DETAILED ACTION
Comments
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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.
Information Disclosure Statement
The IDS of 8/21/2023 has been considered.
Election/Restrictions
Applicant’s election of Invention I in the reply filed on 31 October 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-3, 8-10, 14-18, 20-22, and 108-114 are pending and examined in the instant Office action.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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 8, 14, 111, and 114 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.
Each of claims 8, 14, 111, and 114 incorporate data from tables into the claims. According to MPEP Section 2173.05(s), the relevant data from the tables should be inserted into each of 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.
Claim(s) 1-3, 8-10, 14-18, 20-22, and 108-114 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea/law of nature/natural phenomenon without significantly more. Claims 1-3, 8-10, 14-18, and 20-22 are drawn to methods, and claims 108-114 are drawn to non-transitory computer-readable storage media.
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1 : YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claims 1 and 108 recite the mental step of identifying contamination markers for which the sample has a homozygous haplotype.
Claims 1 and 108 recite the mental step of identifying any cfDNA fragments in the test sample having a different haplotype at one of the identified contamination markers than the homozygous haplotype of the respective contamination marker as a contaminated cfDNA fragment.
Claims 1 and 108 recite the mental step of estimating a contamination level based on any identified contaminated cfDNA fragments.
Claims 1 and 108 recite the mental step of determining whether the contamination level is below a threshold level.
Claims 1 and 108 recite the mental step that in response to determining that the contamination level is below the threshold level, performing cancer classification on the sequence reads on the cfDNA fragments in the test sample to generate a cancer prediction.
Claims 2 and 109 recite the mental step of constraining the contamination markers to comprise SNPs.
Claims 3 and 110 recite the mental step of putting at least one constraint on the types of SNPs that are contamination markers.
Claims 4 and 111 recite the mental step of constraining the sites of the SNPs.
Claims 9 and 112 recite the mental step of constraining the contamination markers to comprise indels.
Claims 10 and 113 recite the mental step of putting at least one constraint on the types of indels that are contamination markers.
Claims 14 and 114 recite the mental step of constraining the sites of the indels.
Claim 15 recites the mental step of requiring each contamination marker to include a probe designed to target each haplotype of the contamination marker.
Claim 16 recites the mental step of constraining the parameters used to estimate the contamination level.
Claim 17 recites the mental step of in response to determining that the contamination level is above a threshold level, forgoing cancer classification.
Claim 18 recites the mental step of constraining the types of classification used in cancer prediction.
These recitations are similar to the concepts of collecting information, analyzing it and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation of generic computer components, then if falls within the “Mental processes” grouping of abstract ideas. As such, claim(s) 1-3, 8-10, 14-18, 20-22, and 108-114 recite(s) an abstract idea/law of nature/natural phenomenon (Step 2A, Prong 1 : YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies or uses the recited judicial exception to affect a particular treatment for a condition. Rather, the instant claims recite additional elements that amount to mere instructions to implement the abstract idea in a generic computing environment or mere instructions to apply the recited judicial exception via a generic treatment.
As such, these limitations equate to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. As such, claims 1-3, 8-10, 14-18, 20-22, and 108-114 is/are directed to an abstract idea/law of nature/natural phenomenon (Step 2A, Prong 2 : NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment.
The article of Cristano et al. [Nature, volume 570, 2019, pages 385-389 with supplemental material; on attached 892 form] teaches that obtaining cfDNA fragment sequence reads is routine and conventional in the prior art.
As discussed above, there are no additional limitations to indicate that the claimed analysis engine requires anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B : No). As such, claims 1-3, 8-10, 14-18, 20-22, and 108-114 is/are not patent eligible.
Claim Rejections - 35 USC § 103
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.
35 U.S.C. 103 Rejection #1:
Claim(s) 1-2, 15-18, 20-22, and 108-109 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fields et al. [WO 2020/232109 A1; on IDS] in view of Hatchwell et al. [WO 2020/033700 A1; on attached 892 form].
Claim 1 is drawn to a method for predicting a presence of cancer in a test sample. The method comprises obtaining the test sample comprising a plurality of sequence reads for cfDNA fragments in the test sample. The method comprises identifying one or more contamination markers from a plurality of contamination markers for which the test sample has a homozygous haplotype. The method comprises identifying any cfDNA fragments in the test sample having a different haplotype at one of the identified contamination markers than the homozygous haplotype of the respective contamination marker as a contaminated cfDNA fragment. The method comprises estimating a contamination level based on any identified contaminated cfDNA fragments. The method comprises determining whether the contamination level is below a threshold level. The method comprises that in response to determining whether the contamination level is below a threshold level, performing cancer classification on the sequence reads of the cfDNA fragments in the test sample to generate a cancer prediction.
Claim 108 is drawn to similar subject matter as claim 1, except claim 108 is drawn to a non-transitory computer readable medium rather than a method.
The document of Fields et al. is drawn to a model-based featurization and classification [title]. Paragraphs 12 and 123-124 of Fields et al. teach obtaining sequence reads of cfDNA from plasma. Paragraph 55 of Fields et al. teaches that the sequence reads are analyzed for hypo- or hyper-methylation. Paragraph 133 of Fields et al. teaches that “a hypermethylated fragment or a hypomethylated fragment may also be referred to as an unusual fragment with extreme methylation (UFXM)”, and other terms which represent “anomalous fragments.” Consequently, the aforementioned fragments are equivalents of “contaminated markers.” Paragraph 133 of Fields et al. teaches filtering out sequence reads of nucleic acid fragments with a methylation state vector having below a threshold p-value score as anomalous fragments. Paragraph 133 of Fields et al. also teaches that fragments with a degree of methylation above a threshold percentage of methylation or unmethylation as hypermethylated and hypomethylated fragments, respectively. Paragraph 245 of Fields et al. teaches use of a feature vector (i.e. representing methylation of a cfDNA fragment) as input to a multiclass cancer classifier to generate a cancer prediction.
Fields et al. does not teach using the threshold in the same direction for classification as recited in the claims. Fields et al. does not teach associating contamination markers with test samples with homozygous haplotypes.
The document of Hatchwell et al. studies methods for assessing the risk of developing progressive multifocal leukencephalopathy caused by John Cunningham Virus by genetic testing [title]. Paragraphs 603-604 of Hatchwell et al. teach associating contamination markers (i.e. in this instance, SNPs) with homozygous haplotypes as indicators of genetic diseases.
With regard to claims 2 and 109, paragraph 336 od Fields et al. teaches SNPs as alternative contamination markers to methylations.
With regard to claim 15, paragraph 128 of Fields et al. teaches use of hybridization probes to target fragments of DNA of interest.
With regard to claim 16-18, paragraphs 19 and 123-124 of Fields et al. teaches that estimation of the contamination level is based on a number of cfDNA fragments in the test sample. Figure 1 of Fields et al. teaches that a threshold level of contamination is used to differentiate whether or not the cancer classifier is applied. Paragraph 91 and Figure 23A of Fields et al. teaches binary cancer classification.
With regard to claims 20-22, paragraph 245 of Fields et al. teaches use of a feature vector (i.e. representing methylation of a cfDNA fragment) as input to a multiclass cancer classifier to generate a cancer prediction. Paragraph 57 of Fields et al. teaches p-value filtering of anomalous fragments. The abstract and Paragraph 58 of Fields et al. teaches machine learning in the form of k-nearest neighbor for sample classification.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the threshold for classification of cfDNA from a lower threshold to an upper threshold because in this obviousness rejection, both the instantly rejected claims and Fields et al. analogously uses a threshold boundary to differentiate between cfDNA classified for cancer and cfDNA not classified for cancer.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the classification of cfDNA containing contamination markers of Fields et al. by use of associating contamination markers with homozygous haplotypes of Hatchwell et al. because it is obvious to combine known elements in the prior art to yield a predictable result. In this instance, both Fields et al. and Hatchwell et al. analogously teach association contamination markers on DNA with genetic diseases.
35 U.S.C. 103 Rejection #2:
Claim(s) 3, 9-10, 110, are 112-113 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fields et al. in view of Hatchwell et al. as applied to claims 1-2, 15-18, 20-22, and 108-109 above, in further view of Hughes et al. [WO 2023/060261 A1; on attached 892 form].
WO 2023/060261 A1 claims benefit to provisional application 63/253,912, filed on 8 October 2021. When Hughes et al. is cited in the instant Office action, citation paragraph numbers refer to location in provisional application ‘912.
Claims 3 and 110 are further limiting wherein the haplotypes of each multiples SNP sites are in Hardy-Weinberg equilibrium.
Claims 9 and 112 are further limiting wherein the plurality of contamination markers includes indel sites.
Claims 10 and 113 are further limiting wherein the indel sites have population frequencies with the range 45% to 55%.
Fields et al. and Hatchwell et al. make obvious associating contamination markers (i.e. in the form of methylations and SNPs) with genetic diseases and cancer, as discussed above.
Fields et al. and Hatchwell et al. do not teach indels as a form of contaminations or the aforementioned constraints on SNPs and indels.
The document of Hughes et al. studies methods and systems for detecting and removing contamination for copy number alteration calling [title]. Paragraph 70 of Hughes et al. teaches that population-wide SNPs are generally found in Hardy-Weinberg equilibrium. Paragraphs 188-190 of Hughes et al. teaches indels as a form of contamination marker. Paragraph 190 of Hughes et al. teaches that limited deviations from the 50% frequency are used for the analysis of cancer.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the classification of cfDNA containing contamination markers of Fields et al. and the associating contamination markers with homozygous haplotypes of Hatchwell et al. by use of the SNP and indel constraints of Hughes et al. wherein the motivation would have been that the addition of indels as contamination markers and the constraints of SNPs and indels facilitate the analysis of cancer [paragraphs 70 and 188-190 of Hughes et al.].
Related Prior Art
The document of Liu et al. [ESMO, volume 31, 30 March 2020, pages 745-759; on IDS] studies sensitive and specific multi-cancer detection and localization using methylation signatures in cfDNA [title]. Liu et al. classifies methylation patterns in cfDNA by machine learning to differentiate cancers versus non-cancer cfDNA.
The document of Klein et al. [ESMO, volume 32, 24 June 2021, pages 1167-1177; on IDS] studies clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set [title]. Klein et al. also classifies methylation patterns in cfDNA by machine learning to differentiate cancers versus non-cancer cfDNA.
E-mail Communications Authorization
Per updated USPTO Internet usage policies, Applicant and/or applicant’s representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300):
Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file.
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Russell Negin, whose telephone number is (571) 272-1083. This Examiner can normally be reached from Monday through Thursday from 8 am to 3 pm and variable hours on Fridays.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s Supervisor, Larry Riggs, Supervisory Patent Examiner, can be reached at (571) 270-3062.
Information regarding the status of the application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only.
/RUSSELL S NEGIN/Primary Examiner, Art Unit 1686 4 January 2026