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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/7/2025 has been entered.
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
The second misnumbered claim 76 has been renumbered 77.
Applicant’s Amendment
Applicant’s Amendment filed 8/7/2025 has been received and entered. Claim 43-46, 51, 64-65, 72 have been amended, claim 77 has been added, and claims 1-42, 47-50, 52, 53, 56-63, 69 have been cancelled.
Claims 43-46, 51, 54, 55, 64-68, 70-77 are pending.
Election/Restriction
Applicant’s election without traverse of Group 3 in the reply filed on 11/12/2019 was acknowledged.
In prosecution, claims drawn to the non-elected inventions of products were cancelled.
Claims 43-46, 51, 54, 55, 64-68, 70-77, drawn to a method of determining genetic changes over time in a tumor are currently under examination.
Priority
This application filed is a 371 National stage filing of PCT/US2015/067717 filed 12/28/2015, which claims benefit to US provisional applications 62/155763 filed 5/1/2015 and 62/098426 filed 12/31/2014.
No comments regarding the summary of priority have been made in the instant response.
Information Disclosure Statement
The three information disclosure statements (IDS) submitted are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
For clarity of the record, it is noted that the cited references are office actions, which have been reviewed. However, no claims nor supporting references are provided for context of the actions, and evaluation of the provided citations has not been performed in the context of the prosecution of the applications from which these were obtained.
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 43-46, 51, 54, 55, 64-68, 70-76 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 because of the embodiments of the ‘molecular barcodes are configured to generate an at least a bi-partite encoded sequence’ and that ‘molecular barcodes and sequences of the plurality of polynucleotides are decoded to identify correspondence’ is withdrawn.
The limitations have been deleted from the claims.
Claims 43-46, 51, 54, 55, 64-68, 70-77 are 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. Specifically, while review of the specification provides for the use of barcodes for attachment and analyzing polynucleotide sequences, a search of the specification fails to provide literal support for ‘dual’ molecular barcodes which has been added to claim 43. It is unclear what the metes and bounds of this recitation, and it is unclear if there is any physical requirement of making a sequence ‘dual’. Further, while the specification provides for polynucleotide sequences as barcodes, it does not broadly provide for any ‘molecular barcode’ which appears to comprise other types of molecular structures, for example a sequence of lipid polymers which are attached. In review of the teaching of the specification, it does not appear that the claims as amended are supported by the present specification and now recite limitations not specifically contemplated. Moreover, the metes and bounds for what is required in the new limitation does not appear clear based on the specification nor the art of record. Dependent claims require the use of the identical dual molecular barcodes in the analysis and are included in the basis of the rejection because they fail to resolve the issue above.
More specifically providing structure to what is comprised in the barcode, or using limitations specifically supported by the specification would address the basis of the rejection.
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 43-46, 51, 54, 55, 64-68, 70-76 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 "the diversity" in claim 43 has been deleted resolving the issue.
Claims 43-46, 51, 54, 55, 64-68, 70-77 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. Specifically, the claims have been amended to recite ‘dual molecular barcodes’ and review of the specification fails to provide any literal support, nor any guidance to the metes and bounds as to any structural requirements of what is encompassed by ‘dual’. While the specification and the art provides for support that a barcode polynucleotide is sequence of a known order, it fails to provide what would make a sequence a dual barcode, or for clear support of any molecular structure besides a polynucleotide. Dependent claims require the use of the identical dual molecular barcodes in the analysis and are included in the basis of the rejection because they fail to resolve the issue above.
More clearly setting forth the nature or structure of the barcode consistent with the teaching of the specification would address 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 43-46, 51, 54, 55, 64-68, 70-77 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
Independent claim 43 has been amended and still is generally directed to identifying somatic changes which are detected in analyzing cfDNA from a subject that has a tumor. More specifically, new steps of analysis for grouping and generating a consensus sequence for families has been added, and it is the consensus sequence which is then aligned and analyzed for changes at different time points. In view of the guidance of the specification, the sequence reads analyzed are obtained from a sample with cfDNA and attaching through ligation a barcode to tag the cfDNA prior to amplification and sequencing. For sequencing, whatever the starting material represented in the cfDNA, only sequencing of a subset for a plurality variants is required. Dependent claims have been amended to more clearly set forth how the data is presented once analyzed, for example claim 46 provides for scaled measure versus time point to provide for a stacked graph. The new steps required are not physical steps of sample processing or sequencing, and provides generically for comparing the sequences of what might be present in the starting sample and does not provide for any specific sequences given the generic steps of ligation and sequencing set forth in the claims, and for the analysis only requires comparing the plurality that may be obtained over time.
Given the guidance of the specification, how sequences are tracked, each sample over time is different and with no specific tagging process required does not appear to associate a specific barcode with any specific sequence that might be present in the sample with respect to ‘decoded’ sequences or any specific ‘correspondence’ as amended.
With respect to any specific use or processing using a ligated barcode, to the extent the claims recites a dual molecular barcode as amended, it appears to encompass generically attached polynucleotide sequence of a known sequence to a cfDNA present in the starting sample, the specification finds literal support and guidance on the use of the term ‘barcode’ 14 times and teaches:
“[00150] Following the isolation/extraction step, any of a number of different sequencing operations may be performed on the cell free polynucleotide sample. Samples may be processed before sequencing with one or more reagents (e.g., enzymes, unique identifiers (e.g., barcodes), probes, etc.). In some cases if the sample is processed with a unique identifier such as a barcode, the samples or fragments of samples may be tagged individually or in subgroups with the unique identifier. The tagged sample may then be used in a downstream application such as a sequencing reaction and individual molecules may be tracked to parent molecules.
[00151] The cell free polynucleotides can be tagged or tracked in order to permit subsequent identification and origin of the particular polynucleotide. The assignment of an identifier to individual or subgroups of polynucleotides may allow for a unique identity to be assigned to individual sequences or fragments of sequences. This may allow acquisition of data from individual samples and is not limited to averages of samples. In some examples, nucleic acids or other molecules derived from a single strand may share a common tag or identifier and therefore may be later identified as being derived from that strand. Similarly, all of the fragments from a single strand of nucleic acid may be tagged with the same identifier or tag, thereby permitting subsequent identification of fragments from the parent strand. In other cases, gene expression products (e.g., mRNA) may be tagged in order to quantify expression. A barcode or barcode in combination with sequence to which it is attached can be counted. In still other cases, the systems and methods can be used as a PCR amplification control. In such cases, multiple amplification products from a PCR reaction can be tagged with the same tag or identifier. If the products are later sequenced and demonstrate sequence differences, differences among products with the same identifier can then be attributed to PCR error. Additionally, individual sequences may be identified based upon characteristics of sequence data for the read themselves. For example, the detection of unique sequence data at the beginning (start) and end (stop) portions of individual sequencing reads may be used, alone or in combination, with the length, or number of base pairs of each sequence read to assign unique identities to individual molecules. Fragments from a single strand of nucleic acid, having been assigned a unique identity, may thereby permit subsequent identification of fragments from the parent strand. This can be used in conjunction with bottlenecking the initial starting genetic material to limit diversity.
[00152] Further, using unique sequence data at the beginning (start) and end (stop) portions of individual sequencing reads and sequencing read length may be used, alone or combination, with the use of barcodes. In some cases, the barcodes may be unique as described herein. In other cases, the barcodes themselves may not be unique. In this case, the use of non-unique barcodes, in combination with sequence data at the beginning (start) and -43-end (stop) portions of individual sequencing reads and sequencing read length may allow for the assignment of a unique identity to individual sequences.”
The new steps for grouping, aligning and graphing results over time are consistent with ‘tracking’ as previously analyzed, and support in the specification which teaches:
“Molecular tracking methods can be useful in such situations. Molecular tracking involves tracking sequence reads from a sequencing protocol back to molecules in an original sample (e.g., before amplification and/or sequencing) from which the reads are derived. Certain methods involve tagging molecules in such a way that multiple sequence reads produced from original molecules can be grouped into families of sequences derived from original molecules. In this way, base calls representing noise can be filtered out. Such methods are described in more detail in, for example, WO 2013/142389 (Schmitt et al.), US 2014/0227705 (Vogelstein et al.) and WO 2014/149134 (Talasaz et al.).”
which appear to provide for the indication that methods of using barcodes for tracking, in ways and methods known in the art, but the claims nor the specification provide for the specific limitations provided in these cited references.
Newly added dependent claim 77 provide for possible result interpretation of types of cfDNA sequences and possible mutations that may be observed or consistent with a ‘consensus sequence’, as amended when tumor heterogeneity or copy number difference may be detected/determined to be present among the genes in the panel of reads.
Additionally, as noted previously ‘generating a tumor response map” by normalizing and applying a scaling factor to provide for a graphical representation in review of the specification for the requirements of this step, at paragraph [00124] teaches a graphical map is:
“FIG. 9B shows an exemplary process to generate genetic reports, including a tumor response map and associated summary of alterations. A tumor response map is a graphical representation of genetic information indicating changes over time in genetic information from a tumor, e.g., qualitative and quantitative changes. Such changes can reflect response of a subject to a therapeutic intervention.”
and for the steps that result in the response map at paragraph [00134] it teaches:
“Next, a tumor response map is generated. To generate the map, the process can comprise normalizing the quantities for each gene alteration for rendering across all test points and then generates a scaling factor (34). As used herein, the term "normalize" generally refers to means adjusting values measured on different scales to a notionally common scale. For example, data measured at different points are converted/adjusted so that all values can be resized to a common scale. As used herein, the term "scaling factor" generally refers to a number which scales, or multiplies, some quantity. For example, in the equation y = Cx, C is the scale factor for x. C is also the coefficient of x, and may be called the constant of proportionality of y to x. The values are normalized to allow plotting on a common scale that is visually-friendly.”
and appears to provide for how the graph is presented for a ‘visually-friendly’ presentation of the data, and does not appear to necessarily change the data and given the broad general nature of the steps appears dependent on the data for what normalization would or could encompass or generally be done, as well as the need for a scaling factor.
In review of the guidance of the specification, none of the new limitations appear to affect the data per se and are consistent with known methods previously used to tag and track nucleic acids to a sample, and for the resulting data may provide for a means to simply interpret the data in graphical form which may be easier to read in a common scale. Overall, the limitations required of the claims do not appear to have affected the scope of the claims with respect to a requirement that a plurality of tagged cfDNA sequences being provided/sequenced over time for analysis except the number initially provided by sequencing; and require providing a series of tagged/barcoded samples containing cfDNA over time, sequencing the cfDNA in the samples, and determining with a computer implemented method any somatic change or variant within the reads over time and representing the results graphically if present. Dependent claims have been amended to correct grammatical issues, and still provide for what the quantitative measure is and how the information from the analysis is presented, as well as the source of the cfDNA being in the blood, plasma or serum and how it is tagged for preparation of sequencing.
For step 1 of the 101 analysis, the claims are found to be directed to a statutory category of a method of providing, sequencing and analyzing tagged cfDNA reads.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of accessing sequence read data for possible sequence changes over time and c) determination of possible changes and graphically presenting the information in a normalized and a scaled presentation if present. As amended the claims still provide the step where a quantitative measure is determined, and now the determination is displayed as a normalized and scaled representation of the step. The step of determining given the guidance of the specification and art of record, requires the step of aligning and comparing sequence to arrive at the identification of possible changes in the read sequences are considered instructional steps. The claim requires computing similarity scores based for potential differences, and thus determine a potentially somatic sequence changes. The judicial exception is a set of instructions for analysis of sequence data and falls into the category of a mental processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion).
In prosecution the claims have been amended to recite ‘sequencing a plurality, reducing the amount of information from at least 1,000,000 (and previously from 5000) of the polynucleotides and in review of the specification the claims do not require any specific means in which the subset is provided or what the panel be assessed is, nor what they represent beyond that they were derived from a sample. In review of the specification and the requirement of the claims, the importance of the ‘plurality’ and what it represents relative to the data analyzed does not suggest a complexity rather simply an amount of reads to be analyzed, and could represent copies of an amplified locus of interest or random reads which are not necessarily informative to the analysis steps. Further, while step a) of the claim as amended appears to be directed to analysis of reads from a single patient, the specification teaches that the plurality can be interpreted as read data, and suggests that alignment and quantification of the types and number of variants at a specific allele/locus of interest would be a simple matter of observation. Given the plain meaning and general guidance of the specification, the plurality can be of one target of interest (see claim 44 for limitation of same locus), making the alignment and comparison straightforward. In view of the guidance of the specification would target sequencing a limited number of specific genes (supported in the explanation and figure 10D for example). Comparison and analysis of specific sequences can be performed by observation in one’s mind or on paper, and can be represented with a simple graph with any choice of colors of any changes if observed in the data.
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 an additional element which is directed to obtaining the read data that is subsequently analyzed in the judicial exception and does not appear to be a practical application of the judicial exception. There is no special barcode or means of attaching beyond that which is known in the art, and the steps generically provide for a barcode attached to a cfDNA which is sequenced for sequence read data which is analyzed. This judicial exception requires steps recited at high level of generality and are only stored on a non-transitory, and is not found to be a practical application of the judicial exception as broadly set forth. Dependent claims set forth further indication of how the results are presented, an indication of the specific sequences analyzed are ‘oncogenes’ (see claim 54), and that over the time period the patient was being treated (claim 64). With respect to treatment, it is noted that this is prior to the sample be analyzed, and the method as a whole is broader than this requirement and in this embodiment simply analyzes samples to observe possible changes or correlations to the presences of detectable cfDNA within a sample.
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 which were well known and conventional as provided by Forshew et al 2012 and Ding et al 2012. Additionally, steps for providing barcodes for sequencing or for tagging sequences for downstream processing were also known noting Schmitt et al, Vogelstein et al and Talasaz et al, as acknowledged in the specification in [0095] which is used for subsequent sequence read analysis. The data obtained from the steps considered the additional element are separate and appear to provide data for subsequent analysis and the judicial exception does not affect these steps, and as such, the claims do not provide for any additional element to consider under step 2B as a practical application or significantly more than analyzing possible changes within a sample as a whole. It is noted that in prosecution the method was amended so that the analysis is ‘by a computer’, however 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 data of cfDNA possibly present in sample. For implementing with a computer, while the instruction are 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.
Response to Applicants arguments
Applicants provide an overview of the invention and the guidance of 101 set forth in Alice. For step 1, describing the limitations of the claims, it is noted that the claims for providing physically tagging with barcodes to provide a cfDNA tagged with a barcode. Noting the guidance of the specification and argue that there are material changes and affects the analysis of a plurality of sequence reads and that a simple generic panel of genes corresponding genomic regions are analyzed over time. Applicants argue that using molecular barcoding and the diversity of polynucleotides is specific and provides structured data and represents a physical manifestation of the original sample. Applicants provide a claim from Ex parte Blundell and Ex parte Zhou from the PTAB for comparison and argue that the fact pattern supports patent eligibility because there is no factual finding that the claims could be practiced in one’s mind.
In response, the analysis of the reads is considered part of the judicial exception, and as amended the claims appears to still provide for the analysis of possible changes to a sequence over time does not appear to be beyond observation. It is unclear what factual evidence is necessary to support that looking at a plurality of aligned sequences that similarities and differences could not be observed. Further, what is required beyond counting the number of reads that possibly align as a means of quantitating the cfDNA that might be present in the original sample. While each prosecution stands on its own merit, the claims provided appear to be different types of data that is being analyzed, 3D molecular structures versus here simple linear sequences. For the instant claims, it is unclear what difficulty exists in comparing aligned sequences for similarity and differences, and the fact pattern of the cited cases do not appear to be consistent nor applicable to the instant claims. The claims provide broadly and generically for steps of comparing sequence reads that have been tagged with a barcode, where the sequences are grouped as possible consensus sequences, then quantitated over time from different samples, all analysis steps which appear could be accomplished for known reference gene sequences.
New amendments for providing adding dual barcodes to sequences in a sample and sequencing them would be expected to provide tagged sequences represented in the sample where previously considered as necessary, and as analyzed above and acknowledged in the specification were well known and conventional for providing tagged sequence reads. What is left it the judicial exception for processing the reads and there does not appear to be any specific processing of applying the barcodes to any specific sequence, and it appears to simply act as a tag and extra sequence information and does not appear to provide an new or element of structured data as argued. For comparisons, with or without a barcode, once a sequence is aligned, ie for aligned sequence reads provided over time, one simply has to scan the aligned reads for possible differences between the aligned reads and appears to be an observational step one can easily perform. Providing a plurality or even a large number of aligned reads or specific gene panels or assessing these for the number of potential variants does not appear to be more than instructions and observation.
Applicants argue that the claims use barcoded to solve a technical problem of analyzing cfDNA that represents tumors to reduce noise by using consensus based calling. Applicants argue that the claims are more than collecting and displaying data and that particular machines are necessary to monitor the changes present in the cfDNA comparing the improvement to that in Adasa v Avery.
As noted previously, with respect to Applicants note Adasa Inc v Avery and the use of MSB in RFIDs that were used to speed processing and communication load to a central database, it does not appear that the fact patterns are the same such that the claims are patent eligible. In Adasa, the process of encoding information were integrated into the process of how RFID functions, whereas here the barcodes are simply additional sequence data and do not appear to be important in processing and appear to provide additional handling and information to process, not less, and do not improve the analysis given the evidence of record. Again, it is noted that there is no requirement or steps provided in the claims that the analysis results necessarily in useful information, or that it is applied to the treatment of a patient for analysis relative a practical application of the judicial exception. The claims have been amended, but there is no specificity to what is collapsed or how, such that there is an improvement. With respect to evidence, for possible improvements over the cited art it is unclear what the improvements are provided by the instant claims, for example it has been noted that Ding et al provide a detailed study of the clonal evolution in AML by whole genome sequencing and provide for over 5000 reads in the analysis. Also, the analysis of Ding et al. of AML samples over time of several specific alleles demonstrates that mutation clusters can be detected, and extend previous studies that copy number, presences of SNPs and other alterations in breast and pancreatic cancer metastases can successfully be analyzed by analyzing sequences over time, and that correlations for specific changes could be identified and correlated to more successful chemotherapeutic treatment and patient care. Similarly, Forshew et al. provide for methods that analyze cfDNA as a non-invasive means for identifying and monitoring cancer mutations by sequence analysis (providing for steps a and b, and analysis elements of c and d). Forshew et al teach isolating cfDNA to study metastasis in cancer patients and demonstrate that several gene alterations can be detected and correlated with patient prognosis/diagnosis. In the methods, Forshew et al. provide for sequencing of alleles/genes of interest where the sample is amplified and PCR barcoded for analysis. The frequency of alterations are identified, and analyzed over time for clinical relevancy. Providing barcodes to a sample source which are known and used in some sequencing platforms and protocols also do not appear to provide any additional improvement to the claims. While it is generally acknowledged that in patient care it is practical to provide clinical analysis of a patients status, and to monitor and treat the patient over time (as appears to be provided by Forshew and Ding and the art of patient care as a whole), the present claims do not appear to provide for significantly more than steps to analyze read data from a cancer patient to identify a possible correlation that may exist in 5000 reads, nor a specific or practical application of the analysis steps as set forth in the claims. The mathematical process of normalizing and scaling of data if necessary appears to be simply a manipulation of the data for possibly variations on graphical views or means of comparison, but do not fundamentally change the data, and it is unclear how a graphical presentation of stat is any improvement over providing the data in a table form and is simply a means of exhibiting the data analysis.
As stated above and in the record, in the basis of the rejection it was noted that changes in cfDNA were known and could be used to monitor cancer progression. Noting the teachings of Forshew et al 2012, analysis of variants/mutations in cfDNA was performed and Forshew et al specifically teach that changes over time over time to monitor for relapse (see page 8, bridging columns 1 and 2 for example). Applicants argument that cancer treatment can be challenging, however the present claims do not provide for treatment and provide for the same type of monitoring of cancer in a patient as provided by Forshew et al who reduce to practice monitoring ovarian cancer in a patient over time. Additionally, the claims do not provide a subsequent step of treatment where the judicial exception of analysis is practically applied, and given the guidance and evidence of record, the steps as a whole do not appear to provide for significantly more. In review of the specification, there does not appear to any guidance on how any specific change would result in any form of treatment or care of a patient if identified among the reads over time.
In prosecution it has been acknowledged that the claims require providing barcoded cfDNA molecules and are tangible elements, and evidence that these claim limitations are not a mental process. Examiner has considered them as additional elements. However, the presence of additional elements is not by itself sufficient to make a recited judicial exception patent eligible. In the current analysis of the claims based on the breadth and guidance of the specification, it was found that the additional elements were known conventional steps for providing sequence reads, and that the judicial exception was a separate process of analyzing the read data that did not affect how the data was obtained. Unlike in Diehr, the analysis provided information about the orientation of the package as it was transported affecting the method as a whole, whereas here the information provided in the form of a plurality of sequence reads are simply analyzed and the analysis results displayed without affecting the process as a whole. As noted, at the time of filing it was known that tumors produce cfDNA and that increased quantities were detected in the circulation which were analyzed by a variety of methods. The claims do not appear to provide for an improvement to sequencing, or as a whole to monitoring variation in cancer/tumor development as evidenced by both Forshew et al 2012 and Ding et al 2012.
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.
Conclusion
No claim is allowed.
In prosecution evidence supports that the use of cfNA or cfDNA was known to represent the whole body and Forshew et al was cited for the teaching isolating cfDNA to study metastasis in cancer patients and demonstrate that several gene alterations can be detected and correlated with patient prognosis/diagnosis. Forshew did focus on a specific panel of genes in the analysis of the cancer, however this was to analyze directly known genes correlated with the cancer they were studying. Further, each of Forshew et al, Vogelstein et al and Ding et al provide for graphical representation of their analysis and both indicate that some alleles would be over-represented and under-represented based on the level of sequence depth and based on the biology of the alleles of the cancer and the progression that is being studied, but they fail to specifically state that the data points should be normalized and scaled for graphical representation.
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