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 .
Election/Restrictions
Claims 109-128 are still pending and herein discussed on their merits.
Priority
It is acknowledged that the instant application is a continuation of international PCT Application PCT/US2022/034382, filed June 21, 2022, and that it claims benefit of provisional application 63/213,050, filed June 21, 2021. The effective filing date is considered to be June 21, 2021.
Information Disclosure Statement
Information disclosure statements from 1/08/25 have been received. One IDS entry from 1/08/25 (4 pg. document) and one IDS entry from 1/08/25 (14 pg. document) have been crossed out and not considered, as they are missing years/dates.
Claim Objections
Claim 110 is objected to because of the following informalities: typographical error/duplication.
In claim 110, the phrase “wherein the wherein the agent…” should be replaced with “wherein the agent...” Appropriate correction is required.
Claim 114 is objected to because of the following informalities: improper grammar.
In claim 114, the phrase “to colon” should be replaced with “to the colon.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 109-128 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 109-128 are rejected because it is unclear whether the term “fragments” recited in claim 109 and claim 114 is meant to include fragments endogenous to the sample, fragments resulting from the contacting of the sample with restriction enzyme(s), both, or something else. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 113 is rejected over the recitation of the phrase “aberrantly high,” which is a relative term. “Aberrantly high” is not defined by the claim, and while the specification provides examples of types of aberrantly high copy numbers, such as duplications or focal amplifications, a complete definition is not provided. It is unclear whether these copy numbers are high relative to healthy tissue from the same individual, or an exogenous reference of some kind. Furthermore, it is unclear if the claims which recite “aberrantly high” includes all copy number variants constituting at least a duplication relative to normal tissue in the same individual, whether every potential site is subject to the same criteria for determining “aberrantly high” copy numbers, or if any other criteria must be satisfied to be considered congruent with the limitation, and a person with ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 109-124 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kennedy et al. (effectively filed January 31, 2019; Patent Publication No. US 20200248272).
Kennedy teaches methods for sequencing captured cfDNA.
Regarding claim 109, Kennedy teaches a method of analyzing DNA in a blood sample comprising partitioning the DNA into a at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, wherein the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (par. 18, 297). Kennedy teaches contacting the DNA in at least one of the subsamples with at least one methylation-sensitive restriction enzyme (MSRE) (par. 329). Kennedy teaches contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set (par. 11), wherein the epigenetic target region set comprises a plurality of type-specific epigenetic target regions that are copy number variants (par. 266), and wherein the type-specific epigenetic target regions are type-specific differentially methylated regions (par. 243, 251). Kennedy also teaches sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (par. 314).
Regarding claim 110, Kennedy teaches a methyl binding reagent (par. 18).
Regarding claims 111-112, Kennedy teaches target regions which are type-specific hyper- and/or hypo- methylated regions (par. 88-89, 420, 462).
Regarding claim 113, Kennedy teaches epigenetic target regions comprising copy number variants (par. 81).
Regarding claim 114, Kennedy teaches type-specific epigenetic target regions specific to the colon (par. 249, 251).
Regarding claim 115, Kennedy teaches determining the methylation levels of the type-specific differentially methylated target regions (par. 314).
Regarding claim 116, Kennedy teaches an epigenetic target region set comprising CTCF binding sites and/or transcription start sites (par. 426, 428)
Regarding claim 117, Kennedy teaches capturing sequence- variable target regions of the DNA, comprising contacting the DNA with a plurality of target- specific probes specific for the sequence-variable target regions (par. 434).
Regarding claims 118-119, Kennedy teaches ligating adapters to the DNA, thereby producing adapter-ligated DNA, wherein the adapters comprise molecular barcodes (par. 15).
Regarding claim 120, Kennedy teaches subsamples pooled prior to the sequencing (par. 79).
Regarding claim 121, Kennedy teaches the DNA as cfDNA (par. 10).
Regarding claim 122, Kennedy teaches sequencing comprising a) generating a plurality of sequencing reads, b) mapping the sequence reads to one or more reference sequences, and c) processing the mapped sequence reads to determine the likelihood that the subject has cancer or precancer (par. 13).
Regarding claim 123, Kennedy teaches the sample being obtained from a subject who was previously diagnosed with a cancer and received one or more previous cancer treatments (par. 474).
Regarding claim 124, Kennedy teaches contacting the first subsample with a methylation-sensitive endonuclease (par. 329).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 125-128 are rejected under 35 U.S.C. 103 over Kennedy et al. (effectively filed January 31, 2019; Patent Publication No. US 20200248272), as applied to claims 109 and 124 above, in view of Dorsey et al. (WO 2019/144057 A1).
Kennedy discloses the limitations of claims 109 and 124 as discussed above.
Kennedy does not teach any methylation-sensitive endonuclease which cleaves at an unmethylated CpG sequence. Kennedy also does not teach any methylation-dependent endonuclease which cleaves at a methylated CpG sequence.
Dorsey teaches methods of measuring methylation levels which differ between cancerous and non-cancerous tissues (Abstract).
Regarding claims 125-126, Dorsey teaches methylation-sensitive endonucleases which cleave at unmethylated sequences, such as HpaII, HhaI, BstUI, and AciI (par. 108).
Regarding claims 127-128, Dorsey teaches a methylation-dependent endonuclease McrBC (par. 108).
Although Dorsey does not explicitly state that these sequences are CpG sequences, Dorsey does discuss measuring methylation levels at CpG sites (par. 77) and recites methods of using endonucleases generally to cleave fragments of CpG site DNA (par. 101). Given that there are a finite number of solutions (i.e. the differentially methylated sites of interest either are or are not within CpG sequences), and there is no evidence of unexpected results, it would have been obvious to a person with ordinary skill in the art to try targeting CpG sequences, in order to observe changes in methylation which may be early signs of neoplastic progression of precancerous lesions (par. 12). This would be desirable for early cancer diagnosis (par. 12).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the invention, to combine the teachings of Kennedy and Dorsey, in order to utilize enzymes suitable to screen for altered methylation patterns (Dorsey, par. 109).
Claims 109-126 are rejected under 35 U.S.C. 103 as unpatentable over Kennedy et al. (published April 30, 2020; Patent Publication No. US 2020/0131566), in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)).
Kennedy teaches methods of evaluating partitioning methods used in the sequencing cfDNA, in the context of determining epigenetic state (Abstract).
Regarding claim 109, Kennedy teaches a method of analyzing DNA in a blood sample comprising partitioning the DNA into a at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, wherein the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (par. 83). Kennedy teaches contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set (par. 246, 301). Kennedy also teaches sequencing the captured DNA and determining levels of epigenetic modification (par. 199).
Kennedy does not teach the use of methylation-sensitive or methylation-dependent restriction endonuclease.
Yuan recites a method of profiling DNA methylation and sequence variation in cancer patients (Abstract).
Yuan teaches the use of methylation-sensitive restriction enzymes (pg. 3445, col. 1, 1st par.).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kennedy and Yuan, in order to adapt existing technology to simultaneously detect methylation and copy number changes (Yuan: pg. 2445, col. 1).
Regarding claims 109, 111-113, and 117, Kennedy does not teach capturing a subset of DNA with probes specific to sets of type-specific epigenetic target regions nor sequence variable target regions, copy number variant regions, nor differentially methylated regions (hypo and/or hyper). However, Kennedy does teach enriching the partitioned sample for polynucleotides belonging to regions of interest (par. 246, 301), identification of cancer specific variants including colon cancer (par. 292), and the use of sequencing for identifying variant sequences (par. 259).
Yuan teaches capturing a subset of DNA with probes specific to sets of epigenetic target regions and sequence variable target regions that are specific to copy number variants and differentially methylated regions, including hypo and/or hyper-methylated regions (pg. 3443, col. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kennedy and Yuan in order to conduct methylation analysis simultaneously with copy number analysis (pg. 3443, col. 2, final par.).
Regarding claim 110, Kennedy teaches a methyl binding reagent for partitioning (par. 129).
Regarding claim 114, Kennedy does not explicitly teach target regions that are specific to colon tissue. However, Kennedy does teach enriching the partitioned sample for polynucleotides belonging to regions of interest (par. 246, 301) and/or using their own method to evaluate colon-specific disease (par. 292), and Yuan suggests targeting regions which are differentially methylated in different tissues (pg. 3451, col. 1, par. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to try targeting colon tissue vs other types of tissue, in order to identify customized or targeted therapies to treat colon cancer (Kennedy: par. 292).
Regarding claim 115, Kennedy teaches determining methylation levels of nucleic acids within a sample (par. 199).
Regarding claim 116, Kennedy teaches target regions specific to CTCF binding sites and/or transcription start sites (par. 114)
Regarding claims 118-119, Kennedy teaches ligating adapters to the DNA, thereby producing adapter-ligated DNA, wherein the adapters comprise molecular barcodes (par. 234).
Regarding claim 120, Kennedy teaches subsamples pooled prior to the sequencing (par. 304).
Regarding claim 121, Kennedy teaches the DNA as cfDNA (par. 226).
Regarding claim 122, Kennedy teaches sequencing comprising a) generating a plurality of sequencing reads (par. 253), b) mapping the sequence reads to one or more reference sequences, and c) processing the mapped sequence reads to determine the likelihood that the subject has cancer or precancer (par. 259).
Regarding claim 123, Kennedy teaches the sample being obtained from a subject who was previously diagnosed with a cancer and received one or more previous cancer treatments (par. 106).
Regarding claims 124-126, Kennedy does not teach methylation-sensitive restriction endonucleases which cleave at unmethylated CpG sequences.
Yuan teaches the use of methylation-sensitive restriction enzymes which cleave at unmethylated CpG sequences, including HpaII (pg. 3445, col. 1, 1st par.).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kennedy and Yuan, in order to conduct methylation analysis simultaneously with copy number analysis (pg. 3443, col. 2, final par.).
Claims 127-128 are rejected under 35 U.S.C. 103 as unpatentable over Kennedy et al. (published April 30, 2020; Patent Publication No. US 2020/0131566) and Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)) as applied to claim 109 above, and further in view of Dorsey et al. (WO 2019/144057 A1).
Kennedy and Yuan teach the limitations of claim 109, as discussed above.
Regarding claim 127-128, the combination of Kennedy and Yuan does not teach the use of any methylation-dependent endonuclease.
Dorsey recites methods of measuring methylation levels which differ between cancerous and non-cancerous tissues (Abstract).
Regarding claims 127-128, Dorsey teaches methylation-dependent endonucleases which cleave a methylated CpG sequence, such as McrBC (par. 108).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kennedy, Yuan, and Dorsey, in order to cut DNA at distinct sites (Dorsey, par. 108).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 109-128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of Patent No. 11,643,693, in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing nucleic acids (ref claim 1). Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, wherein the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (claim 1, 12)
contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set, comprised of target regions that are differentially methylated regions or fragments (claim 1, 7)
sequencing the captured DNA (claim 1)
Although the reference application does not claim a step of using a methylation-sensitive or dependent restriction enzyme, the claims are directed toward profiling of methylation state in DNA, and an obvious embodiment would be the use of methylation-sensitive restriction enzymes (see Yuan, pg. 3445, col 1).
Although the reference application does not explicitly claim that the target regions are copy number variants, it does direct its claims to sequence-variable regions (claim 1) and targeting copy number variants is an obvious embodiment of examining DNA polymorphisms (see Yuan, Abstract).
Although the reference application does not explicitly state that the sequencing is used to determine target region levels, the claims are directed at treatment and analysis of DNA relative to its methylation status. Therefore, the ultimate step of sequencing DNA can be understood to be in pursuit of that objective.
Claims 109-128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of Patent No. 11,946,106, in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing nucleic acids (ref claim 1). Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, wherein the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (claim 26, 27)
contacting the DNA in at least one of the subsamples with at least one methylation-sensitive restriction enzyme (MSRE) (claim 1)
contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set, comprised of target regions that are differentially methylated regions (claim 5)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 1, 28)
Although the reference application does not explicitly claim that the target regions are copy number variants, it does direct its claims to sequence-variable regions (claim 5, 7, 9) and targeting copy number variants is an obvious embodiment of examining DNA polymorphisms (see Yuan, Abstract).
Although the reference application does not explicitly state that the sequencing is used to determine target region levels, the claims are directed at treatment and analysis of DNA relative to its methylation status. Therefore, the ultimate step of sequencing DNA can be understood to be in pursuit of that objective.
Claims 109-128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of Patent No. 12,234,518, in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing nucleic acids (ref claim 1). Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, wherein the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (claim 1, 16)
contacting the DNA in at least one of the subsamples with at least one methylation-sensitive restriction enzyme (MSRE) (claim 8)
contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set, comprised of target regions that are differentially methylated regions (claim 1, 3, 14)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 1, 28)
Although the reference application does not explicitly claim that the target regions are copy number variants, it does direct its claims to sequence-variable regions (claim 6) and targeting copy number variants is an obvious embodiment of examining DNA polymorphisms (see Yuan, Abstract).
Although the reference application does not explicitly state that the sequencing is used to determine target region levels, the claims are directed at treatment and analysis of DNA relative to its methylation status. Therefore, the ultimate step of sequencing DNA can be understood to be in pursuit of that objective.
Claims 109-128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, 9, 12, 16-17, 19, 27-28, 49, 52, 55, 60, 63, 59, 114, 121 of copending Application No. 18/339126, in view of Kennedy et al. (published April 30, 2020; Patent Publication No. US 2020/0131566), and further in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing DNA (claim 1). Both sets of claims require:
contacting the DNA in at least one of the subsamples with at least one restriction enzyme (claim 28)
contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set, comprised of target regions that are copy number variants and differentially methylated regions (claim 16, 19, 55)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 1, 6)
Although the reference application does not claim an initial partitioning step, it would be obvious to include such a step in order to enrich for sequences and modifications of interest (i.e. methylated and/or unmethylated DNA, since claims are directed toward methylation status – see claim 19) as discussed in Kennedy (par. 116).
Although the reference application does not explicitly state that the sequence-specific nuclease is a methylation-sensitive or -dependent restriction endonuclease, the claims are directed toward epigenetically modified DNA and use of methylation-sensitive restriction endonucleases would be an obvious embodiment of the claims (see Yuan, pg. 3445, col. 1).
Although the reference application does not explicitly state that the target regions are copy number variants, it does direct its claims to sequence-variable regions (claim 16) and targeting copy number variants is an obvious embodiment of examining DNA polymorphisms (see Yuan, Abstract).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 109-128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 18/365,744. Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing DNA (claim 1). Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, and the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (claim 21, 22)
contacting the DNA in at least one of the subsamples with at least one agent which affects modified and nonmodified nucleobases differently (claim 23)
contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set (claim 20), comprised of target regions that are copy number variants (claim 15) and differentially methylated regions or fragments (claim 15, 17)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 1)
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 109-128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-8, 12-13, 15, 17-21, 24, 27, 29, 43, 72 of copending Application No. 19/243171, in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing DNA (claim 2). Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, and the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (claim 43)
contacting the DNA in at least one of the subsamples with at least one agent which affects modified and nonmodified nucleobases differently (claim 2, 5, 7, 12, 20)
contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set, comprised of target regions that are differentially methylated regions (claim 72)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 2-8, 12)
Although the reference application does not explicitly state that the target regions are copy number variants, it does direct its claims to sequence-variable regions (claim 72) and targeting copy number variants is an obvious embodiment of examining DNA polymorphisms (see Yuan, Abstract).
Although the reference application does not explicitly state that the procedure which differentially affects a nucleobase based on modification is referring to the use of a methylation-sensitive or -dependent restriction endonuclease, the claims are directed toward methylated DNA and use of methylation-sensitive restriction endonucleases is an obvious embodiment of the claims (see Yuan, pg. 3445, col. 1).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 109-128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-15, 17, 19, 22-23, 25, 27, 29-30 of copending Application No. 19/243,180, in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing DNA. Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, and the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (claim 7, 17, 30)
contacting the DNA in at least one of the subsamples with at least one methylation-sensitive or -dependent endonuclease (claim 9, 14, 15, 17)
enriching DNA in a type-specific manner for members of an epigenetic target region set (claims 1, 6, 7)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 2)
Although the reference application does not explicitly state that the target regions are differentially methylated or copy number variants, it does direct its claims to the identification of hyper- and hypo-methylated sequences (claims 14-15) and sequence-variable target regions (claims 1, 6, 8) and targeting copy number variant regions and differentially methylated regions would be an obvious embodiment of the claims (see Yuan, pg. 3443, col. 2, last par.).
Although the reference application does not explicitly state that the sequencing is used to determine target region levels, the claims are directed at treatment and analysis of DNA relative to its methylation status. Therefore, the ultimate step of sequencing DNA can be understood to be in pursuit of that objective.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 109-128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-49 of copending Application No. 19/276,680 in view of Kennedy et al. (published April 30, 2020; Patent Publication No. US 2020/0131566), and further in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing DNA (claim 1). Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes a modified cytosine, and the first subsample comprises DNA with a modified cytosine in a greater proportion than the second subsample (claim 1, 4)
enriching the DNA for members of an epigenetic target region set, comprised of target regions that are copy number variants and differentially methylated regions (claim 45, 47)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 1, 49)
Although the reference application directs its claims to 5-hydroxymethylcytosine, it would be obvious to substitute methyl cytosine, in order to investigate another methylation variation which could contribute to the development of cancer (Kennedy, par. 2, 124).
Although the reference application directs its claims to bisulfite conversion for mapping of methylated DNA, it does claim fragmenting nucleic acids and amplifying them prior to sequencing (claims 30, 32). Therefore, it would be obvious to substitute methylation-sensitive PCR for analysis of epigenetic modification, in order to validate bisulfite restriction analysis (Yuan, Abstract)
Although the reference application does not explicitly state that the target regions enriched using probes, such a method of enrichment would be an obvious embodiment of the claims (see Yuan, pg. 3443, col 2, last par.).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 109-128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-76 of copending Application No. 19/371162, in view of Yuan et al. (published April 1, 2006; Yuan et al. 2006. Cancer Res; 66: (7)). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods of analyzing DNA. Both sets of claims require:
partitioning the DNA into at least a first and second subsample by contacting the DNA with an agent that recognizes methyl cytosine, wherein the first subsample comprises DNA with a methyl cytosine in a greater proportion than the second subsample (claim 63, 65)
contacting the DNA in at least one of the subsamples with at least one methylation-sensitive or methylation-dependent restriction enzyme (claim 63)
contacting the DNA with a plurality of target-specific probes specific for members of an epigenetic target region set, comprised of target regions that are differentially methylated regions or fragments (claim 54, 63)
sequencing the captured DNA and determining levels of the type-specific epigenetic target regions (claim 1, 22, 60)
Although the reference application does not explicitly claim that the type-specific epigenetic target regions are comprised of copy number variants, it would be an obvious embodiment of the claims for copy number variants to be included in the target regions (see Yuan: Abstract).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/C.M.J./Examiner, Art Unit 1682
/AMANDA HANEY/Primary Examiner, Art Unit 1682