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 on December 10, 2025 is acknowledged and has been entered. Claims 11 and 15 are withdrawn. Claims 1, 18 and 19 are amended. Claims 1-10, 12-14 and 16-20 are pending.
Claims 1-10, 12-14 and 16-20 are discussed in this Office action.
All of the amendments and arguments have been thoroughly reviewed and considered but are not found persuasive for the reasons discussed below. Any rejection not reiterated in this action has been withdrawn as being obviated by the amendment of the claims.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 made FINAL.
Previous Grounds of Rejection
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. 61395850, 61398159, 61426208, 61462972 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 teach components of the method, as claimed, none of these disclosures teach each and every component of the claim. Specifically, while the disclosures of these applications include general teaching of cell-free nucleic acids and isolation from samples that include nucleic acids from multiple individuals including maternal and fetal samples and investigation of specific loci, the only support for a plurality of loci or multiplex amplification (such as including between 20 and 1000 loci, as claimed) is offered in the background and restatement of the state of the art. This is not sufficient teaching to support the earliest priority dates claimed for the instant invention.
The document with the enabling support for the method as claimed is provided by Application number 61448547, with an earliest priority date of March 2, 2011.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 22, 2025 was filed 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 1-2, 5-10, 12-14 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7-14 and 16 of U.S. Patent No. 10,655,180 (May 2020). Although the claims at issue are not identical, they are not patentably distinct from each other because the sets of claims are drawn to overlapping subject matter of analysis of polymorphic SNP loci in individuals and including analysis of the fraction contributed by the different individuals (compare instant claim 1 to claim 1 of ‘180 patent). Furthermore, both sets of claims are drawn to analysis of SNP loci included on chromosome 1, 2 and 3 (compare instant claim 6-8 to claims 11-13 of the ‘180 patent). Furthermore, claims include similar or overlapping subject matter of a sample type including blood (compare claim 2 of ‘180 patent to instant claim 14).
Claims 1-2, 5-10, 12-14 and 16-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 10-11 and 18 of U.S. Patent No. 10,597,709 (March 2020). Although the claims at issue are not identical, they are not patentably distinct from each other because the sets of claims are drawn to overlapping subject matter of amplification of polymorphic SNP loci in individuals and including analysis of the fraction contributed by the different individuals (compare instant claim 1 to claim 1 of ‘709 patent). Furthermore, claims include similar or overlapping subject matter of a sample type including a mixed sample (compare claim 1 to claim 18 of the ‘709 patent) and a plurality of target loci (compare claim 1 and 12-13 to claims 10-11 of the ‘709 patent).
Claims 1-2, 5-10 and 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 8-10, 14-17 and 20 of copending Application No. 16817117 (reference application, ‘117 application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the claims are not identical, they are not patentably distinct. There are some differences between the instant claims and the claims of the ‘117 application but the similarity is sufficient to render the claims not patent eligible.
For example, claim 1 of the instant claims refer to a first and second individual, the claims of the ‘117 application also refer to first and second individual. However, some of the features of instant claim 1 are present in claim 1 of ‘117, where the feature of high throughput sequencing is recited. Further, much of the claimed subject matter overlaps, including with the number of target loci amplified. Instant claim 1 covers 100-1000 target loci, and that number of loci is encompassed by the claims of the ‘117 application. Features such as the biological sample source from blood, plasma or serum (claim 14 of the instant claims compared to claim 2 of the ‘117 application). Therefore, the claims are not patent eligible because the claims are so similar.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 9-10 and 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7 and 15 of copending Application No. 17505588 (reference application, ‘588 application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the claims are not identical, they are not patentably distinct. There are some differences between the instant claims and the claims of the ‘588 application but the similarity is sufficient to render the claims not patent eligible.
For example, claim 1 of the instant claims refer to a first and second individual, the claims of the ‘588 application also refer to first and second individual. Claim 2 of ‘588, recites SNP loci specifically while instant claim 1 recites polymorphic loci. Instant claim 1 covers 100-1000 target loci and the claims of the ‘588 application include at least 1000 loci. Therefore, the claims are not patent eligible because the claims are so similar.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 4-10, 12-13 and 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-8, 12, 16-18 and 20 of copending Application No. 17842118 (reference application, ‘118 application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the claims are not identical, they are not patentably distinct. There are some differences between the instant claims and the claims of the ‘118 application but the similarity is sufficient to render the claims not patent eligible.
For example, claim 1 of the instant claims refer to a first and second individual and the claims of the ‘118 application also refer to first and second individual. However, some of the features of copending claim 1 are present in claim 16 and 20 of ‘118, where the feature of high throughput sequencing is recited. Further, much of the claimed subject matter overlaps, including with the number of target loci amplified. Instant claim 1 covers 100-1000 target loci, and that number of loci is entirely encompassed by the claims of the ‘118 application. Features such as SNP loci measured, sample source and the amount of cf DNA in a sample (compare instant claims 4-10, 12-13 and 16-17 of the instant claims to claims 5-8, 12, 16-18 of the ‘118 application). Therefore, the claims are not patent eligible because the claims are so similar.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5-10, 12-14 and 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 8-14, 16, 18-19 and 24-27 of copending Application No. 17868238 (reference application, ‘238 application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the claims are not identical, they are not patentably distinct. There are some differences between the instant claims and the claims of the ‘238 application but the similarity is sufficient to render the claims not patent eligible.
For example, claim 1 of the instant claims refer to a first and second individual and the claims of the ‘238 application also refer to first and second individual. However, some of the features of copending claim 1 are present in dependent claims. Further, much of the claimed subject matter overlaps, including with the number of target loci amplified. Instant claim 1 covers 100-1000 target loci, which partially overlaps with the number of loci of 100-20,000 loci in the ‘238 application. Features such as the biological sample source from fetus or from blood (claim 10 and 14 of the instant claims compared to claims 2-3 and 19 of the ‘238 application) or the specific chromosomes analyzed (instant claims 6-8 as compared to claims 12-14 of ‘238) are also shared. Therefore, the claims are not patent eligible because the claims are so similar.
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, 3-10, 12-14 and 16-20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by May et al. (US PgPub 20140227691; August 2014).
With regard to claim 1, May teaches a method for preparing a non-naturally occurring composition of amplified DNA from a biological sample containing DNA from a first individual and a second individual, comprising:
isolating cell-free DNA from the biological sample, wherein the isolated cell-free DNA comprises the DNA from the first individual and DNA from the second individual (paragraph 106 and 136, where the sample is cell free nucleic acid; see also Example 1);
amplifying the isolated cell-free DNA at a plurality of polymorphic loci on one or more chromosomes expected to be disomic to obtain a non-naturally occurring composition of
amplified DNA, wherein the plurality of polymorphic loci comprises between 20 and 1,000 polymorphic loci, wherein the amplifying comprises amplifying the between 20 and 1,000 polymorphic loci from the cell-free DNA isolated from the biological sample using between 20 and 1,000 distinct primer pairs configured to target the between 20 and 1,000 polymorphic loci in a single reaction volume (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed);
and preparing the non-naturally occurring composition of amplified at the polymorphic loci for sequencing (p 15, under “DNA sequencing” heading, beginning at paragraph 174).
With regard to claim 3, May 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 (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 4, May teaches a method of claim 2, wherein the enrichment comprises preferentially enriching the DNA at the plurality of loci to minimize an average degree of allelic bias (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 5, May teaches a method of claim 1, wherein the polymorphic loci comprise at least two SNP loci (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 6, May teaches a method of claim 5, wherein the polymorphic loci comprise at least two SNP loci on chromosome 1 (paragraph 67 and 78).
With regard to claim 7, May teaches a method of claim 5, wherein the polymorphic loci comprise at least two SNP loci on chromosome 2 (paragraph 67 and 78).
With regard to claim 8, May teaches a method of claim 5, wherein the polymorphic loci comprise at least two SNP loci on chromosome 3 (paragraph 67 and 78).
With regard to claim 9, May teaches a method of claim 1, wherein sequencing comprises high-throughput sequencing (p 15, under “DNA sequencing” heading, beginning at paragraph 174).
With regard to claim 10, May teaches a method of claim 1, wherein the cell-free DNA comprises DNA from a fetus (paragraph 19).
With regard to claim 12, May teaches a method of claim 1, wherein the amplifying step comprises amplifying between 50 and 1,000 polymorphic loci from the cell-free DNA isolated from the biological sample using between 50 and 1,000 distinct primer pairs configure to target the between 50 and 1,000 polymorphic loci in a single reaction volume (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 13, May teaches a method of claim 1, wherein the amplifying step comprises amplifying between 100 and 1,000 polymorphic loci from the cell-free DNA isolated from the biological sample using between 100 and 1,000 distinct primer pairs configure to target the between 100 and 1,000 polymorphic loci in a single reaction volume (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 14, May teaches a method of claim 1, wherein the biological sample is a blood sample (paragraph 106 and 136, where the sample is cell free nucleic acid; see also Example 1).
With regard to claim 16, May teaches a method of claim 1, wherein the distinct primers are configured to target the polymorphic loci via hybridization (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 17, May teaches a method of claim 1, wherein the distinct primers comprise PCR primers (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 18, May teaches a method of claim 1, wherein the total amount of cell-free DNA in the sample is between 10 pg and 100 pg (Example 1, where the amount of target nucleic acid is measured).
With regard to claim 19, May teaches a method of claim 18, wherein less than or equal to 10, 5, 2, 1, 0.5, 0.1, 0.05, 0.01, or 0.005% of the cell free DNA molecules that have a first locus have a mutation in the first locus (Example 1, where the amount of target nucleic acid is measured).
With regard to claim 20, May teaches a method of claim 18, wherein amplifying the isolated cell-free DNA comprises amplifying from 72%, 69%, 66%, 63%, 59%, or 56% of available cfDNA template fragment molecules (Example 1, where the amount of target nucleic acid is measured).
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 is/are rejected under 35 U.S.C. 103 as being unpatentable over May et al. (US PgPub 20140227691; August 2014) as applied over claims 1, 3-10, 12-14 and 16-20 above and further in view of Oeth et al. (US Patent 8173370; May 2012).
With regard to claim 2, Oeth teaches a method of claim 1, wherein the method further comprises enriching the DNA in the sample at the 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).
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 May 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, multiplexed primer mass extension therefore encompasses [5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 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, 1000 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, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or more polymorphisms. In a related embodiment, the polymorphism is a single nucleotide polymorphism (SNP), 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 May to include the higher level multiplex as taught by Oeth to arrive at the claimed invention with a reasonable expectation for success.
New Ground of Rejection as Necessitated by Amendment
Claim Interpretation
The term “non-naturally occurring composition” as added to the claims, as amended, has not been defined in any way. As noted in the rejection under 112 below, it is not entirely clear if the amendment is intended to indicate that the amplification steps alone result in a non-naturally occurring composition of amplified nucleic acids or if the amendment is intended to impart physically non-natural linkages as described within the specification. For example, regarding the term “non-natural”, the specification describes primers, sequence, nucleotides and linkages between nucleotides (see paragraph 58-60 of specification). Further, the specification describes “primers in the library are non-naturally occurring nucleic acids (such nucleic acids with one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage”) (paragraph 307 of specification).
As the scope and intent of the amendment to the claim is unclear, the term will be interpreted broadly as encompassing the amplification step and more narrowly as requiring the inclusion of any type of non-natural nucleotide, linkage or other non-natural adjustments within an amplification reaction.
Claim Rejections - 35 USC § 112
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 1-10, 12-14 and 16-20 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.
The amendment to claim 1 adds the term “non-naturally occurring composition” throughout the method. However, as noted in the claim interpretation above, it is unclear what is being added to the claimed method through this amendment to the claim. Based just on the language of the claims, it is not entirely clear if the amendment is intended to indicate that the amplification steps alone result in a non-naturally occurring composition of amplified nucleic acids or if the amendment is intended to impart physically non-natural linkages as described within the specification. Clarification of the amendment to the claims is requested.
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.
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) 1, 3-10, 12-14 and 16-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over May et al. (US PgPub 20140227691; August 2014).
With regard to claim 1, May teaches a method for preparing a non-naturally occurring composition of amplified DNA from a biological sample containing DNA from a first individual and a second individual, comprising:
isolating cell-free DNA from the biological sample, wherein the isolated cell-free DNA comprises the DNA from the first individual and DNA from the second individual (paragraph 106 and 136, where the sample is cell free nucleic acid; see also Example 1);
amplifying the isolated cell-free DNA at a plurality of polymorphic loci on one or more chromosomes expected to be disomic to obtain a non-naturally occurring composition of
amplified DNA, wherein the plurality of polymorphic loci comprises between 20 and 1,000 polymorphic loci, wherein the amplifying comprises amplifying the between 20 and 1,000 polymorphic loci from the cell-free DNA isolated from the biological sample using between 20 and 1,000 distinct primer pairs configured to target the between 20 and 1,000 polymorphic loci in a single reaction volume (paragraph 29, where PNA and LNA are included within nucleic acids; paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed);
and preparing the non-naturally occurring composition of amplified at the polymorphic loci for sequencing (paragraph 29, where PNA and LNA are included within nucleic acids; p 15, under “DNA sequencing” heading, beginning at paragraph 174).
With regard to claim 3, May 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 (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 4, May teaches a method of claim 2, wherein the enrichment comprises preferentially enriching the DNA at the plurality of loci to minimize an average degree of allelic bias (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 5, May teaches a method of claim 1, wherein the polymorphic loci comprise at least two SNP loci (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 6, May teaches a method of claim 5, wherein the polymorphic loci comprise at least two SNP loci on chromosome 1 (paragraph 67 and 78).
With regard to claim 7, May teaches a method of claim 5, wherein the polymorphic loci comprise at least two SNP loci on chromosome 2 (paragraph 67 and 78).
With regard to claim 8, May teaches a method of claim 5, wherein the polymorphic loci comprise at least two SNP loci on chromosome 3 (paragraph 67 and 78).
With regard to claim 9, May teaches a method of claim 1, wherein sequencing comprises high-throughput sequencing (p 15, under “DNA sequencing” heading, beginning at paragraph 174).
With regard to claim 10, May teaches a method of claim 1, wherein the cell-free DNA comprises DNA from a fetus (paragraph 19).
With regard to claim 12, May teaches a method of claim 1, wherein the amplifying step comprises amplifying between 50 and 1,000 polymorphic loci from the cell-free DNA isolated from the biological sample using between 50 and 1,000 distinct primer pairs configure to target the between 50 and 1,000 polymorphic loci in a single reaction volume (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 13, May teaches a method of claim 1, wherein the amplifying step comprises amplifying between 100 and 1,000 polymorphic loci from the cell-free DNA isolated from the biological sample using between 100 and 1,000 distinct primer pairs configure to target the between 100 and 1,000 polymorphic loci in a single reaction volume (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 14, May teaches a method of claim 1, wherein the biological sample is a blood sample (paragraph 106 and 136, where the sample is cell free nucleic acid; see also Example 1).
With regard to claim 16, May teaches a method of claim 1, wherein the distinct primers are configured to target the polymorphic loci via hybridization (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 17, May teaches a method of claim 1, wherein the distinct primers comprise PCR primers (paragraph 74 and 76 where many loci can be analyzed using multiple pairs of primers and where reactions can be highly multiplexed).
With regard to claim 18, May teaches a method of claim 1, wherein the total amount of cell-free DNA in the sample is between 10 pg and 100 pg (Example 1, where the amount of target nucleic acid is measured).
With regard to claim 19, May teaches a method of claim 18, wherein less than or equal to 10, 5, 2, 1, 0.5, 0.1, 0.05, 0.01, or 0.005% of the cell free DNA molecules that have a first locus have a mutation in the first locus (Example 1, where the amount of target nucleic acid is measured).
With regard to claim 20, May teaches a method of claim 18, wherein amplifying the isolated cell-free DNA comprises amplifying from 72%, 69%, 66%, 63%, 59%, or 56% of available cfDNA template fragment molecules (Example 1, where the amount of target nucleic acid is measured).
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 May to include non-natural nucleotides within the amplification product as described by May to arrive at the claimed invention with a reasonable expectation for success. May teaches “in certain embodiments, nucleic acids, can include polydeoxyribonucleotides (containing 2-deoxy-D-ribose), polyribonucleotides ( containing D-ribose), and any other type of nucleic acid that is an N- or C-glycoside of a purine or pyrimidine base, as well as other polymers containing nonnucleotidic backbones, for example, polyamide ( e.g., peptide nucleic acids (PNAs)) and polymorpholino
(commercially available from the Anti-Virals, Inc., Corvallis, Oreg., as Neugene) polymers, and other synthetic sequence-specific nucleic acid polymers providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA” (paragraph 29 of May. Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of May to include non-natural nucleotides within the amplification product as described by both May and Mitra to arrive at the claimed invention with a reasonable expectation for success.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over May et al. (US PgPub 20140227691; August 2014) as applied over claims 1, 3-10, 12-14 and 16-20 above and further in view of Oeth et al. (US Patent 8173370; May 2012).
With regard to claim 2, Oeth teaches a method of claim 1, wherein the method further comprises enriching the DNA in the sample at the 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).
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 May 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, multiplexed primer mass extension therefore encompasses [5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 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, 1000 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, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or more polymorphisms. In a related embodiment, the polymorphism is a single nucleotide polymorphism (SNP), 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 May to include the higher level multiplex as taught by Oeth to arrive at the claimed invention with a reasonable expectation for success.
Response to Arguments
Applicant's arguments filed December 10, 2025 have been fully considered but they are not persuasive.
Applicant traverses the rejection over May. While the rejections have in part been adjusted to address the amendment to the claims, the remarks will be briefly addressed as the rejection over May is maintained.
First, Applicant argues “May does not teach that the chromosome is expected to be
disomic, or that 20 to 1,000 polymorphic target loci are analyzed in a single reaction volume" (p 6 of remarks)
Next, regarding the issue of enrichment, Applicant argues “Applicant notes that claim 2 is not anticipated by May, as May does not teach a step of enriching the DNA at a plurality of polymorphic loci prior to the amplifying step. As claims 3 and 4 further limit the enrichment step of claim 2, claims 3 and 4 are therefore novel over the cited prior art" (p 6 of remarks)
Regarding the combination of May and Oeth, Applicant argues “"nowhere does Oeth teach enriching the DNA at a plurality of polymorphic loci prior to the amplifying step, as recited in claim 2, least not in the excerpts pointed to in the Office Action." (p 7 of remarks)
Finally, Applicant argues the claims recite "one or more chromosomes expected to be disomic" and that the claims of the 10597709 and 17505588 do not recite those limitations. Applicant also requests these rejections under obviousness type double patenting.
Applicant’s arguments are not persuasive. First, the request to hold the obviousness type double patenting in abeyance has been denied. The obviousness type double patenting rejection is not the only issue pending in the case and Applicant’s arguments are not persuasive. Therefore, the rejections are maintained.
Next, while Applicant’s arguments regarding the step of enrichment within the method, as claimed, particularly as recited in claims 2-4 has been considered, the arguments are not persuasive. The claims, especially regarding claims 2-4 effectively claim a further step of enrichment that is achieved by amplifying plural loci before an additional step of amplification. However, even the specification refers to amplification and enrichment as nearly synonymous. See for instance paragraph 620 of the specification which states "The selective enrichment and/or amplification may involve tagging each individual molecule with different tags, molecular barcodes, tags for amplification, and/or tags for sequencing. The clinician may then sequence the plasma sample, and also possibly also the prepared maternal and/or paternal DNA" (emphasis added). Then again, paragraph 633 of the specification states, "the DNA from the plasma sample may involve sequencing DNA that has been preferentially enriched, for example through targeted amplification, at a plurality of polymorphic or non-polymorphic loci". If there is an intended difference or distinction between the enrichment step, as claimed, and the step of amplification that is recited in claims 2-4, the distinction is not clear, at all. If the step of enrichment is intended to include a step which is nested or hemi-nested as recited in paragraph 619 of the specification, for example, that physical difference in steps should be made clear within the claims. However, as currently recited, the step of enrichment is indistinguishable from the existing steps of amplification and therefore the arguments regarding enrichment as taught by both May and Oeth are not persuasive and the rejection is maintained.
Next, regarding the issue of the terminology where the polymorphic loci are present “on one or more chromosomes expected to be disomic”, Applicant’s argument that May does not teach that the chromosome is expected to be disomic is not persuasive. Throughout, the method of May, including the portion cited in response to this part of the claims, is focused on the determination of aneuploidy where aneuploidy is a determination of more or less than two chromosomes in a human sample. While May may not have explicitly discussed or mentioned the term disomic, May throughout when describing aneuploidy and chromosomes discusses deviation from normal (see paragraph 67 and 98), or the expectation for a typical disomic complement of two chromosomes. Therefore, while the argument has been considered, it is not persuasive.
Conclusion
No claims are allowed. All claims stand rejected.
THIS ACTION IS MADE FINAL. 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.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681