DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Claims 31-40 are currently pending and have been examined herein.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted on April 5, 2024, August 30, 2024, and April 2, 2025 have been received. It is noted that the references cited on the IDS filed August 30, 2024 have been crossed off because this IDS appears to be a duplicate of the IDS filed on April 5, 2024.
Nucleotide and/or Amino Acid Sequence Disclosures
4. REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
I. Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Figures 1A and 1B.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
II. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 102
5. The following is a quotation of the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
6. Claims 31, 33-36, and 38 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Taylor (Cancer Research 2007 67(18) pages 8511-8518).
Regarding Claim 31 Taylor teaches that a massively parallel sequencing-by-synthesis method (454 sequencing) was used to directly sequence >100 bisulfite PCR products in a single sequencing run without subcloning (abstract). Taylor teaches that DNA samples were obtained from 40 specimens, 10 of each from MCL, CLL, FL, and ALL. Equal amounts of nucleic acid from each patient sample were pooled by disease type. Additionally commercial peripheral blood lymphocytes were obtained and combined to create a DNA pool referred to as normal PBL. DNA from each pool was treated with sodium bisulfite. Taylor teaches that disease specific primers were developed for 25 genes. Taylor teaches that the genes included in this study were previously shown to be methylated in hematologic neoplasms. Taylor teaches that each gene has a core primer sequence that is identical across all groups and a 4 nucleotide disease specific tag was added to the 5’ end of each core primer sequence so that each group could be computationally separated after 454 sequencing analysis. Taylor teaches for each gene, five disease specific amplicons were generated by PCR. One hundred twenty two amplicons were then pooled in a single tube before sequencing by 454 Life Sciences Corp according to Margulies et al (9). Taylor teaches that 454 sequencing requires library preparation and emulsion PCR. Taylor teaches that on average 1,697 sequence reads were obtained from each amplicon (page 8512, col 1, 8513, col 1-2, Fig 1). Thus Taylor teaches a method comprising identifying one or more cancer-associated loci (the 25 genes) in nucleic acid obtained from a sample from a subject by comparing nucleic acid sequence from a cancer cell from said subject to nucleic acid from a normal cell; generating an assay (ultradeep bisulfite sequencing by 454 Sequencing) to detect said one or more cancer-associated loci identified; and conducting said assay, wherein said assay comprises: i) preparing a library of nucleic acid suspected of containing said one or more cancer-associated loci (454 library preparation); ii) amplifying nucleic acid in said library (emulsion PCR); and iii) sequencing said library to identify sequences associated with said one or more cancer-associated loci (454 Sequencing). Taylor teaches a method wherein conducting comprises enriching the sample for nucleic acid comprising said one or more cancer-associated loci (the 25 genes are enriched by PCR), if present; adding index tags to the nucleic acid (the disease specific tags); and sequencing amplicons over 1000 times (1,697 times).
Regarding Claim 33 Taylor teaches a method wherein one of the cancer associated loci is p53 (Fig 2).
Regarding Claim 34 Taylor teaches a method wherein the cancer-associated loci comprise CpG dinucleotide loci (Fig 2).
Regarding Claim 35 Taylor teaches that 20 of 25 amplicons examined showed an increase in methylation in various types of disease compared with normal PBL controls (page 8515). Thus Taylor teaches a method wherein one or more cancer-associated loci are differentially methylated in cancer samples compared to normal samples.
Regarding Claim 36 Taylor teaches a method wherein enriching comprises amplification of said nucleic acid with one or more primers that selectively amplify a cancer-associated locus (page 8512, col 1 and Fig 1).
Regarding Claim 38 Taylor teaches that library preparation for 454 requires performing emulsion PCR amplification (page 8513, col 2).
Claim Rejections - 35 USC § 103
5. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
6. Claim 32 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Taylor (Cancer Research 2007 67(18) pages 8511-8518) in view of Leamon (US 2006/0228721 Pub 10/26/2006).
The teachings of Taylor are presented above.
Taylor does not teach a method comprising sequencing amplicons over 100,000 times (clm 31).
However Leamon teaches an ultra-deep sequencing method that can sequence over 100,000 or over 300,000 different copies of an allele per picotiter plate (para 0037).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Taylor by sequencing amplicons over 100,000 times as suggested by Leamon. One of skill in the art would have been motivated to sequence an amplicon over 100,000 times for the benefit of being able to detect rare variants.
7. Claim 37 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Taylor (Cancer Research 2007 67(18) pages 8511-8518) in view of Zou (Cancer Epidemiol Biomarkers Prev 2007 16(12) Dec 2007).
The teachings of Taylor are presented above.
Taylor does not teach a method wherein the cancer associated loci are associated with colorectal cancer.
However Zou teaches that they evaluated genes frequently methylated in colorectal neoplasia to identify the most discriminant ones. Zou teaches that this study shows BMP3, EYA2, ALX4, and vimentin genes are methylated in most colorectal neoplasms but rarely in normal epithelia (abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Taylor by identifying colorectal cancer associated loci and then generate an assay for detecting the colorectal cancer associated loci as suggested by Zou. One of skill in the art would have been motivated to do this for the benefit of being able to further evaluate these markers in screening or diagnostic applications for colorectal neoplasia (page 2694, col 1, 2695, col 2).
8. Claim 39 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Taylor (Cancer Research 2007 67(18) pages 8511-8518) in view of Margulies (Nature Vol 437 September 2005).
The teachings of Taylor are presented above.
Taylor teaches library preparation for 454 sequencing comprises performing emulsion PCR. Taylor does not specifically teach that the emulsion PCR is digital PCR.
However Margulies teaches library preparation for 454 sequencing. Margulies teaches that they randomly fragment the entire genome, add specialized common adapters to the fragments, capture the individual fragments on their own beads and, within the droplets of an emulsion, clonally amplify the individual fragment (page 376, col 2, Fig1). It is noted that the instant specification (para 0035) teaches that the term “digital PCR” refers to PCR that is configured to provide amplification product or signal from a single starting molecule. Thus the emulsion based PCR of Margulies is considered a digital PCR method.
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Taylor by performing digital PCR on the nucleic acid library as suggested by Margulies. One of skill in the art would have been motivated to perform digital PCR for the benefit of obtaining emulsion beads each carrying multiple copies of a unique DNA template.
9. Claim 40 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Taylor (Cancer Research 2007 67(18) pages 8511-8518) in view of Basheer (Nucleic Acids Research 2009 Vol 37 No 6 e42).
The teachings of Taylor are presented above.
Taylor does not teach a method wherein the PCR comprises nested PCR.
However Basheer teaches a library preparation method wherein DNA is fragmented, adapters are added to the ends of the fragments, and then the library is amplified by nested PCR (page 3, col 2).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Taylor by performing nested PCR on the nucleic acid library as suggested by Basheer. One of skill in the art would have been motivated to perform nested PCR for the benefit of improving specificity when trying to amplify regions of interest.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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