that are generated and analyzed by comparing a plurality of reads for any possible variants. The pre-amble has a ‘method for detecting at least one genetic variation’ which is accomplished through analyzing the reads that are generated from the cell free sample and DNA that is present within. Given the breadth of the claims and guidance of the specification the claims are directed to steps of obtaining sequence reads form an analyzer following a computer implemented method where the two sets of sequence suns are analyzed for their presence and possible variants that might exist. Dependent claim 21 has been deleted for the use of different sources of the sample but still comprised within the breadth of the independent claim, and remaining claims set forth physical limitations that the sample analyzed, blood and further details on the analysis of the reads data that is obtained.
For step 1 of the 101 analysis, the claims are found to be directed to a statutory category of a process.
The claims provide for a method that is used to obtain sequence read data and instructions for analysis for possible variants that may exist in the resulting read data.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of accessing and analyzing sequence data at two different time points and assigning a confidence interval to the information that is used a diagnosis based on the variant and correlation of the variant with disease or health of a patient. In view of the guidance of the specification the analysis requires aligning and comparing sequence to arrive at the identification of variants/mutations wherein the observation is converted to a confidence interval for a given sample and patient and appear to be abstract instructional steps for the analysis of the read data. The source of the reads is not defined, and the claim does not necessitate or require that any genetic variation exist, nor does the claim have any specific platform for the reads or interpretation that the reads necessarily comprise reads with ‘noise’ for potential variations introduced in a process of obtaining reads where if a variant existed it would represent ‘noise’ (again it is noted that there are no steps required for obtaining the reads only obtaining the data set for a locus). The judicial exception is a set of instructions for analysis of sequence data and appears to fall into the category of Mental Processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion). Here sequences representing sequences associated with a disease or health of a patient are simply compared and used to provide a diagnosis. With respect to reviewing or assessing the reads at any possible locus, it does not appear that reviewing reads directed to any specific locus is necessary, and the analysis required is simply a difference between aligned sequences which can easily be observed, and if they exist could be counted as part of the analysis steps set forth in the claims. For the analysis and calculations encompassed by the claims, a review of the specification provides general guidance for what a confidence value may be, but appears to rely on the art to determine a variant and co-variants for the final correlation/diagnosis step of the claims. For example the specification teaches at [000103] that:
“Co-variate detection may increase the probability, likelihood, and/or confidence
that a variant is accurately detected. For co-variate genetic variants, the presence of one genetic variant is associated with the presence of one or more other genetic variants. Based on the detection of a co-variate genetic variation, it may be possible to infer the presence of an associated co-variate genetic variation, even where the associated genetic variation is present below a detection limit. Alternately, based on the detection of a co-variate genetic variation, the diagnostic confidence indication for the associated genetic variation may be increased. Further, in some instances where a co-variate variant is detected, a detection threshold for a co-variate variant detected below a detection limit may be decreased. Non-limiting examples of co-variate variations or genes include: driver mutations and resistance mutations, driver mutations and passenger mutations. As specific example of co-variants or genes is EGFR L858R activating mutation and EGFR T790M resistance mutation, found in lung cancers. Numerous other co- variate variants and genes are associated with various resistance mutations and will be recognized by one having skill in the art.”
In all, the practice of the analysis steps considered to be the judicial exception appear to be steps that one can perform in one’s mind, like the recognition of co-variants or genes is EGFR L858R activating mutation and EGFR T790M resistance mutation found in lung cancers or as stated in the specification other co- variate variants and genes are associated with various resistance mutations and will be recognized by one having skill in the art (see paragraph [000101]).
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 have the additional element of obtaining sequence reads by known conventional means, and the judicial exception does not appear to be a practical application of sequencing, rather analysis of the data obtained. The claims do not have an additional element that follows or applies the judicial exception, and provided the instruction to use the correlation as a means of identification of a variant if one is identified in the data that is first provided. This judicial exception requires steps recited at high level of generality and in implementation with a computer are instructions that are only stored on a non-transitory, 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 encompasses additional elements and are found to be the steps of obtaining sequence data. See for example the general guidance at [00086] for the term "DNA sequencing system" and the general guidance that effectively any sequencing technique can be used to provide the data.
The claims now require two sequence runs, where the data between two runs is used in the analysis. A search of the art provides evidence that analyzing read data from two or more runs was known, as evidenced by Wall et al (2014) who teach estimating genotype error rates from high-coverage next-generation sequence data from different samples, different depths and different runs. As such, the claims do not provide for any additional element to consider under step 2B that appears to be significantly more. With respect to the use of a computer for the analysis 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." Here, there does not appear to be a specialized computer or that the analysis steps make the computer function in any particular way, they are only steps for instructions to compare and use sequences that can be correlated to a diagnosis.
Response to Applicant’s arguments
Initially it is noted that Applicants provide arguments for ‘tagging DNA molecules’, and some use thereof, however while encompassed this requirement has been deleted from the claims. There is no specific use of barcodes required of the claims.
Applicants note that claims have been amended to indicate that the DNA molecules analyzed were tagged or tracked with barcodes to single nucleic acids.
In response, to the extent the claims can encompass tagged DNA the amendments have been acknowledged and analyzed above. Also, with respect to tagging and sequencing DNA in a sample as proposed, an active step of tagging and sequencing to obtain reads for further analysis is found to fall under the analysis of step 2B, and given the broad general nature of the claim requirements appear to be routine and conventional steps for obtaining reads as discussed in prosecution and as taught in the specification. Steps of sequencing which use barcoding and analysis of cfDNA were known in the art given the evidence of record.
Applicants note the amendments and argue that the claims provide for structured data for the variants and barcodes when analyzing cfDNA noting the fact pattern here of Guardant can be compared to that in Adasa v Avery.
In response, the fact pattern of the instant claims and the invention of Adasa for a memory block in a RFID do not appear to be similar. For Adasa, it appears to material affect the function of the RFID whereas here there is not structured data generated, rather it is simply the data analyzed and the interpretation of what the reads may represent once analyzed. There is no structured data resulting from practicing the method steps, rather it is the result of the analysis and provides a confidence value based possible variants detected in the data. Once the data is obtained, steps c)-e) are steps that analyze and interpret the analysis of sequence data and are found to be a judicial exception for instructions that fall into the category of mental process and can be performed in ones mind or with the use of paper. Even if multiple sequences are to be compared, the comparison of two aligned sequences for possible differences does not appear to be beyond a mental process that can be performed by observation. The conclusion of the analysis of a ‘diagnositic confidence indication’ generically provides that if the two time points are the same, then you are confident that the information corraborates itself, if it does not lower one’s confidence of what the data represents.
As analyzed under 2B, given the breadth and general nature of using a barcode attached to a cfDNA to obtain read data it is found that the means of tagging or using a barcode for obtaining sequences (like the process of PCR) are known conventional techniques known in the art and are not to be new or inventive. What is left is whether the claims address a problem or overcome a difficulty. Here, it can be acknowledged that the analysis of sequence data must ensure a measure of ‘confidence indication’ in what is provided. The proposed solution the instant claims provide is to survey two different time points and compare the sequence data obtained from these two time points. For simplicity, if the samples from two different time points are identical, then the solution the claims provide is test the sample twice to ensure the resulting sequence process and data provide the same sequence. However, the claims do not provide steps for obtaining the sequence data, and the claims provide additional potential complications if the sample are not identical and could provide different sequences. In this case, the confidence indicator would be irrelevant or misleading if the samples represent different sources, and serve to create problems or caveats in Applicant’s arguments.
It is noted that the claims have been amended from the sue of 1000 reads to one or more and providing a plurality of reads which are to be analyzed, which previously Applicants argue could comprise billions of information data related to genomes which cannot be performed in the human mind. With respect to the judicial exception and ability to practice this in ones mind, having only a plurality of reads is much less than 1000 reads or billions as noted in the specification. With respect to the interpretation of the claims, an evaluation of the guidance of the specification was provided to illustrate the limitations and breadth of the claims. For example step a) requires ‘generating’ however given the lack of specific definition this can be interpreted as the physical steps of generating reads using a sequencing platform (as discussed in step 2B) or alternatively the data is generated by processing read data for example from a data source representing whole genome sequencing data to come to the 1000 sequence reads for analysis in the subsequent steps. The overall guidance of the specification is acknowledged, and the claim analysis has been performed in light of its review, however specific limitations and requirements are not imported into the claims unless expressly defined. In the explanation of the claim limitations the claims were given the plain meaning, and the note to the teachings of the specification was provided as examples of contemplated embodiments that could be performed in one’s mind. In response, the amendments have been analyzed above but there are no necessary requirements that the read data contain any errors/noise, nor that any genetic variant even exist between the two sources of read data. With using a ‘large’ plurality, it has been noted that the concept of deep sequencing was known, and accessing and reviewing many aligned reads for possible variants does not appear to be an improvement to a sequencing process as it is assessing the sequencing process, not affecting the process itself.
Applicants arguments and the claim amendments have been fully considered, but not found persuasive. 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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 10, 11, 19-20, 22 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Wall et al (2014) and Lo et al.
Claim 59 has been amended and provides a method of analyzing a disease state of a subject by analyzing sequence reads in two different sequence runs, where when a variant/mutation is seen in both runs, this indicates that the variant/mutation has a higher confidence of not being an error introduced by the processing and then can be associated with a disease as provided by the use of diagnostic confidence factors in the comparison as a form of the outputted data. To the extent the invention requires analyzing a wide source of samples to detect possible variants or mutations, Lo et al. is noted for the teaching of a method to detect one or more genetic variations and/or amount of genetic variation in a subject It is noted that Lo et al fails to teach the need or necessity to provide for a comparison to update a diagnostic ‘confidence indication’ or that a diagnostic confidence indication is indicative of a probability of identifying one or more genetic variations, in particular since many mutations or variants known in the art (and which the present claims/specification relies on to enable the present claims) are associated with diagnosis or prognosis without the need of confidence indicator. However, evaluation of the quality of read data was well known. For example, Wall et al. provide a summary of various conditions, platforms and analysis means for estimating genotype error rates from high-coverage next-generation sequence data. While Wall et al. do not specifically teach to provide two runs to compare possible errors associated with the processing to sequence read data, it is clear that data integrity associated with processing is a recognized issue. Given the detailed guidance for various issues associated with various conditions as provided by Wall et al. it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to rely on more than two reads to establish that a variation in the read data was in fact related to the source and sample versus an issue introduced with processing. One having ordinary skill in the art would have been motivated to ensure that any novel variant was in fact reflective of the source of material which the data represents and would provide the necessary conditions, such as analyzing a sample twice or more to confirm that the data truly represents the sample. Given that the method requires known techniques to obtain the sequence reads, and the detailed guidance of issues pertaining to various conditions and possible considerations that might arise, there would have been a reasonable expectation of success to provide read data from two runs and to evaluate the reads to confirm the existence or to evaluate differences between the data runs, to provide a higher confidence in the data before providing any medical or research application to the data.
Thus, the claimed invention as a whole was clearly prima facie obvious.
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.
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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/Joseph Woitach/ Primary Examiner, Art Unit 1687