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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-12 in the reply filed on 10/14/2025 is acknowledged. Accordingly, the claims 13 and 15 are withdrawn from consideration as being drawn to a non-elected invention.
Priority
This application is a 371 of PCT/US2021/024231 filed 03/25/2021 which claims benefit of 63/001,062 filed 03/27/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/14/2025 and 9/25/2022 are 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.
Drawings
The drawings were received on 9/27/2022 is acknowledged. These drawings are found acceptable by the examiner.
Specification
The disclosure is objected to because of the following informalities:
(a) The disclosure is objected to because the disclosure comprises of sequences of <10 nucleotides at paragraph [0085], Table 7 at pages 25-27 and Table 8 at pages 28-29 that are not represented by a proper sequence identifier (SEQ ID NO:) as discussed at MPEP 2417 and supported in the RAW sequence listing and CRFe filed on 9/27/2022. Appropriate correction is required.
Claim Objections
Claim 7 is objected to because of the following informalities:
(a) Claim 7 is objected for the abbreviations “ABMR”, “TCMR”, “ATN”. It is suggested inserting the full name of the abbreviation into the claim. Appropriate correction is required.
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.
Claim(s) 1-6, 8-12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schutz et al {Schutz, used interchangeably herein} (US 20170327869, published November 16, 2017, equivalent to US Patent 10570443).
It is noted applicant has provided evidence in the filing of an IDS that the subject matter disclosed in the prior art reference were owned by, or subject to an obligation of assignment to, the same entity as the applicant, Chronix Biomedical, and inventors, Schutz et al., not later than the effective filing date of the claimed invention, or the subject matter disclosed in the prior art reference was developed and the claimed invention was made by, or on behalf of one or more parties to a joint research agreement in effect not later than the effective filing date of the claimed invention. However, although reference US 20170327860 has been excepted as prior art under 35 U.S.C. 102(a)(2), it is still applicable as prior art under 35 U.S.C. 102(a)(1) that cannot be excepted under 35 U.S.C. 102(b)(2)(C).
Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by 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 therefore not prior art under 35 U.S.C. 102(a)(1). Alternatively, applicant may rely on the exception under 35 U.S.C. 102(b)(1)(B) by providing evidence of a prior public disclosure via an affidavit or declaration under 37 CFR 1.130(b).
The claimed invention is directed to a method of quantifying cfDNA of an interrogated target, e.g., from a tumor, fetus, or a transplanted organ, by differentiating cfDNA that originates from cells of interest in a subject, e.g., cancer cells, fetal, cells, or transplanted tissue. The methods employ at least two PCR reactions that generate amplicons of different lengths to assess the degree of fragmentation of germline DNA present in cfDNA compared to that of non-germline DNA present in cfDNA in order to quantify the amount of the desired target nucleic acid.
Regarding claim 1, Schutz teaches a 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 (see abstract, paragraphs [0004 –[0010]; [0030] - [0032] which discuss PCR control reactions, and para. [0040] – [0041] which discuss the use of “Controls with Diagnostic PCR” and claims 1, 3 & 4 at page 6);
(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 (see abstract, paragraphs [0004 – [0010]; [0030] - [0032] which discuss PCR control reactions, para. [0040] – [0041] which discuss the use of “Controls with Diagnostic PCR” and claims 1, 3 & 4 at page 6);
(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 (abstract, paragraphs [0004 – [0010], [0029], [0056] – [0060] which teaches quantification techniques and claim 1 at page 6);
(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 (abstract, paragraphs [0004] – [0010], [0029], [0056] – [0060] which teaches quantification techniques and claim 1 at page 6); and
(e) determining the amount of diagnostic cfDNA present in the cfDNA sample ((abstract, paragraphs [0004] – [0010], [0029], [0056] – [0060] and claim 1 at page 6 which teaches “a method of estimating the proportion of DNA in a cfDNA sample that is amplifiable in a PCR reaction, 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, wherein the first amplification targets a first single copy genomic locus and results in production of a first amplicon a second amplification targets a second single copy genomic locus and results in production of a second amplicon, wherein the first and second amplicon differ in length by at least 50 base pairs; (c) determining the proportion of the first or second amplicon in the total amplified product from the digital PCR of step (b) to provide a correction factor for the amplifiable fraction of the cfDNA sample, and (d) correcting a diagnostic digital PCR performed on the cfDNA sample to evaluate the level of chimeric DNA present in the sample using the correction factor determined in step (c).”).
Regarding claim 2, Schutz et al teach wherein the target sequence in (a) and (b) are different sequences (para. [0022], [0033], and claim 1).
Regarding claim 3, Schutz wherein the target sequence in (a) and (b) is the same sequence (para. [0018]).
Regarding claim 4, Schutz teaches wherein the amount of diagnostic cfDNA determined in (e) is determined as a percentage ([0013] – [0015], [0052] – [0057] and Figures 1-5).
Regarding claim 5, Schutz teaches wherein the amount of diagnostic cfDNA determined in (e) is determined as a concentration ([0012], [0013], [0015], [0031], [0052], [0054], [0057], [0059]; see also Figures 1-5).
Regarding claim 6, Schutz teaches wherein the subject is a transplant patient and the diagnostic cfDNA is from a donor graft ({0010], [0017], [0040] and claim 5).
Regarding claim 8, Schutz teaches wherein the subject is a cancer patient and the diagnostic cfDNA is from tumor cells ([0010], [0017] and [0040], see also claim 6).
Regarding claim 9, Schutz teaches wherein the subject is a pregnant patient and the diagnostic cfDNA is from fetal cells ([0010] and [0040], see also claim 7).
Regarding claim 10, Schutz teaches 1wherein the patient is a human ([0010], [0041] and claim 8).
Regarding claim 11, Schutz teaches further comprising an amplification reaction that targets DNA that was added to the blood, serum, or plasma sample prior to extraction ([0004], [0047] – [0048] and claim 2).
Regarding claim 12, Schutz teaches wherein the two or more PCR reactions are performed in a multiplex assay ([0004], [0031], [0059] and claim 1). Thus, Schutz meets the limitations of the claims recited above.
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.
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.
Double Patenting
14. 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.
15. Claims 1, 8, 9, 10, 11, 12 are 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.
Conclusion
16. No claims are allowed. 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