DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This application is the national stage of PCT/US2021/024242, filed 03/25/2021, claiming priority to US provisional applications 63/023,731 (filed 05/12/2020) and 63/001,150 (filed 03/27/2020). The International Search Report and Written Opinion issued in the PCT application have been received and reviewed.
Election/Restrictions
Applicant’s election without traverse of the species of the combination of a single nucleotide polymorphism (SNP)/single nucleotide variant (SNV) frequency and microsatellite instability in the reply filed on August 28, 2025 is acknowledged. Claims 1, 59-69, 73, and 78 correspond to the elected species.
Claims 70-72 and 74-77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 28, 2025.
Claim Objections
Claim 78 is objected to because of the following informalities: the claim recites the limitation “obtaining an extra-chromosomal deoxyribonucleic acid (ecDNA) data” where it should recite simply limitation “obtaining extra-chromosomal deoxyribonucleic acid (ecDNA) data” (as is done in claim 1, given that “data” is plural and the claim requires multiple types of such data). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)/second paragraph/Claim Interpretation
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 1, 59-69, 73, and 78 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.
Claims 1, 59-69, and 73 are indefinite because the preamble of claim 1 recites a “method of treating a cancer”, however the only “treating” of the claim - which states “treating the subject with an immune checkpoint inhibitor on the basis of the ecDNA status” - does not make sufficiently clear how “ecDNA status” relates to and would result in treating with an immune checkpoint inhibitor. The language “treating….on the basis of the ecDNA status” is too vague to reasonably apprise one of skill in the art as to what type of ecDNA status would result in performing this “treating”. Further, while it is clear (based on the language of dependent claim 61, which states that such a treating is performed “if the ecDNA signature data…is below the threshold”) that treating with an immune checkpoint inhibitor is not necessarily required by the claims (given the conditional/contingent recitation in claim 61), the preamble of claim 1 states that the invention is a “method of treating”, and thus the claim is also confusing with regard to whether an alternative (unspecified) treating is to be performed in cases when “treating…with the immune checkpoint inhibitor” is not indicated. Accordingly, clarification is required. It is noted that as the claim does not clearly require an active step of “treating”, for purposes of comparing the claimed invention to the prior art the broadest reasonable interpretation of the claim encompasses methods in which only the recited “obtaining” and “classifying” are performed.
Claim 78 is indefinite because the preamble of the claim recites a “method of treating a cancer”, however the only “treating” of the claim, recited at c), states “treating the subject….if the ecDNA status is ecDNA positive”. The claim as written does not require a particular outcome (positive or negative) regarding ecDNA status, and also fails to make any reference to a “treating” that occurs if ecDNA status is not ecDNA positive. It is thus not clear whether the claim actually requires “treating a cancer” (as is suggested by the preamble), or whether the claim in fact encompasses methods in which “treating” is only required in instances when the condition specified in the “treating” step of the claim are met. It is noted that as the claim only clearly recites a method step in which “treating” is conditional/contingent on a specific outcome, for purposes of comparing the claimed invention to the prior art the broadest reasonable interpretation of the claim does not necessarily require an action corresponding to “treating”; however, as the preamble of the claim states “method of treating…”, further clarification is required.
Claim 78 is indefinite over the recitation in (b) of the limitation “the ecDNA status”, because there is insufficient antecedent basis for this term in the claim. While it appears that b) of the claim is intended to simply require “classifying ecDNA status of the sample” as ecDNA positive (corresponding to presence of ecDNA in the sample) or ecDNA negative (corresponding to absence of ecDNA in the sample), the recitation of “the ecDNA status” suggests that this term may require something else/more specific that the claim fails to previously define or otherwise reference. It is noted that this rejection may be overcome by simply amending the claim to recite “classifying ecDNA status as…” (in the same manner done in independent claim 1).
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(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.
Claim(s) 1, 59-69, 73, and 78 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Indraccolo et al (Clinical Cancer Research 25(6):1828 [15 March 2019]; cited herein), as evidenced by Verhaak et al (Nature Reviews 19:283 [May 2019]; cited herein).
Indraccolo et al disclose performing genetic, epigenetic, and immunological profiling glioblastoma (GBM) samples collected at diagnosis and again at recurrence (see entire reference). Among the testing performed by Indraccolo et al were immunohistochemistry (IHC) assays (including evaluation of MMR status as well as PD-L1 expression level), whole exome sequencing (WES), and microsatellite instability (MSI) testing; it is further noted that the Indraccolo et al disclose processing their sequencing data regarding SNPs and SNVs to exclude common SNPs and synonymous SNVs, with the remaining functional variants used in determination of tumor mutational burden (TMB) (see entire reference, particularly the Abstract and the Materials and Methods at page 1829-1830). Indraccolo et al also report analyzing EGFRvIII mutation status and EGFR amplification ascertaining via FISH, stating that “EGR mutations have been reported to coexist with gene amplification in GBM”, and teaching that “we observed a high grade of gene amplification displayed as double minutes”; see page 1833 (starting at the right column) bridging to the left column of page 1834, and Table 2). It is particularly noted that Indraccolo et al teach that some samples exhibited gene amplification while others did not (see page 1833, right column-page 1834, left column, and again see Table 2).
As evidenced by the teachings of Verhaak et al, it is a property of “double minutes” that they are a known type of ecDNA (see entire reference, particularly page 283, right column, second full paragraph). (Additionally, while not necessary for purposes of the instant rejection [given what is claimed and the teachings of Indraccolo et al referenced above], it is also noted that Verhaak et al disclose that gene amplification in GBM, including of EGFRvIII, is known to originate from ecDNA [see “ecDNA is frequent in cancer cells” at pages 3-5 of Verhaak et al].)
Thus, as evidenced by Verhaak et al, Indraccolo et al obtained ecDNA signature data “for a sample from a subject” having cancer (glioblastoma), including SNP/SNV frequency data and MSI data (i.e., the elected combination of data types), as well as direct visualization of ecDNA via FISH (another type of ecDNA signature data not required by, but encompassed by, the claims). Indraccolo et al also teach classifying samples as ecDNA negative or positive “based on the ecDNA signature data”; again, see Table 2. As the “treating” of each of claims 1 and 78 is not clearly required by the present claim language, Indraccolo et al thus anticipate claims 1 and 78. It is also noted that even to the extent that the claims may require some type of “treating” based on ecDNA status, this is a conditional/contingent limitation, as it is performed based on an outcome with respect to ecDNA. As stated in MPEP 2111.04(II): “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”. As Indraccolo et al teach that some of their samples were positive for gene amplification/ecDNA while others were not, Indraccolo et al – even to the extent that some type of “treating” is required for subjects having one type of outcome of the “obtaining” and “classifying” – anticipates the claims with regard to those subjects not classified as having an ecDNA status triggering the recited “treating” of the claims.
With further regard to dependent claims 59-61, the “classifying….based on a threshold of ecDNA signature data” of is disclosed by Indraccolo et al at least by their disclosure of confirming gene amplification via the use of FISH to observe double minutes (again see page 1833, including Table 2); dependent claims 60-61 recite activities that occur “when” or “if” a certain result occurs, which are not required by the BRI of these claims. Regarding claims 62-63, the tumor samples disclosed by Indraccolo et al meet the requirements of the claims (see, e.g., page 1829 and 1831). Regarding claims 64-65, Indraccolo et al teach variant analysis (including of SNPs/SNVs) that meets the requirements of the claims at page 1830 (where analysis of the nature of variants with respect to known/control frequencies are taught), and Indraccolo et al also teach comparing frequencies of different sample types (as again, both “diagnosis” and “relapse” samples were tested; e.g., page 1831); it is also noted that claim 65 recites what is indicated by an increase but does not require such an increase (i.e., the obtaining and classifying/comparing are sufficient to meet the requirements of both claims). Regarding claims 66-67, the above noted comparing of SNP/SNV data is sufficient to meet the requirements of these claims as well (particularly as nothing more than a mental comparison/conclusion/classification is required by the claim language, so long as some type of control data/reference is employed). Regarding claim 68, it is reiterated that Indraccolo et al teach WES (see above). Regarding claim 69, Indraccolo et al disclose glioblastoma/GBM, a type of brain cancer. Regarding claim 73, it is reiterated that the claim as written does not require the “treating” of c) of claim 1, such that claim 73 is anticipated for the same reasons given regarding claim 1 (it is also noted that Indraccolo et al disclose that one potentially intended application of their methods is identification of “response predictive biomarkers’, including with regard to immune checkpoint inhibitors [page 1828, right column; the Discussion at pages 1835-1836]). Thus, Indraccolo et al (as evidenced by Verhaak et al) anticipate all of claims 1, 59-69, 73, and 78.
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, 59-69, 73, and 78 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. Independent claims 1 and 78 each recite a “method of treating” comprising obtaining ecDNA signature data for a sample from a subject (comprising particular elected types of data) and “classifying ecDNA status of the sample….based on the ecDNA signature data” (see (a) and (b) of each of claims 1 and 78). It is noted that the claims state obtaining data “for a sample”, not the actual obtaining and physical analysis of a sample, and the “classifying” of the claims corresponds to a mental conclusion regarding whether the “status” of the sample is positive or negative. The claims thus recite activities – obtaining and thinking about different types of data and classifying/comparing those data – that may be performed entirely in the human mind, which constitute abstract ideas (i.e., a type of judicial exception (JE)). This judicial exception is not integrated into a practical application because the obtaining and classifying of data as recited in the claim – even to the extent that they may require some type of physical gathering of data – are data gathering steps that do not add a meaningful limitation to the method as they constitute insignificant extrasolution activity. While each of these claims also recited a final step of “treating the subject…”, as discussed above the language of the claims with regard to what is encompassed by “treating” is unclear, and the claims as written must be interpreted as encompassing at least some embodiments in which no physical/active “treating” occurs (i.e., the broadest reasonable interpretation (BRI) of the claims does not require that any active “treating” be performed). As stated in MPEP 2106.03(II): “A claim whose BRI covers both statutory and non-statutory embodiments embraces subject matter that is not eligible for patent protection and therefore is directed to non-statutory subject matter”. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because again, nothing more than a JE is clearly required by the claims; further, it is noted that even to the extent that the claims may require the physical gathering of data regarding ecDNA “signature data”, such activities were well-known, routine, and conventional before Applicant’s effective filing date (see, e.g., Indraccolo et al and Verhaak et al, cited above; see also Erson-Omay et al [Genome Medicine 9(12):1-10 [2017]; cited herein) regarding exome sequencing and SNV analysis of a subject exhibiting chromothripsis/double minutes, and Bonneville et al [JCO Precis Oncol 1;1-15 [2017]; cited in IDS] and Wang et al [Scientific Reports 8:17546 [2018]; cited herein] with particular regard to MSI classification).
With further regard to dependent claims 59-61, these claims recite more specific types of abstract ideas, but do not require anything more, or a practical application, that alters the above analysis (regarding claim 61 in particular, it is noted that the claim states treating “if” signature data is below a threshold, but does not require such an outcome). Regarding dependent claims 62-63, these claims recite more particular sources of data/information, but do not add anything amounting to a practical application or something “significantly more” than a JE. Regarding claims 64-66, these claims recite gathering and thinking about more particular types of data/information, but do not recite any type of application/implementation of a JE, or add anything more than a JE. Claim 67 (like claims 62-63) recites a more particular source of data, not any type of implementation/application, or the addition of anything more than a JE. Claim 68 requires a more particular type of data gathering (sequencing), rather than any type of practical application, and the alternative types of sequencing recited clearly correspond to well-understood, routine, and conventional activities as of Applicant’s effective filing date. Claim 69 recites numerous different alternative types of cancer about which data may be gathering for classifying; this again constitutes a further data gathering activity (i.e., insignificant extra-solution activity, rather than a practical application), and the analysis of data (including data of the type specified in the claims) regarding any/all of such cancers was routine as of Applicant’s effective filing date. Claim 73 sets forth a further limitation on a contingent/conditional step that is not required by the claimed method, such that the analysis applied to claim 1 also applies to this claim.
Accordingly, none of claims 1, 59-69, 73, and 78 is directed to patent eligible subject matter.
Conclusion
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682