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
Election/Restrictions
Applicant’s election of group I, species DNA modification and graft versus host disease in the reply filed on 10/07/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further consideration the specifies requirement for Species B: skin, heart, kidney, liver, lung, stomach, bladder, spleen or pancreas has been withdrawn.
Claims 28, 30, 73-85, 87-88, and 90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/7/2025.
Claims 1-2, 13-18, 20-21, and 25 are under examination. Claim 2 is under examination with respect to DNA modification.
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, 13-18, 20-21, and 25 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 the limitation "the profiles of an epigenetic marker" in line 3 of the claim. There is insufficient antecedent basis for this limitation in the claim. None of the preceding steps require a profile of an epigenetic marker. It is suggested to amend the claim to recite a profile of an epigenetic marker.
Claim 1 recites the limitation "the tissues" in line 5 of the claim. There is insufficient antecedent basis for this limitation in the claim. None of the preceding steps require a tissue. It is suggested to amend the claim to recite identifying a tissue of origin or identifying tissues of origin.
Claim 25 recites “the method of claim 1, wherein detecting tissue damage at about 30 days post-HCT” renders the claim indefinite. Claim 1 does not require HCT and it is unclear how detecting tissue damage at about 30 day post-HCT is indicative of graft rejection or developing graft rejection when claim 1 does not require or recite any hematopoietic cell transplantation. Because it is unclear how detecting tissue damage post HCT relates to the method of claim 1, the metes and bounds of the claim is indefinite and one of ordinary skill in the art would not be apprised of infringing on the claimed method.
Claims 2, 13-18, 20-21, and 25 depend from claim 1 and are indefinite for the reasons applied to claim 1.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), 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.
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 25 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, 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.
Claim 25 recites “The method of claim 1, wherein detecting tissue damage at about 30 days post-HCT”. Claim 1 does not require or recite any HCT. Claim 25 does not further limit claim 1 because claim 1 does not require hematopoietic cell transplantation (HCT). Because claim 1 does not require HCT, claim 25 does not further limit claim 1 as claim 25 requires 30 days post HCT.
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, 13-18, 20-21, and 25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and natural laws without significantly more.
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 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.
Claim 25 and 26 add an additional judicial exception that are both a mental process and sets forth a natural law correlation. Claim 25 recites “detecting tissue damage…is indicative of graft rejection or a risk of developing graft rejection”. Claim 26 recites “wherein the tissue damage is indicative of graft-versus-host disease”. of detecting tissue damage is indicative of graft rejection or risk of developing graft rejection.
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. 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 15-16 further defines the biological sample. Claim 17 defines the control level. Claims 19, 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.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 14-15, 18, 20-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lo (US2018/0149636A1)
With regard to claim 1, 14-15, 18, 20-23, Lo teaches a method of determining methylation levels of cell free DNA in a sample. Lo teaches tissue specific methylation patterns can be used to determine different tissue types. Lo teaches the biological sample can be bodily fluid, such as blood, plasma, urine, saliva (see para 47) (claim 15). Lo teaches methylation signatures can be identified for different tissues and cell types (see para 72). Lo teaches that plasma cfDNA from different tissues can be ascertained by genome wide bisulfite sequencings (see par 72) (claim 2). Lo teaches analyzing urine cfDNA with tissue specific methylation patters to determine urinary cfDNA from different tissues, the analysis can determine diseases tissue type (See para 73). Lo teaches whole genome bisulfite sequencing for cfDNA from transplant HSCT patients (see para 109) (the subject has undergone HCT) (claim 14). Lo teaches methylation levels to determine bladder tissue and bladder cancer (see para 127) (claim 18, 20-21).
Claims 1-2, 13, 18, 21, 26 are rejected 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)
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. 102(a)(2) 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) if the same invention is not being claimed; 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 in the reference 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.
With regard to claim 1, 2, 18 and 21, 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 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) (kidney, solid organ) (claim 18, 21) (see para 82-83).
With regard to claim 13, De Vlaminck teaches single strand DNA sequencing libraries from cfDNA of a biological sample (see para 47-59).
With regard to claim 26, De Vlaminck teaches analysis of cfDNA to determine tissue injury in the graft (see ex 8).
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) in view of DiLoreto (2017, cited on IDS)
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 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 13, 18, 21, 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 10, of U.S. Patent No. 11781188. Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of ‘188 comprises a method of subjecting cfDNA isolated from a sample from a subject to bisulfite treatment, preparing single stranded sequencing library of the treated cfDNA, obtaining a methylation profile of the cfDNA and determining the tissue of origin based on the methylation profile and this claim anticipates claim 1-2, 13 of the instant application. Both claims require detecting tissue of origin by obtaining cfDNA and determining methylation profiles. Additionally, claim 17 of ‘188 comprises quantifying the proportion to identify tissue damage. Dependent claim 2 of ‘188 comprises kidney transplant recipient and encompasses tissue of origin is a solid organ and kidney which anticipates claim 18 and 21 of the instant application.
Conclusion
No claims are allowable.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699