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 Status
Claims 2, 4, 5, 7-14, 17, 19, 21, 23, 25, & 31 filed on 01/12/2026 are pending. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 101
Claims 2, 4, 5, 7-14, 17, 19, 21, 23, 25, & 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for determining if a subject has or is at risk of having a disease through amplification and sequencing of nucleic acid molecules from a cell-free biological sample of the subject. This recitation is a natural correlation between the nucleic acid sequences in cell free samples and having or risk of having a disease. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “determining that a subject has or is at risk of having a disease”, “processing of a plurality of breakpoint sequences against a plurality of reference breakpoint sequences”, “processing said sequence to monitor a progression or regression”, which are recitations of an abstract idea because they encompasses comparisons, conclusions, and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of obtaining a cell-free biological sample from a subject, using a plurality of nucleic acid molecules derived from the sample to generate circular nucleic acid molecules, subjecting the plurality of circular nucleic acid sequences to amplification to generate a plurality of amplification products, subjecting the amplified circular nucleic acid molecules to sequencing to identify a plurality of breakpoint sequences, and then comparing the plurality of breakpoint sequences to a plurality of reference breakpoint sequences, however, this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the step of obtaining a sample is considered insignificant post solution activity. The steps of detecting whether a subject is at risk of having a disease are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. In addition, the steps are not only a mere data gathering and data analysis steps, but the general recitation of detection of known nucleic acids are well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that claim 2 recites additional elements that, as a whole, add “significantly more” to the alleged judicial exceptions because they include a combination of elements that are not well-understood, routine, and/or not conventional and further that the combination of elements in (a)-(d) of claim 2 are not judicial exceptions and are also not conventional nor well-understood because this combination of steps is not routinely used and not conventional in the art of determination of breakpoint sequences of cell-free nucleic acids as claimed. These arguments have been thoroughly reviewed but were not found persuasive. First, claim 2 is directed to judicial exceptions as claim 2 recites a method for determining if a subject has or is at risk of having a disease through amplification and sequencing of nucleic acid molecules from a cell-free biological sample of the subject which is a recitation of natural correlation between the nucleic acid sequences in cell free samples and having or risk of having a disease. Further, the claimed invention also recites “determining that a subject has or is at risk of having a disease”, “processing of a plurality of breakpoint sequences against a plurality of reference breakpoint sequences”, “processing said sequence to monitor a progression or regression”, which are recitations of an abstract idea because they encompasses comparisons, conclusions, and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions. Second, claim 2, as currently amended, is drawn to a method of detecting nucleic acid molecules derived from a cell-free biological sample for determining if a subject has or is at risk of having a disease in which the detection of known nucleic acids and the amplification and sequencing of nucleic acid sequences is well understood, routine, and conventional (see MPEP 2106.05(d)(II)). Further, the steps of detecting whether a subject is at risk of having a disease are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited, i.e. steps of obtaining cell-free nucleic acids, amplification, sequencing, and processing against a reference.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 2, 4, 5, 12-14, & 17 are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer), in view of Rabinowitz et al. (U.S. Patent Application Publication #2019/0309358).
Regarding claim 2, Braig teaches the use of cell-free DNA as diagnostic biomarkers for cancer (determining if a subject is at risk for having a disease) (pg. 1148 paragraph 1 lines 2-3; pg. 1150 column 1 paragraph 2 lines 1-3; pg. 1159 column 1 paragraph 1 lines 2-7); amplifying and sequencing the breakpoint DNA (pg. 1150 column 1 paragraph 4 lines 5-10; pg. 1153 column 1 2nd full paragraph lines 10-14); and comparing the breakpoint sequences to human genome (reference sequence) (pg. 1150 column 1 paragraph 4 lines 5-10; pg. 1153 column 1 2nd full paragraph lines 10-14). In addition, Braig teaches that the cell free DNA was amplified with primers (primers must attach to a 5’ end and a 3’ end) (pg. 1152 column 1 paragraph 1 lines 1-5).
Braig fails to teach that the cell-free DNA are used to generate a plurality of circular nucleic acid molecules in which those circular nucleic acid molecules are sequenced to generate a plurality of sequence reads in claim 2.
Rabinowitz teaches ligation of the 3’ end and 5’ end of a target DNA to create a circular DNA molecule where the target DNA is obtained from extracting cell-free DNA from a biological sample of a subject (pg. 68 column 1 lines 2-6). Rabinowitz also teaches that the unamplified genetic material of the target individual may be circularized, amplified, and then sequenced (paragraph [0238] lines 12-15 & lines 19-24). Rabinowitz also teaches that the circularized DNA molecule may be amplified by methods including rolling circle amplification (RCA), multiple displacement amplification (MDA), or other amplification protocols (paragraph [0238] lines 12-19). From here the amplified circular DNA molecules can be sequenced by a variety of sequencing methods to measure the genetic material on the target genome (encompassed in the circular DNA molecule). Rabinowitz et al. also teaches these sequencing methods includes high throughput sequencing (paragraph [0238] lines 19-24). Finally, Rabinowitz teaches that circularizing DNA molecules followed by high throughput sequencing provides better genotypic data and more accurate results (paragraph [0240] lines 8-13).
Braig and Rabinowitz are considered to be analogous to the claimed inventions because they are in the same field of determining if a subject has or is at risk for a disease using cell-free DNA and sequencing methods. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of amplifying, sequencing, and comparing breakpoint sequences in cell-free DNA samples for disease detection taught in Braig to incorporate the teachings of Rabinowitz to circularize the plasma DNA (cell-free DNA molecules) before sequencing because Rabinowitz teaches that circularizing target DNA molecules followed by high throughput sequencing provides better genomic data and more accurate results.
Regarding claim 4, Rabinowitz teaches the approach of circularizing DNA molecules where the target region of DNA, with the addition of appropriate polymerases and/or ligases, have the inverted ends of the target DNA ligated together to create a circular loop of DNA (paragraph [0234] lines 3-11).
Regarding claim 5, Rabinowitz teaches that a probe (adaptor) can anneal to a target region of DNA in an inverted manner such that the addition of DNA polymerase and DNA ligase can ligate the 3’end to the 5’ end with the probes (adaptors) attached to create a circular DNA molecule (paragraph [0235] lines 1-11).
Regarding claim 12, Braig teaches that blood samples were processed to extract cell-free DNA from the plasma of the sample (pg. 1149 column 2 4th full paragraph lines 1-11; pg. 1150 column 1 2nd full paragraph lines 1-5).
Regarding claim 13, Braig teaches investigating circulating tumor DNA and the analysis of tumor tissue, blood samples, and clinical data (abstract lines 1-3; pg. 1149 column 2 3rd full paragraph lines 4-6).
Regarding claim 14, Braig teaches that this method of processing breakpoint sequences are quantified during the course of treatment (monitor progression or regression of said disease) as a means to detect tumor recurrence to timely localize and treat recurrences (abstract lines 9-11 & 14-16; pg. 1157-1159 paragraph bridging pg. 1157 & pg. 1159 lines 13-15).
Regarding claim 17, Braig teaches that the cell free biological sample is from blood and plasma (pg. 1149 column 2 4th full paragraph lines 1-11; pg. 1150 column 1 2nd full paragraph lines 1-5).
Claim(s) 7 & 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer) and Rabinowitz (Rabinowitz et al.; U.S. Patent Application Publication #2019/0309358), as applied to claim 2 above, and in further view of Dean (Dean et al.; “Rapid Amplification of Plasmid and Phage DNA Using Phi29 DMA Polymerase and Multiply-Primed Rolling Circle Amplification”, March 22nd, 2001, pages 1095-1099, Genome Research).
The teachings of Braig and Rabinowitz with respect to claim 2 are discussed above.
Regarding claim 7 & 9, Rabinowitz teaches that the circular DNA molecules may be amplified by methods including rolling circle amplification (RCA), multiple displacement amplification (MDA), or other amplification protocols (paragraph [0238] lines 12-19).
Braig and Rabinowitz does not teach that the polymerase used in the amplification step has strand displacement activity (see claim 7). Braig and Rabinowitz does not teach that the circular DNA molecule in the rolling circle amplification step amplified in a reaction comprising random primers (see claim 9).
Dean teaches that phi-29 is used in rolling circle amplification and has excellent strand displacement activity (pg. 1097 column 2 paragraph 2 lines 10-12). Dean also teaches that this method of rolling circle amplification using phi-29 DNA polymerase and random primers has an increased rate of synthesis and yield (pg. 1095 abstract paragraph 1 lines 2-5; pg. 1095 column 1 paragraph 3 lines 5-12; pg. 1097 column 2 paragraph 1 lines 1-20 & paragraph 2 lines 1-3).
Braig, Rabinowitz, and Dean are considered to be analogous to the claimed inventions because they are in the same field of DNA amplification methods in order to sequence the DNA. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of circularization and amplification of cell-free DNA taught in Rabinowitz to incorporate the teachings of Dean to use a polymerase that has strand displacement activity and amplify circular DNA molecules with random primers because Dean teaches this would allow for the amplification of the circular DNA molecules at in increased rate of synthesis and yield to generate a plurality of sequences reads with the goal of amplifying the signal that is used to determine if a subject has or is at risk of having a disease.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer) and Rabinowitz (Rabinowitz et al.; U.S. Patent Application Publication #2019/0309358), as applied to claim 2 above, and in further view of Edelman (Edelman; WO Patent Application Publication #2018/115855).
The teachings of Braig and Rabinowitz with respect to claim 2 are discussed above.
Regarding claim 8, Rabinowitz teaches that a method to form circularized DNA molecules by hybridizing probes, performing a gap fill to fill in the bases of the two ends of the hybridized probes and then ligating the two ends to form a circular DNA molecules (paragraph [0238] lines 3-6).
Braig and Rabinowitz fail to teach that the DNA polymerase in this method does not have strand-displacement activity.
Edelman teaches a method where nucleic acid molecules are amplified by rolling circle amplification thus resulting in circularized nucleic acid products in which these circularized products are used as the template for a second rolling circle amplification step in which a polymerase that lacks strand displacement (such as Phusion polymerase or T4 DNA polymerase) can be used (pg. 129 lines 30-33; pg. 130 lines 5-7).
Braig, Rabinowitz, and Edelman are considered to be analogous to the claimed inventions because they are in the same field of nucleic acid sequencing methods. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of circularization and amplification of cell-free DNA taught in Rabinowitz to incorporate the teachings of Edelman to use a DNA polymerase that does not have strand-displacement activity to obtain predictable results by simple substitution of one known element for another.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer) and Rabinowitz (Rabinowitz et al.; U.S. Patent Application Publication #2019/0309358), as applied to claim 2 above, and in further view of Gong (Gong et al.; “Multiplex real-time PCR assay combined with rolling circle amplification (MPRP) using universal primers for non-invasive detection of tumor related mutations”, July 23rd, 2018, pages 27375-27381, Nucleic Acids Research).
The teachings of Braig and Rabinowitz with respect to claim 2 are discussed above.
Regarding claim 10, Braig and Rabinowitz fail to teach contacting the circular nucleic acid molecules to an amplification reaction mixture comprising one or more primers where each specifically hybridizes to a different target sequence via sequence complementary.
Gong teaches a multiplex method with rolling circle amplification with cell-free DNA in which padlock probes (primers) can only ligate with target DNA that is completely complementary to it allowing for the ligation of different probes (primers) with different target sequences with sequence complementary (pg. 27376 paragraph that bridges column 1 and 2 lines 1-23; pg. 27376 column 2 1st full paragraph lines 5-10). In addition, Gong teaches that method increases the sensitivity over other advanced PCR methods (pg. 27375 abstract paragraph 1 lines 6-7).
Braig, Rabinowitz, and Gong are considered to be analogous to the claimed inventions because they are in the same field of cell-free DNA and sequencing methods. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of circularization and amplification of cell-free DNA taught in Rabinowitz to incorporate the use of padlock probes (primers) that specifically hybridize to different target sequence via complementarity as taught in Gong because Gong teaches the use an amplification mixture of one or more primers in which each specifically hybridizes to a different target sequences would allow for the detection of cancer-related mutations and risk for disease in a method that provides better sensitivity.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer) and Rabinowitz (Rabinowitz et al.; U.S. Patent Application Publication #2019/0309358), as applied to claim 2 above, and in further view of Sanchez (Sanchez et al.; “New insights into structural features and optimal detection of circulating tumor DNA determined by single-stranded DNA analysis”, November 23rd, 2018, pages 1-12, Nature Partner Journals Genomic Medicine).
The teachings of Braig and Rabinowitz with respect to claim 2 are discussed above.
Regarding claim 11, Braig and Rabinowitz fail to teach that the nucleic acid molecules are single stranded.
Sanchez teaches sequencing single stranded cell-free DNA (pg. 1 abstract paragraph 1 lines 1-2 & 4-6). Sanchez also teaches that sequencing short single strand molecules provide higher sensitivity when detecting genetic or epigenetic alterations when testing cancer patient plasma (pg. 9 column 1 3rd full paragraph lines 1-4).
Braig, Rabinowitz, and Sanchez are considered to be analogous to the claimed inventions because they are in the same field of determining if a subject has or is at risk for a disease using cell-free DNA and sequencing methods. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of Braig and Rabinowitz to incorporate the use of single stranded nucleic acid molecules as taught in Sanchez because Sanchez teaches that sequencing single stranded cell-free DNA molecules would allow for detection of having or risk of having a disease (detecting genetic and epigenetic alterations) with higher sensitivity.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer) and Rabinowitz (Rabinowitz et al.; U.S. Patent Application Publication #2019/0309358), as applied to claim 2 above, and in further view of Yi Shen (Yi Shen et al.; “Sensitive tumor detection and classification using plasma cell-free DNA methylomes”, November 14th, 2018, pages 579-585, Nature Letters).
The teachings of Braig and Rabinowitz with respect to claim 2 are discussed above.
Regarding claim 19, Braig and Rabinowitz fail to teach computer processing a sequence to identify an epigenetic modification wherein the epigenetic modification is selected from methylation, phosphorylation, ubiquitination, sumoylation, acetylation, ribosylation, citrullination, and fragmentation.
Yi Shen teaches a machine learning (computer processing) method for detecting DNA methylation in cell-free DNA samples with the goal of detecting, intercepting, or classifying early-stage cancers (pg. 579 abstract paragraph 1 lines 1-19; pg. 585 column 2 paragraph 3 lines 1-5). Yi Shen also teaches that this method is robust and sensitive (pg. 583 column 1 1st full paragraph lines 1-3).
Braig, Rabinowitz, and Yi Shen are considered to be analogous to the claimed inventions because they are in the same field of determining if a subject has or is at risk for a disease using cell-free DNA and sequencing methods. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of Braig and Rabinowitz to incorporate the use of computer processing as taught in Yi Shen to computer process sequences to identify methylation because Yi Shen teaches that doing so would allow for detection of DNA methylation in cell-free nucleic acid molecules with high sensitivity.
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer) and Rabinowitz (Rabinowitz et al.; U.S. Patent Application Publication #2019/0309358), as applied to claim 2 above, and in further view of Harris (Harris et al.; Scientific Reports, Vol. 6, pages 1-9, July 2016).
The teachings of Braig and Rabinowitz with respect to claim 2 are discussed above.
Regarding claim 21, Braig teaches the method of amplifying, sequencing, and comparing breakpoint sequences in cell-free DNA samples for disease detection in soft tissue myxoid liposarcomas (disease of cancer) (abstract lines 1-9; pg. 1149 column 2 2nd full paragraph lines 1-4). In addition, Braig teaches that the use of cell-free DNA holds potential to improve and simplify cancer detection and treatments and has currently been mostly adapted to epithelial cancers of lung, breast, and colon cancer (pg. 1157-1159 paragraph bridging pg. 1157 & pg. 1159 lines 2-5).
Braig and Rabinowitz fail to teach that the cancer is selecting from the group according to claim 21.
Harris teaches a method of detecting breakpoints through amplification and sequencing in cell-free DNA samples obtained from ovarian cancer samples (pg. 2 3rd full paragraph lines 1-4; pg. 4 1st full paragraph lines 1-9). In addition, Harris teaches that this method can be an effective way to monitor cancer patients for relapse and therapeutic efficacy using cfDNA (abstract lines 13-15).
Braig, Rabinowitz, and Harris are considered to be analogous to the claimed invention because they are all in the same field of determining if a subject has or is at risk for a disease using cell-free DNA and sequencing methods. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the detection of breakpoint sequences in soft tissue sarcomas (cancer) in Braig to incorporate the detection of breakpoint sequences in ovarian cancer as taught in Harris because Harris teaches that doing so would provide an effective way to monitor cancer patients for relapse and therapeutic effect using cfDNA.
Claim(s) 23, 25, & 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braig (Braig et al.; “Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas”, February 19th, 2019, pages 1148-1161, International Journal of Cancer) and Rabinowitz (Rabinowitz et al.; U.S. Patent Application Publication #2019/0309358), as applied to claim 2 above, and in further view of Lanman (Lanman et al.; “Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA”, October 16th, 2015, pages 1-27, PLOS One).
The teachings of Braig and Rabinowitz with respect to claim 2 are discussed above.
Regarding claims 23, 25, & 31, Braig and Rabinowitz fail to teach that at least a subset of plurality breakpoint sequences are identified in an electronic report that indicates in the subject has or is at risk of having a disease (see claim 23). In addition, Braig and Rabinowitz fail to teach that at least a subset of plurality breakpoint sequences is used to provide a therapeutic intervention to a subject (see claim 25). Finally, Braig and Rabinowitz fail to teach using at least a subset of plurality breakpoint sequences to monitor a subject for progression or regression of a disease (see claim 31).
Lanman teaches a method of digital sequencing of cell-free DNA and using a software to compare to wild-type cell-free DNA (reference sequences) to asses a patients cancer status (electronic report) (pg. 1 abstract paragraph 1 lines 15-20; pg. 18 paragraph 2 line 1; pg. 19 1st full paragraph lines 1-3 & lines 12-17). Lanman also teaches this method can be used to re-evaluate whether new targeted therapeutics are needed for a patient in addition to adaptively managing the progression or regression of their evolving cancer (disease) (pg. 1 abstract paragraph 1 lines 15-20; pg. 17 paragraph bridging pg. 16 and pg. 17 lines 9-13). In addition, Lanman teaches this method of sequencing reduces complications, time delays, and failure rates compared to other sequencing methods (pg. 17 1st full paragraph lines 11-13) while also being highly specific (pg. 14 3rd full paragraph lines 1-5).
Braig, Rabinowitz, and Lanman are considered to be analogous to the claimed inventions because they are in the same field of determining if a subject has or is at risk for a disease using cell-free DNA and sequencing methods. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of Braig and Rabinowitz to incorporate the use at least a subset of plurality sequence reads to indicate if the subject has or is at risk of having a disease, to provide a therapeutic intervention to a subject, and to monitor the progression or regression of a disease as taught in Lanman because Lanman teaches that doing so would allow for determination if a subject has or is at risk of having a disease, monitoring the disease, and determining when to administer a therapeutic with high specificity and reduced sequencing complications.
Response to Arguments
The response traverses the rejection. The response asserts that in the present invention, breakpoint sequences are determined from the fused 3’ and 5’ end junction sequence, created through circular ligation, a result of the lab process, which is in contrast to the method of detecting cancer described in Braig that uses chromosomal breakpoints that occurred naturally through chromosomal translocation during cancer development and that this is different from the claimed sequence of 3’ and 5’ ends of cfDNA which are created through DNA fragmentation during the process of degradation. The response further asserts that Rabinowitz also does not provide any teaching of breakpoints because the reference is focused on determining ploidy status using a circularized probe and not a circularized cfDNA and such circular probes does not capture the end information of the cfDNA fragments and it is not teaching how to detect the ends of the cfDNA fragment through circularization of the cfDNA itself. Further, the response asserts that neither Braig nor Rabinowitz disclose, teaches, or even suggests using circular nucleic acid molecules to identify breakpoint sequences of a cell-free nucleic acid molecule as in claim 2. These arguments have been thoroughly reviewed but were not found persuasive. First, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, claim 2, as currently amended does not require the breakpoint sequences occur as the result of a lab process. Third, the recitation of “each of said plurality of breakpoint sequences comprises a 5’ end and a 3’ end of a nucleic acid molecule” in claim 2 as currently amended, is given its broadest reasonable interpretation to encompass a breakpoint sequence comprising a 5’ end and a 3’ end in which, as discussed previously and above, Braig teaches that the cell free DNA was amplified with primers (primers must attach to a 5’ end and a 3’ end encompassing a breakpoint sequence comprising a 5’ end and a 3’ end) (pg. 1152 column 1 paragraph 1 lines 1-5) therefore comprising a 5’ end and a 3’ end of a nucleic acid molecule derived from cell-free biological sample. Fourth, Rabinowitz does teaches ligation of the 3’ end and 5’ end of a target DNA to create a circular DNA molecule where the target DNA is obtained from extracting cell-free DNA from a biological sample of a subject (circularized cfDNA) (pg. 68 column 1 lines 2-6). Lastly, Braig and Rabinowitz are considered to be analogous to the claimed inventions because they are in the same field of determining if a subject has or is at risk for a disease using cell-free DNA and sequencing methods. Therefore, it would have been prima facie obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of amplifying, sequencing, and comparing breakpoint sequences in cell-free DNA samples for disease detection taught in Braig to incorporate the teachings of Rabinowitz to circularize the plasma DNA (cell-free DNA molecules) before sequencing because Rabinowitz teaches that circularizing target DNA molecules followed by high throughput sequencing provides better genomic data and more accurate results.
The response also asserts that the methods taught in Braig and Rabinowitz use standard library preparation with end repair steps, which extend or degrade the natural ends of the cell-free nucleic acid molecule and fail to preserve the ends of the cell-free nucleic acid molecules and, in contrast, the claim method circularizes the cell-free nucleic acid molecules, thereby preserving the natural ends of the cell-free nucleic acid molecules and their sequences. This arguments has been thoroughly reviewed but was not found persuasive as claim 2, as currently amended, does not recite specifics with regards to natural ends of the cell-free nucleic acid molecules and instead recites “each of said plurality of breakpoint sequences comprises a 5’ end and a 3’ end of a nucleic acid molecule”, which is given its broadest reasonable interpretation to encompass a breakpoint sequence comprising a 5’ end and a 3’ end in which as discussed previously and above, Braig teaches that the cell free DNA was amplified with primers (primers must attach to a 5’ end and a 3’ end encompassing a breakpoint sequence comprising a 5’ end and a 3’ end) (pg. 1152 column 1 paragraph 1 lines 1-5) therefore comprising a 5’ end and a 3’ end of a nucleic acid molecule derived from cell-free biological sample.
The response also asserts that claims 4, 5, 12-14, and 17 are also not obvious over Braig in view Rabinowitz at least because they depend from claim 2 and recite additional elements of particular advantage and utility. This argument was thoroughly reviewed but was not found persuasive for the reasons set forth above.
Further, the response asserts that claims 7-11, 19, 21, 23, 25, and 31 are not obvious over the cited references, of Dean, Edelman, Gong, Sanchez, Yi Shen, Harris, and Lanman, because they depend from claim 2 and recite additional elements of particular advantage and utility. In addition, the response asserts Braig and Rabinowitz do not teach all of the elements of claim 2, much less the combination of the elements of claim 7-11, 19, 21, 23, 25, and 31, and the additional references do not cure the above-mentioned deficiencies of Braig and Rabinowitz. These arguments were thoroughly reviewed but were not found persuasive for the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 2, 4, 5, 7-14, 17, 19, 21, 23, 25, & 31 are 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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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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