DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 22 April 2026 has been entered.
Applicant's response has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 22-24, 26, 53-55, 58-67, and 97 are currently pending and under exam herein.
Claims 1-21, 25, 27-52, 56-57, 68-96, and 98 have been cancelled.
Specification
Note: All references to the Specification herein pertain to the PG publication: US20220195530.
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 22-24, 26, 53-55, 58-67, and 97 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The instant rejection reflects the framework as outlined in the MPEP at 2106.04:
Framework with which to Evaluate Subject Matter Eligibility:
(1) Are the claims directed to a process, machine, manufacture or composition of matter;
(2A) Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
(2B) If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1 Analysis: Are claims directed to process, machine, manufacture/composition of matter
With respect to step (1): yes, the claims are directed to a method of producing a selector set for a cancer.
Step 2A, Prong 1 Analysis: Do claims recite abstract idea
With respect to step (2A)(1), the claims recite abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the (2A)(1) evaluation, the claims are found herein to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and/or mathematical concepts (in particular mathematical relationships and formulas).
The claim steps to abstract ideas are as follows:
Claim 22:
(a) identifying genomic regions comprising mutations in one or more subsets from a population of subjects suffering from the cancer, which under the plain meaning of “identifying” is a mental operation where one can mentally observe data and identify genomic regions.
(b) ranking the genomic regions based on a Recurrence Index (RI), wherein the RI of the genomic region is determined by dividing the number of subjects or tumors with mutations in the genomic region by the size of the genomic region, wherein said operation is a mathematical process that requires division and is abstract. Further steps of “ranking” are also directed to mental concepts wherein one can “rank” by making a list from highest to lowest or lowest to highest, for example. Other concepts of “ranking” include doing so with respect to a certain criteria.
(c) producing a selector set based on the RI, wherein producing a set is a mathematical operation based on producing a unique collection or membership or element or values, for example based on a certain criteria, wherein producing comprises:
(i) selecting exons from known drivers with the highest recurrence index that identify at least one new patient that is not from the population of subjects of step (a), which is an abstract mental operation that requires making a choice of based on a particular criteria of items;
(ii) selecting exons with the highest RI that identify at least one new patient when compared to step (i), wherein exons of (ii) have SNVs covering >/= 5 patients in a population of subjects of step (a), which is an abstract mental operation that requires making a choice of based on a particular criteria of items;
(iii) identifying remaining exons of known drivers with a Recurrence Index..SNVs covering >/=3 patients in a relevant database that result in the largest reduction in patients with only 1 SNV…(iv) repeating step (iii) using RI >/=20, which is a step directed to making an identification and is abstract as indicated above pertaining to the plain meaning of “selecting”;
(v) adding in all exons…(vi) adding for known recurrent rearrangement the introns mode frequently implicated in the fusion event…wherein said operations pertain to steps directed to mental operations of including further data to the steps of exon selection and are abstract.
(d) generating a selector probe set based on the selector set, wherein the selector probe set comprises a plurality of oligonucleotides that are capable of hybridizing to a plurality of genomic regions that correspond to the genomic regions contained in the selector set, wherein said operation is interpreted as on that takes place in the bioinformatics environment and is directed to representing the probe set according to some aspect of the selector set as particular sequence and/or probe information.
Claim 23: at least a subset…are exon regions, intron regions…which further defines the set membership and is a further limitation to the recited abstract mathematical process as above.
Claim 24: selector set based on the RI comprises selecting genomic regions that have a recurrence index in the top 70th, 75th…or greater percentile, wherein said operation is one that one that is a mental operation directed to making a selection by assessment of an RI value (it is noted this could as well be mathematical).
Claim 26: producing the selector set comprises applying an algorithm selecting genomic regions that:(i) maximize a median number of mutations per subject of the selector set.,(ii) minimize the total size of the genomic regions, or(iii) minimize the total size of the genomic regions, wherein said step of “selecting” a value is a mental operation under the plain meaning of what it is to select something, absent any further claim steps to the contrary. Further, applications of an algorithm are directed to abstract mental operations of applying algorithmic mathematics to maximize and minimize as claimed.
Claim 53: detecting a presence of one or more mutations in one or more samples from a subject, wherein the one or more mutations are based on the selector set of claim 22; determining a mutation type of the one or more mutations present in the sample; and determining a statistical significance of the selector set by calculating a ctDNA detection index based on a p-value of the mutation type of mutations present in the one or more samples, wherein the p-value is estimated by Monte Carlo sampling, wherein the detection, and determination of a mutation, absent steps to the contrary, can be performed mentally by merely looking at the appropriate data to assess a “mutation” in a sequence region, for example. Steps directed to statistical significance using p-values are mathematical operations.
Claim 54 is directed to a conditional observation step which is an abstract mental operation of assessing a value.
Claim 59 is directed to a conditional observation step which is an abstract mental operation of assessing a value and a further assessment of p-value, which is an abstract mathematical operation.
Claim 60 includes utilization of a Fischer’s statistical method, which is an abstract mathematical operation.
Claims 61: further limits to the types of data to be that of SNV mutation data and thus limits that abstract idea above.
Claim 62 includes utilization of Monte Carlo sampling, which is an abstract mathematical operation.
Claims 63: further limits to the types of data to be that of indel mutation data and further limits the abstract idea.
Claim 64 is directed to a conditional observation step which is an abstract mental operation of assessing a value and a further assessment of p-value, which is an abstract mathematical operation.
Claims 65: further limits to the types of data to be that of SNV mutation data and thus limits that abstract idea above.
Claim 66 is directed to an assessment of p-value, which is an abstract mathematical operation.
Claims 67: further limits to the types of data to be that of indel mutation data and further limits the abstract idea.
Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined herein to each cover performance either in the mind (calculations by hand or pen and paper or by the aid of a computer as a tool) and performance by mathematical operation. There are no specifics as to the methodology involved in “identifying” or in “ranking” and “producing”, for example and thus, under the BRI, one could simply, for example, perform said operation with pen and paper, or, alternatively with the aid of a generic computer as a tool to perform said mathematics. These recitations are similar to the concepts of collecting information, analyzing it and providing certain results from the collection and analysis (Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations (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 with pen and paper, and can include mathematical concepts.
Further, see MPEP § 2106.04(a)(2), subsection III. The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation (see, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674: noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016): holding that claims to a mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper"). Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind" (see Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016): holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by humans without a computer").
Step 2A, Prong 2 Analysis: Integration to a Practical Application
Because the claims do recite judicial exceptions, direction under (2A)(2) provides that the claims must be examined further to determine whether they integrate the abstract ideas into a practical application (MPEP 2106.04(d). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim is said to fail to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
With respect to the instant recitations, the claims recite the following additional elements:
There are no recited steps in the claims that are in addition to the steps directed to abstract (mental/mathematical) operations. As such, said claims fail to provide integration of any judicial exception herein.
Step 2B Analysis: Do Claims Provide an Inventive Concept
The claims are lastly evaluated using the (2B) analysis, wherein it is determined that because the claims recite abstract ideas, and do not integrate that abstract ideas into a practical application, the claims also lack a specific inventive concept. Applicant is reminded that the judicial exception alone cannot provide the inventive concept or the practical application and that the identification of whether the additional elements amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements of data gathering described above do not rise to the level of significantly more than the judicial exception. As directed in the Berkheimer memorandum of 19 April 2018 and set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, said claims do not include any additional elements beyond the recitations of abstract mental/mathematical operations. As such, said claims fail to provide an inventive concept herein.
For these reasons, the claims, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Response to Applicant’s Arguments
Response to Applicant’s Arguments
1. Applicant states that, “the claimed method if not a mental process and cannot be performed entirely in the human mind or with the aid of pen and paper not directed to a mental process”.
It is respectfully submitted that this is not persuasive. As outlined in the above rejection, and in previous Office Actions each of the steps of claim 22 (exemplary independent claim) are directed to judicial exceptions (abstract ideas). There are no steps in the instant claim that are “additional elements” that would provide either integration of the recited judicial exceptions or an inventive concept when considered in combination with said judicial exceptions in the claim. Applicant will kindly note that steps directed to the design of the selector include only steps that are abstract mental processes that may, indeed, be performed mental or with the aid of a computer. The courts do not distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind" (see Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016): holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by humans without a computer").
2. Applicant further includes that “the selector probe set is not directed to sequence information but is rather a tangible set of probes that comprise a plurality of oligonucleotides that are capable of hybridizing to a plurality of genomic regions that correspond to the genomic regions contained in the selector set. Numerous sections of the specification state that the selector probes are oligonucleotides. For instance, paragraph 21 states "Selecting the cfNA may comprise (i) hybridizing the cell-free nucleic acid sample to a plurality of selector set probes comprising a specific binding member", paragraph 42 states "The set of selector probes may comprise oligonucleotides comprising sequences from at least 300 regions from Table 2", paragraph 43 states "Hybrid selection may comprise of use of one or more selector set probes", paragraph 149 states "The array may comprise a plurality of probes for selective hybridization of one or more genomic regions based on a selector set", paragraph 522 states "In order to use the selector set for patient diagnostic and prognostic methods, a set of selector probes may be generated from the selector set library", and paragraph 553 states "A set of selector set probes therefore may have the complexity of the selector set from which it is obtained. Selector probes may be synthesized using conventional methods, or generated by any other suitable molecular biology approach. Selector probes may be hybridized to cfDNA for hybrid capture". Accordingly, Applicant submits that, all throughout the specification the selector probes set are referred to as oligonucleotides that hybridize to genomic regions and are thus tangible compositions of matter that are not directed to bioinformatic sequence information. Additionally, amended claim 22 states that the selector probe set comprises a plurality of oligonucleotides”.
It is respectfully submitted that this is not persuasive. The Specification discloses that the generation of a selector probe set based on a selector set is a process that is generated in a bioinformatics construct comprising selector set sequence information as at [0522]. The claim is not interpreted as one wherein a particular probe set is actually manufactured or synthesized. There are no specifics in step (d) as to the intention of how, based on the selector set, a selector probe is generated and therefore under the BRI of the claim, the claim recited abstract, mental operations.
Even if the step of “generating a probe” were to be considered an “additional element” in the claim, which it is not (see above rejection), the claim fails to include a step beyond what is well-known, routine and conventional as pertains to a step that would then be considered “extra-solution” activity. The court has established that routine laboratory operations are those which are well-known, routine and conventional the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity, for example, in the following: (see MPEP 2106.05(d)II.): determining the level of a biomarker in blood by any means (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)); detecting DNA or enzymes in a sample (Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017)); Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546; and Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
In addition, the instant Specification provides that, for example, [0053]…selector probes may comprise a binding moiety that allows capture of the hybrid. Various binding moieties (e.g., tags) useful for this purpose are known in the art, including without limitation biotin, HIS tags, MYC tags, FITC, and the like.
As such, Applicant’s arguments fail to be persuasive with respect to the instant claims.
3. Applicant states that, “as discussed in the previous response, the specification discloses numerous improvements the selector set and selector probe set produced by the claimed methods achieves. For instance, as stated by the examples, the selector probe set was able to identify a median of 4 point mutations covering a majority of the patients analyzed, i.e., over 80%, which was four-fold higher than random sampling. A selector probe set produced by the claimed methods was also able to identify a large number of patients, i.e., greater than 90%, having colon, rectal, and endometroid uterine carcinoma from the populations tested. In addition to the high levels of coverage, the selector probe set produced by the claimed methods also allowed for improved sensitivity in non-invasive cancer detection. Specifically, the selector probe set was able to detect tumor-derived DNA in plasma at as low as 0.02%. Thus, a selector probe set produced by the claimed method provides lower limits of detection not shown with other sequencing-based techniques and are particularly useful in applications where ctDNA is below 2% such as when monitoring tumor burden or where patients typically have lower levels of ctDNA.
It is re-iterated herein, respectfully, that this is not persuasive. Instant claim 1, for example, contains no limitations whereby a selector set probe was applied to a patient whereby any specific cancer (i.e., colon, rectal, and endometroid uterine carcinoma) was elucidated. In addition, claim 1, for example, is not even limited to applications wherein ctDNA is below any particular threshold of detection or to any particular detection step for a particular probe or cancer. As such, said assertions are not persuasive herein. As such, any likening to, for example, Vanda Pharmaceuticals, is not persuasive.
All responses from prior Office Actions also pertain to the instant application.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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 following form via EFS-Web or Central Fax (571-273-8300): PTO/SB/439. Applicant is encouraged to do so as early in prosecution as possible, so as to facilitate communication during examination.
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web 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.
Inquiries
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lori A. Clow, whose telephone number is (571) 272-0715. The examiner can normally be reached on Monday-Thursday from 12:00PM to 10:00PM ET.
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/Lori A. Clow/Primary Examiner, Art Unit 1687
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