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 1, 3, 6, 7, 22-24, 28, 31, 32, 34, 46, 48, 49, 51, 53-55, 144, & 145 filed on 12/11/2025 are pending. Claims 10, 37, 57, 60, & 61 are withdrawn from consideration as being drawn to a non-elected invention. Claims 3, 6, 7, 10, 31, 34, & 37 are currently under examination directed to the elected species of at least 10 cancers of sarcoma, myeloid neoplasm, prostate cancer, breast cancer, uterine cancer, ovarian cancer, bladder and urothelial cancer, cervical cancer, liver and bile duct cancer, and pancreas and gallbladder cancer in claim 3 and of List 6 (including all of SEQ ID NOs: 277796 to 330645) in claims 6, 7, 10, 31, 34, & 37 (see response dated 05/08/2025). 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Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.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 § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 6, 7, 22-24, 28, 31, 32, 34, 46, 48, 49, 51, 53-55, 144, & 145 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding newly amended claims 1 & 31, claims 1 & 31 have been amended to recite the limitation “and is immobilized to a solid support”. The specification of the instant application has been thoroughly reviewed but support for this newly added limitation was not found. While there is no in haec verba requirement, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure. In the instant situation, this limitation of “each bait oligonucleotide … is immobilized to a solid support” is not expressly recited in the specification of the instant application. Additionally, there also does not appear to be implicit or inherent support for this limitation of immobilization of bait oligonucleotides to a broad solid support as currently amended. The specification of the instant application, at paragraph [0151], discloses that for example a biotin moiety can be added to the 5’-end to create a biotinylated probe to facilitate isolation of target nucleic acids hybridized to probes using a streptavidin-coated surface (e.g., streptavidin-coated beads), however this is a specific species of an oligonucleotide immobilized on a solid surface and is not representative of the broad species of being immobilized to a solid support. Since the response does not explain how the how the newly added limitations are implicitly or inherently disclosed, the claims are rejected under 35 USC 112(a). In response, applicant may cancel the new matter, or provide explanations as to where the limitations find express, implicit, or inherent support.
Claims 3, 6, 7, 22-24, 28, 48, 49, 51, 53-55, 144, & 145 are rejected due to their dependence on claim 1 and claims 32, 34, & 46 are rejected due to their dependence on claim 31.
Claim Rejections - 35 USC § 101
Claims 1, 3, 6, 7, 22-24, 28, 31, 32, 34, 46, 48, 49, 51, 53-55, 144, & 145 are rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without significantly more. This judicial exception is not integrated into a practical application and the claims 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, part II.
The unpatentability of natural products was confirmed by the U.S. Supreme Court in Association for Molecular Pathology v. Myriad Genetics, Inc., , 133 S. Ct. 2107, 2116, (2013).
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 claims were 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 claims were 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)]. In the absence of a step(s) or element(s) that integrate the JE into a practical application, the additional elements/steps have been considered to determine whether they add significantly more to the JE (STEP 2B) [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)]. It was found that the present claims fail to meet the elements required for patent eligibility.
The claims are directed to bait oligonucleotides (nucleic acid sequences), and as such are directed to products. Accordingly, the claims are directed to one of the four statutory categories of invention.
The claims are drawn to bait oligonucleotides (nucleic acid sequences) including DNA, which hybridize to at least 200 target genomic regions where are naturally occurring sequences. As such the claims are directed to a product of nature which is a judicial exception.
This judicial exception is not integrated into a practical application because the nucleic acid molecules encompassed by the claims convey the same genetic information as their naturally occurring counterparts. The Supreme Court has made clear "separating [DNA] from surrounding genetic material is not an act of invention" Myriad, 133 S. Ct. at 2117. In Myriad v. Ambry CAFC 2014-1361,1366, December 17, 2014, the CAFC further (regarding a claim directed to a pair of primers) stated “In fact, the naturally occurring genetic sequences at issue here do not perform a significantly new function. Rather, the naturally occurring material is used to form the first step in a chain reaction—a function that is performed because the primer maintains the exact same nucleotide sequence as the relevant portion of the naturally occurring sequence. One of the primary functions of DNA’s structure in nature is that complementary nucleotide sequences bind to each other. It is this same function that is exploited here—the primer binds to its complementary nucleotide sequence. Thus, just as in nature, primers utilize the innate ability of DNA to bind to itself.”
The detection agents encompassed by the claims include bait oligonucleotides (nucleic acid sequences) that hybridize to, as well as fragments of naturally occurring target genomic regions. None of these molecules or cells are patent eligible, whether isolated or not, pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics Inc., US (June 13, 2013). Accordingly, the claims are rejected as being directed to non patentable subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that claims 1 and 31 are amended to recite that the oligonucleotides are “immobilized to a solid support” and oligonucleotides are not naturally immobilized to a support and as such oligonucleotides according to claims 1 and 31 are not natural products and neither are the compositions according to claims depending therefrom. This argument has been thoroughly reviewed but was not found persuasive as broadly being immobilized to a solid support does not require physical attachment of the bait oligonucleotides to a solid support and, therefore, the amendment of “immobilized to a solid support” does not do anything to structurally change the product of nature of bait oligonucleotides of the amended claims and instead is focused on linking the judicial exception to the same technological environment with no specificity. If amended claims 1 and 31 recited a probe that was biotinylated and attached to a bead then this would be persuasive in providing a specific structurally altered product.
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) 1, 3, 6, 7, 22-24, 28, 31, 32, 34, 46, 48, 49, 51, 53, 54, 144, & 145 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toung (U.S. Patent Application Publication No. US 2017/0175205 A1), as cited on the IDS dated 04/20/2022, in view of Mortimer (WO 2017/181146 A1), as cited on the IDS dated 04/20/2022.
Regarding newly amended claim 1 & claim 22, Toung teaches a method for identifying cancers based on methylation data covering a plurality of sites from genomic DNA (target genomic regions) using trained classifier in which the classifier is trained and distinguishes over 10 types of cancer (at least one target genomic region that is differentially methylated between pairs of cancer types in a set comprising at least 10 cancer types) (paragraph [0010] lines 1-16; paragraph [0024] lines 1-4; Figure 8) and in which a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I in 20 major cancer types (at least 10 cancer types) as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I). The vast number of methylation sites (target genomic regions) listed in Table I are sufficient for covering at least 200 target genomic regions (target capture probes (bait oligonucleotides) hybridize to at least 200 target genomic regions) (Table I). Toung also teaches that the methylation of genomic CpG positions can be detected using an array of probes (bait oligonucleotides) attached to a substrate (bait oligonucleotides is immobilized to a solid support) (paragraph [0073] lubes 1-5). Finally, Toung teaches the target capture probes (bait oligonucleotides) are designed to target sequences (target genomic regions) with greater than 4 CpG sites (each target genomic region comprises a plurality of CpG sites) (paragraph [0158] lines 4-5).
Toung does not teach that the target capture probes (bait oligonucleotides) are at least 45 nucleotides in length.
Mortimer teaches a method for early cancer detection through capturing (baiting) cell-free DNA (cfDNA) molecules from one or more regions from a sample to detect differentially methylated regions (paragraph [0005] lines 1-9; paragraph [0013] lines 1-2). Mortimer also teaches that capturing (baiting) sequences encompasses the use of oligonucleotide probes (bait oligonucleotides) that are about 60 to 120 bases long (at least 45 nucleotides in length) that hybridize to the sequence of interest (target genomic region) (paragraph [0152] lines 1-4). Finally, Mortimer teaches that the effectiveness of sequence capture of a sequence of interest (target genomic region) depends on, in part, the length of the sequence in the target molecule (target genomic region) that is complementary to the sequence of the probe (bait oligonucleotide) (paragraph [0152] lines 5-7).
Toung and Mortimer are considered to be analogous to the claimed invention because they are all in the same field of detection of cancer through determining differential methylation in target genomic regions using capture (bait) oligonucleotides. 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 target capture probes (bait oligonucleotides) in Toung to incorporate the size requirement of 60 to 120 nucleotides for the oligonucleotide probes (bait oligonucleotides) as taught in Mortimer because Mortimer teaches that doing so would provide an effective length bait oligonucleotide for capturing target genomic regions.
Regarding newly amended claim 3, Toung teaches the cancer are bladder cancer, breast cancer, cervical cancer, liver cancer, pancreatic cancer, prostate cancer, sarcoma, uterine cancer, lung cancer, and thyroid cancer (paragraph [0029] lines 1-10; Figure 8).
Regarding newly amended claim 6, it is noted that the broadly encompasses a plurality of different bait oligonucleotides that hybridize to at least 200 genomic regions from the elected List 6 (including all of SEQ ID NOs: 277796 to 330645). The specification teaches that samples used for genomic region selection include The Cancer Genome Atlas (TCGA) data which was collected by hybridization of bisulfite-converted DNA fragments from 8809 sample to methylation-sensitive oligonucleotide arrays (pg. 83 of the instant specification). Therefore, for the purposes of this rejection, it is interpreted that the at least 200 target genomic regions are selected from TCGA data.
Toung teaches a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I (at least 200 target genomic regions are selected from List 6) in 20 major cancer types as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I).
Regarding newly amended claim 7, it is noted that the broadly encompasses a plurality of different bait oligonucleotides that hybridize to at least 200 genomic regions from the elected List 6 (including all of SEQ ID NOs: 277796 to 330645). The specification teaches that samples used for genomic region selection include The Cancer Genome Atlas (TCGA) data which was collected by hybridization of bisulfite-converted DNA fragments from 8809 sample to methylation-sensitive oligonucleotide arrays (pg. 83 of the instant specification). Therefore, for the purposes of this rejection, it is interpreted that the at least 200 target genomic regions are selected from TCGA data.
Toung teaches a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I (at least 200 target genomic regions comprise at least 500 target genomic regions in List 6) in 20 major cancer types as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I).
Regarding claim 23, Mortimer teaches that capturing (baiting) sequences encompasses the use of oligonucleotide probes (bait oligonucleotides) that are about 60 to 120 bases long that hybridize to the sequence of interest (target genomic region) (bait oligonucleotides hybridize to at least 45 nucleotides of a target genomic region) (paragraph [0152] lines 1-4).
Regarding claim 24, Toung teaches the cfDNA is converted with bisulfite (converted cfDNA fragments) (paragraph [0161] lines 1-4).
Regarding claim 28, Mortimer teaches that capturing (baiting) sequences encompasses the use of oligonucleotide probes (bait oligonucleotides) that are about 60 to 120 bases long (each bait oligonucleotide is between 50 and 300 bases in length) that hybridize to the sequence of interest (target genomic region) (paragraph [0152] lines 1-4).
Regarding newly amended claim 31, it is noted that the broadly encompasses a plurality of different bait oligonucleotides that hybridize to at least 100 genomic regions from the elected List 6 (including all of SEQ ID NOs: 277796 to 330645). The specification teaches that samples used for genomic region selection include The Cancer Genome Atlas (TCGA) data which was collected by hybridization of bisulfite-converted DNA fragments from 8809 sample to methylation-sensitive oligonucleotide arrays (pg. 83 of the instant specification). Therefore, for the purposes of this rejection, it is interpreted that the at least 100 target genomic regions are selected from TCGA data.
Toung teaches a method for identifying cancers based on methylation data covering a plurality of sites from genomic DNA (target genomic regions) using trained classifier in which the classifier is trained and distinguishes over 10 types of cancer (at least one target genomic region that is differentially methylated between pairs of cancer types in a set comprising at least 10 cancer types) (paragraph [0010] lines 1-16; paragraph [0024] lines 1-4; Figure 8) and in which a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I (at least 100 target genomic regions selected from List 6) in 20 major cancer types (at least 10 cancer types) as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I). The vast number of methylation sites (target genomic regions) listed in Table I are sufficient for covering at least 100 target genomic regions (target capture probes (bait oligonucleotides) hybridize to at least 100 target genomic regions) (Table I). Toung also teaches that the methylation of genomic CpG positions can be detected using an array of probes (bait oligonucleotides) attached to a substrate (bait oligonucleotides is immobilized to a solid support) (paragraph [0073] lubes 1-5). Finally, Toung teaches the target capture probes (bait oligonucleotides) are designed to target sequences (target genomic regions) with greater than 4 CpG sites (each target genomic region comprises a plurality of CpG sites) (paragraph [0158] lines 4-5).
Toung does not teach that the target capture probes (bait oligonucleotides) are at least 45 nucleotides in length.
Mortimer teaches a method for early cancer detection through capturing (baiting) cell-free DNA (cfDNA) molecules from one or more regions from a sample to detect differentially methylated regions (paragraph [0005] lines 1-9; paragraph [0013] lines 1-2). Mortimer also teaches that capturing (baiting) sequences encompasses the use of oligonucleotide probes (bait oligonucleotides) that are about 60 to 120 bases long (at least 45 nucleotides in length) that hybridize to the sequence of interest (target genomic region) (paragraph [0152] lines 1-4). Finally, Mortimer teaches that the effectiveness of sequence capture of a sequence of interest (target genomic region) depends on, in part, the length of the sequence in the target molecule (target genomic region) that is complementary to the sequence of the probe (bait oligonucleotide) (paragraph [0152] lines 5-7).
Toung and Mortimer are considered to be analogous to the claimed invention because they are all in the same field of detection of cancer through determining differential methylation in target genomic regions using capture (bait) oligonucleotides. 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 target capture probes (bait oligonucleotides) in Toung to incorporate the size requirement of 60 to 120 nucleotides for the oligonucleotide probes (bait oligonucleotides) as taught in Mortimer because Mortimer teaches that doing so would provide an effective length bait oligonucleotide for capturing target genomic regions.
Regarding claim 32, Toung teaches a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I in 20 major cancer types (at least 10 cancer types) as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I). The vast number of methylation sites (target genomic regions) listed in Table I are sufficient for covering at least 200 target genomic regions (the at least 100 target genomic regions comprises at least 200 target genomic regions) (Table I).
Regarding newly amended claim 34, it is noted that the broadly encompasses a plurality of different bait oligonucleotides that hybridize to at least 100 genomic regions from the elected List 6 (including all of SEQ ID NOs: 277796 to 330645). The specification teaches that samples used for genomic region selection include The Cancer Genome Atlas (TCGA) data which was collected by hybridization of bisulfite-converted DNA fragments from 8809 sample to methylation-sensitive oligonucleotide arrays (pg. 83 of the instant specification). Therefore, for the purposes of this rejection, it is interpreted that the at least 100 target genomic regions are selected from TCGA data.
Toung teaches a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I (at least 100 target genomic regions comprise at least 500 target genomic regions in List 6) in 20 major cancer types as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I).
Regarding claim 46, Toung teaches the cfDNA is converted with bisulfite (converted cfDNA fragments) (paragraph [0161] lines 1-4).
Regarding claim 48, Toung teaches the cfDNA was extracted from plasma samples from humans (cfDNA fragments from a subject) (paragraph [0159] lines 1-4).
Regarding newly amended claim 49, Toung teaches the cfDNA is converted with bisulfite (converted cfDNA fragments) (paragraph [0161] lines 1-4).
Regarding claim 51, Toung teaches the target capture probes (bait oligonucleotides) are designed to target sequences (target genomic regions) with greater than 4 CpG sites (each target genomic region comprises at least 5 CpG dinucleotides) (paragraph [0158] lines 4-5).
Regarding newly amended claim 53, Toung teaches the target capture probes (bait oligonucleotides) are designed in a set of 2 probes (bait oligonucleotides) (sets of two or more bait oligonucleotides) that target a genomic regions that includes a completely methylated probe (bait oligonucleotide) and a completely unmethylated probe (bait oligonucleotide) (each bait oligonucleotide is configured to bind to converted DNA molecules from the same target genomic region with different methylation statuses) (paragraph [0158] lines 4-10).
Regarding newly amended claim 54, it is noted that the instant specification teaches that the term “hypomethylated” or “hypermethylated” refers to a methylation status of a DNA molecule containing multiple CpG sites where a high percentage (e.g., any other percentage within the range of 50%-100%) are unmethylated or methylated, respectively.
Toung the target capture probes (bait oligonucleotides) are designed in a set of 2 probes (bait oligonucleotides) (ratio of 0.5) for targets having greater than 4 CpG sites (target genomic region) that includes a completely methylated probe (bait oligonucleotide) that has G nucleotides that complement the C position of each CpG site (hybridize to hypomethylated target regions where 100% of the CpG sites are unmethylated) and a completely unmethylated probe (bait oligonucleotide) that has an A nucleotides that complements the U as expected to result from bisulfite conversion of each of the C positions of a CpG site (hybridize to hypermethylated target regions where 100% of the CpG sites are methylated) (paragraph [0158] lines 4-10).
Regarding newly amended claim 144, Toung teaches the target capture probes (bait oligonucleotides) are designed in a set of 2 probes (bait oligonucleotides) (sets of two or more bait oligonucleotides) that target a genomic regions that includes a completely methylated probe (bait oligonucleotide) and a completely unmethylated probe (bait oligonucleotide) in which the completely unmethylated probe (bait oligonucleotide) has an A nucleotide that complements the U that is expected to result from bisulfite conversion of each of the C positions of a CpG site (at least 3% of the different bait oligonucleotides comprise no G) (paragraph [0158] lines 4-10).
Regarding claim 145, Toung teaches the target capture probes (bait oligonucleotides) are designed to target sequences (target genomic regions) from cfDNA with greater than 4 CpG sites (binding sites comprise exclusively CpG) (paragraph [0158] lines 4-5; paragraph [0159] lines 1-2).
Claim(s) 55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toung (U.S. Patent Application Publication No. US 2017/0175205 A1), as cited on the IDS dated 04/20/2022, and Mortimer (WO 2017/181146 A1), as cited on the IDS dated 04/20/2022, further in view of Hodges (Hodges et al.; Genomic Research, Vol. 19, pages 1593-1605, July 2009).
The teachings of Toung and Mortimer with respect to claims 1 & 54 are discussed above.
Regarding claim 55, Toung teaches the target capture probes (bait oligonucleotides) are designed in a set of 2 probes (bait oligonucleotides) (comprises one or more pairs of bait oligonucleotides comprising a first bait oligonucleotide and a second bait oligonucleotide) that target a genomic regions (paragraph [0158] lines 4-10).
Toung and Mortimer does not teach that each bait oligonucleotide comprises a 5’ end and a 3’ end, a sequence of at least X nucleotide bases at the 3’ end of the first bait oligonucleotide is identical to a sequence of X nucleotide bases at the 5’ end of the second bait oligonucleotide, and that X is at least 20, at least 25, or at least 30 bases long.
Hodges teaches a method of detecting CpG islands in the human genome for detection of aberrant DNA methylation with an array where two sets of capture probes (bait oligonucleotides) were designed and the capture probes (bait oligonucleotides) were 60 nucleotides in length that were tiled every six bases (each capture probe (bait oligonucleotide) has a 54-base pair overlap (sequence X is identical and at least 30 nucleotide bases)) across the target intervals (target genomic regions) (pg. 1595 column 2 1st full paragraph lines 1-11; pg. 1595 column 2 3rd full paragraph lines 1-3 & 17-21). In addition, Hodges teaches that this 60 nucleotide probe (bait oligonucleotide) tiling every six bases design allows for efficient capture of the target region (pg. 1595 column 2 3rd full paragraph lines 17-21).
Toung, Mortimer, and Hodges are considered to be analogous to the claimed invention because they are all in the same field of determining differential methylation in target genomic regions using capture (bait) oligonucleotides. 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 method of designing a set of 2 probes (bait oligonucleotides) in Toung to incorporate the probe (bait oligonucleotide) design of 60 nucleotides tiling every six bases as taught in Hodges because Hodges teaches that doing so would provide a probe (bait oligonucleotide) design that efficiently captures the target genomic region.
Response to Arguments
The response traverses the rejection. The response asserts that none of the cited references disclose or reasonably suggest at least the combination of elements of bait oligonucleotides that collectively hybridize to at least 200 genomic targets which are differentially methylated in at least one cancer type to a different cancer type or relative to non-cancer and that the at least 200 target genomic regions comprise, for at least 80% of all possible pairs of cancer types selected from a set comprising at least 10 cancer types, at least one target genomic region that is differentially methylated between the pair of cancer types. Further, the response asserts that with respect to claim 1, the Office does not explain how an ability to classify different types of cancer amounts to a disclosure that individual target genomic regions are differentially methylated as between 80% of all possible pairs of cancer types selected from a set comprising at least 10 cancer types in Toung and that Mortimer does not provide the missing teaching in this regard. Further, the response asserts that claim 1 is amended to further specify that “each target genomic region of the at least 200 target genomic regions comprises a plurality of CpG sites” in which this element is also missing from the cited references. Specifically, the response asserts that although Toung postulates the design of probes that may include multiple CpGs, this is not a requirement of any number of target sequences, much less 200 of them and moreover the methylated target sites identified in Toung are individual CpGs. Further, the response asserts that Mortimer fails to provide the missing teaching as Mortimer does not identify any particular target genomic regions differentially methylated in at least 10 cancer types. These arguments have been thoroughly reviewed but were not found persuasive. First, Toung teaches a method for identifying cancers based on methylation data covering a plurality of sites from genomic DNA (target genomic regions) using trained classifier in which the classifier is trained and distinguishes over 10 types of cancer (at least one target genomic region that is differentially methylated between pairs of cancer types in a set comprising at least 10 cancer types) (paragraph [0010] lines 1-16; paragraph [0024] lines 1-4; Figure 8) and in which a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I in 20 major cancer types (at least 10 cancer types) as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I). The vast number of methylation sites (target genomic regions) listed in Table I are sufficient for covering at least 200 target genomic regions (target capture probes (bait oligonucleotides) hybridize to at least 200 target genomic regions) (Table I). Toung also teaches the target capture probes (bait oligonucleotides) are designed to target sequences (target genomic regions) with greater than 4 CpG sites from the target 9,921 CpG sites (each target genomic region comprises a plurality of CpG sites) (paragraph [0158] lines 4-5). Therefore, Toung teaches does teach the limitation in claims 1 and 31, as currently amended, of bait oligonucleotide probes that targets in a target genomic region a plurality of CpG sites. Second, as discussed above and previously, Toung teaches a method for identifying cancers based on methylation data covering a plurality of sites from genomic DNA (target genomic regions) using trained classifier in which the classifier is trained and distinguishes over 10 types of cancer (at least one target genomic region that is differentially methylated between pairs of cancer types in a set comprising at least 10 cancer types) in which Figure 5 of Toung further teaches methylation scores (differential methylation) between different types of cancer and normal sample and methylation levels of up to 100% in comparison to paired cancer and normal tissue samples (Fig. 5). Therefore, Toung teaches the limitation of comprising at least 200 genomic targets which are differentially methylated in at least one cancer type to a different cancer type or relative to non-cancer and that the at least 200 target genomic regions comprise, for at least 80% of all possible pairs of cancer types selected from a set comprising at least 10 cancer types, at least one target genomic region that is differentially methylated between the pair of cancer types as recited in currently amended claims 1 and 31.
The response also asserts that the Office does not identify any target genomic regions from among Lists 1-16 as actually being disclosed in either Toung or Mortimer and that it is not clear that the TCGA data mentioned in Toung was completely coextensive with the TCGA information referred to in the present application, or that the information was being processed with the same parameters and as such it cannot be assumed that Toung identified any of the Target genomic regions in Lists 1-16. These arguments have been thoroughly reviewed but were not found persuasive. First, it is noted that the broadly encompasses a plurality of different bait oligonucleotides that hybridize to at least 100 genomic regions from the elected List 6 (including all of SEQ ID NOs: 277796 to 330645). The specification teaches that samples used for genomic region selection include The Cancer Genome Atlas (TCGA) data which was collected by hybridization of bisulfite-converted DNA fragments from 8809 sample to methylation-sensitive oligonucleotide arrays (pg. 83 of the instant specification). Therefore, the claim is given its broadest reasonable interpretation to comprise that the at least 100 target genomic regions are selected from TCGA data. Further, Toung teaches a method for identifying cancers based on methylation data covering a plurality of sites from genomic DNA (target genomic regions) using trained classifier in which the classifier is trained and distinguishes over 10 types of cancer (paragraph [0010] lines 1-16; paragraph [0024] lines 1-4; Figure 8) and in which a pan-cancer panel of a plurality of different target capture probes (bait oligonucleotides) are designed to target 9,921 CpG sites listed in Table I (at least 100 target genomic regions selected from List 6) in 20 major cancer types as selected from The Cancer Genome Atlas Database (TCGA) (paragraph [0157] lines 1-8; paragraph [0158] lines 1-13; Figure 1; Table I). Further, it is noted as discussed previously and above that the vast number of methylation sites (target genomic regions) listed in Table I are sufficient for covering at least 100 target genomic regions (target capture probes (bait oligonucleotides) hybridize to at least 100 target genomic regions) (Table I).
The response also asserts that claim 55 ultimately depends from claim 1 and as explained above claim 1 is unobvious over Toung and Mortimer and Hodges fails to provide the missing teaching. This argument has been thoroughly reviewed but was 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.
Double Patenting
Claims 1, 33, 51, 55, 144, & 145, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 136, & 164 of copending Application No. 17/393,625 (reference application).
Regarding claim 1, copending Application No. 17/393,625 claims a composition of a plurality of different bait oligonucleotides wherein each bait oligonucleotide is at least 45 nucleotides in length, the plurality of different bait oligonucleotides comprises a different set of bait oligonucleotides for each of at least 10 cancer types, and each set of bait oligonucleotides collectively hybridize to DNA molecules derived from at least 100 target genomic regions that are differentially methylated in the respective cancer types relative to a different cancer type or relative to non-cancer (see claim 1).
Regarding claim 33, copending Application No. 17/393,625 claims each bait oligonucleotide is less than 300 nucleotides in length (see claim 164).
Regarding claim 51, copending Application No. 17/393,625 claims each target genomic region comprises at least 5 methylation (CpG) sites (see claim 164).
Regarding claim 55, copending Application No. 17/393,625 claims that each set of bait oligonucleotides comprises pairs of bait oligonucleotides, each pair of oligonucleotides comprises a first bait and second bait oligonucleotide, each bait oligonucleotide has a 5’ end and a 3’ end with a sequence of at least X nucleotide bases at the 3’ end and is identical to a sequence of X nucleotide bases at the 5’ end wherein X is at least 25 or 30 bases (see claim 136).
Regarding claim 144, copending Application No. 17/393,625 claims at least 3% of the bait oligonucleotides comprise no guanines (G) (see claim 164).
Regarding claim 145, copending Application No. 17/393,625 claims each bait oligo nucleotide comprises multiple binding sites to methylation sites of converted cfDNA molecules, wherein at least 83% of the multiple binding sites comprise exclusively either CpG or CpA (see claim 164).
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The response traverses the rejection and requests that it be held in abeyance until an otherwise allowable set of claims has been identified. The response asserts that in the event that this provisional double patenting rejection is the only outstanding rejection , that applicant directs the Office’s attention to MPEP §804(I)(B)(1)(b)(i) which provides the examiner should withdraw the rejection in the application having the earlier patent term filing date. This argument has been thoroughly reviewed but was not found persuasive as claims 1, 3, 6, 7, 22-24, 28, 31, 32, 34, 46, 48, 49, 51, 53-55, 144, & 145 have 112(a), 101, or 103 rejections that have been maintained and applied to the newly amended claims. Therefore, as there are other rejections remaining in the instant application MPEP §804(I)(B)(1)(b)(i) does not apply.
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 1, 3, 6, 7, 22-24, 28, 31, 32, 34, 46, 48, 49, 51, 53-55, 144, & 145 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682