DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 1-20 are currently pending and under exam herein.
Priority
The instant Application is a Divisional application of US 15/647,824, filed 12 July 2017, now US Patent 11,274,347, which is a Continuation application of 13/842,209, filed 15 March 2013, now US Patent 9,732,390, claiming the benefit of priority to US Provisional application 61/703,512, filed 20 September 2012.
Priority to US Provisional application 61/703,512, filed 20 September 2012 is hereby denied, as said application fails to disclose determinations of a tissue source using DNA methylation profiling. Rather, the Specification in the ‘512 application is directed to bisulfite sequencing of plasma and genomic DNA; methylation landscape of plasma DNA molecules; construction of fetal epigenetic maps from maternal plasma; detection of methylation landscapes of a placenta from maternal plasma; deduction of methylation levels of selected regions; detection of imprinted fetal alleles in maternal plasma; and fragment length as linked to DNA methylation. As such, for purposes of priority assignment here, the instant application is awarded priority to the parent application with a date of 15 March 2013.
Information Disclosure Statement
The Information Disclosure Statements filed 14 March 2023; 2 August 2023; 5 September 2025; and 31 December 2025 are in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. Signed copies of the IDS documents are included with this Office Action.
Drawings
The Drawings filed 10 March 2022 and the Replacement Drawings filed 10 May 2022 are accepted.
Specification
Note: All references to the Specification herein pertain to the PG publication: US 20220267861.
Claim Objections
Claims 1 and 20 are objected to because of the following informalities:
Claims 1 and 20, at lines 7 and 8, respectively, recite, “the at least about 1000,000 sequence reads”, wherein said number recitation appears to be a typographical error which should be corrected to read, “the at least 100,000 sequence reads”
Appropriate correction is required.
Claim Rejections - 35 USC § 112, 2nd-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 1-20 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 and 20 recite, “a method of analyzing a biological sample from a subject…and wherein the sequence reads comprise at least 100,000 sequence reads…analyzing, including aligning to a reference genome, the at least 1000,000 sequence reads to determine a methylation profile…”, wherein the claims are unclear with respect to the “subject” and “genome” in the claims as not all “subjects” and/or “genomes” are methylated, such as those of certain fungi for example. As such, it is not clear as to the metes and bounds of the instant claim limitations. Suggestions for amendment could include limiting the claims to a “human subject” as in the Specification disclosure and the genome to be that of a “human genome”, as also disclosed herein. See the Specification at least at [0046]; [0047]; [0049]; [0066]. Clarification is requested herein.
Claims 1 and 20 recite, “determining a tissue source for at least a portion of the cell-free DNA molecules from the biological sample based, at least in part, on the methylation profile” wherein the claims are unclear with respect to the parameters necessary to “determine a tissue source for a portion of the cell-free DNA molecules…based at least in part, on the methylation profile”. With respect to tissue source determination, the claims do not reflect the relationship between a methylation profile that would “determine” a tissue source as currently claimed. It is noted that dependent claim 5 appears to include that the comparison of methylation to a reference methylation profile to detect changes in methylation status of CpG islands (presumably with respect to a reference as compared to the subject). It is suggested that the claims be amended to reflect, for example, comparison of a reference methylation profile to that of a cancer subject profile to determine the changes in methylation status of the CpG islands, or the like. Clarification is requested through clearer claim language.
It is further unclear as to the contents of the methylation profile such that said determination takes place. It is suggested to incorporate the limitation of claim 6 into the claim steps of 1 and 20 for further clarification.
Last, it is unclear as to the “source” in the claims. It would appear as if the “source” is intended to be that of a cancer derived source, as claims 3 and 7-8make clear, however the independent claims are not clear with respect to the metes and bounds herein. Clarification is requested through clearer claim language.
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 1-10 and 12-20 are 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 analyzing a biological sample from a subject and a non-transitory computer readable medium of analyzing a biological sample from a subject.
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 (including an observation, evaluation, judgment, opinion) MPEP 2106.04(a)(2)(III).
The claim steps to abstract ideas are as follows:
Claim 1 and 20: (c) determining a tissue source for at least a portion of the cell-free DNA molecules from the biological sample based, at least in part, on the methylation profile, wherein making a determination based on a generated profile (data) is a mental operation wherein there are no specific steps defining said “determination” other than mere observation of gained data. As such, the step is an abstract mental process.
Claim 2: determining the tissue source comprises: comparing the methylation profile to one or more reference methylation profiles, wherein making a determination and comparing to other gained data based on a generated profile (data) is a mental operation wherein there are no specific steps defining said “determination” other than mere observation of gained data. As such, the step is an abstract mental process.
Claim 3: wherein at least one of the one or more reference methylation profiles is determined from methylation statuses of one or more reference sample obtained from another subject known to have cancer, wherein making a determination based on a generated profile (data) is a mental operation wherein there are no specific steps defining said “determination” other than mere observation of gained data. As such, the step is an abstract mental process.
Claim 5: wherein the comparison of the methylation profile to the one or more reference methylation profiles detects changes in methylation status of CpG islands, is a mental operation wherein there are no steps of how “detecting” of changes occur via a comparison and as such the claim is recited at a high level of generality and interpreted as only as comparison data sets to make a determination. As such, the step is an abstract mental process.
Claim 7: comprising determining a type of cancer of the subject based, at least in part, on the methylation profile, wherein the claim is recited at a high level of generality and interpreted as only as comparison data sets to make a determination. As such, the step is an abstract mental process.
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 be directed to mental processes as identified above. For example, there are no specifics as to the methodology involved in “determining a tissue source…based, at least in part on the methylation profile” and thus, under the BRI, one could simply, for example, make a “determination” other by mere observation of gained data or, alternatively with the aid of a generic computer as a tool to perform said operations. 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)); 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)); and comparing BRCA sequences and determining the existence of alterations where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014). The courts have identified such concepts that can be practically performed in the human mind with pen and paper, and/or can include mathematical concepts, as abstract.
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:
Claims 1 and 20: (a) obtaining sequence reads for cell-free DNA molecules from the biological sample of the subject, wherein the sequence reads include methylation statuses for the cell-free DNA molecules at single nucleotide resolution, and wherein the sequence reads comprise at least 100,000 sequence reads; (b) analyzing, including aligning to a reference genome, the at least 1000,000 sequence reads to determine a methylation profile for a plurality of sites based on the methylation statuses for the plurality of sites, which are operations that are routine laboratory operations and serve to get the data for the determination step recited as the abstract idea.
Claims 4, 6-10, 12-19 further limit the types of data as obtained in claim 1, wherein each of said limiting steps further serves to gather the data for determination of a tissue source (the abstract idea) using routine laboratory methods.
Claim 20: non-transitory computer-readable medium; computer processor; computer system, limited to a generic computer system and not a particular machine.
Further with respect to the additional elements in the instant claims, those steps directed to data gathering perform functions of collecting the data needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract idea, or on how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application. (MPEP 2106.05(g).
The courts have recognized the following laboratory techniques as insignificant extra-solution activity. See further, the MPEP at 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)).
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, the additional elements do not contribute significantly more to well-known and conventional steps to obtain genetic data, performed with routine laboratory equipment, and analyzed by one with ordinary skill in the art as of the effective filing date. The instant claims and references cited in the specification recite steps known in the art by molecular biologists, that include sequencing genetic data with massively parallel and bisulfite sequencing and are limitations equating to well-understood, routine and conventional activities. See the instant Specification at, for example [0061]; [0062]; [0065]; [0072] and the like.
As such, the Specification provides that the additional steps herein are routine, well-understood and conventional in the art.
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in 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 (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)).
The dependent claims have been analyzed with respect to step 2B and none of these claims provide a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception.
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.
It is noted herein that there are no actual sequencing steps performed in claims 1-10 and 12-20, but rather data gathering by “obtaining” data to determine a methylation profile.
Eligible Claim: Claim 11 recites actual sequencing steps that include methylation-aware sequencing that comprises bisulfite sequencing and if incorporated into the independent claims would provide for a step, in addition, that appears non-conventional in the realm of cfDNA and analysis wherein it is understood that methylation aware sequencing is necessarily performed using massively parallel sequencing.
Prior Art of Relevance
1. Chimonidou et al. (IDS reference) teach detection of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in the peripheral blood of patients with tumors. Chimonidou et al. do not teach or fairly suggest sequence reads comprising at least 15000 sequence reads or analysis of methylation sites and establishment of a methylation profile for comparison between cancer samples and a reference profile.
2. Liggett et al. (IDS reference) teach the analysis of methylation patterns of DNA for cancer diagnostic purposes. Liggett et al. teach differential methylation pattern analysis in ovarian cancer patients as compared with benign ovarian disease (page 114).
3. Van de Voorde et al. (2012) (IDS reference) teaches DNA methylation-based biomarkers in patients with breast cancer.
4. Wu et al. (2011) (IDS reference) teaches statistical quantification of methylation levels by next-generation sequencing.
The closest prior art does not appear to teach or fairly suggest, however, sequence reads from cell-free DNA molecules wherein sequence reads comprise methylation status at one or more sites of each of the cell-free DNA molecules; wherein sequence reads are at least 100,000 sequence reads; obtain methylation profiles for a plurality of sites; and determine a tissue source based on the methylation profile, as instantly claimed.
Conclusion
No claims are allowed.
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/Lori A. Clow/ Primary Examiner, Art Unit 1687
Prosecution Insights