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 .
Status of the Application
Claims 1-15 are pending and under examination
The following Office Action is in response to Applicant's communication dated 01/31/2024.
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 1-15 are rejected under 35 U.S.C. 101 because the claimed invention(s) is/are directed to one or more judicial exceptions (i.e., product of nature, a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claims 1 recites a method to “detect a mutation from a liquid biopsy of a patient, the method comprising the steps of ” (i) collect DNA sample, (ii) prepare DNA library; (iii) sequencing the DNA library; (iv) identifying DNA variant; (v) grouping DNA fragments base on sizes; and (vi) detecting a mutation as tumorous or healthy based on the presence of the DNA variant fragments is directed to one or more of a law of nature, a natural phenomenon, a product of nature, and an abstract idea. Specifically, step (vi) of comprises concept(s) represent the natural correlation between measured biomarkers and a disease state (e.g. tumorous or healthy), being a law of nature and/or natural phenomena as per MPEP 2106.04(b)(I). Therefore, the claim recites one or more judicial exceptions as per Prong One of the revised Step 2A analysis from the 2019 Revised Patent Subject Matter Eligibility Guidance issued Jan. 7, 2019 in the Federal Register Vol. 84, No. 4. The same Guidance requires analysis of Prong Two, which is whether the claim recites additional elements that integrate the exception(s) into a practical application of that exception(s). In the instant case, the additional element(s) is/are (i) collect DNA sample, (ii) prepare DNA library; (iii) sequencing the DNA library; (iv) identifying DNA variant; and (v) grouping DNA fragments base on sizes do not represent a practical application of the exception(s) since they simply are routine laboratory and bioinformatic techniques to obtain and analyze data used to observe the natural correlation. Such activities constitute insignificant extra-solution activity and required data-gathering steps rather than a practical application of judicial exception. See MPEP 2106.05 (d) and (g). Therefore, the claims must further be analyzed to identify additional elements to determine whether the claim as a whole amounts to significantly more than the judicial exception (i.e. Step 2B of the analysis).
For claim 1, the additional elements consist of (i) collect DNA sample, (ii) prepare DNA library; (iii) sequencing the DNA library; (iv) identifying DNA variant; and (v) grouping DNA fragments base on sizes do not represent a practical application of the exception(s), since these constitute routine, convention, and well-understood activities known in the industry at the time of the invention, specified as a high level of generality, and therefore, are not enough to qualify as "significantly more" when recited with the judicial exception of the claim. Further, as discussed in MPEP 2106.05(g), when the additional steps (i.e., other than the judicial exception(s)) are limitations that are well known or amount to necessary data gathering steps, they are considered to be Insignificant extra-solution activities does not amount to an inventive concept. Note that the Supreme Court in Parker v. Flook, 437 U.S. 584, 588-89, 198 USPQ 193, 196 (1978) reasoned that "[t]he notion that post-solution activity, no matter how conventional or obvious in itself, can transform an unpatentable principle into a patentable process exalts form over substance." This is conclusion is equally true both when considering the steps individually and as an ordered combination.
Claims 2-4, 6, 8, and 15 merely add particular decision criteria (mutation frequency threshold, comparison of first and second groups, or additional applications of the same fragments length analysis). These limitations define how natural correlation is interpreted. They do not alter the finding that the claims still directed to the judicial exception without significantly more. See Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017).
Claim 5 limits DNA library to a single-stranded or a double-stranded DNA library. Library in either format was routine, conventional, and well understood at the time of filling and therefore cannot transform judicial exception into patent eligible subject matter. See Genetic Technologies Ltd. v. Merial LLC, 818 F.3d 1369, 1377, 118 USPQ2d 1541, 1547 (Fed. Cir. 2016).
Claim 7 and 13 merely limits the circumstances to which liquid biopsy is obtained (e.g. before a treatment, during a treatment, after a treatment, remission phase, relapsed phase). This limitation identifies the timing of data collection and do not amount to significantly more. See MPEP 2106.05 (h) & (g).
Claims 9 are also directed to the same judicial exception discussed with respect to claim 1 because claim 9 expressly require performing the method of claim 1, includes detecting a mutation as tumorous or healthy based on the presence of the DNA variant fragments in the first group and in the second group, which recites the natural correlation discussed above. The additional limitations of sequencing a tumor biopsy, identifying mutations, designing a patient specific sequencing panel, characterizing mutations merely provide additional data gathering and analysis used to detect and characterize the natural correlation recites in claim 1. The additional steps are conventional sequencing and probe design techniques and do not integrate the judicial exception into a practical application. Additionally, these steps considered individually or in combination do not amount to significantly more than the judicial exception.
Claim 10 merely limits the circumstances to which liquid biopsy is obtained (e.g. remission phase). This limitation identifies the timing of data collection and do not amount to significantly more. See MPEP 2106.05 (h) & (g).
Claims 11 and 12 further recite adapting and applying treatment based on the personal mutation profile. However, the claims do not identify any particular therapeutic agents, dosage, treatment regimen, or protocol. Rather, the claims broadly encompass adapting or applying any treatment base on the diagnostic information generated from the judicial exception. Accordingly, these limitations are not sufficient to integrate the judicial exception into a practical application and do not add significant more. See MPEP 2106.04(d)(2) for discussion of what constitutes "particular treatment" steps that may be applied to integrate the claim as a whole into a practical application.
Claim 14 further recites generating a theranostic report. Generating or presenting diagnostic information is only the outputs results obtained from application if the judicial exception and does not integrate judicial exception into a practical application and does not amount to significantly more. See MPEP 2106.05 (g).
For further information, please see the latest revision of M PEP 2104-2106 {Patent Subject Matter Eligibility Under 35 U.S.C. 101 }, including M PEP 2106.04 {Eligibility Step 2A: Whether a Claim is Directed to a Judicial Exception} and 2106.05 {Eligibility Step 2B: Whether a Claim Amounts to Significantly More}, as well as the guidance on Subject Matter Eligibility, including the 2019 Guidance issued Jan. 7, 2019, and the October 2019 Update, provided on the US PTO website at https://www.uspto.gov/patent/laws-and-regulations/examination-policy/subject-mattereligibility.
Claim Rejections - 35 USC § 102
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.
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-5, 7, 8, and 15 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Jiang et al. (WO2018195483A1, disclosed in IDS).
Regarding claim 1, Jiang discloses method to detect a mutation from a liquid biopsy of a patient, the method comprising the steps of: (i) collecting DNA fragments from said liquid biopsy (e.g. cfDNA fragments obtained from the test sample, such as: blood, saliva, urine, and other biological fluid [¶0005])
(ii) preparing a DNA library of the DNA fragments from said liquid biopsy by preserving DNA fragments length; (e.g. prepare library from cfDNA fragments extracted from a sample, wherein the library preserves fragment lengths of the cfDNA fragments [¶0007])
(iii) sequencing the DNA library and collecting sequencing data of the DNA fragments of the DNA library, wherein sequencing the DNA library is done by a targeted sequencing using a targeted panel, wherein the targeted panel either defines a plurality of mutations known to be tumorous in general or a plurality of mutations being identified from a sample of the patient taken prior to the liquid biopsy; (iv) identifying DNA variant fragments of the DNA fragments having a same mutation based on the sequencing data; (e.g. enriching cfDNA fragments having sequences corresponding to one or more selected genomic regions where simple nucleotide variants associated with tumors are located (i.e. targeted sequence enrichment), preparing a library, sequencing the cfDNA fragments to obtain sequences and sizes of the cfDNA fragments, use the sequencing information to determine tumor variant. [¶0007])
(v) associating the identified DNA variant fragments to a first group, if the DNA variant fragments are shorter than a first intermediate length threshold, wherein the first intermediate length threshold is between 150 bp and 166 bp, associating the identified DNA variant fragments to a second group, if the DNA variant fragments are longer than a second intermediate length threshold, wherein the second intermediate length threshold is between 150 bp and 166 bp, wherein preferably the first intermediate length threshold and the second intermediate length threshold are equal; (vi) detecting a mutation as tumorous or healthy based on the presence of the DNA variant fragments in the first group and in the second group. (e.g producing a call that a tumor variant exists in the cfDNA fragments using the sequences and sizes of the cfDNA fragments [¶0007]. Fig 1A shows the fragment size threshold for assigning cancer/ and Fig. 1C compares allele frequencies for shorter cfDNA fragments (shorter than or equal to 150 bp) and longer cfDNA fragments (longer than 150bp). Fig 8 and 9 also shows tumor derived cfDNA are shorter than normal cfDNA.)
Regarding claim 2, Jiang discloses detecting the mutation as tumorous or healthy is based on: (i) the presence of the DNA variant fragments in the first group and in the second group; and (ii) the mutation frequency of the mutation. (e.g producing a call that a tumor variant exists in the cfDNA fragments using the sequences and sizes of the cfDNA fragments, including assigning the cfDNA fragments into different fragment sizes bins. The reference further comprises determining an allele frequency of the variant of interest in a prioritized set of bins base on applicable criteria and make variant call base on the comparison. [¶0007-0010])
Regarding claim 3, Jiang discloses the mutation is detected as tumorous, if the DNA variant fragments are present more often in the first group than in the second group and if the mutation has a mutation frequency below a frequency threshold, wherein the frequency threshold is between 2% and 50%. (e.g. tumor derived cfDNA are shorter than normal cfDNA fragments [Fig. 1A, 8, and 9, ¶00257-00258]. The reference also discloses for 32 true positive mutations including simple nucleotide variants (SNV), prioritized bins including mutant fragments, fold change values are larger than 1 in 31 of the 32 mutations, and bins containing fragments shorter than 150 bp detected 30 out of 32 mutations with fold change larger than 1 [¶00259]. This teaches that tumor mutation signal is higher in shorter fragment bins. Further, the short fragment prioritized bin method improve detection across different raw allele frequencies (whether mutated gene is expressed low or high quantity). The method is particularly beneficial for low frequency mutations (mutants often show up in small or trace amount from cfDNA liquid samples), and Fig. 10 show mutant allele frequency 0.25% to 31.69%, which is within the claimed 2.0% and 50%. The method even shows higher analytical sensitivity because it detects allele frequency as low as 0.16%. [¶00260-00261 and Fig 10].)
Regarding claim 4, Jiang discloses the DNA variant fragments are associated to the second group, if the DNA variant fragments are longer than the second intermediate length threshold and shorter than an upper length threshold. (e.g. producing a call that a tumor variant exists in the cfDNA fragments using the sequences and sizes of the cfDNA fragments [¶0007]. Fig 1A shows the fragment size threshold for assigning cancer/ and Fig. 1C compares allele frequencies for shorter cfDNA fragments (shorter than or equal to 150 bp) and longer cfDNA fragments (longer than 150bp). Fig 9 shows the upper threshold could go up to 380bp)
Regarding claim 5, Jiang discloses the DNA library is a single-stranded or a double-stranded DNA library. (e.g sample library may be in double- stranded form or single-stranded [00177]).
Regarding claim 7, Jiang discloses liquid biopsy is performed on the patient in at least one of the following stages: (i) having a tumor before a treatment, (ii) having a tumor during a treatment [e.g. plasma sample of a patient affected by a tumor [¶00134])
Regarding claim 8, Jiang discloses (i) identifying DNA variant fragments of the DNA fragments having the respective mutation based on the sequencing data; (e.g. enriching cfDNA fragments having sequences corresponding to one or more selected genomic regions where simple nucleotide variants associated with tumors are located (i.e. targeted sequence enrichment), preparing a library, sequencing the cfDNA fragments to obtain sequences and sizes of the cfDNA fragments, use the sequencing information to determine tumor variant. [¶0007])
(ii) associating the identified DNA variant fragments of the respective mutation to a first group, if the DNA variant fragments of the respective mutation are shorter than a first intermediate length threshold, wherein the first intermediate length threshold is between 150 bp and 166 bp, and associating the identified DNA variant fragments of the respective mutation to a second group, if the DNA variant fragments of the respective mutation are longer than a second intermediate length threshold, wherein the second intermediate length threshold is between 150 bp and 166 bp, wherein preferably the first intermediate length threshold and the second intermediate length threshold are equal; (iii) detecting, if the respective mutation is tumorous or healthy based on the presence of the DNA variant fragments of the respective mutation in the first group and in the second group, wherein the respective mutation is detected as tumorous, if the DNA variant fragments are present more often in the first group than in the second group. (e.g producing a call that a tumor variant exists in the cfDNA fragments using the sequences and sizes of the cfDNA fragments [¶0007]. Fig 1A shows the fragment size threshold for assigning cancer/ and Fig. 1C compares allele frequencies for shorter cfDNA fragments (shorter than or equal to 150 bp) and longer cfDNA fragments (longer than 150bp). Fig 8 and 9 also shows tumor derived cfDNA are shorter than normal cfDNA.)
Regarding claim 15, Jiang discloses the mutation is detected as tumorous, if the DNA variant fragments are present more often in the first group than in the second group. (e.g producing a call that a tumor variant exists in the cfDNA fragments using the sequences and sizes of the cfDNA fragments [¶0007]. Fig 1A shows the fragment size threshold for assigning cancer/ and Fig. 1C compares allele frequencies for shorter cfDNA fragments (shorter than or equal to 150 bp) and longer cfDNA fragments (longer than 150bp). Fig 8 and 9 also shows tumor derived cfDNA are shorter than normal cfDNA.)
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.
Jiang et al. and Mouliere et al.
Claim(s) 6, 9-12, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al. (WO2018195483A1, EFD: April 20 2018, disclosed in IDS) in view of Mouliere (WO2020094775A1 EFD: November 7th 2019, disclosed in IDS)
Regarding claim 6, Jiang discloses tumor derived cfDNA fragments are shorter than normal cfDNA fragments and short fragment bins enrich tumor mutation signal. However, Jiang does not explicitly mention classifying a mutation as healthy/non-tumorous when mutation is found in the longer fragment group.
Mouliere discloses distinguishing tumor derived circulating tumour DNA (ctDNA) (i.e. ctDNA is from a cell-free DNA (cfDNA) liquid sample [page 1, line 4-5]) from non-cancerous variant DNA, including CHIP/clonal hematopoiesis, using fragment size feature [page 2, lines 20-26].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to call a mutant healthy/non-cancerous when its variant fragments are found only in longer fragment group because the prior arts taught using fragment size information to separate tumor derived variants from non-cancerous variants.
Regarding claim 9, Jiang discloses method comprising the steps of: (i) collecting DNA from a tumorous sample of the patient; (ii) sequencing said DNA from the tumorous sample; (iii) identifying mutations from said sequencing; (v) performing the method of claim 1 (e.g. cfDNA fragments obtained from the test sample, such as: blood, saliva, urine, and other biological fluid [¶0005]; enriching cfDNA fragments having sequences corresponding to one or more selected genomic regions where simple nucleotide variants associated with tumors are located (i.e. targeted sequence enrichment), preparing a library, sequencing the cfDNA fragments to obtain sequences and sizes of the cfDNA fragments, use the sequencing information to determine tumor. [¶0007])
However, Jiang does not disclose designing a panel of specific DNA probes targeting the identified mutations; and characterizing the personalized mutation profile of the tumor based on the detection of tumorous and/or healthy mutations.
Mouliere discloses collecting sample from cancer patient, identifying fragment sized and sequencing DNA, call variants from tumor sequencing data, design personalized hybrid capture sequencing panels to cover patient’s specific variants, Tailored panel sequencing (TAPAS). The reference further discloses distinguishing ctDNA and cfDNA containing somatic mutations of non-cancerous origin (including CHIP), and classify as being of tumor origin or being of CHIP origin based on fragment size features. [Fig. 2&4, page 12 lines 28-31, page 32 lines 11-19]).
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to incorporate Mouliere’s TAPAS workflow into Jiang’s cancer inform targeted cfDNA workflow because such personalized diagnostic enables accurately characterize a patient’s tumor mutation profile and avoid misclassifying non-tumorous variant as tumor derived. Jiang already recognized that target enrichment/targeted sequencing is important for accurately detecting tumor associated variants, the reference goal is improving detection by combining sequence information and fragment size. It is obvious that a skilled artisan would have been motivated to further increase diagnostic accuracy by implementing Mouliere’s TAPAS, including identify both cancerous and non-cancerous mutants, workflow and avoid false positives, tailor treatment for best results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Regarding claim 10, Mouliere discloses the liquid sample is from a patient having a tumor remission phase. (e.g. DNA sample may used to presence of, growth of, prognosis of, regression of, treatment response of, or recurrence of a cancer in a subject from which the sample has been obtained. [page 8, lines 16-20])
Regarding claim 11 and 12, Mouliere discloses a treatment is adapted to the characterization of the personalized mutation profile of the tumor. (e.g. knowing the detail analysis of cfDNA release into blood can mark cfDNA with specific fragmentation signatures, potentially providing precise information about cell type, gene expression, oncogenic potential or action of treatment [page 1 line 33-page 2 line 1]).
Regarding claim 14, Mouliere does not expressly using the term “ theranostic report”, but Mouliere discloses longitudinal post treatment monitoring and comparison with clinical diseases status [Fig 10], tumor/healthy classification and genetic level alteration detection [Fig 14], and pre- and post- treatment molecular alteration profiles [Fig 16]. As of the application’s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to generate a report summarizing these mutation results for clinical use because such report is useful for diagnostic, monitoring, and treatment decision making.
Jiang et al.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al. (WO2018195483A1, EFD: April 20 2018, disclosed in IDS).
Regarding claim 13, Jiang does not explicitly disclose the liquid sample is from a patient in a tumor relapse phase. However, Jiang discloses samples can be obtained from sources, including samples from different developmental stages of the same or different individuals, samples obtained at different stages of a disease in an individual, samples obtained from an individual subjected to different treatments for a disease, samples from individuals subjected to different environmental factors, samples from individuals with predisposition to a pathology [00170]. As of the application’s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to apply Jiang’s cfDNA tumor variant detection method to a liquid sample from a patient suspected of or undergoing tumor relapse because relapse monitoring is a routine clinical use of liquid biopsy tumor mutation detection.
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
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