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 .
Applicant cancels claims 5-6, 8-9, 11-13, 15, 17-27, 36-38, 40-41, 44 and 46-48. Claims 1-4, 7, 10, 14, 16, 28-35, 39, 42-43, 45 and 49-50 are currently pending and under examination.
Information Disclosure Statement
The Information Disclosure Statement filed October 21, 2022 has been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
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 patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (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 the USPTO patent electronic filing system 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 the USPTO patent electronic filing system 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.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1),
1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response – Applicant must:
Amend the Sequence Listing Incorporation by Reference paragraph at page 1 of the
specification. It is noted the Sequence Listing Incorporation by Reference paragraph lists the size of the ASCII text file as 90 kilobytes, whereas the ASCII text file itself lists the size as 91,716 bytes.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Page 22, Lines 11-12, Page 37, Lines 13-14). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms Dragen® Ion Torrent® Oxford Nanopore® SMRT Sequencing® Illumina® GS FLX TITANIUM™, Illumina® MiSeq™, HiSeq2500™, NextSeq™, MiniSeq™, NovaSeq™, which are trade names or marks used in commerce, has been noted in this application (see Page 2-3, [0004]—[0006], Page 7, [0026], Page 13, [0064] and [0066], Page 25, [0099], Page 34, [0120], Page 65, [0167], Page 67, [0172], Page 70, [0185], Page 73, [0193] and Examples 3-6 and 9). The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 2, 3, 16, 28, 29, 32, 43 and 49-50 are objected to because of the following informalities:
In claim 1, line 19, “desoxyribonucleoside triphosphates” should read “deoxyribonucleoside triphosphate”.
In claim 2, line 1, the terms “comprising as first step” should read “comprising as a first step, ”.
In claim 3, line 19, the terms “desoxyribonucleoside triphosphates” should read “deoxyribonucleoside triphosphate”.
In claim 16, line 3, the terms “a NGS system” should read “a Next Generation Sequencing system”.
In claim 28, line 11, the terms “desoxyribonucleoside triphosphates” should read “deoxyribonucleoside triphosphate”.
In claim 29, line 11, the terms “desoxyribonucleoside triphosphates” should read “deoxyribonucleoside triphosphate”.
In Claim 32, line 2, the terms “sequence is capable of binding to a substrate” should read “sequence binds to a substrate”.
In Claim 43, lines 3-5, the terms “a sequence being highly similar to the target sequence, preferably having a sequence identity of 97% or more”, should read “a sequence being highly similar to the target sequence, having a sequence identity of 97% or more”.
In Claim 49, line 5, the terms “sequence is capable of binding to a substrate” should read “sequence binds to a substrate”.
In Claim 50, line 5, the terms “sequence is capable of binding to a substrate” should read “sequence binds to a substrate”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claim 1-4, 7, 10, 14, 16, 28-35, 39, 42-43, 45 and 49-50, 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “a first strand cDNA copy of at least a portion of the RNA to be sequenced”, and the claim also recites “preferably a gene sequence” which is the narrower statement of the range/limitation. Claims 2, 7, 10, 14, 16, 30-35, 39, 42-43 and 45 depend from claim 1 and are therefore included in this rejection. Additionally, claim 2 recites the broad recitation “first step the extraction of RNA from a sample obtained from a subject”, and the claim also recites “preferably by sample lysis.” which is the narrower statement of the range/limitation. Additionally, claim 2 recites the broad recitation “first step the extraction of RNA from a sample obtained from a subject”, and the claim also recites “preferably by sample lysis.” which is the narrower statement of the range/limitation. Additionally, claim 4 recites the broad recitation “first step the extraction of RNA from a sample obtained from a subject”, and the claim also recites “preferably by sample lysis.” which is the narrower statement of the range/limitation. Additionally, claim 16 recites the broad recitation “a step of sequencing the amplicon”, and the claim also recites “preferably with a NGS system” as well as “such as Illumina, Ion Torrent, Oxford Nanopore, or SMRT Sequencing” which is the narrower statement of the range/limitation. Additionally, claim 32 recites the broad recitation “binding to a substrate”, and the claim also recites “preferably a sequence chip or flow cell” which is the narrower statement of the range/limitation. Additionally, claim 33 recites the broad recitation “a target sequence”, and the claim also recites “preferably a viral gene or a part of a viral genome, a leukocyte antigen- associated gene, or a blood group antigen associated gene.” which is the narrower statement of the range/limitation. Additionally, claim 34 recites the broad recitation “a viral gene of a coronavirus”, and the claim also recites “preferably a SARS-CoV-2 virus gene or genomic portion, or a part of it” as well as “more preferably 5'UTR, 3'UTR, ORFlab, Orf3a, Orf6, Orf7a, Orf7b, OrfB, Orfl0, M gene region, E gene region, N gene region, or S gene region of SARS-CoV-2.” which is the narrower statement of the range/limitation. Additionally, claim 42 recites the broad recitation “2, 3, 4, 5, 6, 7,8, 9, 10 or more target sequences are simultaneously”, and the claim also recites “preferably, wherein 2 or 3 target sequences are simultaneously amplified.” which is the narrower statement of the range/limitation. Additionally, claim 49 recites the broad recitation “binding to a substrate”, and the claim also recites “preferably a sequence chip or flow cell” which is the narrower statement of the range/limitation. Additionally, claim 49 recites the broad recitation “a target sequence”, and the claim also recites “wherein said target sequence is preferably a viral gene or a part of a viral genome, a leukocyte antigen-associated gene, or a blood group antigen associated gene” which is the narrower statement of the range/limitation. Additionally, claim 49 recites the broad recitation “a viral gene of a coronavirus”, and the claim also recites “preferably a SARS-CoV-2 virus gene or genomic portion, or a part of it” as well as “more preferably 5'UTR, 3'UTR, ORFlab, Orf3a, Orf6, Orf7a, Orf7b, OrfB, Orfl0, M gene region, E gene region, N gene region, or S gene region of SARS-CoV-2.” which is the narrower statement of the range/limitation. Additionally, claim 50 recites the broad recitation “binding to a substrate”, and the claim also recites “preferably a sequence chip or flow cell” which is the narrower statement of the range/limitation. Additionally, claim 50 recites the broad recitation “a target sequence”, and the claim also recites “wherein said target sequence is preferably a viral gene or a part of a viral genome, a leukocyte antigen-associated gene, or a blood group antigen associated gene” which is the narrower statement of the range/limitation. Additionally, claim 50 recites the broad recitation “a viral gene of a coronavirus”, and the claim also recites “preferably a SARS-CoV-2 virus gene or genomic portion, or a part of it” as well as “more preferably 5'UTR, 3'UTR, ORFlab, Orf3a, Orf6, Orf7a, Orf7b, OrfB, Orfl0, M gene region, E gene region, N gene region, or S gene region of SARS-CoV-2.” which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For the purposes of examination, claim 1 is interpreted as the RNA to be sequenced is a gene sequence, claims 2 and 4 are interpreted as including sample lysis, claim 16 is interpreted as including sequencing using Next Generation Sequencing (NGS), claims 32, 49 and 50 are interpreted as the substrate being a chip or flow cell, claims 33, 49 and 50 are interpreted as the target sequence being a viral gene, a part of a viral genome, a leukocyte antigen- associated gene, or a blood group antigen associated gene, claims 34, 49 and 50 are interpreted as including the viral gene being a SARS-CoV-2 virus gene, claim 42 is interpreted as 2 or more target sequences are simultaneously amplified.
Claim 1 is additionally considered vague and indefinite for the following reasons:
In claim 1, line 7, the term “suitable” is unclear and confusing. It is unclear as to what makes the conditions suitable? Are there specific conditions that are required to make the primer suitable?
Claims 2, 7, 10, 14, 16, 30-35, 39, 42-43 and 45 depend from claim 1 and are therefore included in this rejection.
Claim 3 is considered vague and indefinite for the following reasons:
In claim 3, line 8, the term “suitable” is unclear and confusing. It is unclear as to what makes the conditions suitable? Are there specific conditions that are required to make the primer suitable?
Claim 4 depends from claim 3 and is therefore included in this rejection.
Claim 16 is additionally considered vague and indefinite for the following reasons:
In Claim 16, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 16 contains the trademark/trade name Illumina®, Ion Torrent® Oxford Nanopore® and SMRT Sequencing®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe Next Generation Sequencing systems and, accordingly, the identification/description is indefinite.
Claim 28 is considered vague and indefinite for the following reasons:
In claim 28, line 3, the term “suitable” is unclear and confusing. It is unclear as to what makes the conditions suitable? Are there specific conditions that are required to make the primer suitable?
Claim 49 depends from claim 28 and is therefore included in this rejection.
Claim 29 is considered vague and indefinite for the following reasons:
In claim 29, line 3, the term “suitable” is unclear and confusing. It is unclear as to what makes the conditions suitable? Are there specific conditions that are required to make the primer suitable?
Claim 50 depends from claim 29 and is therefore included in this rejection.
Claim 30 is considered vague and indefinite for the following reasons:
In claim 30, line 2, the term “said adaptor” is unclear and confusing. It is unclear as to which adaptor the claim is referring; the first or second forward adaptor sequence or the first or second reverse adaptor sequence?
Claim 31 is considered vague and indefinite for the following reasons:
In claim 31, line 2, the term “said indexing primer” is unclear and confusing. It is unclear as to which indexing primer the claim is referring; the forward indexing primer or reverse indexing primer?
Claim 32 is considered vague and indefinite for the following reasons:
In claim 32, line 2, the term “said adaptor” is unclear and confusing. It is unclear as to which adaptor the claim is referring; the first or second forward adaptor sequence or the first or second reverse adaptor sequence?
Claim 33 is considered vague and indefinite for the following reasons:
In claim 33, line 3, the term “said target specific primer” is unclear and confusing. It is unclear as to which target specific primer the claim is referring; the forward or reverse target specific primer?
Claim 33 recites the limitation "said target specific primer pair" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 34 is considered vague and indefinite for the following reasons:
Claim 34 recites the limitation "or a part of it" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim.
Claim 35 is considered vague and indefinite for the following reasons:
Claim 35, lines 4-5, It is unclear if the information in parentheses “(reference genome with NCBI Reference Sequence No: NC_045512.2; SEQ ID NO: 63)”, is intended to be a claim limitation or not? If so, is the position according to SEQ ID NO: 63 or NCBI Reference Sequence No: NC_045512.2?
Claim 49 is considered vague and indefinite for the following reasons:
In claim 49, lines 1 and 5, the term “said adaptor” is unclear and confusing. It is unclear as to which adaptor the claim is referring; the first or second forward adaptor sequence or the first or second reverse adaptor sequence?
In claim 49, line 3, the term “said indexing primer” is unclear and confusing. It is unclear as to which indexing primer the claim is referring; the forward indexing primer or reverse indexing primer?
In claim 49, line 7, the term “said target specific primer” is unclear and confusing. It is unclear as to which target specific primer the claim is referring; the forward or reverse target specific primer?
Claim 49 recites the limitation "said target specific primer pair" in line 7. There is insufficient antecedent basis for this limitation in the claim.
Claim 49 recites the limitation "or a part of it" in line 12. There is insufficient antecedent basis for this limitation in the claim.
Claim 49, lines 16-17, It is unclear if the information in parentheses “(reference genome with NCBI Reference Sequence No: NC_045512.2; SEQ ID NO: 63)”, is intended to be a claim limitation or not? If so, is the position according to SEQ ID NO: 63 or NCBI Reference Sequence No: NC_045512.2?
Claim 50 is considered vague and indefinite for the following reasons:
In claim 50, lines 1 and 5, the term “said adaptor” is unclear and confusing. It is unclear as to which adaptor the claim is referring; the first or second forward adaptor sequence or the first or second reverse adaptor sequence?
In claim 50, line 3, the term “said indexing primer” is unclear and confusing. It is unclear as to which indexing primer the claim is referring; the forward indexing primer or reverse indexing primer?
In claim 50, line 7, the term “said target specific primer” is unclear and confusing. It is unclear as to which target specific primer the claim is referring; the forward or reverse target specific primer?
Claim 50 recites the limitation "said target specific primer pair" in line 7. There is insufficient antecedent basis for this limitation in the claim.
Claim 50 recites the limitation "or a part of it" in line 12. There is insufficient antecedent basis for this limitation in the claim.
Claim 50, lines 16-17, It is unclear if the information in parentheses “(reference genome with NCBI Reference Sequence No: NC_045512.2; SEQ ID NO: 63)”, is intended to be a claim limitation or not? If so, is the position according to SEQ ID NO: 63 or NCBI Reference Sequence No: NC_045512.2?
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.
(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 28-29 and 49-50 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Drukker et al. (WIPO International Application Publication WO 2017/060316 A1, published April 13, 2017).
Regarding claim 28, Drukker teaches a kit for preparing an RNA sample for next generation sequencing in a one-step target enrichment (Abstract, Page 2, Third Paragraph, Page 17, Fourth Paragraph, Page 45, Last Paragraph and Page 54, Fourth Paragraph). Drukker teaches a reverse transcriptase (RT) and one or more target-specific reverse primers, suitable for the preparation of a target specific cDNA (Page 9, First Paragraph, Page 35, Last Paragraph, Page 5, Second Paragraph, Page 6, Second Paragraph, Page 16, First Paragraph, Page 23, Fourth Paragraph and Page 36, First Paragraph). Drukker teaches a forward target specific primer comprising a first forward adaptor sequence, and a reverse target specific primer comprising a first reverse adaptor sequence (Abstract, Page 5, First—Second Paragraph and Page 15, First Paragraph).; d) a forward indexing primer comprising a first forward adaptor sequence, a forward indexing sequence and a second forward adaptor sequence and a reverse indexing primer, comprising a first reverse adaptor sequence, a reverse indexing sequence (Abstract, Page 3, Last Paragraph, Page 5, First—Second Paragraph, Page 49, First—Second Paragraph). Drukker teaches the reverse indexing sequence is different from the forward indexing sequence, and a second reverse adaptor sequence (Abstract and Page 49, First Paragraph). Drukker teaches deoxyribonucleoside triphosphates (dNTPs) and a DNA polymerase (Page 37, Second Paragraph and Page 16, Fourth Paragraph).
Regarding claim 29, Drukker teaches aa kit for preparing a DNA sample for next generation sequencing in a one-step target enrichment (Abstract, Page 2, Third Paragraph, Page 17, Fourth Paragraph and Page 54, Fourth Paragraph). Drukker teaches one or more target-specific forward primers and one or more target specific reverse primers, suitable for the preparation of a target specific DNA (Abstract, Page 5, Second Paragraph, Page 6, Second Paragraph, Page 15, First Paragraph, Page 16, First Paragraph, Page 23, Fourth Paragraph and Page 36, First Paragraph). Drukker teaches a forward target specific primer comprising a first forward adaptor sequence, and a reverse target specific primer comprising a first reverse adaptor sequence (Abstract, Page 5, First—Second Paragraph and Page 15, First Paragraph). Drukker teaches a forward indexing primer comprising a first forward adaptor sequence, a forward indexing sequence, a second forward adaptor sequence and a reverse indexing primer, comprising a first reverse adaptor sequence and a reverse indexing sequence (Abstract, Page 3, Last Paragraph, Page 5, First—Second Paragraph, Page 49, First—Second Paragraph). Drukker teaches the reverse indexing sequence is different from the forward indexing sequence, and a second reverse adaptor sequence (Abstract and Page 49, First Paragraph). Drukker teaches deoxyribonucleoside triphosphates (dNTPs) and a DNA polymerase (Page 37, Second Paragraph and Page 16, Fourth Paragraph).
Regarding claim 49, Drukker teaches said adaptor sequence has a length of about 8 to 45 nucleotides (Page 29, Fifth Paragraph).
Regarding claim 50, Drukker teaches said adaptor sequence has a length of about 8 to 45 nucleotides (Page 29, Fifth Paragraph).
Drukker teaches each and every limitation of claims 28-29 and 49-50, therefore Drukker anticipates claims 28-29 and 49-50.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7, 10, 14, 16, 30-33 and 42-43 are rejected under 35 U.S.C. as being unpatentable over Drukker et al. (WIPO International Application Publication WO 2017/060316 A1, published April 13, 2017), in view of Pel et al. (“Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers”, PLoS One. 2018 Dec 5;13(12):e0208283, published December 5, 2018).
Regarding claim 1, Drukker teaches a method for preparing an RNA sample for a target specific next generation sequencing comprising performing a one-step target enrichment in a single reaction vessel or in a single reaction mixture (Page 2, Third Paragraph, Page 17, Fourth Paragraph and Page 54, Fourth Paragraph). Drukker teaches enrichment comprises the steps exposing the RNA to be sequenced in a single reaction vessel to a mixture comprising a reverse transcriptase, a DNA polymerase (Page 7, Third Paragraph, Page 16, Fourth Paragraph, Page 25, Second Paragraph, Page 35, Last Paragraph, Page 36, Last Paragraph, Page 38, Last Paragraph, and Page 41, Second Paragraph). Drukker teaches one or more target-specific reverse primers, suitable for the preparation of a target specific cDNA (Page 5, Second Paragraph, Page 6, Second Paragraph, Page 16, First Paragraph, Page 23, Fourth Paragraph and Page 36, First Paragraph). Drukker teaches a forward target specific primer comprising a first forward adaptor sequence, and a reverse target specific primer comprising a first reverse adaptor sequence (Abstract, Page 5, First—Second Paragraph and Page 15, First Paragraph). Drukker teaches a forward indexing primer comprising a first forward adaptor sequence, a forward indexing sequence and a second forward adaptor sequence and a reverse indexing primer, comprising a first reverse adaptor sequence, a reverse indexing sequence (Abstract, Page 3, Last Paragraph, Page 5, First—Second Paragraph, Page 49, First—Second Paragraph), Drukker teaches the reverse indexing sequence is different from the forward indexing sequence, and a second reverse adaptor sequence (Abstract and Page 49, First Paragraph). Drukker teaches deoxyribonucleoside triphosphates (dNTPs) (Page 37, Second Paragraph). Drukker teaches subjecting the reaction mixture to a series of temperature changes under conditions sufficient to yield a first strand cDNA copy of at least a portion of the RNA to be sequenced, preferably a gene sequence (Page 4, Third Paragraph, Page 6, Third Paragraph, Page 37, First and Second Paragraph, Page 53, Last Paragraph, Page 70, Third Paragraph, Page 35, Last Paragraph and Page 36, Last Paragraph). Drukker teaches a target specific amplicon (Page 48, Second Paragraph).
Regarding claim 2, Drukker teaches a first step of RNA extraction from a sample obtained from a subject by lysis (Page 38, First Paragraph and Page 59, Third Paragraph).
Regarding claim 3, Drukker teaches a method for preparing a DNA sample for a target specific next generation sequencing comprising performing a one-step target enrichment in a single reaction vessel or in a single reaction mixture (Page 2, Third Paragraph, Page 17, Fourth Paragraph and Page 54, Fourth Paragraph). Drukker teaches said enrichment comprises exposing the DNA to be sequenced in a single reaction vessel to a mixture comprising a DNA polymerase (Page 16, Fourth Paragraph, Page 25, Second Paragraph, Page 30, Second Paragraph, Page 38, Last Paragraph, and Page 41, Second Paragraph). Drukker teaches one or more target-specific forward primers and one or more target specific reverse primers, suitable for the preparation of a target specific DNA (Abstract, Page 5, Second Paragraph, Page 6, Second Paragraph, Page 15, First Paragraph, Page 16, First Paragraph, Page 23, Fourth Paragraph and Page 36, First Paragraph). Drukker teaches a forward target specific primer comprising a first forward adaptor sequence, and a reverse target specific primer comprising a first reverse adaptor sequence (Abstract, Page 5, First—Second Paragraph and Page 15, First Paragraph). Drukker teaches a forward indexing primer comprising a first forward adaptor sequence, a forward indexing sequence and a second forward adaptor sequence, a reverse indexing primer, comprising a first reverse adaptor sequence and a reverse indexing sequence (Abstract, Page 3, Last Paragraph, Page 5, First—Second Paragraph, Page 49, First—Second Paragraph). Drukker teaches the reverse indexing sequence is different from the forward indexing sequence, and a second reverse adaptor sequence (Abstract and Page 49, First Paragraph). Drukker teaches deoxyribonucleoside triphosphates (dNTPs) (Page 37, Second Paragraph). Drukker teaches subjecting the reaction mixture of (i) to a series of temperature changes under conditions sufficient to yield a target specific amplicon (Page 4, Third Paragraph, Page 6, Third Paragraph, Page 37, First and Second Paragraph, Page 53, Last Paragraph, Page 70, Third Paragraph, Page 35, Last Paragraph and Page 36, Last Paragraph).
Regarding claim 4, Drukker teaches a first step of RNA extraction from a sample obtained from a subject by lysis (Page 38, First Paragraph and Page 59, Third Paragraph).
Regarding claim 7, Drukker teaches the method additionally comprises a control amplification of one or more additional target sequences (Abstract and Page 5, First Paragraph).
Regarding claim 10, Drukker teaches sample registration, which is performed previous to the enrichment (Figure 6).
Regarding claim 14, Drukker teaches a purification of the amplicon and a step of quantifying the amplicon (Page 11, Second Paragraph, Page 19, Third Paragraph and Page 48, Second Paragraph).
Regarding claim 16, Drukker teaches a step of sequencing the amplicon with a NGS system such as Illumina (Page 28, Last Paragraph—Page 29, First Paragraph).
Regarding claim 30, Drukker teaches said adaptor sequence has a length of about 8 to 45 nucleotides (Page 29, Fifth Paragraph).
Regarding claim 31, Drukker teaches said indexing primer sequence has a length of about 4 to 20 nucleotides (Page 29, Sixth Paragraph).
Regarding claim 32, Drukker teaches an adaptor sequence as discussed above.
Regarding claim 33, Drukker teaches said target-specific primer or said target-specific primer pair is specific for a target sequence (Abstract, Page 5, Second Paragraph, Page 6, Second Paragraph, Page 16, First Paragraph, Page 23, Fourth Paragraph and Page 36, First Paragraph). Drukker teaches said target sequence is preferably a viral gene or a part of a viral genome (Page 6, Third Paragraph, Page 7, Third Paragraph, Page 36, First Paragraph, Page 38, First Paragraph and Tables 3 and 12-13).
Regarding claim 42, Drukker teaches 2, 3, 4, 5, 6, 7,8, 9, 10 or more target sequences are simultaneously amplified (Page 6, Fourth Paragraph).
Regarding claim 43, Drukker teaches qualitative detection of the target sequence (Page 11, First Paragraph, Page 50, Second Paragraph). Drukker teaches the target sequence having a sequence identity of 97% or more (Page 2, Second Paragraph, Page 28, Second Paragraph, Page 54, Sixth-Seventh Paragraph).
Drukker does not teach or suggest the specific structure starting from the 5'- to the 3'-end a second forward adaptor sequence, a forward indexing sequence, a first forward adaptor sequence, a forward target specific primer sequence, target sequence, a reverse target specific primer sequence, a first reverse adaptor sequence, a reverse indexing sequence and a second reverse adaptor sequence. Drukker does not teach or suggest said adaptor sequence binds to a substrate. Drukker does not teach or suggest said adaptor binds to a sequence chip or flow cell.
Pel teaches enrichment of nucleic acids in single reaction workflow using Next Generation Sequencing (Abstract, Page 2, Third Paragraph, Page 3, First Paragraph, Page 9, First Paragraph). Pel teaches using a forward and reverse universal primer and target specific primer as well as a first and second forward and reverse adapter and a forward and reverse index (Fig. 1). Pel teaches the adaptors may bind to a substrate, specifically a flow cell (Page 3, Second Paragraph). Pel teaches the specific structure starting from the 5'- to the 3'-end a second forward adaptor sequence, a forward indexing sequence, a first forward adaptor sequence, a forward target specific primer sequence, target sequence, a reverse target specific primer sequence, a first reverse adaptor sequence, a reverse indexing sequence and a second reverse adaptor sequence (Page 11, Last Paragraph and Fig. 1). Pel teaches using these methods increase NGS and target capture as wells as reduction in workflow time and cost (Page 8, Second Paragraph).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the teachings of Drukker with the teachings of Pel, to use the specific structure from the 5'- to the 3'-end a second forward adaptor sequence, a forward indexing sequence, a first forward adaptor sequence, a forward target specific primer sequence, target sequence, a reverse target specific primer sequence, a first reverse adaptor sequence, a reverse indexing sequence and a second reverse adaptor sequence and an adaptor bound to a flow cell. Using these methods would allow for an increase in Next Generation Sequencing and target capture, as wells as reduction in workflow time and cost as taught by Pel (Page 8, Second Paragraph).
Claims 34 and 45 are rejected under 35 U.S.C. as being unpatentable over Drukker et al. (WIPO International Application Publication WO 2017/060316 A1, published April 13, 2017) and Pel et al. (“Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers”, PLoS One. 2018 Dec 5;13(12):e0208283, published December 5, 2018), as applied to claims 1-4, 7, 10, 14, 16, 30-33 and 42-43 above, in view of Hossain et al. ("A Massively Parallel COVID-19 Diagnostic Assay for Simultaneous Testing of 19200 Patient Samples", XP055822933, publishes March 20, 2020, cited on the IDS filed October 21, 2022.
Regarding claim 34, Drukker teaches analysis of gene regions (Page 23, Fourth Paragraph). Drukker teaches said virus target sequence as discussed above.
Regarding claim 45, Drukker teaches target enrichment as discussed above.
Drukker does not teach or suggest said target sequence is a viral gene of a coronavirus, preferably a SARS-CoV-2 virus gene or genomic portion, or a part of it, more preferably the 5'UTR, 3'UTR, ORFlab, Orf3a, Orf6, Orf7a, Orf7b, OrfB, Orfl0, M gene region, E gene region, N gene region, or S gene region of SARS-CoV-2. Drukker does not teach or suggest enrichment for a rapid virus detection, or for an enrichment for a rapid leukocyte antigen-associated gene identification, or for an enrichment for a rapid blood group associated gene identification.
Hossain teaches massively parallel Covid-19 diagnostic assay for simultaneous testing of multiple targets (Title and Abstract). Hossain teaches using forward and reverse target specific primers with unique barcode sequences and adapters (Abstract, Page 6, Last Paragraph and Fig. 1). Hossain teaches rapid virus detection (Page 3, Second Paragraph). Hossain teaches Sasrs-CoV-2 as the target sequence (Page 2, Second Paragraph and Page 4, First Paragraph). Using this approach provides for improved quantification of Sars-CoV-2 targets as well as improved automation (Abstract).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the teachings of Drukker and Pell with the teachings of Hossain, using Sars-CoV-2 as the target sequence for rapid virus detection. Using this approach allows for improved quantification of Sars-CoV-2 targets as well as improved automation as taught by Hossain (Abstract).
Claim 35 is rejected under 35 U.S.C. as being unpatentable over Drukker et al. (WIPO International Application Publication WO 2017/060316 A1, published April 13, 2017) and Pel et al. (“Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers”, PLoS One. 2018 Dec 5;13(12):e0208283, published December 5, 2018), as applied to claims 1-4, 7, 10, 14, 16, 30-33 and 42-43 above, in view of Lange et al. ( "Cost-efficient high-throughput HLA typing by MiSeq amplicon sequencing", BMC GENOMICS, vol. 15, no. 1, published January 24, 2014), cited on the IDS filed October 21, 2022.
Regarding claim 35, Drukker teaches said target sequence as discussed above.
Drukker does not teach or suggest said target sequence comprises one or more of the following nucleotide positions according to the nucleotide numbering of the reference genome of SARS-CoV-2: 100, 733, 1264 , 2749, 3267, 3828, 5388, 5648, 6319, 6573, 6613, 6954, 7600, 7851, 10667, 11078, 11288-11296, 11824, 12964, 12778, 13860, 17259, 19602, 19656, 21614, 21621, 21638, 21765-21770, 21974, 21991-21993, 22132, 22812, 23012, 23063, 23271, 23525, 23604, 23709, 24506, 24642, 24914, 26149, 27853, 27972, 28048, 28111, 28167, 28253, 28262, 28280, 28512, 28628, 28877, 28975, 28977, 29722, 29754. Drukker does not teach or suggest said target sequence is a leukocyte antigen-associated gene selected from: HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLA-DRA1, HLA-DRB1, HLA-DRB3/4/5, HLA- DQA1, HLA-DQB1, HLA-DPA1, or HLA-DPB1. Drukker does not teach or suggest said target sequence is a blood group associated antigen associated with one or more of the ABO, MNS, Rhesus, Lutheran, Kell, Lewis, Duffy, Kidd, Diego, Yt, Scianna, Dombrock, Colton, Cromer, or Vel blood group antigens.
Lange teaches high-throughput HLA typing using MiseqTM amplicon sequencing in a single run (Title and Abstract). Lange teaches using a forward and reverse indexing primer with a first and second forward and reverse adapter sequences that are different (Abstract and Fig. 3). Lange teaches using at least 48 different samples (Figs 1-3). Lange teaches using said target sequence is a leukocyte antigen-associated gene selected from: HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLA-DRA1, HLA-DRB1, HLA-DRB3/4/5, HLA- DQA1, HLA-DQB1, HLA-DPA1, or HLA-DPB1 (Abstract, Page 4, Left Column, Second Paragraph, Page 5, Right Column, Second Paragraph, Page 7, Right Column, Last Paragraph and Fig. 4). Lange teaches using these methods allows for greatly simplifying sample preparation methods as well as greatly reducing cost (Page 2, Left Column First Paragraph).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the teachings of Drukker and Pel with the teachings of Lange, having the target sequence being a leukocyte antigen-associated gene selected from: HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLA-DRA1, HLA-DRB1, HLA-DRB3/4/5, HLA- DQA1, HLA-DQB1, HLA-DPA1, or HLA-DPB1. Using these methods allows for greatly simplifying sample preparation methods as well as greatly reducing cost as taught by Lange (Page 2, Left Column First Paragraph).
Claim 39 is rejected under 35 U.S.C. as being unpatentable over Drukker et al. (WIPO International Application Publication WO 2017/060316 A1, published April 13, 2017) and Pel et al. (“Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers”, PLoS One. 2018 Dec 5;13(12):e0208283, published December 5, 2018), as applied to claims 1-4, 7, 10, 14, 16, 30-33 and 42-43 above, in view of Yang et al. (U.S. Patent Application Publication US 2021/0130812 A1, published May 06, 2021, effectively filed March 26, 2020).
Regarding claim 39, Drukker teaches said reverse indexing primer as discussed above. Drukker does not teach or suggest said reverse indexing primer is a primer selected from the group comprising primers of SEQ ID NO: 40 to SEQ ID NO: 51.
Yang teaches purifying an amplified product using primer pairs (i.e., forward and reverse primers, Page 1, [0031]). Yang teaches one of the primers (reverse primer) may be nucleotide sequence SEQ ID NO: 9 (which is identical to SEQ ID NO: 43 of the instant application, Page 2, [0040]). Yang teaches the method provided is suitable for library construction for Next Generation Sequencing (Page 3, [0077]).
As a common field of endeavor Drukker, Pel and Yang all disclose methods using primers in Next Generation Sequencing.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Drukker and Pel with the teachings of Yang, using SEQ ID NO: 9 (identical to Instant SEQ ID NO: 43) as a reverse primer because it has been held that the simple substitution of one known element for another to obtain predictable results is obvious. In re Fout, 213 USPQ 532 (CCPA 1982), In re O'Farrell, 7 USPQ2d 1673 (Fed. Cir. 1988). Simply substituting the reverse primer of Yang with the reverse primer of Drukker would obtain predictable results because both Drukker and Yang teach using primer pairs (forward and reverse) for Next Generation Sequencing.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA DANIELLE PARISI whose telephone number is (571)272-8025. The examiner can normally be reached Mon - Friday 7:30-5:00 Eastern with alternate Fridays off.
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, Heather Calamita can be reached at 571-272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JESSICA D PARISI/Examiner, Art Unit 1684
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684