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 1-10 are pending and will be examined.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 8, 2024; 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. 61448547, 61462972, 61426208, 61398159, 61395850, 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 universal adaptors or universal amplification and mutation detection, none of these priority documents include sufficient (or any) support for the inclusion of barcodes or barcode primers, or the inclusion of cancer or tumor or that polymorphic loci are associated with tumor or cancer.
Therefore, the claims are entitled to an earliest priority date of October 3, 2011 as recited in the 61542508 application (‘508 application) and also the 10017812 patent.
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.
Claim 1-2 and 12-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2 of U.S. Patent No. 11,519,035 (‘035 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because while the patents are not identical, they are drawn to very similar subject matter. The instant claims require tagging adaptors on to cell free DNA with universal tails, followed by amplification and then sequencing the products. The final step of the method includes high throughput sequencing. The claims of the ‘035 patent and the instant method include loci associated with cancer.
The differences between the instant claims and the claims of the ‘035 patent arise in the different ways universal adaptors are used in the ‘035 patent as compared to the instant claims. However, it is the shared features between the methods that renders the claims patent ineligible. For example, besides the similarities noted above, both methods are focused on isolation of cell free DNA from a blood sample and analysis of loci associated with cancer.
Therefore, while the claims are not the same, they are also not patentably distinct.
Claim 1-2, 4-5 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 and 10 of U.S. Patent No. 11,525,162 (‘162 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because while the patents are not identical, they are drawn to very similar subject matter. The instant claims require tagging adaptors on to cell free DNA with universal tails, followed by amplification, introducing a barcode and sequencing tag and then sequencing the products. The final step of the method includes high throughput sequencing.
The method of the ‘162 patent and the instant method are nearly identical. Both methods focus on extracting cell free DNA from blood samples, include enrichment of a large plurality of loci and high throughput sequencing. The differences between the claims are primarily in the preamble of the ‘162 patent. Compare the dependent claims 2-6 and 8-14 of the ‘162 patent. The other independent claim of the ‘162 patent is claim 7, same as the instant method. The overlapping subject matter includes plural loci of up to 2000 loci (compare claims 2-3 of the ‘162 patent to instant claims 4-5), fraction of DNA of cancer origin (compare claim 10 of the ‘162 patent to instant claim 10). Therefore, while the claims are not the same they are also not patentably distinct.
Claims 1-2, 4-5 and 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 6 of copending Application No. 18678417 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the patents are not identical, they are drawn to very similar subject matter. The instant claims require tagging adaptors on to cell free DNA with universal tails, followed by universal amplification, then sequencing the products. The final step of the method includes high throughput sequencing.
The claims differ in that the instant claims include a step of analysis of cancer specific mutations and including analysis of a large plurality of loci. Claim 1 and 5-6 of the ‘417 application focuses on the method within a tumor sample. The ‘417 application includes analysis of mutations in cancer and includes high throughput sequencing.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2 and 5-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2 and 5-9 of copending Application No. 18733681 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the patents are not identical, they are drawn to very similar subject matter. The instant claims require tagging adaptors on to cell free DNA with universal tails, followed by amplification, introducing a barcode and sequencing tag and then sequencing the products. The final step of the method includes high throughput sequencing.
The claims differ in that the instant claims include a step of analysis of cancer specific mutations and including analysis of a large plurality of loci. Claim 1, 3 and 10 of the ‘681 application focuses on the method within a tumor sample. The ‘681 application includes analysis of mutations in cancer and includes high throughput sequencing.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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) 1-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pieprzyk et al. (US PgPub 20140186827; July 2014), Gnirke et al. (Nature Biotechnology, 2009, 27(2):182-189) and Gormally et al. (Mutation Research, 2007, 635:105-117).
With regard to claim 1, Pieprzyk teaches a method for preparing a DNA fraction from a biological sample of a subject useful for analyzing genetic or epigenetic features involved with cancer, comprising:
(a) extracting cell-free DNA from the biological sample (paragraph 57, 172-173, 225, 713, where whole blood or maternal whole blood is used for extraction; see also pp 185, 191, 299, where the method is applicable to cancer patients);
(1) introducing at least one adaptor containing a universal priming sequence to the extracted cell-free DNA or their derivatives and producing a plurality of adapted DNA sequences containing the universal priming sequence (paragraph 71, which points to Figure 11A-B and Example 13, paragraph 501, where universal tags are included; see also Example 13 and Example 14, where universal or common sequences are used in amplification; see also paragraph 173, where sequencing libraries are also generated in different embodiments),
(2) performing universal amplification on the plurality of adapted DNA sequences using the universal priming sequence, thereby producing a plurality of amplified adapted DNA sequences (paragraph 71, which points to Figure 11A-B and Example 13, paragraph 501, where universal tags are included; see also Example 13 and Example 14, where universal or common sequences are used in amplification; see also paragraph 173, where sequencing libraries are also generated in different embodiments).
With regard to claim 2, Pieprzyk teaches a method of claim 1, wherein the biological sample is a blood, plasma, serum, or urine sample (paragraph 57, 172-173, 225, 713, where whole blood or maternal whole blood is used for extraction; see also pp 185, 191, 299, where the method is applicable to cancer patients).
With regard to claim 4, Pieprzyk teaches a method of claim 1, wherein step (b) comprises selectively enriching for 1,000- 500,000 preselected loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 5, Pieprzyk teaches a method of claim 1, wherein step (b) comprises selectively enriching for 10,000-200,000 preselected loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 6, Pieprzyk teaches a method of claim 1, wherein the selectively enriching comprises targeted multiplex amplification (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 8, Pieprzyk teaches a method of claim 1, wherein the adaptor further comprises a molecular barcode, wherein sequence reads derived from the same original cell-free DNA molecule are identified using the molecular barcode (see Example 10, where cell free nucleic acids are used for determination of fetal aneuploidy and which recites the reasons why barcodes are important to the implementation of the method of Pieprzyk as applies to the determination of fetal aneuploidy).
With regard to claim 9, Pieprzyk teaches a method of claim 1, wherein the universal amplification introduces a sample-specific barcode, and wherein the enriched DNA sequences of multiple samples are pooled together and sequenced in the same sequencing run (see Example 10, where cell free nucleic acids are used for determination of fetal aneuploidy and which recites the reasons why barcodes are important to the implementation of the method of Pieprzyk as applies to the determination of fetal aneuploidy).
Regarding claim 1, while Pieprzyk teaches enrichment, Pieprzyk does not particularly teach selective enrichment of plural loci.
Regarding claim 7, while Pieprzyk teaches enrichment of short nucleic acids, Pieprzyk does not teach the use of hybrid capture probes. Further, while Pieprzyk teaches sequencing, Pieprzyk is not specific regarding massively parallel sequencing.
With regard to claim 1, Gnirke teaches
(3) selectively enriching for a subset of the plurality of amplified adapted DNA sequences or their derivatives that contain one or more preselected loci, thereby producing enriched DNA sequences (Abstract, Figure 1, where hybrid capture probe enrichment is described) and
(b) producing an enriched fraction of DNA by:
(c) performing massively parallel sequencing on the enriched DNA sequences or their derivatives and obtaining sequence reads containing at least a portion of one or more of the preselected loci (p. 186, col. 2 “Discussion” heading; p 188, “Catch processing and sequencing” heading).
With regard to claim 7, Gnirke teaches a method of claim 1, wherein the selectively enriching comprises capturing some of the plurality of amplified adapted DNA sequences or their derivatives that contain one or more preselected loci using hybrid capture probes (Abstract, Figure 1, where hybrid capture probe enrichment is described)
Regarding claims 1 and 7, while Gnirke teaches massively parallel sequencing, neither Pieprzyk or Gnirke are specific in detecting cancer specific mutations using the method, as claimed.
With regard to claims 1, 3 and 10, Gormally teaches methods that would include:
obtaining an identification of one or more genetic or epigenetic features involved with cancer (Fig 1, p 107-108, where the role of cell free DNA in mutation detection is generally described; Table 3, p 112, col. 1, top of page).
With regard to claim 3, Gormally teaches a method of claim 1, wherein the genetic or epigenetic features involved with cancer comprises single nucleotide polymorphism or variant, copy number variation, insertion, deletion, or differential methylation (Fig 1, p 107-108, where the role of cell free DNA in mutation detection is generally described; Table 3, p 112, col. 1, top of page; see also p 112, “4.2 CFDNA in case-control studies” heading, where tumoral origin in CFDNA samples is described).
With regard to claim 10, Gormally teaches a method of claim 1, wherein the cell-free DNA comprises cancer DNA, and wherein the method further comprises estimating the fraction of cancer DNA in the cell-free DNA based on the sequence reads (Fig 1, p 107-108, where the role of cell free DNA in mutation detection is generally described; Table 3, p 112, col. 1, top of page; see also p 112, “4.2 CFDNA in case-control studies” heading, where tumoral origin in CFDNA samples is described).
Further, 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 Pieprzyk to include the hybrid capture probes, enrichment and massively parallel sequencing techniques as taught by Gnirke to arrive at the claimed invention with a reasonable expectation for success. Pieprzyk teaches a method of sequencing of cell-free nucleic acids using steps of analysis of cell free nucleic acids for amplification and sequencing. While Pieprzyk does not specifically teach the inclusion of hybrid capture probes, Gnirke teaches specific library based enrichment of nucleic acids with the inclusion of hybrid capture probes. Gnirke teaches “We developed a capture method that uses biotinylated RNA ‘baits’ to fish targets out of a ‘pond’ of DNA fragments. The RNA is transcribed from PCR-amplified oligodeoxynucleotides originally synthesized on a microarray, generating sufficient bait for multiple captures at concentrations high enough to drive the hybridization. We tested this method with 170-mer baits that target 415,000 coding exons (2.5 Mb) and four regions (1.7 Mb total) using Illumina sequencing as read-out”. As noted in that statement, Gnirke also focuses on massively parallel sequencing and also notes “With further optimization, routine implementation of hybrid selection would enable deep, targeted next-generation sequencing of thousands of exons as well as of megabase-sized candidate regions implicated by genetic screens. Targeting based on hybrid selection may be potentially useful for a variety of other applications as well, where traditional singleplex PCR is either too costly or too specific in that specific primers may fail to produce a PCR product that represents all genetic variation in the sample. Examples are enrichment of precious ancient DNA that is heavily contaminated with unwanted DNA, deep sequencing of viral populations in clinical samples, or metagenomic analyses of environmental or medical specimens” (p. 186, col. 2 “Discussion” heading). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Pieprzyk to include the hybrid capture probes, enrichment and massively parallel sequencing as taught by Gnirke to arrive at the claimed invention with a reasonable expectation for success.
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 Pieprzyk and Gnirke to apply the method to detection of cancer as described by Gormally to arrive at the claimed invention with a reasonable expectation for success. First, Pieprzyk specifically teaches the method could be useful in cancer, “These enrichment/selective tagging methods can be combined with methods described above to further facilitate the detection and or quantification of target sequences in samples having mixed length nucleic acids (e.g. fetal DNA in maternal plasma or tumor DNA in plasma from cancer patients.”. Pieprzyk also notes “These methods can also be employed in determinations DNA or RNA copy number. Determinations of aberrant DNA copy number in genomic DNA is useful, for example, in the diagnosis and/or prognosis of genetic defects and diseases, such as cancer” (paragraph 299). These methods can be carried out, for example, to determine a fetal genotype or determine the presence of a mutation or fetal aneuploidy” (paragraph 60). Pieprzyk also teaches “These methods can be carried out, for example, to determine a fetal genotype or determine the presence of a mutation or fetal aneuploidy” (paragraph 176). Next, Gormally teaches “the technical issues involved in obtaining, using and analyzing CFDNA in cancer or healthy subjects.We also summarize the literature available on the mechanisms of CDNA release as well as on cross-sectional or prospective studies aimed at assessing the clinical and biological significance of CFDNA. These studies show that, in some circumstances, CFDNA alterations are detectable ahead of cancer diagnosis, raising the possibility of exploiting them as biomarkers for monitoring cancer occurrence” (Abstract). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Pieprzyk and Gnirke to apply the method to detection of cancer as described by Gormally to arrive at the claimed invention with a reasonable expectation for success.
Conclusion
No claims are allowed. All claims stand rejected.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681
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