DETAILED ACTION
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 . Applicant’s amendment filed 4/27/2026 is acknowledged. Claims 1 and 7 have been amended. Claim 14 has been canceled. Claims 1-13 and 15 are pending. Claims 13 and 15 are withdrawn from consideration as being drawn to a non-elected invention.
All of the amendment and arguments have been thoroughly reviewed and considered.
Any rejection not reiterated in this action has been withdrawn as being obviated by the amendment of the claims.
This action is made Final.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejections
Status:
(a) The objection to the specification is withdrawn in view of Applicant’s amendment and submission of a substitute specification filed 4/27/2026.
(b) The objection to the claim 7 is withdrawn in view of Applicant’s amendment of the claim.
(c) The prior art rejection under 35 USC 102(a)(1) directed to the claims 1-6 and 8-12 as being anticipated by Schutz et al is withdrawn in view of Applicant’s amendment of the claims.
(d) The prior art rejection under 35 USC 102(a)(2) directed to claims 1-12 as being anticipated by Moshkevich is withdrawn in view of Applicant’s amendment of the claims.
(e) The double patenting rejection is maintained and discussed below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/27/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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, 8, 9, 10, 11, 12 are finally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No.10570443 {US Patent ‘443 used interchanbeably herein}.
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claim(s) because the examined 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).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the claims 1, 11 and 12 of the instant invention and the claims 1 and 2 of US Patent ‘443 are drawn to a method of quantifying cfDNA in a sample from a patient, the method comprising: (a) providing a cell-free DNA (cfDNA) sample from a blood, serum or plasma sample obtained from a patient; (b) performing a multiplex digital PCR comprising at least a first amplification and a second amplification on the cfDNA sample to quantify the amount of cfDNA sample , wherein the first amplification targets a first single copy genomic locus in the patient genome and results in production of a first amplicon; and a second amplification targets a second single copy genomic locus in the patient genome and results in production of a second amplicon, wherein the first and second amplicon differ in length by at least 10 base pairs; (c) determining the proportion of the first or the second amplicon in the total amplified product and quantifying the level of DNA.
The claim 8 of the instant invention embodies the limitation of claim 6 of US Patent ‘443.
The claim 9 of the instant invention embodies the limitation of claim 7 of US Patent ‘443.
The claim 10 of the instant invention embodies the limitation of claim 8 of US Patent ‘443.
The claim 11 of the instant invention embodies claim 2 of US Patent ‘443.
The claim of the instant invention only differs slightly in wording from the claims 1-8 of US Patent ‘443 and appear broader in scope than the claims 1-8 of US Patent ‘443. Likewise, the recited claims of instant invention recite quantifying yield whereas the claims 1-8 of US Patent recite correcting a diagnostic PCR performed on a cfDNA sample using a correction factor to quantify the level of DNA. The instant invention defines the use of a correction factor for quantifying DNA at paragraph [0004] and cites the instant application. Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to incorporate a correcting step comprising a correction faction as recited by US Patent ‘443. The ordinary artisan would have been motivated at the time of the effective filing date of the claimed invention to do so for the obvious benefit of improving accuracy and efficiency of quantification results.
Response to Arguments
9. Applicant requested the rejections be held in abeyance until patentable subject matter is determined. Under 37 CFR 1.111(b), applicants may request that certain objections or requirements “as to form” be held in abeyance until allowable subject matter in indicated. However, MPEP 804.02 clarifies that a non-statutory double patenting rejection is not “as to form” – it is a substantive rejection based on the doctrine of obviousness-type double patenting. Therefore, this rejection cannot be held in abeyance until the required action is taken. To overcome the double patenting rejection, a proper terminal disclaimer under 37 CFR 1.321 is required to overcome the double patenting rejections noted above.
New Ground(s) of Rejections
THE NEW GROUND(S) OF REJECTIONS WERE NECESSITATED BY APPLICANT’S AMENDMENT OF THE CLAIMS:
Claim Rejections - 35 USC § 102
10. NOTE: The following are new grounds of rejections necessitated by Applicant's amendments. Although the claims were previously rejected as being anticipated and/or unpatentable over the same reference(s), Applicant's amendments have necessitated the inclusion of new grounds of rejections in this Office action. It is noted that, to the extent that they apply to the present rejection; Applicant's arguments are addressed following the rejection.
11. 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.
12. Claim(s) 1-12 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Moshkevich et al {Moshkevich, used interchangeably herein} (US 20210198733, effective filing date July 3, 2018).
Regarding claim 1, Moshkevich teaches method to quantify the amount of a diagnostic cfDNA in a cell-free DNA (cfDNA) sample from a subject using two or more PCR reactions, wherein the diagnostic cfDNA deviates from germline DNA of the subject; the method comprising: (a) performing a first PCR on cfDNA from the sample that amplifies a first region that comprises a target sequence that differs in germline DNA from the subject and the diagnostic cfDNA to obtain a first amplicon;
(b) performing at least a second PCR on cfDNA from the sample that amplifies a second region that comprises a target sequence that differs in germline DNA from the subject and the diagnostic cfDNA to obtain a second amplicon that differs in length from the first amplicon by at least 10 base pairs;
(c) quantifying the yield of the first amplicon that is generated from the diagnostic cfDNA and the yield of the first amplicon that is generated from germline cfDNA;
(d) quantifying the yield of the second amplicon that is generated from the diagnostic cfDNA and the yield of the second amplicon that is generated from germline cfDNA; and
(e) determining the amount of diagnostic cfDNA present in the cfDNA sample (see para. [0005] – [0009] which teaches quantifying the amount of donor-derived cell-free DNA (dd-cfDNA) in a blood sample of a transplant recipient, comprising: extracting DNA from the blood sample of the transplant recipient, wherein the DNA comprises donor-derived cell-free DNA and recipient-derived cell-free DNA; performing targeted amplification at 500-50,000 target loci in a single reaction volume using 500-50,000 primer pairs, wherein the target loci comprise polymorphic loci and non-polymorphic loci, and wherein each primer pair is designed to amplify a target sequence of no more than 100 bp; and quantifying the amount of donor-derived cell-free DNA in the amplification products; [0011], [0016], which teaches quantifying steps, [0030] which teaches target loci that are amplified in amplicons as varying lengths, [0064] –[0069] which teaches multiple amplification of fragments or multiplex amplification ([0153] of multiple target loci from one or both transplant donor and transplant recipient samples and [0154], [0158], [0296]- [0298] which further discuss quantitative measurement of results and targeted specific amplification.
With regards to Applicant’s arguments at step (e), “determining the amount of diagnostic cfDNA present in the cfDNA sample by interpolating the amplicon length of (a) and (b) to zero, Moshkevich et al teach “linearity was measured by linear regression against the targeted donor fraction, and accuracy was measured by linear regression against the ddPCR-measured donor fraction. The linear regression results are shown in Tables 9 and 10 below. The donor fraction measurement was shown to be highly linear (R.sup.2 greater than 0.99 in all models) and accurate (slope approximately 1, intercept approximately zero) (para. [0705]). At paragraph [0715], Moshkevich teaches that measurements were based on cell line-derived reference samples and performance was estimated to be equivalent or superior using a smaller number of plasma-derived cfDNA samples. Similarly, the method was confirmed to have high accuracy based on linear regression with respect to an orthogonal measurement, with linear regression parameter confidence intervals including slope equal to one and intercept equal to zero, based on 349 related and 285 unrelated measurements.
The instant specification supports the teachings of Moshkevich by teaching that linear regression was performed with the length of the individual amplicon as independent and the measured dd-cfDNA percentage as dependent variable (see specification at paragraph [0052].
Regarding claim 2, Moshkevich, et al teach wherein the target sequence in (a) and (b) are different sequences (para. [0005] – [0009], [0154], [0158], [0296]- [0298]).
Regarding claim 3, Moshkevich, wherein the target sequence in (a) and (b) is the same sequence ([0034] teaches repeating steps which inherently encompasses analyzing the same sample sequences.
Regarding claim 4, Moshkevich, teaches wherein the amount of diagnostic cfDNA determined in (e) is determined as a percentage ([0011], [0082], [0678]).
Regarding claim 5, Moshkevich teaches wherein the amount of diagnostic cfDNA determined in (e) is determined as a concentration ([see e.g., [0144], [0672] and [0674]).
Regarding claim 6, Moshkevich teaches wherein the subject is a transplant patient and the diagnostic cfDNA is from a donor graft (Abstract, [0004] –[0007], [0092], Figure 1).[0044], [0095], [0108], [0135], [0144], [0607] and Figures 4, 17, 43, 52)
Regarding claim 7, Moshkevich teaches wherein the length of the dd-cfDNA is determined to distinguish between ABMR, TCMR and ATN in kidney recipients ([0044], [0095], [0108], [0135], [0144], [0607] and Figures 4, 17, 43, 52)
Regarding claim 8, Moshkevich teaches wherein the subject is a cancer patient and the diagnostic cfDNA is from tumor cells ([0317], [0323] and [0330]; see also [0550] – [0580])
Regarding claim 9, Moshkevich teaches wherein the subject is a pregnant patient and the diagnostic cfDNA is from fetal cells ([0274], [0306], [0325]).
Regarding claim 10, Moshkevich teaches 1wherein the patient is a human ([0009]).
Regarding claim 11, Moshkevich teaches further comprising an amplification reaction that targets DNA that was added to the blood, serum, or plasma sample prior to extraction ([0005] – [0007], [0011], [0152], [0631], [0670]).
Regarding claim 12, Moshkevich teaches wherein the two or more PCR reactions are performed in a multiplex assay ([0067]-[0068], [0152] – [0153], [0317]). In view of foregoing, Moshkevich meets the limitations of the claims recited above.
Conclusion
13. No claims are allowed. Applicant's amendment and submission of an information disclosure statement under 37 CFR 1.97(c) 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 CYNTHIA B WILDER whose telephone number is (571)272-0791. The examiner can normally be reached Flexible.
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/CYNTHIA B WILDER/Primary Examiner, Art Unit 1681
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