Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is in response to applicants correspondence mailed 10/07/2025. The amendment to the claims mailed 10/07/2025 has been entered
Claim Status
Currently, claims 1-2, 13, 15, 17-18, 20-21, 28, 30, 73-85, 87-88, 90 are pending in the instant application. Claim 3-12, 14, 16, 19, 22-27, 29, 31-72, 86, and 89 have been canceled and claims 28, 30, 73-85, 87-88, and 90 are withdrawn. This action is written in response to applicant' s correspondence submitted 05/20/2026. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are either newly presented, as necessitated by amendment, or are reiterated from the previous office action. Any rejections not reiterated in this action have been withdrawn as necessitated by applicant' s amendments to the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. This action is FINAL.
Claims 1-2, 13, 15, 17-18, 20-21 are under examination. Claim 2 is under examination with respect to DNA modification.
Withdrawn Rejections
The rejection of claims 1-2, 13-18, 20-21, and 25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 14-15, 18, 20-23 under 35 U.S.C. 102(a)(1) as being anticipated by Lo (US2018/0149636A1) is withdrawn in view of the amendment to the claims.
The rejection of claims 1-2, 13, 18, 21, 26 under 35 U.S.C. 102(a)(1) and 35 USC 102(a)(2) as being anticipated by De Vlaminck (WO2018/187521, A2, cited on IDS or US2020/0048713A1, WO2018/187521 is the PCT/US2018/026163 of PgPub, cited by WO2018/187521 A2) is withdrawn in view of the amendment to the claims.
The nonstatutory double patenting rejection of claims 1-2, 13, 18, 21, 26 as being unpatentable over claims 1-3, 10, of U.S. Patent No. 11781188 is withdrawn in view of the amendment to the claims.
New Grounds of Rejection – Necessitated by Amendment to the Claims
Claim Rejections - 35 USC § 112(b)
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 1-2, 13, 15, 17-18, 20-21 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.
Claim 1 recites determining profiles of an epigenetic marker within cfDNA molecules, identifying tissues of origin of the cfDNA molecule based on profiled determined, measuring the level of cfDNA from an identified tissue of original wherein the level or an increased level of cfDNA from identified tissue of origin is indicative of damage in said tissue of origin and wherein detecting tissue damage at about 30 days HCT is indicative of a risk of developing graft versus host disease. It is unclear when tissue damage is detected and indicative of risk of developing graft versus host disease when the claim requires measuring the level or increased level of cfDNA and is indicative of damage. The claim requires any level or increased level of cfDNA is indicative of damage, as such it is unclear how measuring level of cfDNA results in detecting tissue damage at about 30 days post HCT when any level of cfDNA is indicative of damage as recited in the measuring step. Additionally it is unclear when the subject is treated as treatment occurs when there is indication of risk of GVHD however GVHD is dependent on level or increased level of cfDNA molecules are measured. The measuring step appears to include any analysis of cfDNA molecules measured and any analysis will be indicative or risk of developing GVHD. Because the claim recites the level or an increased level of cfDNA molecules the metes and bounds of the claim are vague and indefinite. One of ordinary skill in the art would not be reasonably apprised of infringing on the claimed method because the metes and bounds of detecting tissue damage that is indicative of risk of developing graft versus host disease and treating the subject with immunoregulatory agent when there is an indicative of graft-versus host disease.
Claims 2, 13, 15, 17-18, 20-21 depend from claim 1 are rejected for the reasons applied to claim 1.
Claim Rejections - 35 USC § 103
Claims 1-2, 14-18, 20-21, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Duque-Afonso (2018, cited on IDS) as evidence by Wasch (Bone Marrow Transplant, 2000, 26:243-250) in view of De Vlaminick (WO2018/187521 cited on IDS or US20200048713A1). This is a new grounds of rejection.
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Duque-Afonso teaches isolating cell free DNA from plasma after allogeneic cell transplantation. Duque-Afonso teaches obtaining blood samples (claim 15) from patients that had allogeneic cell transplantation (alloHSCT) (see pg. 137, 2nd column and patient samples). Duque-Afonso teaches a control group of 21 healthy blood donors was included. Duque-Afonso teaches increase in cfDNA in patients that had graft versus host disease (increase in cfDNA indicative of tissue damage) (see fig 2 and fig 4). Duque-Afonso teaches patients were investigated at days 30, 100, and 365 post-transplant (see patient samples) (claim 16 and 25). Duque-Afonso teaches GvHD prophylaxis was performed as previously described by Wasch. Wasch teaches low regiment of fludarabine, carmustine, melphalan for GvHD prophylaxis (treating with immunoregulatory agent). Duque-Afonso teaches DNA concentrations of No GVHD, healthy donors (control samples) (see table 2) (claim 17). Duque-Afonso teaches successful treatment for acute GVHD results in reduced recipient cfDNA over time suggesting that the recipient cfDNA could be derived by cell disruption in GVHD target organs (see discussion, 2nd column). Duque-Afonso teaches that further studies using tissue specific circulating nucleic acid are needed to correlate analysis with the organ of origin to direct early diagnostic and treatment options (see pg. 141). Duque-Afonso does not teach epigenetic profile to determine tissue of origin.
De Vlaminck teaches a method of obtaining a sample, bisulfite treating the sample, preparing a sequencing library from the sample, and sequencing for DNA methylation (see para 21). De Vlaminck teaches the step of analyzing DNA methylation comprising determining the tissue of origin by aligning to a methylation reference panel (see para 22). De Vlaminck teaches single strand DNA sequencing libraries from cfDNA of a biological sample (see para 47-59).De Vlaminck teaches determining tissue of origin from bodily fluid samples (urine, plasma). De Vlaminck teaches that an increase in kidney derived cfDNA in urine sample may indicate BKV nephropathy (tissue damage) (see para 82-83). With regard to claim 26, De Vlaminck teaches analysis of cfDNA to determine tissue injury in the graft (see ex 8).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to improve the method of determining cfDNA for GVHD of allo-HCT as taught by Duque-Afonso to include epigenetic profile to determine the tissue origin because De Vlaminck teaches measuring epigenetic profiles to quantify tissue of origin by ssDNA library preparation method. The ordinary artisan would have been motivated to improve the method of analysis of cfDNA levels in HCT as taught by Duque-Afonso and include measuring methylation patterns in cfDNA because De Vlaminck teaches measuring methylation levels in cfDNA can determine the tissue of origin and organ type and Duque-Afonso suggests identifying tissue of origin in cfDNA in HCT subjects. The ordinary artisan would have had a reasonable expectation of success that the use of epigenetic profiling to identify tissue of origin could be used in the method of Duque-Afonso because De Vlamuinck teaches measuring methylation levels to identify tissue of origins and Duque-Afonso suggests identifying the tissue of origin for cfDNA of HCT subjects.
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, 13, 15, 17-18, 20-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and natural laws without significantly more. This rejection was previously presented and has been rewritten to address the amendment to the claims.
The claims recite “identifying the tissues of origin of the cfDNA molecules based on the profiles determined” and this step encompasses a data analysis process (i.e. the process of reviewing the profiles and drawing inferences about tissue origin) which could be practiced in the mind. The claim additionally sets forth a comparison of the level of increased level of cfDNA as compared to a control level which is a mental process.
The claim recites “wherein detecting tissue damage at about 30 days post HCT is indicative of a risk of developing graft-versus-host disease”. This step encompasses a mental process and sets forth a natural law correlation. The broadest reasonable interpretation is a step that is accomplished mentally be evaluating data and critical thinking process such that one mentally reads information regarding cfDNA levels and draws a mental conclusion. Such steps of indicating risk of developing graft versus host disease may be performed mentally and this is an abstract idea.
The claims additionally set forth identifying the tissue of origin based on the epigenetic profile of the cfDNA, and this sets forth the correlation between the methylation profile and the tissue of origin which is a law of nature. The claims additionally include identifying damage of tissue origin based on the level of cfDNA from the identified tissue of origin and sets for the correlation between the level of cfDNA and damage of tissue which is a law of nature.
These judicial exception are not integrated into a practical application because the steps in addition to the judicial exceptions are data gathering steps that do not apply or integrate the judicial exceptions in any way. While the claim recites treating the subject with immunoregulatory agent, this is a conditional step because the claim further recites when there is indication of a risk of developing graft versus host disease. The step of treating only occurs when there is an indication of risk of developing GVHD, however if this is not indicated then treatment does occur. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exception are data gathering steps recited at a high level of generality employing techniques that were well-established, routine and conventional at the time of the invention. The courts have recognized that amplifying and sequencing nucleic acid sequences is among the well-understood, routine, conventional activity in the life science arts when claimed in a merely generic matter. Here, the claims include steps of sample DNA, preparing a single stranded sequencing library of cfDNA, and epigenetic profiles. Prior to the invention, Lo (2018) teaches epigenetic profiles analysis in cfDNA and De Vlaminck (WO2018/187521) teaches single stranded DNA library to identify epigenetic profile in cfDNA.
Claims 2 further define the epigenetic marker that is identified. Claim 14 further defines the subject as undergone HCT. Claim 15 further defines the biological sample. Claim 17 defines the control level. Claims 20, 21 further define the tissue of origin. Each of these limitations are a field of use limitation that does not amount to significantly more than the judicial exception.
Claim 13 add additional step of a library of cfDNA molecules is prepared, which is addressed in De Vlaminck (WO2018/187521 A2).
The additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide inventive concept necessary to render the claims patient eligible. There is no combination of elements in this step that distinguishes it from well-understood, routine and conventional data gathering activity engaged in by scientists prior to applicant’s invention and at the time the application was filed. Many cited prior art references in this record demonstrate that these techniques were conventional at the time of the invention. For example, the prior art of Lo (US2018/0149636A1) Lo teaches tissue specific methylation patterns of cfDNA can be used to determine different tissue types. Lo teaches whole genome bisulfite sequencing for cfDNA from transplant HSCT patients. Lo teaches methylation levels to determine bladder tissue and bladder cancer.
Thus the prior art and specification demonstrates it was routine, well-known and conventional in the art to determine epigenetic profiles in cfDNA to identify tissue origin in biological samples including blood samples. The dependent claims do not provide significantly more to the claims outside of the judicial exception as they encompass conventional techniques as described in the instant specification as noted above.
Response to Amendment
The response traverses the rejection pages 9-11 of the remarks mailed 05/20/2026. The response asserts that the treatment step of claim 1 applies the natural relationship in a manner integrating it into a practical application and is equivalent to finding of eligibility at step 2A prong two, MPEP 2106.04(b). This response has been reviewed but not found persuasive. The step of treating in the instant claims is a conditional step and only occurs when there is an indication of a risk of developing GVHD, however the claims encompass analysis of not detecting risk of developing GVHD. Therefore the treatment step is not a particular treatment step that applies the natural relationship in a manner that integrates it into a practical application. The treatment step does not apply the judicial exception to effect a particular treatment for a disease or medical condition. For example the treating step occurs when detecting risk of developing GVHD and the risk of developing GVHD occurs whenever cfDNA molecules are detected. The steps recited in the claims are nominal and insignificant relationships to the exception and the extra solution activity. For example the step of detecting risk of GVHD occurs regardless of the level of cfDNA molecules as the measuring step includes any level and any level is indicative of damage to a tissue of origin. The step of treating is conditional and only occurs when there is an indication of risk of GVHD.
The response further asserts that the claims as amended requires a specific action that changes the subjects treatment regimen when the claimed assay indicates elevated GVHD risk. The response assert this is not a claim to detecting risk in the abstract and recites a method of treatment in which the risk indication is used to direct a specific therapeutic intervention for a particular patient population. This response asserts the claim applies a natural correlation to affect a specific treatment outcome is integrated into a practical application and therefore not directed to the judicial exception. The response points to Vanada. This response has been reviewed but not found persuasive. In Vanda, the claims encompassed treating a subject with a specific genotype and specific therapeutic, however in the instant case the claims encompass any level of cfDNA identifies tissue damage and treating occurs when tissue damage is identified. The treatment step is not specific and there is no recitation of a treatment regimen that is changed. The claim does not treat a subject not identified with tissue damage. The claim further is not a method of treating a subject post HCT, the claim is directed to a method of detecting and treating tissue damage wherein the detecting tissue damage recites both an abstract idea and natural correlation of which neither judicial exception is integrated to a practical application. The step of detecting tissue damage encompasses an abstract idea and further encompasses any and all cfDNA levels and any tissue damage detected includes risk of developing GVHD. Therefore the step of treating although conditional is not specific or particular to a patient population. While the claim encompasses patient 30 day post HCT, this is not a specific patient population tied to the judicial exceptions. As such the amendment tot eh claims does not integrate the judicial exception recited within the claims.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 14-18, 20-21, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Duque-Afonso (2018, cited on IDS) as evidence by Wasch (Bone Marrow Transplant, 2000, 26:243-250) in view of DiLoreto (2017, cited on IDS). This rejection was previously presented and has been rewritten to address the amendment to the claims.
Duque-Afonso teaches isolating cell free DNA from plasma after allogeneic cell transplantation. Duque-Afonso teaches obtaining blood samples (claim 15) from patients that had allogeneic cell transplantation (alloHSCT) (see pg. 137, 2nd column and patient samples). Duque-Afonso teaches a control group of 21 healthy blood donors was included. Duque-Afonso teaches increase in cfDNA in patients that had graft versus host disease (increase in cfDNA indicative of tissue damage) (see fig 2 and fig 4). Duque-Afonso teaches patients were investigated at days 30, 100, and 365 post-transplant (see patient samples) (claim 16 and 25). Duque-Afonso teaches GvHD prophylaxis was performed as previously described by Wasch. Wasch teaches low regiment of fludarabine, carmustine, melphalan for GvHD prophylaxis (treating with immunoregulatory agent). Duque-Afonso teaches DNA concentrations of No GVHD, healthy donors (control samples) (see table 2) (claim 17). Duque-Afonso teaches successful treatment for acute GVHD results in reduced recipient cfDNA over time suggesting that the recipient cfDNA could be derived by cell disruption in GVHD target organs (see discussion, 2nd column). Duque-Afonso teaches that further studies using tissue specific circulating nucleic acid are needed to correlate analysis with the organ of origin to direct early diagnostic and treatment options (see pg. 141). Duque-Afonso does not teach epigenetic profile to determine tissue of origin.
DiLoreto teaches measuring epigenetic marks within cfDNA can be used to quantify tissue of origin. DiLoreto teaches genome-wide patterns of DNA methylation has been shown to be sufficient to decompose the organ type which contribute to plasma cfDNA (see pg. 277, 1st column).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to improve the method of determining cfDNA for GVHD of allo-HCT as taught by Duque-Afonso to include epigenetic profile to determine the tissue origin because DiLoreto teaches measuring epigenetic profiles to quantify tissue of origin. The ordinary artisan would have been motivated to improve the method of analysis of cfDNA levels in HCT as taught by Duque-Afonso and include measuring methylation patterns in cfDNA because DiLoreto teaches measuring methylation levels in cfDNA can determine the tissue of origin and organ type and Duque-Afonso suggests identifying tissue of origin in cfDNA in HCT subjects. The ordinary artisan would have had a reasonable expectation of success that the use of epigenetic profiling to identify tissue of origin could be used in the method of Duque-Afonso because DiLoreto teaches measuring methylation levels to identify tissue of origins and Duque-Afonso suggests identifying the tissue of origin for cfDNA of HCT subjects.
Response to Arguments
The response traverses the rejection on pages 12-16 of the remarks mailed 05/20/2026. The response asserts Duque-Afonso does not teach or suggest identifying tissue of origin of cfDNA or biological sample obtained from a subject 30 days post HCT or detecting tissue damage 30 days post HCT indicative of risk of developing GvHD. This response has been reviewed but not found persuasive. Duque-Afonso does teach obtaining biological samples of subject post 30 days post HCT and teaches increased cfDNA levels to indicate risk of GvHD (see patient samples, table 2 and fig 3). Duque-Afonso as addressed in the rejection does not teach identifying tissue of origin. However DiLoreto teaches identifying tissue of origin of cfDNA.
The response asserts that DiLoreto raises the speculation of future direction and provides no information for one of skill in the art to perform such a method and therefore is not enabled. The response asserts that DiLoreto states precision measurement of epigenetic marks contained within cdDNA can be considered to address the limitations of cdDNA in GvHD. This response has been reviewed but not found persuasive. The teachings of DiLoreto are equivalent to that of the direction of the instant specification. The specification provides no information for one of skill in the art to detect epigenetic changes to identify tissue of origin. While the specification provides generically methods of methylation profile of cfDNA (see pg. 10-14, pg. 15-16), the specification does not provide guidance on methylation profile on cfDNA other than the reference methylome were obtained from publicly available information (see para 171). The teachings of DiLoreto provide the same amount of guidance as the instant specification. DiLoreto teaches genome-wide pattern of DNA methylation can be detected by bisulfite sequencing of plasma DNA and has been shown to be sufficient to decompose the organ type. DiLoreto teaches analysis of cfDNA fragment profile to extrapolate footprint of tissue of origins. DiLoreto cites references that provide such guidance. As such DiLoreto teaches that epigenetic profiles can be used to identify tissue of origin. The claims do not require a specific methylation pattern is detected or that a specific tissue of origin is detected. DiLoreto enables one of ordinary skill in the art to use methylation patterns to identify tissue of origins. The specification and the art both teach methylation analysis of cfDNA for tissue origin. There is a reasonable expectation of success that the ordinary artisan would have able to measure methylation analysis of cfDNA for tissue origin and organ type as taught by DiLoreto.
The response further asserts that Duque-Afonso is directed to chimerism analysis. The response addresses this assay distinguishes donor derived from recipient derived cfDNA and this assay does not identify any tissue of origin. The response asserts cfDNA was observed only in patients with active or worsening GvHD making it a concurrent marker of damage already occurring. This response has been reviewed but not found persuasive. Duque Afonso teaches that increased cfDNA is associated with GvHD and thus along it was a concurrent marker of damage it is still a marker of GvHD. Additionally the rejection did not cite Duque Afonso for identifying tissue of origin, as addressed int eh rejection above. While Duque Afonso teaches chimerism, Duque Afonso additionally teaches increased cfDNA that is associated with GvHD. The response asserts that the combination of Duque-Afonso and DiLoreto do not teach or suggest every element of claim 1. The response asserts that one would not have had a reasonable expectation of success to arrive at the claimed method before the effective filing date of the instant application. The response asserts that GVHD can manifest in skin, gut, liver or combinations thereof and the cited art provides no basis to predict that any single pan-solid-organ signal at about the one month post HCT would cleanly identify subject which would later develop GVHD from those which would not. The response further asserts that the conditioning regiment administered prior to HCT is known in the art to cause dramatic patient specific perturbations in cfDNA during early post-transplant period. The response asserts that the skilled artisan would have viewed the signal to noise problem as formidable and outcome unpredictable. The response asserts that one of skill in the art would not have had a reasonable expectation that early tissue of origin cfDNA levels would provide a robust generalizable predictor of future GvHD in aa subject undergone HCT. This response has been reviewed but not found persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., pan-solid-organ signal at one month post HCT identifies a subject that will later develop GVHD) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Even arguendo this limitation was cited in the claims, Duque-Afonso teaches cfDNA levels predict GVHD, thus teaching subject that will later develop GVHD by measuring increased cfDNA levels post HCT.
With regard to applicants remarks that there is no expectation that early tissue of origin cfDNA levels would provide robust generalized predictor of future GVHD in a subject having undergone HCT, Duque Afonso does teaches increased cfDNA that is associated with GvHD and teaches analysis at 30 days post HCT, therefore Duque-Afonso teaches increased cfDNA is associated with GVHD and DiLoreto teaches that methylation analysis of cfDNA can determine tissue of origin. Therefore, based on the general knowledge available to one of ordinary skill in the art, the ordinary artisan would have been motivated with a reasonable expectation of success to determine the tissue of origin based on the teaching of DiLoreto in the method of Duque-Afonso. Furthermore, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Therefore, absent secondary consideration such as evidence demonstrating unpredictability of identifying methylation of tissue of origin, the ordinary artisan would have combined analysis of methylation to identify tissue of origin in cfDNA as taught by DiLoreto in the method of Duque-Afonso to detect GVHD in patients post 30 day HCT as demonstrated in the prior art. Additionally, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As previously addressed based on the combined teaching, an ordinary artisan would have included analysis of methylation patterns in cfDNA to identify tissue of origin as taught by DiLoreto and detect GVHD by cfDNA analysis in subjects post 30 day HCT.
Additionally, as stated in MPEP 2145, I, An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. In the instant case the assertion that a skilled artisan would have viewed the signal to noise problem as formidable and the outcome unpredictable, early tissue of origin cfDNA levels would not have a provided a robust generalized predictor of future GVHD in a subject having undergone HCT, and the cited art would not cleanly identify subjects which would later develop GVHD from those which would not is not factual evidence. This should not be construed as an invitation for providing evidence, see MPEP 716.01 regarding the timely submission of evidence.
The response addresses Fig 2C of the instant application that shows cfDNA tissue of origin measurement can be used to predict GVHD. The response asserts that the use of the measurement of solid-organ derived cfDNA at one month post HCT to discriminate GVHD would not have been expected by one of skill in the art. The response asserts the magnitude of early predictive discrimination occurring before clinical diagnosis would not have led a skilled artisan to pursue the claimed method. This response has been reviewed but not found persuasive. Initially Duque-Afonso teaches identifying GVHD by increased cfDNA at 30 days post HCT. Furthermore it is noted that figure 2A-C demonstrate that cfDNA only increased at month 1 since transplant. However there is no identification of a specific organ and the measurement is not methylation to identify tissue origin but solid organ cfDNA concentration in general, which is also taught by Duque-Afonso. Figure 2C does not demonstrate any unexpected results nor does figure 2C demonstrate identifying any tissue of origin other than generally solid organ cfDNA concentration but this is not utilizing methylation to identify tissue origin, which is required in the claims.
The response asserts that Duque-Afonso group confirmed that their 2018 cfDNA work did not solve tissue of origin identification and recognized this limitation. It is noted that Duque-Afonso was not cited to identifying tissue of origin but was cited to teach increased cfDNA is associated with GvHD and analysis of post-30 day HCT. While the response asserts that the publication asserts it was not able to develop a method to achieve the results as Applicants claim, this reference was not cited to teach the entire method of the claimed invention, the reference was cited to teach increased cfDNA in post-30 day HCT is associated with GVHD. DiLorenzo teaches using methylation in cfDNA to identify tissue of origin, therefore the ordinary artisan would have used the method of Duque-Afonso with DiLorenzo to identify tissue of origin. There is a reasonable expectation of success based on the teaching of Duque-Afonso, the rejection is not an obvious to try without more, here there is a reasonable expectation of success. Both the specification and the prior art teach increased cfDNA levels in subjects post 30 day HCT to predict GVHD. The specification teaches a smaller sample size and Duque-Afonso teaches a larger sample. There only needs to be a reasonable expectation of success not an absolute. The specification further asserts that the number of samples from patients diagnosed with hepatic and gastrointestinal GVHD was insufficient to test performance of the assay to pinpoint GVHD related injury to liver or gut (see para 182). The specification teaches response of GVHD treatment from three patients (See para 183). As such the specification teaches a sample size of three patients while Duque-Afonso teaches a sample size of 196 samples. In the instant case, Duque-Afonso in combination with DiLoreto render obvious the claimed invention. For these reasons and reasons of record this rejection is maintained.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAE L BAUSCH whose telephone number is (571)272-2912. The examiner can normally be reached M-F 9a-4p.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699
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