DETAILED ACTION
Applicant’s response, filed 10 Oct. 2025 has been fully considered. 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on 10 Oct. 2025 has been entered.
Status of Claims
Claims 15-47, 49-81, 83-103, 105-117, 119-157 are cancelled.
Claims 1-14, 48, 82, 104, 118, and 158 are pending.
Claims 3-5, 9-11, 13, 48, 104, and 118 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 Dec. 2023.
Claims 1-2, 6-8, 12, 14, 82, and 158 are rejected.
Priority
The effective filing date for the instant application is 19 April 2012.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10 Oct. 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Claim Rejections - 35 USC § 112 (pre-AIA ), second paragraph
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.
Claim 7 is rejected under 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 applicant, regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claim 7 is indefinite for recitation of “…wherein the systemic disease is inflammation, infection, or sepsis”. Claim 6, from which claim 7 depends, recites “wherein the risk associated with the transplant is a risk of having or developing a systemic disease”. Claim 1, from which claim 7 ultimately depends, also recites “administering…a therapeutic agent that treats a systemic disease, wherein the systemic disease is inflammation, infection, or sepsis”, but claim 1 does not require the determined risk is a risk of having or developing systemic disease. As a result, it is unclear if “the systemic disease” in claim 1 is intending to refer to the systemic disease the risk is associated with claim 6, the systemic disease the therapeutic agent treats in claim 1, or if these are all intended to refer to the same systemic disease. For purpose of examination, claim 7 is interpreted to refer to the systemic disease of claim 6.
Claim 12 is indefinite for recitation of “The method of claim 1, further comprising: extracting the cell-free DNA from the biological sample”. Claim 1, from which claim 12 depends, already recites “obtaining a biological sample from the subject, extracting cell-free DNA comprising nucleic acids from the biological sample”, and therefore already require extracting cell-free DNA from the biological sample. As a result, it is unclear if claim 12 intends to recite a second step of extracting the cell-free DNA from the biological sample, as suggested by “further comprising”, or if claim 12 intends to refer to the same extraction step as in claim 1, given claim 12 references extracting “the cell-free DNA” (i.e. the same cell-free DNA extracted in claim 1). Therefore, the metes and bounds of the claims are unclear. Given Applicant’s specification does not appear to disclose two separate steps of extracting cell-free DNA from the same sample, claim 12 is interpreted to refer to the same step of extracting the cell-free DNA from the biological sample as in claim 1.
Claim Rejections - 35 USC § 112 (pre-AIA ), fourth paragraph
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This rejection is newly recited and necessitated by claim amendment.
Claim 12 recites “The method of claim 1, further comprising: extracting the cell-free DNA from the biological sample”. Claim 1, from which claim 12 depends, already recites “obtaining a biological sample from the subject, extracting cell-free DNA comprising nucleic acids from the biological sample”, and therefore already require extracting cell-free DNA from the biological sample. Furthermore, as discussed above in the 112 (pre-AIA ), second paragraph rejection of claim 12, claim 12 is interpreted to refer to the same step of extracting the cell-free DNA from the biological sample as in claim 1, rather than requiring a second extraction step in light of Applicant’s specification. Therefore, claim 12 fails to further limit the subject matter of claim 1, from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-2, 6-8, 12, 14, 82, and 158 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. The basis for this rejection remains the same; any newly recited portions are necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1, 82, and 158 being representative) is directed to a method for analyzing cell-free DNA. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 1 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas.
analyzing nucleic acids….to identify a plurality of loci, the nucleic acids comprising first nucleic acids of the subject and second nucleic acids not native to the subject;
determining an allele of each of the plurality of loci;
selecting at least one informative locus from the plurality of loci based on the determining of the allele;
calculating an estimated allele frequency of a first allele at the at least one informative locus using a statistical distribution;
determining an amount of cell-free DNA not native to the subject in the cell-free DNA, based on the estimated allele frequency;
determining a risk in the subject based on comparing the amount of the cell-free DNA not native to the subject in the cell-free DNA to a threshold value…; and
wherein the method is performed within 10 days of receiving the transplant;
Claim 82 recite the following steps which fall under the mental processes grouping of abstract ideas:
quantifying the amount of cell-free DNA extracted from a biological sample obtained from the recipient of a transplant; and
determining a risk of a systemic disease in the recipient of a transplant based on the determined amount of the cell-free DNA, wherein the method is performed within 10 days of receiving the transplant.
Claim 158 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas.
analyzing nucleic acids from the cell-free DNA extracted from a biological sample obtained from the subject to identify a plurality of loci, the nucleic acids comprising first nucleic acids of the subject and second nucleic acids not native to the subject;
determining an allele of each of the plurality of loci;
selecting at least one informative locus from the plurality of loci based on the determining of the allele;
calculating an estimated allele frequency of a first allele at the least one informative locus using a statistical distribution;
comparing the determined amount of the cell-free DNA not native to the subject to a threshold value of cell-free DNA;
identifying the subject as being at risk of transplant rejection, an anatomical problem with the transplant or injury to the transplant, or having or developing a systemic disease, wherein the systemic disease is inflammation, infection, or sepsis when the determined amount of the cell-free DNA not native to the subject is greater than the threshold value of cell-free DNA; and
wherein the method is performed within 10 days of receiving the transplant.
The identified claim limitations falls into one of the groups of abstract ideas of mental processes. The steps of analyzing nucleic acid from cell-free DNA containing subject nucleic acid and non-native nucleic acid, determining an allele of each of a plurality of loci, selecting an informative locus from the plurality of loci based on the determined allele, calculating an estimated allele frequency, and determining an amount of cell-free DNA not native to the subject can be practically performed in the human mind for the following reasons. For example, analyzing nucleic acids from cell-free DNA encompasses evaluating reads at a plurality of loci to determine a number of reads at each locus; determining an allele at each locus involves analyzing the reads of each particular locus to determine an allele present at each locus; selecting an informative locus from the loci involves selecting an allele that is homozygous at a particular locus; calculating an estimated allele frequency using a binomial statistical distribution involves determining a binomial distribution of reads containing one of two alleles and determining a likely allele frequency of the first allele based on the distribution; and determining an amount of cell-free DNA not native to the subject can be performed mentally by determining the allele frequency of the informative locus deviates from an expected allele frequency assuming no non-native nucleic acid is present to estimate an amount of non-native nucleic acid. Furthermore, determining a risk in the subject based on the determined amount encompasses determining the subject is at an increased risk of disease if a higher amount of non-native DNA is present in the subject as compared to a threshold (as recited in claim 158). Similarly, comparing the determined amount of non-native cell-free DNA to a threshold value can be performed mentally by performing data comparisons, which is a mental process. Further regarding claim 82, the step of determining/quantifying an amount of cell-free DNA not native to the subject and determining a risk in the subject based on the determined amount, can be performed mentally for the same reasons discussed above. Last, performing any of the above steps within 10 days of receiving a transplant merely specifies the timing of when the abstract idea is performed, and thus is part of the abstract idea. Therefore, nothing in the claims precludes the steps from being practically performed in the mind. See MPEP 2106.04(a)(2) III.
The limitations of estimating an allele frequency of a first allele using a statistical distribution further recite a mathematical concept. A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the "mathematical concepts" grouping. A See MPEP 2106.04(a)(2) I. C. In the instant case, estimating an allele frequency of an allele, using a binomial statistical distribution, amounts to a textual equivalent to performing mathematical calculations to calculate a numerical value. See MPEP 2106.04(a)(2) I. B. Therefore, these limitations recite a mathematical concept.
The claims further recite the law of nature of a natural correlation between an amount of non-native cell-free DNA present in a subject and an amount of risk in the subject. See MPEP 2106.04(b) I.
Dependent claims 2, 6-8, and 14 further recite an abstract idea and/or are part of the abstract idea. Claim 2 further limits the mental process of analyzing cell-free DNA to be from a recipient of a transplant and determining a risk associated with the transplant. Dependent claims 6-7 further limit the mental process of determining a risk to be a risk of having or developing the system disease of inflammation, infection, or sepsis. Dependent claim 8 further limit the mental process of claim 1 to involve analyzing donor-specific cell-free DNA. Dependent claim 14 further recites the mental process of detecting the first allele and a second allele at a locus and determining the first nucleic acids are homozygous for the second allele at the at least one informative locus and the second nucleic acids are heterozygous or homozygous for the first allele at the at least one informative locus. Therefore, claims 1-2, 6-8, 12, 14, 82, and 158 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 1-2, 6-8, 14, and 82 recite an abstract idea, as discussed above, but do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception. Claim 12 fails to further limit the subject matter of claim 1, and thus does not recite any additional elements in addition to those of claim 1.
The additional elements of claims 1, 82, and 158 include:
obtaining a biological sample from the subject, extracting cell-free DNA comprising nucleic acids from the biological sample, and analyzing the nucleic acids (e.g. in an assay) (claims 1 and 158);
administering an anti-rejection therapy, a therapeutic agent that treats a systemic disease, wherein the systemic disease is inflammation, infection, or sepsis, or a combination thereof to the subject when the amount of the cell-free DNA not native to the subject is greater than the threshold value (claims 1 and 158); and
administering a therapeutic agent that treats the inflammation, infection, or sepsis to the subject based on the determined risk (claim 82).
The additional elements of administering an anti-rejection therapy, a therapeutic agent that treats inflammation, infection, or sepsis, or a combination thereof to the subject in claims 1 and 158, and administering a therapeutic agent that treats the inflammation, infection, or sepsis, to the subject based on the determined risk in claim 82 are not sufficient to integrate the recited judicial exception into a practical application for the following reasons.
First, MPEP 2106.04(d)(2), states that examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. In the instant case, claims 1 and 158 do not require the treatment is administered under the broadest reasonable interpretation of the claims, because the administration step is contingent upon the condition of the amount of the cell-free DNA not native to the subject being greater than a threshold value. Because the condition is not required to be met by the claims, the administration is also not required by the claims. See MPEP 2111.04 II.
Second, the treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). See MPEP 2106.04(d)(2) a.. In the instant case, under the broadest reasonable interpretation of the claims, each of claims 1, 82, and 158 only recite administering a “therapeutic agent that treats” the inflammation, infection, or sepsis, which is analogous to the non-particular treatment of "administering a suitable medication to a patient” exemplified in MPEP 2106.04(d)(2) a. Therefore the claims do not integrate the recited judicial exception into the practical application of affecting a particular treatment, and instead the additional element amount to mere instructions to apply the exception. See MPEP 2106.05(f).
The additional elements of obtaining a biological sample from the subject, extracting cell-free DNA from the biological sample, and physically analyzing the DNA only serves to collect information for analysis by the abstract idea, which amounts to insignificant extra-solution activity that does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Therefore, the additionally recited elements amount to insignificant extra-solution activity and/or amount to mere instructions to apply the exception, and, as such, the claims as a whole do no integrate the abstract idea and law of nature into practical application. Thus, claims 1-2, 6-8, 12, 14, 82, and 158 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Dependent claims 1-2, 6-8, 14, and 82 recite an abstract idea, as discussed above, but do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception. Claim 12 fails to further limit the subject matter of claim 1, and thus does not recite any additional elements in addition to those of claim 1.
The additional elements of claims 1, 82, and 158 include:
obtaining a biological sample from the subject, extracting cell-free DNA comprising nucleic acids from the biological sample, and analyzing the nucleic acids (e.g. in an assay) (claims 1 and 158);
administering an anti-rejection therapy, a therapeutic agent that treats a systemic disease, wherein the systemic disease is inflammation, infection, or sepsis, or a combination thereof to the subject when the amount of the cell-free DNA not native to the subject is greater than the threshold value (claims 1 and 158); and
administering a therapeutic agent that treats the inflammation, infection, or sepsis to the subject based on the determined risk (claim 82).
The additional elements of obtaining a biological sample, extracting cell-free DNA from a biological sample, and analyzing the physical cfDNA are well-understood, routine, and conventional. This position is supported by Applicant’s specification, which discloses at pg. 16, para. 1 that cf-DNA can be extracted from a biological sample using any method known in the art, citing a plurality of commercially available extraction kits. With respect to physically analyzing, DNA, the courts have also found the following laboratory techniques as well-understood, routine, and conventional: using polymerase chain reaction to amplify and detect DNA, Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015); detecting DNA 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); and amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
The additional elements of administering an anti-rejection therapy, a therapeutic agent that treats inflammation, infection, or sepsis, or a combination thereof to the subject when the amount of the cell-free DNA not native to the subject is greater than the threshold value, in claims 1 and 158, and administering a therapeutic agent that treats the inflammation, infection, or sepsis, to the subject based on the determined risk in claim 82 are not sufficient to provide significantly more and are well-understood, routine, and conventional. First, the administration step in claims 1 and 158 are not sufficient to provide significantly more because they are not required under the broadest reasonable interpretation of the claims as discussed above under Step 2A, Prong 2. Furthermore, even if the administration were required in claims 1 and 158, as required in claim 82, Applicant’s specification at pg. 20, para. 3 to pg. 21, para. 2 discloses therapies can include anti-rejection therapies and these therapies are known to those of ordinary skill in the art. Applicant’s specification at pg. 21, para. 3 further discloses administration of treatment or therapy may be accomplished by any method or known in the art and that compositions for different routes of administration are well known in the art.
Last, Sharma et al. (Mass spectrometric based analysis, characterization and applications of circulating cell free DNA isolated from human body fluids, 2011, International Journal of Mass Spectrometry, 304, pg. 172-183; previously cited) reviews the application of circulating cell-free DNA as a clinical diagnostic tool (Abstract). Sharma discloses hundreds of papers have been published on circulating cell-free DNA (pg. 172, col. 2, para. 2 to pg. 173, col. 1, para. 1) in addition to various studies analyzing cell-free DNA in transplant recipients (pg. 173, col. 1, para. 4 and col. 2, para. 4; Table 2), and further discusses cell-free DNA as biomarkers for organ transplantation (pg. 172, col. 1, para. 1; pg. 181, col. 2, para. 2). Accordingly, even considering the additional elements in combination, extracting cell-free DNA in a clinical diagnosis context is well-understood, routine, and conventional.
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 10 Oct. 2025 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Applicant remarks independent claims 1, 82, and 158 have been amended to recite steps of obtaining a biological sample, extracting cell-free DNA, and administering a therapy to the subject, and that Vanda Pharmaceutical Inc. v. West-Ward Pharmaceuticals applies as the claims include steps of administering a therapy, therapeutic agent, or combination thereof, and thus the claims are directed to a practical application (Applicant’s remarks at pg. 7, para. 3-5). Applicant further remarks consideration of whether additional elements of a claim represent well-understood, routine, or conventional activity is excluded in the analysis to determine whether or not a claim is directed to a judicial exception (Applicant’s remarks at pg. 7, para. 6 to pg. 8, para. 2).
This argument is not persuasive. While claims 1, 82, and 158 do recite a treatment step, the additional element is not sufficient to integrate the recited judicial exception into a practical application for the reasons set forth in rejection above, and reiterated below.
First, MPEP 2106.04(d)(2), states that examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. In the instant case, claims 1 and 158 do not require the treatment is administered under the broadest reasonable interpretation of the claims, because the administration step is contingent upon the condition of the amount of the cell-free DNA not native to the subject being greater than a threshold value. Because the condition is not required to be met by the claims, the administration is also not required by the claims. See MPEP 2111.04 II.
Second, the treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). See MPEP 2106.04(d)(2) a.. In the instant case, under the broadest reasonable interpretation of the claims, each of claims 1, 82, and 158 only recite administering a “therapeutic agent that treats” the inflammation, infection, or sepsis, which is analogous to the non-particular treatment of "administering a suitable medication to a patient” exemplified in MPEP 2106.04(d)(2) a. Therefore the claims do not integrate the recited judicial exception into the practical application of affecting a particular treatment, and instead the additional element amount to mere instructions to apply the exception. See MPEP 2106.05(f).
Last, while it is agreed that if a claim is eligible under step 2A, prong 2, then the analysis does not proceed to step 2B where the conventionality of the additional elements are analyzed, the claims are not eligible under step 2A, prong 2, and therefore the analysis proceeds to step 2B. Under step 2B, the additional elements were found to be well-understood, routine, and conventional, even considered in combination.
Claim Rejections - 35 USC § 103
The rejection of claims 1-2, 8, 12, 14 and 158 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Snyder (2011) in view of Chu (2010) in the Office action mailed 11 Sept. 2024 has been withdrawn in view of claim amendments received 10 Oct. 2025.
The rejection of claims 6-7 and 82 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Snyder in view of Chu, as applied to claim 2 above, and further in view of Rocha (2003) in the Office action mailed 11 Sept. 2024 has been withdrawn in view of claim amendments received 10 Oct. 2025.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-2, 8, 12, 14 and 158 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Snyder (2011). This rejection is newly recited and necessitated by claim amendment; however, the basis for this rejection remains the same, but no longer relies upon Chu (2010) in light of claim amendments.
Cited references:
Snyder et al., Universal noninvasive detection of solid organ transplant rejection, 2011, PNAS, 108(15), pg. 6229-6234 and suppl.; cited in IDS filed 08 Oct. 2019; supplementary included in PTO-892; previously cited.
Regarding claim 1, Snyder discloses a method for detecting transplant rejection in a subject (Abstract), which comprises the following steps:
Snyder discloses analyzing cell-free DNA extracted from blood samples obtained from a subject to identify a plurality of loci (FIG. 1; pg. 6299, col. 1, para. 2-3; pg. 6232, col. 1, para. 2, e.g. 25,000 SNP containing reads), wherein the DNA (i.e. nucleic acids) comprise nucleic acids native to the subject and non-native donor DNA (i.e. the first and second nucleic acids) (pg. 6299, col. 1, para. 3; Figure 1).
Snyder discloses determining an allele of each locus (pg. 6234, col. 2, para. 3, e.g. reads aligned to reference to identify alleles at each SNP site).
Snyder discloses selecting informative loci where the subject has a homozygous SNP in both alleles (i.e. based on the determined allele) (pg. 6231, col. 1, para. 4 to col. 2, para. 1, e.g. "each usable SNP…").
Snyder discloses calculating an allele count (i.e. an estimated allele frequency) of an allele of each informative locus (i.e. a first allele at the at least one informative locus), based on counting a number of reads that falls into recipient, donor, or error bins (i.e. using a statistical categorical distribution) (pg. 6231, col. 2, para. 1-3; Fig. S3).
Snyder discloses determining a percentage of donor DNA (i.e. an amount of cell-free DNA not native to the subject in the cell-free DNA) based on the estimated allele frequency of the informative loci (pg. 6231, col. 2, para. 3, e.g. counts used to calculate donor percentages; Figure 1).
Snyder further discloses determining a risk of organ rejection in the subject based comparing the amount of non-native cell-free DNA in the subject to a threshold value (pg. 6230, col. 1, para. 2, to col. 2, para. 1, e.g. 2.0% donor DNA threshold captures 80% true positive rate; 6233, col. 1, para. 2, e.g. donor DNA levels used to indicate organ rejection; FIG. 4).
Regarding the step of administering the anti-rejection therapy or a therapeutic agent, the limitation is contingent on the amount of the cell-free DNA not native to the subject being greater than the threshold value. 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. See MPEP 2111.04. Therefore, the administering step is not required under the broadest reasonable interpretation of the claims.
Further regarding claim 1, Snyder does not disclose the following limitations:
While Snyder discloses performing the non-invasive method at day 14 after transplant (pg. 6234, col. 2, para. 3; Figure 4), Snyder does not explicitly disclose performing the non-invasive organ rejection method within 10 days of receiving the transplant.
However, Snyder discloses that the method of detecting organ rejection is noninvasive, which reduces the number of biopsies required from the subject and reduces medical costs (pg. 6233, col. 2, para. 2), and further discloses early detection of rejection enables early intervention to prevent full blown organ rejection (pg. 6233, col. 1, para. 3 to col. 2, para. 2). Snyder further discloses biopsies are taken weekly (i.e. within 7 days) after transplant to check for organ rejection (pg. 6234, col. 1, para. 3).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Snyder and Rocha, to have performed the method within 10 days of receiving the transplant based on applying the known non-invasive organ rejection method of Snyder to the method of checking for organ rejection weekly (i.e. within 7 days) using a biopsy of Snyder (pg. 6234, col. 1, para. 3). As discussed by Snyder, the non-invasive organ rejection technique is intended to reduce the number of biopsies required of the subject (pg. 6233, col. 2, para. 2), such that organ rejection can be checked non-invasively rather than via biopsy. Furthermore, one of ordinary skill in the art would have recognized that applying the non-invasive organ rejection method of Snyder to a sample of the subject taken in the first week after transplantation would have resulted in a less-invasive and less expensive procedure for the subject, as shown by Snyder (pg. 6233, col. 2, para. 2), and furthermore enabled earlier detection of organ rejection, as shown by Snyder (pg. 6233, col. 1, para. 3 to col. 2, para. 2).
Regarding claim 2, Snyder further discloses the subject is a recipient of a transplant (Abstract) and that the risk is a risk of organ rejection (i.e. a risk associated with the transplant) (pg. 6233, col. 1, para. 1).
Regarding claim 8, Snyder discloses the non-native cell-free DNA is donor-specific cell-free DNA (pg. 6229, col. 1, para. 3; Fig. 1).
Regarding claim 12, Snyder further discloses collecting (i.e. extracting) cell-free DNA from plasma of the subject (Fig. 1).
Regarding claim 14, Snyder discloses selecting the at least one informative locus by determining alleles at SNP sites (i.e. a first and second allele at a locus) (pg. 6234, col. 2, para. 3; pg. 6231, col. 1, para. 4); and
Snyder discloses determining the informative loci comprises determining SNP sites where the recipient has a homozygous allele (i.e. determining the first nucleic acids are homozygous for the second allele) that differs from the donor's genotype (i.e. the second nucleic acids are heterozygous or homozygous for the first allele, different than the second allele) (pg. 6234, col. 2, para. 3).
Regarding claim 158, Snyder discloses a method for detecting transplant rejection in a subject (Abstract), which comprises the following steps:
Snyder discloses (a) analyzing cell-free DNA extracted from blood samples obtained from a subject to identify a plurality of loci (FIG. 1; pg. 6299, col. 1, para. 2-3; pg. 6232, col. 1, para. 2, e.g. 25,000 SNP containing reads) and determining a percentage of donor DNA (i.e. an amount of cell-free DNA not native to the subject in the cell-free DNA) based on the estimated allele frequency of the informative loci (pg. 6231, col. 2, para. 3, e.g. counts used to calculate donor percentages; Figure 1), by performing the following steps:
Snyder discloses (i) analyzing the cell-free DNA from blood samples obtained from a subject to identify a plurality of loci (FIG. 1; pg. 6299, col. 1, para. 2-3; pg. 6232, col. 1, para. 2, e.g. 25,000 SNP containing reads), wherein the DNA (i.e. nucleic acids) comprise nucleic acids native to the subject and non-native donor DNA (i.e. the first and second nucleic acids) (pg. 6299, col. 1, para. 3; Figure 1).
Snyder discloses (ii) determining an allele of each locus (pg. 6234, col. 2, para. 3, e.g. reads aligned to reference to identify alleles at each SNP site).
Snyder discloses (iii) selecting informative loci where the subject has a homozygous SNP in both alleles (i.e. based on the determined allele) (pg. 6231, col. 1, para. 4 to col. 2, para. 1, e.g. "each usable SNP…").
Snyder discloses (iv) calculating an allele count of an allele of each informative locus (i.e. a first allele at the at least one informative locus), based on counting a number of reads that falls into recipient, donor, or error bins (i.e. using a statistical categorical distribution) (pg. 6231, col. 2, para. 1-3; Fig. S3).
Snyder discloses (b) comparing the amount of non-native cell-free DNA in the subject to a threshold percentage of donor DNA (pg. 6233, col. 1, para. 1, e.g. donor DNA levels used to indicate organ rejection; pg. 6230, col. 1, para. 2 to col. 2, para. 1, e.g. threshold of 2% donor DNA).
Regarding, steps (c)-(d), the steps of identifying the subject at risk and administering an anti-rejection therapy or a therapeutic agent are contingent on the determined amount of the cell-free DNA not native to the subject being greater than the threshold value of cell-free DNA. Because the claims do not require the determined amount of the cell-free DNA not native to the subject is greater than the threshold value of cell-free DNA, the steps of identifying the subject at risk and administering an anti-rejection therapy or therapeutic agent are not required by the claim. See MPEP 2111.04.
Regardless, Snyder also discloses (c) determining a risk of organ rejection in the subject when the amount of donor DNA is above the threshold percent of donor DNA (pg. 6233, col. 1, para. 1, e.g. donor DNA levels used to indicate organ rejection; pg. 6230, col. 1, para. 2 to col. 2, para. 1, e.g. threshold of 2% donor DNA).
Further regarding claim 158, Snyder does not disclose the following limitation:
While Snyder discloses performing the non-invasive method at day 14 after transplant (pg. 6234, col. 2, para. 3; Figure 4), Snyder does not explicitly disclose performing the non-invasive organ rejection method within 10 days of receiving the transplant.
However, Snyder discloses that the method of detecting organ rejection is noninvasive, which reduces the number of biopsies required from the subject and reduces medical costs (pg. 6233, col. 2, para. 2), and further discloses early detection of rejection enables early intervention to prevent full blown organ rejection (pg. 6233, col. 1, para. 3 to col. 2, para. 2). Snyder further discloses biopsies are taken weekly (i.e. within 7 days) after transplant to check for organ rejection (pg. 6234, col. 1, para. 3).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Snyder and Rocha, to have performed the method within 10 days of receiving the transplant based on applying the known non-invasive organ rejection method of Snyder to the method of checking for organ rejection weekly (i.e. within 7 days) using a biopsy of Snyder (pg. 6234, col. 1, para. 3). As discussed by Snyder, the non-invasive organ rejection technique is intended to reduce the number of biopsies required of the subject (pg. 6233, col. 2, para. 2), such that organ rejection can be checked non-invasively rather than via biopsy. Furthermore, one of ordinary skill in the art would have recognized that applying the non-invasive organ rejection method of Snyder to a sample of the subject taken in the first week after transplantation would have resulted in a less-invasive and less expensive procedure for the subject, as shown by Snyder (pg. 6233, col. 2, para. 2), and furthermore enabled earlier detection of organ rejection, as shown by Snyder (pg. 6233, col. 1, para. 3 to col. 2, para. 2).
Therefore the invention is prima facie obvious.
Claims 6-7 and 82 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Snyder, as applied to claim 2 above, and further in view of Rocha (2003). This rejection is newly recited and necessitated by claim amendment.
Cited reference: Rocha et al., Effector mechanisms in transplant rejection, 2003, Immunol Rev., 196, pg. 51-64; cited in IDS filed 12 Dec. 2023; previously cited.
Regarding claims 6-7, Snyder discloses the method of claim 2 as applied above.
Regarding claim 82, Snyder discloses a method for non-invasively detecting transplant rejection in a subject that received a transplant (Abstract), which comprises the following steps:
Snyder discloses determining a percentage of donor DNA from cell-free DNA collected from a biological sample obtained from the recipient of the transplant (i.e. quantifying an amount of cell-free DNA not native to the recipient of the transplant in the cell-free DNA) based on the estimated allele frequency of the informative loci (pg. 6231, col. 2, para. 3, e.g. counts used to calculate donor percentages; Figure 1, e.g. cell-free DNA collected from plasma and used to monitor Donor DNA level).
Snyder further discloses determining a risk of organ rejection in the subject based on the amount of non-native cell-free DNA in the subject (pg. 6233, col. 1, para. 1, e.g. donor DNA levels used to indicate organ rejection).
Further regarding claims 6-7 and 82, Snyder does not disclose the following limitations:
Regarding claims 6 and 82, Snyder does not disclose the risk associated with the transplant is a risk of having or developing a systemic disease.
Regarding claims 7 and 82, Snyder does not disclose the systemic disease is inflammation, infection, or sepsis.
However, regarding claims 6-7 and 82, Rocha overviews mechanisms in transplant rejection (Abstract), and discloses that transplant rejection triggers inflammatory mediators that contribute to the pathogenesis of transplant rejection and transplant rejection is associated with systemic immune responses (Abstract; pg. 54, col. 2, para. 3 to pg. 55, col. 1, para. 1; pg. 55, col. 2, para. 3 to pg. 56, col. 1, para. 1), and that various inflammatory responses, including pro-inflammatory T-cell response (pg. 54, col.2 , para. 2), leukotrienes response (pg. 56, col. 2, para. 3), and complement pathway activation are involved (pg. 57, col. 2, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the time of the invention, to have modified determined a risk of transplant rejection in the subject based on the determined amount of donor DNA of Snyder, to have determined a risk of systemic inflammation in the subject, given Rocha discloses that the mechanisms that cause organ transplant rejection also cause systemic inflammation (Abstract; pg. 54, col. 2, para. 3 to pg. 55, col. 1, para. 1; 55, col. 2, para. 3 to pg. 56, col. 1, para. 1; pg. 54, col. 2, para. 2; pg. 56, col. 2, para. 3; pg. 57, col. 2, para. 2). One of ordinary skill in the art would have been motivated to combine the method of Snyder and Rocha based on the simple substitution of the risk of transplant rejection in Snyder with the systemic disease of inflammation of Rocha, given Rocha discloses that the mechanisms that cause organ transplant rejection also cause inflammation (Abstract; pg. 55, col. 2, para. 3 to pg. 56, col. 1, para. 1; pg. 54, col. 2, para. 2; pg. 56, col. 2, para. 3; pg. 57, col. 2, para. 2). Therefore, one of ordinary skill in the art would have been able to substitute the determining the risk of systemic disease of transplant rejection with the systemic disease of inflammation, and the results of the substitution would have been predictable given Rocha discloses inflammation occurs with transplant rejection, as discussed above.
Further regarding claim 82, while Snyder discloses treating the subject with an anti-rejection therapy based on a subject being at risk for organ rejection (e.g. as determined through a biopsy) (pg. 6231, col. 1, para. 2; pg. 6233, col. 1, para. 1; Abstract), Snyder does not disclose administering a therapeutic agent that treats inflammation, infection, or sepsis to the subject based on the determined risk.
However, Snyder does disclose the amounts of donor-derived DNA in plasma is a promising biomarker for the onset of organ rejection and that the level of donor DNA declines following treatment (pg. 6233, col. 1, para. 1). Snyder further discloses using amounts of donor-DNA as a biomarker provides a noninvasive test that replaces endomycocardial biopsy in heart transplant recipients (Abstract). Furthermore, given Rocha discloses systemic inflammation is suppressed in long term transplant survival and increased in transplant rejection (pg. 55, col. 1, para. 1 to 3), a treatment for transplant rejection is considered a treatment for inflammation (i.e. preventing the immune system from rejecting the transplant).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Snyder to have administered an anti-rejection therapy that treats inflammation based on the determined risk, given Snyder discloses the level of donor DNA declines following treatment and suggests using the amount of donor-derived DNA as a biomarker for organ rejection (pg. 6233, col. 1, para. 1). One of ordinary skill in the art would have been motivated to apply the determined amount of donor DNA to determine to administer an anti-rejection therapy to the subject to provide a non-invasive test for determining a risk of transplant rejection, as shown by Snyder (Abstract). This modification would have had a reasonable expectation of success given Snyder discloses treating a subject at risk for organ rejection and that an amount of DNA can be used as a biomarker for the risk of organ rejection (pg. 6231, col. 1, para. 2; pg. 6233, col. 1, para. 1; Abstract).
Further regarding claim 82, while Snyder discloses performing the non-invasive method at day 14 after transplant (pg. 6234, col. 2, para. 3; Figure 4), Snyder does not explicitly disclose performing the non-invasive organ rejection method within 10 days of receiving the transplant.
However, Snyder discloses that the method of detecting organ rejection is noninvasive, which reduces the number of biopsies required from the subject and reduces medical costs (pg. 6233, col. 2, para. 2), and further discloses early detection of rejection enables early intervention to prevent full blown organ rejection (pg. 6233, col. 1, para. 3 to col. 2, para. 2). Snyder further discloses biopsies are taken weekly (i.e. within 7 days) after transplant to check for organ rejection (pg. 6234, col. 1, para. 3).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Snyder and Rocha, to have performed the method within 10 days of receiving the transplant based on applying the known non-invasive organ rejection method of Snyder to the method of checking for organ rejection weekly (i.e. within 7 days) using a biopsy of Snyder (pg. 6234, col. 1, para. 3). As discussed by Snyder, the non-invasive organ rejection technique is intended to reduce the number of biopsies required of the subject (pg. 6233, col. 2, para. 2), such that organ rejection can be checked non-invasively rather than via biopsy. Furthermore, one of ordinary skill in the art would have recognized that applying the non-invasive organ rejection method of Snyder to a sample of the subject taken in the first week after transplantation would have resulted in a less-invasive and less expensive procedure for the subject, as shown by S