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 .
Claims 1-20 are pending and will be examined.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 17, 2025, August 27, 2025 and July 21, 2026 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62147377, 61516996, 61395850, 8825412, 61994791, 61987407, 61683331, 61675020, 61634431, 61571248, 61448547, 61462972, 61426208, 61398159, 13780022, 13683604 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. While each of these priority documents include support for multiplex amplification and sequencing, none of these priority documents include sufficient (or any) support for the inclusion of transplant or transplantation patients. Therefore, as the priority documents of US Patent 10655180, 62148173, 62146188, 61982245 for example, provide support, the claims are afforded an earliest priority of April 21, 2014.
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 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18751083 (reference application, ‘083 application herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant application are focused on analysis of 100 polymorphic loci while the claims of the ‘083 application are focused on analysis of 100 genomic loci. While there is a difference in language between a plurality of genomic loci and a plurality of polymorphic loci and while the claims of the ‘083 application include some additional steps, the scope of the claims encompass the same inventive method. Next, the dependent claims are nearly identical when the scope of the claims are examined, as well. Compare claim 6 of the instant claims and claims 11-13 of the ‘083 application, where the specific chromosomes 1, 2 and 3 are analyzed. Further, compare instant claims 16 and 20 to claims 1 and 14 of the ‘083 application where the claims are drawn to high throughput sequencing. For at least these reasons, the claims of the instant application are not patentable in view of the claims of the ‘083 application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18751153 (reference application, ‘153 application herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant application are focused on analysis of 100 polymorphic loci while the claims of the ‘153 application are focused on analysis of more than 100 SNP loci. While there is a difference in language between a plurality of polymorphic loci and a plurality of SNP loci and while the claims of the ‘153 application include some additional steps, the scope of the claims encompass the same inventive method. Next, the dependent claims are nearly identical when the scope of the claims are examined, as well. Compare claim 6 of the instant claims and claims 11-13 of the ‘153 application, where the specific chromosomes 1, 2 and 3 are analyzed. Further, compare instant claims 16 and 20 to claims 1 and 14 of the ‘153 application where the claims are drawn to high throughput sequencing. For at least these reasons, the claims of the instant application are not patentable in view of the claims of the ‘153 application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 15-17 and 19-22 of U.S. Patent No. 12,649,946 (reference application, ‘946 Patent herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed method of the instant claims and the method of the ‘946 Patent share many of the same steps, including extraction of cell free nucleic acids from a first and second individual, multiplex or targeted PCR amplification of 100 or more target loci and sequencing. The claims encompass nearly identical scope of the claimed methods. For example, dependent claims cover similar subject matter, as well. Compare, for instance claim 9 and 19 of the instant claims to claims 3 and 22 of the ‘946 Patent, where each claim includes cell free DNA from a transplant. Further, compare claims 8-9 and 18-19 of the instant claims to claims 2 and 22 of the ‘946 patent where the sample source includes blood. Compare claims 1, 7 and 17 of the instant claims and claims 8-13 of the ‘946 Patent, where these claims specify how many loci are amplified together. Compare instant claims 4 to claim 21 of the ‘946 Patent where bias of PCR amplification is determined. For at least these reasons, the claims of the instant application are not patentable in view of the claims of the ‘946 Patent.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 102
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 and 5-16 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Sparks et al. (US Patent 10,308,981; June 2019).
With regard to claim 1, Sparks teaches a method for preparing a biological sample containing DNA from a first individual and a second individual, comprising:
isolating cell-free DNA from the biological sample that comprises the DNA from the first individual and DNA from the second individual Abstract; col 2, lines 9-24, where circulating nucleic acids are extracted and can be used for identification of CNV in mixed samples);
and amplifying the isolated cell-free DNA or DNA derived therefrom at a plurality of polymorphic loci, wherein the plurality of polymorphic loci comprises between 100 and 1,000 polymorphic loci, wherein the amplifying comprises amplifying the between 100 and 1,000 polymorphic loci from the isolated cell-free DNA or DNA derived therefrom using between 100 and 1,000 distinct primers configure to target the between 100 and 1,000 polymorphic loci (col. 50 lines 48-63, where the samples can be amplified with 96 or more primer pairs in multiplex format);.
With regard to claim 5, Sparks teaches a method of claim 1, wherein the polymorphic loci are SNP loci (col. 24, lines 35-46, which references Figure 2, where unique sequences in mixed samples are analyzed for frequency of each target locus to determine the presence of an abnormality in a given sample).
With regard to claim 6, Sparks teaches a method of claim 5, wherein the polymorphic loci comprise SNP loci on chromosome 1, chromosome 2, and/or chromosome 3 (Example 6, col. 49, where chromosomes 1-16 can be analyzed for fetal DNA).
With regard to claim 8, Sparks teaches a method of claim 1, wherein the biological sample is a blood sample or part thereof, and wherein the cell-free DNA comprises DNA from a fetus (col. 16, lines 20-36, where the source of the ‘mixed sample’ can include blood, serum or plasma).
With regard to claim 9, Sparks teaches a method of claim 1, wherein the biological sample is a blood sample or part thereof, and wherein the cell-free DNA comprises DNA from a transplant (col. 16, lines 20-36, where the source of the ‘mixed sample’ can include blood, serum or plasma).
With regard to claim 10, Sparks teaches a method of claim 1, wherein the distinct primers are circularizing probes (Abstract; col. 2, lines 9-24, where circulating nucleic acids are extracted and can be used for identification of CNV in mixed samples).
With regard to claim 11, Sparks teaches a method of claim 1, wherein the distinct primers are configured to target the polymorphic loci via hybridization (col. 50 lines 48-63, where the samples can be amplified with 96 or more primer pairs in multiplex format).
With regard to claim 12, Sparks teaches a method of claim 1, wherein the distinct primers comprise PCR primers (col. 50 lines 48-63, where the samples can be amplified with 96 or more primer pairs in multiplex format).
With regard to claim 13, Sparks teaches a method of claim 1, wherein the total amount of cfDNA in the sample is between 10 pg and 100 pg (Example 5, col. 48).
With regard to claim 14, Sparks teaches a method of claim 13, wherein less than or equal to 10, 5, 2, 1, 0.5, 0.1, 0.05, 0.01, or 0.005% of the cfDNA molecules that have a first locus have a mutation in the first locus (Example 5, col. 48).
With regard to claim 15, Sparks teaches a method of claim 13, wherein amplifying the isolated cell-free DNA comprises amplifying from 72%, 69%, 66%, 63%, 59%, or 56% of available cfDNA template fragment molecules (col. 48 and Example 5, Table 1).
With regard to claim 16, Sparks teaches a method of claim 1, wherein method further comprises performing high-throughput sequencing on the amplified DNA (col. 24, lines 35-46, which references Figure 2, where unique sequences in mixed samples are analyzed for frequency of each target locus to determine the presence of an abnormality in a given sample).
Claim Rejections - 35 USC § 103
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.
Claim(s) 2-4 and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sparks et al. (US Patent 10,308,981 B2; June 2019) as applied over claims 1 and 5-16 above and further in view of Oeth et al. (US Patent 8173370; May 2012).
With regard to claim 17, Sparks teaches a method for preparing a biological sample containing DNA from a first individual and a second individual, comprising:
isolating cell-free DNA from the biological sample that comprises the DNA from the first individual and DNA from the second individual (Abstract; col. 2, lines 9-24, where circulating nucleic acids are extracted and can be used for identification of CNV in mixed samples);
and amplifying the enriched DNA at the plurality of SNP loci, wherein the amplifying comprises amplifying the between 100 and 1,000 SNP loci from the enriched DNA using between 100 and 1,000 distinct primers configure to target the between 100 and 1,000 SNP loci (col. 5, lines 48-63, where the samples can be amplified with 96 or more primer pairs in multiplex format).
With regard to claim 18, Sparks teaches a method of claim 17, wherein the biological sample is a blood sample or part thereof, and wherein the cell-free DNA comprises DNA from a fetus (col. 16, lines 20-36, where the source of the ‘mixed sample’ can include blood, serum or plasma).
With regard to claim 19, Sparks teaches a method of claim 17, wherein the biological sample is a blood sample or part thereof, and wherein the cell-free DNA comprises DNA from a transplant (col. 16, lines 20-36, where the source of the ‘mixed sample’ can include blood, serum or plasma).
With regard to claim 20, Sparks teaches a method of claim 17, wherein method further comprises performing high-throughput sequencing on the amplified DNA (col. 24, lines 35-46, which references Figure 2, where unique sequences in mixed samples are analyzed for frequency of each target locus to determine the presence of an abnormality in a given sample).
Regarding claim 16, while Sparks teaches the method of extraction and multiplex amplification, Sparks does not teach enrichment of cell free DNA.
With regard to claim 2, Oeth teaches a method of claim 1, wherein the method further comprises enriching the DNA in the sample at a plurality of polymorphic loci prior to the amplifying step (col. 1 lines 58-65; col. 20, lines 45-62, where cell-free DNA is extracted from maternal plasma).
With regard to claim 3, Oeth teaches a method of claim 2, wherein the enrichment comprises:
obtaining a plurality of target-specific primers designed to hybridize to regions of DNA upstream and downstream of the polymorphic loci;
hybridizing the target-specific primers to the DNA; and amplifying the DNA using the polymerase chain reaction to form amplicons (col. 1 lines 58-65; col. 20, lines 45-62, where cell-free DNA is extracted from maternal plasma).
With regard to claim 4, Oeth teaches a method of claim 2, further comprising preferentially enriching the DNA at a plurality of loci to minimize an average degree of allelic bias (col. 1 lines 58-65; col. 20, lines 45-62, where cell-free DNA is extracted from maternal plasma).
With regard to claim 7, Oeth teaches a method of claim 1, wherein the plurality of polymorphic loci comprises at least 200 polymorphic loci, wherein the amplifying comprises amplifying the at least 200 polymorphic loci from the cell-free DNA isolated from the biological sample (col. 1 lines 58-65: coL 20, lines 45- 62, where cell-free DNA is extracted from maternal plasma).
With regard to claim 17, Oeth teaches enriching the isolated cell-free DNA or DNA derived therefrom at a plurality of SNP loci to obtain enriched DNA, wherein the plurality of SNP loci comprises between 100 and 1,000 SNP loci (col. 1 lines 58-65: coL 20, lines 45-
62, where cell-free DNA is extracted from maternal plasma).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Sparks to include the higher level
multiplex as taught by Oeth to arrive at the claimed invention with a reasonable expectation for success. Oeth teaches "Accordingly, 1 multiplexed primer mass extension therefore encompasses 5 or more, 6 or more. 7 or more, 8 or more. 9 or more, JO or 1nore, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or 1nore, 17 or more, 18 or more, 19 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more. 70 or more, 80 or more, 100 or more. 200 or more, 500 or more, HX)0 or more, 2000 or more primer mass extension reactions. Multiplexed amplification and primer mass extension reactions also encompass 21, 22, 23, 24, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 100, 1000 or more reactions" ( col. 17, lines 42 to col. 18, line 2). Oeth also teaches "The plurality of polymorphisms may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, n, 14, 15, 16, 17, rn, 19, 20, 2s, 30, 35, 4.0, 45, 50, 60, 70, so, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or rnore polymorphisms. 1n a related embodiment, the polymorphism is a single nucleotide polymorphism (SNPt insertion/deletion, short tandem repeats STRs), RFLPs or any other alternate form of a gene, genomic DNA or non-coding region of DNA that occupies the same position on a chromosome" (col. 11, lines 40-47, where the number of loci amplified is taught). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Sparks to include the higher level multiplex as taught by Oeth to arrive at the claimed invention with a reasonable expectation for success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE KANE MUMMERT whose telephone number is (571)272-8503. The examiner can normally be reached M-F 9:00-5:30.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681
