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 .
Status of the Claims
Claims 1-21 are pending and under consideration in this action.
Priority
The instant application is a 371 of PCT/KR2021/007912, filed 6/23/2021, which claims priority to Republic of Korea Application 10-2020-0077423, filed 6/24/2020, as reflected in the filing receipt mailed on 4/11/2023. Acknowledgment is made of Applicant's claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The claims to the benefit of priority are acknowledged and the effective filing date of claims 1-21 is 6/24/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/20/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS’s has been considered by the examiner.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description:
Reference character “100” in Fig. 1 is not mentioned in the Specification.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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/PatentLegalFramework), 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:
Nucleotide and/or amino acid sequences appearing in the drawings (Fig. 3, 5-6, and 11B) 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Pg. 2, Para. 5; Pg. 3, Para. 3; and Pg. 31, Para. 1). 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 NCBI (Pg. 2, Para. 4), GenBank (Pg. 26, Para. 4), and EMBL (Pg. 26, Para. 4), which are trade names or marks used in commerce, has been noted in this application. 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.
The listing of references in the specification is not a proper information disclosure statement (see at least Pg. 1, Para. 3; Pg. 2; Para 1 and 5; Pg. 3, Para. 3; Pg. 10, Para. 5; Pg. 12, Para. 1; Pg. 14, Para. 5 and 7; Pg. 16, Para. 4; Pg. 18, Para. 6; Pg. 19, Para. 1-2; Pg. 24, Para. 4; Pg. 25, Para. 3; and Pg. 66, Para. 1). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 3-4 are objected to because of the following informalities:
Claims 3 and 4 recite the phrase “public-accessible nucleotide database”, which should be corrected to “publicly-accessible nucleotide database” for clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-21 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 1 and 21 recite the limitation “inputting sequences of an oligonucleotide set, wherein the oligonucleotide set includes a primer pair and a probe as oligonucleotides” in lines 4-5 and 5-6 of the claims, respectively. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. The limitation recites inputting sequences, but it is unclear what the sequences are being input into (e.g., an algorithm, a computer, a database, etc.). The instant Specification (see Pg. 10, Para. 2) discloses that the method is implemented on a computer, and the sequences of the oligonucleotide set are input to a user interface. Therefore, it appears the sequences are input into user interface, but it is unclear if this is the intended interpretation. This rejection can be overcome by amendment of claims 1 and 21 to clarify what the sequence are being input into. Claims 2-20 are also rejected due to their dependency from claim 1.
Claims 1 and 21 recites the limitation “wherein the match or mismatch information indicates the number of matches or mismatches” in lines 12-13 and 13-14 of the claims, respectively. There is insufficient antecedent basis for the number of matches or mismatches in the claim, since there is no prior mention of this phrase earlier in the claim. This rejection can be overcome by amendment of claims 1 and 21 to recite “wherein the match or mismatch information indicates a number of matches or mismatches”. Claims 2-20 are also rejected due to their dependency from claim 1.
Claim 4 contains the trademarks/trade names GenBank and EMBL. 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 the publicly accessible nucleotide database and, accordingly, the description is indefinite.
Claim 6 recites the limitation “wherein the probe-hybridized amplicons in step (d) are generated in the order of the forward primer and the probe, the probe and the reverse primer, or the forward primer, the probe and the reverse primer” in lines 1-4 of the claim. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. Since there are multiple members of each group, it is unclear which members are part of which group. The claim also appears to be missing an “and” before the last member of the group. Based on the Specification (Pg. 35, Para. 4), the order is “the forward primer and the probe, the probe and the reverse primer or the forward primer, the probe and the reverse primer”. Examiner suggests separating the order by semicolons for clarity, e.g., amendment of claim 6 to recite “wherein the probe-hybridized amplicons in step (d) are generated in the order of the forward primer and the probe; the probe and the reverse primer, or the forward primer; and the probe and the reverse primer”.
Claim 7 recites the limitation “wherein the length indicates a length from a nucleotide at the 5’-end of a forward and/or reverse primer to a nucleotide at the 3’-end of an amplicon amplified by the forward and/or the reverse primer” in lines 5-7 of the claim. There is insufficient antecedent basis for the 3’-end and the 5’-end in the claim, since there is no prior mention of this phrase in claim 1, to which this claim depends. This rejection can be overcome by amendment of claim 7 to recite “wherein the length indicates a length from a nucleotide at a 5’-end of a forward and/or reverse primer to a nucleotide at a 3’-end of an amplicon amplified by the forward and/or the reverse primer”.
Claim 8 recites the limitations “a ratio of the sum of the number of mismatches and the number of partial nucleotides in oligonucleotides included in a combination of oligonucleotides…” and “a ratio of the number of mismatches in a region from the 3'-end of a primer to a nucleotide spaced apart from the 3'-end of the primer by a predetermined length relative to the number of primers included in a combination of oligonucleotides” in lines 5-8 of the claim. There is insufficient antecedent basis for the sum, the number of partial nucleotides, the 3’-end, and the number of primers in the claim, since there is no prior mention of these phrases in claim 1, to which this claim depends. This rejection can be overcome by amendment of claim 8 to recite “a ratio of a sum of the number of mismatches and a number of partial nucleotides in oligonucleotides included in a combination of oligonucleotides…” and “a ratio of the number of mismatches in a region from a 3'-end of a primer to a nucleotide spaced apart from the 3'-end of the primer by a predetermined length relative to a number of primers included in a combination of oligonucleotides”.
Claim 9 recites “wherein the method further comprises after step (d), the following steps: d-2) grouping…; and d-3) providing information…”. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. It is unclear if step d-1), recited in claim 8, needs to precede steps d-2) and d-3), recited in claim 9. If step d-1) in claim 8 does not need to precede steps d-2) and d-3), the numbering of steps d-2) and d-3) should be changed accordingly. This rejection can be overcome by amendment of claim 9 to change the dependency to claim 8 (and recite “after step d-1)”), or change the numbering of steps d-2) and d-3) accordingly.
Claim 12 recites the phrase “ratios of nucleic acid sequences covered by combinations of the oligonucleotides relative to the total nucleic acid sequence” in lines 6-7 of the claim. There is insufficient antecedent basis for the total nucleic acid sequences in the claim, since there is no prior mention of this phrase in claim 1, to which this claim depends. This rejection can be overcome by amendment of claim 12 to recite “ratios of nucleic acid sequences covered by combinations of the oligonucleotides relative to a total nucleic acid sequence”.
Claim 15 recites the limitation “inputting sequences of at least one oligonucleotide set, which are different from the sequences of the oligonucleotide set in step (a)” in lines 2-3 of the claim. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. Analogous to claims 1 and 21, it is unclear what the sequences are being input into (e.g., a computer or algorithm). The instant Specification (see Pg. 10, Para. 2) discloses that the method is implemented on a computer, and the sequences of the oligonucleotide set are input to a user interface. Therefore, it appears the sequences are input into user interface, but it is unclear if this is the intended interpretation. This rejection can be overcome by amendment of claim 15 to clarify what the sequence are being input into. Claims 16-19 are also rejected due to their dependency on claim 15.
Claim 16 recites the limitation “wherein, the at least one oligonucleotide set in step a-1) is the same as or different from the oligonucleotide set in step (a) in view of a nucleic acid molecule or organism to be covered” in lines 1-4 of the claim. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. It is unclear how the oligonucleotide set could be the same, when claim 15 (to which this claim depends) explicitly requires the sequences to be different (i.e., claim 15 recites “wherein the method further comprises, after step (a), a-1) inputting sequences of at least one oligonucleotide set, which are different from the sequences of the oligonucleotide set in step (a)”). This rejection can be overcome by amendment of claim 16 to clarify how the sequences in the oligonucleotide set can be the same.
Claim 20 recites the limitation “comparing the resultant in step (e) and the resultant in step (e) of step (f)” in lines 5-6 of the claim. There is insufficient antecedent basis for the resultant in the claim, since there is no prior mention of this phrase in claim 1, to which this claim depends. This rejection can be overcome by amendment of claim 20 to recite “comparing the provided nucleic acid sequences with and/or without the generation of probe-hybridized amplicons of step (e) and the provided nucleic acid sequences with and/or without the generation of probe-hybridized amplicons of step (f)”, or similar.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 recites the limitation “wherein the sequence of the at least one oligonucleotide of the oligonucleotides included in the at least one oligonucleotide set in step a-1) is different from the sequences of the oligonucleotides included in the oligonucleotide set in step (a)”. Claim 15, to which claim 17 depends, recites the limitation “wherein the method further comprises, after step (a), a-1) inputting sequences of at least one oligonucleotide set, which are different from the sequences of the oligonucleotide set in step (a)”. Claim 15 already requires that the sequences in the oligonucleotide sets of step (a) and step (a-1) are different. Therefore, claim 17 does not further limit the subject matter of claim 15.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite both (1) mathematical concepts (mathematical relationships, formulas or equations, or mathematical calculations) and (2) mental processes, i.e., concepts performed in the human mind (including observations, evaluations, judgements or opinions) (see MPEP § 2106.04(a)).
Step 1:
In the instant application, claims 1-20 are directed towards a method, which falls into one of the categories of statutory subject matter (Step 1: YES).
Claim 21 is directed towards a computer readable storage medium, which does not fall within one of the categories of statutory subject matter (Step 1: NO). Regarding claim 21, the BRI of computer readable storage medium encompasses non-statutory forms of signal transmission and therefore equates to “signals per se”. Claims that equate to “signals per se” are not a statutory category of invention (see MPEP § 2106.03). However, claim 21 could be amended to be statutory subject matter by replacing the phrase “computer readable storage medium” with the phrase “non-transitory computer readable storage medium”. Nonetheless, this amendment would still result in a rejection of the claim under 35 U.S.C 101 for recitation of a judicial exception without significantly more. In the interest of compact prosecution, claim 21 has been analyzed using the Alice/Mayo two-part test below.
Step 2A, Prong One:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong One). The following instant claims recite limitations that equate to one or more categories of judicial exceptions:
Claims 1 and 21 recite a mental process (i.e., an evaluation of data to input) in “inputting sequences of an oligonucleotide set, wherein the oligonucleotide set includes a primer pair and a probe as oligonucleotides”; a mental process (i.e., an evaluation of oligonucleotides to determine match or mismatch patterns) in “providing match or mismatch information and position information of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences by confirming whether the sequences of the oligonucleotide set are mismatched to the plurality of nucleic acid sequences contained in the nucleotide database, wherein the match or mismatch information indicates the number of matches or mismatches and/or a mismatch pattern of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences”; a mental process (i.e., an evaluation of the oligonucleotide sets based on the mismatched information to determine generation of probe-hybridized amplicons) in “confirming whether probe-hybridized amplicons are generated by the oligonucleotide set for each of the plurality of nucleic acid sequences, wherein the primer pair includes a forward primer and a reverse primer; the probe-hybridized amplicons are products amplified by the forward primer and/or reverse primer and indicate amplicons detected by hybridization of the probe included in the oligonucleotide set; and at least one of the probe-hybridized amplicons is formed by a combination of the oligonucleotides according to the match or mismatch information and position information of each of the 2 5 oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences”; and a mental process (i.e., an observation of the provided sequences) in “providing nucleic acid sequences with the generation of probe-hybridized amplicons by the oligonucleotide set and/or nucleic acid sequences without the generation of probe-hybridized amplicons by the oligonucleotide set, wherein the nucleic acid sequences with the generation of probe-hybridized amplicons are covered by the oligonucleotide set and the nucleic acid sequences without the generation of probe-hybridized amplicons are not covered by the oligonucleotide set”.
Claim 2 recites a mental process (i.e., an evaluation of the oligonucleotide set) in “wherein the oligonucleotide set in step (a) further comprises at least one oligonucleotide selected from the oligonucleotides consisting of at least one forward primer, at least one probe, and at least one reverse primer”.
Claim 3 recites a mental process (i.e., an evaluation of the composition of the nucleotide database) in “wherein the nucleotide database in step (b) is a nucleotide database containing nucleic acid sequences collected by an identifier selected from identifiers composed of taxonomy ID, taxonomy name, organism name, and target nucleic acid molecule name, from a public-accessible nucleotide database or a nucleotide database obtaining by downloading the public-accessible nucleotide database, or a nucleotide database containing nucleic acid sequences collected by a user”.
Claim 4 recites a mental process (i.e., an evaluation of the publicly-accessible nucleotide database) in “wherein the public-accessible nucleotide database is a nucleotide database selected from the group consisting of GenBank, European Molecular Biology Laboratory (EMBL), and DNA DataBank of Japan (DDBJ)”.
Claim 5 recites a mental process (i.e., an evaluation of the nucleic acid sequences) in “wherein the plurality of nucleic acid sequences in step (b) include a plurality of target nucleic acid sequences and/or a plurality of non-target nucleic acid sequences”.
Claim 6 recites a mental process (i.e., an evaluation of the order of the generated amplicons) in “wherein the probe-hybridized amplicons in step (d) are generated in the order of the forward primer and the probe, the probe and the reverse primer, or the forward primer, the probe and the reverse primer”
Claim 7 recites a mental process (i.e., an evaluation of whether the generated amplicons satisfy criteria) in “wherein the probe-hybridized amplicons in step (d) are generated or selected to satisfy at least one of the following criteria: (i) a probe-hybridized amplicon length being less than a predetermined value, wherein the length indicates a length from a nucleotide at the 5'-end of a forward and/or reverse primer to a nucleotide at the 3'-end of an amplicon amplified by the forward and/or reverse primer; and (ii) the number of mismatches in each of oligonucleotides included in a combination of oligonucleotides being less than a predetermined value”.
Claim 8 recites a mental process (i.e., an evaluation of the selection criteria to for priority of the probe-hybridized amplicon) in “wherein the method further comprises, after step (d), d-1) selecting, as a main probe-hybridized amplicon, a probe-hybridized amplicon satisfying at least one of selection criteria considering the following priorities, from the at least one formed probe-hybridized amplicon: (i) a ratio of the sum of the number of mismatches and the number of partial nucleotides in oligonucleotides included in a combination of oligonucleotides relative to the number of the oligonucleotides included in the combination of oligonucleotides, wherein the oligonucleotides included in the combination of oligonucleotides include a probe and a forward primer and/or a reverse primer, and the lower the ratio, the higher the priority; (ii) the number of mismatches in a probe included in a combination of oligonucleotides, wherein the smaller the number, the higher the priority; (iii) a ratio of the number of mismatches in a region from the 3'-end of a primer to a nucleotide spaced apart from the 3'-end of the primer by a predetermined length relative to the number of primers included in a combination of oligonucleotides, wherein the lower the ratio, the higher the priority; and (iv) the number of mismatches in a primer included in a combination of oligonucleotides, wherein the smaller the number, the higher the priority”.
Claim 9 recites a mental process (i.e., an evaluation of sequence identify to determine grouping) in “d-2) grouping, according to sequence identity, sequences having a mismatch pattern for each of types of oligonucleotides included in the combination of the oligonucleotides, wherein the grouped sequences having a mismatch pattern has a mismatch pattern having the same mismatch position between the oligonucleotide and the nucleic acid sequence in oligonucleotides of the same type having the mismatch pattern and has a mismatch pattern having the same base between oligonucleotide sequences and between nucleic acid sequences at the mismatch position; and the oligonucleotide type indicates a type of oligonucleotides as a forward primer, a probe, and a reverse primer”; and a mental process (i.e., an observation of provided information on the mismatch for the oligonucleotides) in “d-3) providing information on the mismatch pattern for each combination of oligonucleotides having the same mismatch pattern and generating probe-hybridized amplicons by combining oligonucleotides having the grouped sequences having a mismatch pattern, wherein the information on the mismatch pattern indicates oligonucleotide sequences and nucleic acid sequences having the mismatch pattern, the number of nucleic acid sequences having the mismatch pattern, or a list of identifiers”.
Claim 10 recites a mental process (i.e., an evaluation of whether nucleic acid sequences satisfy criteria) in “wherein the nucleic acid sequences with the generation of probe-hybridized amplicons by the oligonucleotide set in step (e) include nucleic acid sequences satisfying the following criteria (i) and (ii) and nucleic acid sequences satisfying the following criteria (iii) and (iv): (i) a predetermined probe-hybridized amplicon length range; (ii) the number of mismatches for nucleic acid sequences in all the oligonucleotides included in a combination of the oligonucleotides being 0 (zero); (iii) exceeding the length range of (i); and (iv) the number of mismatches in at least one oligonucleotide of the oligonucleotides included in a combination of the oligonucleotides being less than a predetermined value.”
Claim 11 recites a mental process (i.e., an evaluation of how the predetermined probe-hybridized amplicon length range is determined) in “wherein the predetermined probe-hybridized amplicon length range of (i) is determined by a user or determined by a probe-hybridized amplicon length of high frequency among the lengths of the probe-hybridized amplicons generated by a combination of oligonucleotides having no mismatches for a plurality of nucleic acid sequences”.
Claim 12 recites a mental process (i.e., an evaluation of the information contained in the nucleic acid sequences) in “wherein the nucleic acid sequences in step (e) contain information on nucleic acid sequences selected from the group consisting of the number of nucleic acid sequences, accession numbers of the nucleic acid sequences (Accession Nos.), taxonomy names to which the nucleic acid sequences belong, taxonomy IDs assigned to the taxonomy names, ratios of nucleic acid sequences covered by combinations of the oligonucleotides relative to the total nucleic acid sequences, and mismatch patterns of oligonucleotides included in the combination of the oligonucleotides”.
Claim 13 recites a mental process (i.e., an evaluation of the sequences in the database to determine that the oligonucleotide set is covered) in “when the plurality of nucleic acid sequences contained in the nucleotide database of step (b) are a plurality of target nucleic acid sequences, step (e) provides nucleic acid sequences with the generation of probe-hybridized amplicons by the oligonucleotide set, thereby providing a plurality of target nucleic acid sequences covered by the oligonucleotide set”.
Claim 14 recites a mental process (i.e., an evaluation of the sequences in the database to determine that the oligonucleotide set is not covered) in “wherein the plurality of nucleic acid sequences contained in the nucleotide database of step (b) are a plurality of non-target nucleic acid sequences, and step (e) provides information on nucleic acid sequences without the generation of probe-hybridized amplicons by the oligonucleotide set, thereby providing a plurality of non-target nucleic acid sequences not covered by the oligonucleotide set”.
Claim 15 recites a mental process (i.e., an evaluation of data to input that is different from the first set of input sequences) in “after step (a), a-1) inputting sequences of at least one oligonucleotide set, which are different from the sequences of the oligonucleotide set in step (a)”.
Claim 16 recites a mental process (i.e., an evaluation of the oligonucleotide sets) in “wherein, the at least one oligonucleotide set in step a-1) is the same as or different from the oligonucleotide set in step (a) in view of a nucleic acid molecule or organism to be covered”.
Claim 17 recites a mental process (i.e., an evaluation of the sequences differences) in “wherein the sequence of at least one oligonucleotide of the oligonucleotides included in the at least one oligonucleotide set in step a-1) is different from the sequences of the oligonucleotides included in the oligonucleotide set in step (a)”.
Claim 18 recites a mental process (i.e., a comparison of coverage) in “f) comparing the coverage for a plurality of nucleic acid sequences by the oligonucleotide set in step (a) with the coverage for a plurality of nucleic acid sequences by at least one oligonucleotide set in step a-1)”.
Claim 19 recites a mental process (i.e., an evaluation of the timing of oligonucleotide set input) in “wherein the oligonucleotide set in step (a) and the at least one oligonucleotide set in step a-1) are oligonucleotide sets designed at different time points”.
Claim 19 recites a mental process (i.e., repeating the steps of the method) in “(f) performing steps (a) to (e) on a nucleotide database provided at a different time point from that in step (b)”; and a mental process (i.e., a comparison of data) in “(g) comparing the resultant in step (e) and the resultant in step (e) of step (f)”.
These recitations are similar to the concepts of collecting information, and displaying certain results of the collection and analysis is Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)), and organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships.
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification, and are determined to be directed to mental processes that in the simplest embodiments are not too complex to practically perform in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Specifically, claims 1 and 21 involve nothing more inputting sequence data, determining mismatch counts/patterns, generating probe-hybridized amplicons based on match or mismatch information, and providing sequence data. Since there are no specifics in the methodology, the steps of inputting sequence data, determining mismatch counts/patterns, generating probe-hybridized amplicons based on match or mismatch information, and providing sequence data, are something that under BRI, one could perform mentally. Therefore, the claimed steps are not further defined beyond something that reads on merely looking at data and making a determination using a computer as a tool. As such, said steps are directed to judicial exceptions. The instant claims must therefore be examined further to determine whether they integrate the abstract idea into a practical application (Step 2A, Prong One: YES).
Step 2A, Prong Two:
In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP § 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP § 2106.04(d)(I)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP § 2106.04(d)(III)). The following independent claims recite limitations that equate to additional elements:
Claims 1 and 21 recite “providing a nucleotide database, wherein the nucleotide database contains a plurality of nucleic acid sequences”
Claim 21 also recites “a computer readable storage medium comprising instructions to configure a processor to perform a method”.
Regarding the above cited limitations in claims 1 and 21 of (i) providing a nucleotide database, wherein the nucleotide database contains a plurality of nucleic acid sequences. These limitations equate to insignificant, extra-solution activity of mere data gathering because these limitations gather data before the recited judicial exceptions of providing match or mismatch information, confirming generation of probe-hybridized amplicons, and providing nucleic acid sequences (see MPEP § 2106.04(d)).
Regarding the above cited limitation in claim 21 of (ii) a computer readable storage medium comprising instructions to configure a processor to perform a method. This limitation requires only a generic computer component, which does not improve computer technology. Therefore, this limitation equates to mere instructions to implement an abstract idea on a generic computer, which the courts have established does not render an abstract idea eligible in Alice Corp. 573 U.S. at 223, 110 USPQ2d at 1983. As such, claims 1-21 are directed to an abstract idea (Step 2A, Prong Two: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The instant independent claims recite the same additional elements described in Step 2A, Prong Two above.
Regarding the above cited limitation in claim 21 of (ii) a computer readable storage medium comprising instructions to configure a processor to perform a method. This limitation equates to instructions to implement an abstract idea on a generic computing environment, which the courts have established does not provide an inventive concept (see MPEP § 2106.05(d) and MPEP § 2106.05(f)).
Regarding the above cited limitations in claims 1 and 21 of (i) providing a nucleotide database, wherein the nucleotide database contains a plurality of nucleic acid sequences. These limitations when viewed individually and in combination, are WURC limitations as taught by Chun et al. (WIPO Publication WO 2017/209575 A1; published 12/07/2027; cited in the IDS dated 12/20/2022). Chun et al. discloses a computer-based method for evaluating the specificity of oligonucleotides (Abstract, Para. [27]). Chun et al. further discloses that the method includes a step for comparing against a nucleotide sequence database, where the database contains information related to nucleotide sequences, for example, their specific sequences and identities (limitation (i)) (Para. [139]-[141]).
These additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the instant claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 1-21 are not patent eligible.
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.
Claims 1-5, 7, 13-14, and 20-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chun et al. (WIPO Publication WO 2017/209575 A1; published 12/07/2027; cited in the IDS dated 12/20/2022).
Regarding claim 1, Chun et al. teaches a computer-based method for evaluating the specificity of oligonucleotides (Abstract, Para. [27]). The number of match/mismatches per each portion can be predefined for evaluating specificity, and then the coverage, inclusivity and exclusivity of the nucleotide can be evaluated (i.e., a computer-implemented method for providing a coverage of an oligonucleotide set for a plurality of nucleic acid sequences) (Para. [245]). Chun et al. further teaches that the method includes a step where an oligonucleotide to be evaluated is provided. The oligonucleotide is a primer or a probe, which is used for amplifying and detecting a target nucleic acid sequence (Para. [71]). The oligonucleotide may be one of a plurality of oligonucleotides for amplifying or detecting a plurality of target nucleic acid sequences (Para. [134]). The oligonucleotide may be one of a pair of primers (e.g., a forward primer and a reverse primer) for amplifying a target nucleic acid sequence (i.e., inputting sequences of an oligonucleotide set, wherein the oligonucleotide set includes a primer pair and a probe as oligonucleotides) (Para. [135]). Chun et al. further teaches that the method includes a step for comparing against a nucleotide sequence database (Para. [139]). The database of nucleotide sequences is a set of data relating two or more nucleotide sequences derived from various sources. The database of nucleotide sequences may comprise information related to nucleotide sequences, for example, their specific sequences and identities (i.e., providing a nucleotide database, wherein the nucleotide database contains a plurality of nucleic acid sequences) (Para. [141]). Chun et al. further teaches that the method includes a step of analyzing portion-by-portion match/mismatch between the oligonucleotide and each of the reference nucleotide sequences to provide individual match results (Para. [24]). The oligonucleotide is aligned with each of the extracted reference nucleotide sequences on the basis of the homology region thereof, and the numbers or ratios of matched or mismatched bases are then analyzed in individual portions (Para. [193]). The match/mismatch analysis between the oligonucleotide and each of the reference nucleotide sequences provides the number or ratio of matched or mismatched bases between individual portions of the oligonucleotide and each of the reference nucleotide sequences (i.e., providing match or mismatch information and position information of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences by confirming whether the sequences of the oligonucleotide set are mismatched to the plurality of nucleic acid sequences contained in the nucleotide database, wherein the match or mismatch information indicates the number of matches or mismatches and/or a mismatch pattern of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences) (Para. [50]). Chun et al. further teaches that the analysis of the resulting homologous sequences to check whether the designed oligonucleotide hybridizes only to a desired target nucleic acid sequence. Such specificity evaluation process has become a very useful tool for assessing the suitability or workability of primers and probes (Para. [12]). The evaluated oligonucleotide may be one of a pair of primers (e.g., a forward primer and a reverse primer) for amplifying a target nucleic acid sequence (i.e., confirming whether probe-hybridized amplicons are generated by the oligonucleotide set for each of the plurality of nucleic acid sequences, wherein the primer pair includes a forward primer and a reverse primer; the probe-hybridized amplicons are products amplified by the forward primer and/or reverse primer and indicate amplicons detected by hybridization of the probe included in the oligonucleotide set) (Para. [135]). Additionally, for oligonucleotides where the match in the Z portion is more important than the match in the X portion in terms of specificity, the presence of mismatches between the Z portion of the oligonucleotide and the target nucleic acid sequence provides a strong basis for the user to select other oligonucleotides instead of the designed oligonucleotide. On the other hand, the presence of mismatches in the X portion provides a hint for the user to decide whether to use the oligonucleotide in view of hybridization conditions, since the oligonucleotide even with mismatched base pairs in the X portion may hybridize to a target nucleic acid sequence under certain conditions. As such, match/mismatch results of the X and Z portions are very useful in evaluating specificity of oligonucleotides. The specificity of the oligonucleotide can be evaluated by combining the specificity evaluation in each portion, thereby determining the nucleotide sequences to which the oligonucleotide is annealed or hybridized (i.e., at least one of the probe-hybridized amplicons is formed by a combination of the oligonucleotides according to the match or mismatch information and position information of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences) (Para. [191] and [244]). Chun et al. further teaches that primers or probes may also hybridize with reference nucleotide sequences with a few mismatches under certain hybridization conditions. Therefore, in order to evaluate the suitability or workability of the designed primer or probe, it is necessary to check perfectly matched reference nucleotide sequences as well as partially matched reference nucleotide sequences. To this end, the method of the present invention provides a list and the number of reference nucleotide sequences belonging to each group, and biological properties of each of the reference nucleotide sequences in a simple and intuitive manner. Additionally, the number of match/mismatches per each portion can be predefined for evaluating specificity, and then the coverage, inclusivity and exclusivity of the oligonucleotide can be evaluated. Further, the coverage, inclusivity and exclusivity of the oligonucleotide can be modulated, if needed, by adjusting the hybridization conditions and the like (i.e., providing nucleic acid sequences with the generation of probe-hybridized amplicons by the oligonucleotide set and/or nucleic acid sequences without the generation of probe-hybridized amplicons by the oligonucleotide set, wherein the nucleic acid sequences with the generation of probe-hybridized amplicons are covered by the oligonucleotide set and the nucleic acid sequences without the generation of probe-hybridized amplicons are not covered by the oligonucleotide set) (Para. [245] and [257]).
Regarding claim 2, Chun et al. teaches that the oligonucleotide is a primer or a probe, which is used for amplifying and detecting a target nucleic acid sequence (Para. [71]). The oligonucleotide may be one of a plurality of oligonucleotides (Para. [134]). The oligonucleotide may be one of a pair of primers (e.g., a forward primer and a reverse primer) (i.e., wherein the oligonucleotide set in step (a) further comprises at least one oligonucleotide selected from the oligonucleotides consisting of at least one forward primer, at least one probe, and at least one reverse primer) (Para. [135]).
Regarding claim 3, Chun et al. teaches that the term "database of nucleotide sequences", "nucleotide sequence database", "nucleotide database", or "database" as used herein refers to a set or collection of data relating to two or more nucleotide sequences derived from various sources. The database of nucleotide sequences may comprise information related to nucleotide sequences, for example, their specific sequences and identities. The database may be publicly available, commercially available, or generated by the inventor (i.e., wherein the nucleotide database in step (b) is a nucleotide database containing nucleic acid sequences collected by an identifier selected from identifiers composed of taxonomy ID, taxonomy name, organism name, and target nucleic acid molecule name, from a public accessible nucleotide database or a nucleotide database obtaining by downloading the public-accessible nucleotide database, or a nucleotide database containing nucleic acid sequences collected by a user) (Para. [141]).
Regarding claim 4, Chun et al. teaches that examples of databases well known in the art include, but are not limit to, a GenBank database, an EST database, an EMBL nucleotide sequence database, an Entrez nucleotide database, and a LIFESEQTM database (i.e., wherein the public-accessible nucleotide database is a nucleotide database selected from the group consisting of GenBank and European Molecular Biology Laboratory (EMBL)) (Para. [142]).
Regarding claim 5, Chun et al. teaches that the biological features of the reference nucleotide sequences may be useful in evaluating specificity of an oligonucleotide. The user analyzes the list of reference nucleotide sequences comprising a region homologous to the designed oligonucleotide and their specific sequence information, thereby determining whether the designed oligonucleotide amplifies or detects (or hybridizes to) only the target nucleic acid sequence, but not the non-target nucleic acid sequence. The presence of a target nucleic acid sequence and the absence of non-target nucleic acid sequences in the list of reference nucleotide sequences indicate that the oligonucleotide is suitable for amplification or detection of a target nucleic acid sequence. In contrast, the presence of non-target nucleic acid sequences in the list of reference nucleotide sequences indicates that the oligonucleotide is not suitable for amplification or detection of a target nucleic acid sequence (i.e., wherein the plurality of nucleic acid sequences in step (b) include a plurality of target nucleic acid sequences and/or a plurality of non-target nucleic acid sequences) (Para. [251]).
Regarding claim 7, Chun et al. teaches an example where with regard to the specificity of the X portion, it is determined whether there are two or less mismatches between the X portion and a reference nucleotide sequence, and with regard to the specificity of the Z portion, it is determined whether there is one or less mismatch between the X portion and a reference nucleotide sequence (i.e., wherein the probe-hybridized amplicons in step (d) are generated or selected to satisfy at least one of the following criteria: (ii) the number of mismatches in each of the oligonucleotides included in a combination of oligonucleotides being less than a predetermined value) (Para. [243]).
Regarding claims 13 and 14, Chun et al. teaches that the biological features of the reference nucleotide sequences may be useful in evaluating specificity of an oligonucleotide. The user analyzes the list of reference nucleotide sequences comprising a region homologous to the designed oligonucleotide and their specific sequence information, thereby determining whether the designed oligonucleotide amplifies or detects (or hybridizes to) only the target nucleic acid sequence, but not the non-target nucleic acid sequence. The presence of a target nucleic acid sequence and the absence of non-target nucleic acid sequences in the list of reference nucleotide sequences indicate that the oligonucleotide is suitable for amplification or detection of a target nucleic acid sequence. The presence of non-target nucleic acid sequences in the list of reference nucleotide sequences indicates that the oligonucleotide is not suitable for amplification or detection of a target nucleic acid sequence, which becomes a strong basis for selecting other oligonucleotides. The biological features of the reference nucleotide sequences include information conducive to determination of the target coverage of the oligonucleotide (i.e., wherein, when the plurality of nucleic acid sequences contained in the nucleotide database of step (b) are a plurality of target nucleic acid sequences, step (e) provides nucleic acid sequences with the generation of probe-hybridized amplicons by the oligonucleotide set, thereby providing a plurality of target nucleic acid sequences covered by the oligonucleotide set; and wherein the plurality of nucleic acid sequences contained in the nucleotide database of step (b) are a plurality of non-target nucleic acid sequences, and step (e) provides information on nucleic acid sequences without the generation of probe-hybridized amplicons by the oligonucleotide set, thereby providing a plurality of non-target nucleic acid sequences not covered by the oligonucleotide set) (Para. [251]-[252]).
Regarding claim 20, Chun et al. teaches that the information provided may be used to determine whether the oligonucleotide exhibits the same match results as those that have been reviewed at the time of initial design. For example, assuming that the oligonucleotide was designed to match five target nucleic acid sequences in the mismatch type "0I0" (the number of mismatched bases in the X portion is zero and the number of mismatched bases in the Z portion is zero), to match three target nucleic acid sequences in the mismatch type "1I0" and to match two target nucleic acid sequences in the mismatch type "1I1", it is possible to determine whether the same results are obtained as the mismatch results considered in the design, by comparing the designed oligonucleotide against a database containing only the target nucleic acid sequences, and identifying the numbers of target nucleic acid sequences belonging to the mismatch types "0I0", "1I0", and "1I1", respectively. In addition, the further results of classification may be used to verify the coverage of the oligonucleotide. The user can analyze the results of classification and identify the target nucleic acid sequences to be amplified or detected using the designed oligonucleotide, so that the results of classification can be used to verify the coverage of the oligonucleotide (i.e., performing steps (a) to (e) on a nucleotide database provided at a time point different from that in step (b); and comparing the resultant in step (e) and the resultant in step (e) of step (f)) (Para. [262]-[263]).
Regarding claim 21, Chun et al. teaches that a computer readable storage medium containing instructions to configure a processor to perform a method for evaluating the specificity of a nucleotide is provided (i.e., computer readable storage medium comprising instructions to configure a processor to perform a method for providing a coverage of an oligonucleotide set for a plurality of nucleic acid sequences) (Para. [284]). Chun et al. further teaches the limitations of inputting sequences of an oligonucleotide set, wherein the oligonucleotide set includes a primer pair and a probe as oligonucleotides; providing a nucleotide database, wherein the nucleotide database contains a plurality of nucleic acid sequences; providing match or mismatch information and position information of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences by confirming whether the sequences of the oligonucleotide set are mismatched to the plurality of nucleic acid sequences contained in the nucleotide database, wherein the match or mismatch information indicates the number of matches or mismatches and/or a mismatch pattern of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences; confirming whether probe-hybridized amplicons are generated by the oligonucleotide set for each of the plurality of nucleic acid sequences, wherein the primer pair includes a forward primer and a reverse primer; the probe-hybridized amplicons are products amplified by the forward primer and/or reverse primer and indicate amplicons detected by hybridization of the probe included in the oligonucleotide set; and at least one of the probe-hybridized amplicons is formed by a combination of the oligonucleotides according to the match or mismatch information and position information of each of the oligonucleotides included in the oligonucleotide set for each of the plurality of nucleic acid sequences; and providing nucleic acid sequences with the generation of probe-hybridized amplicons by the oligonucleotide set and/or nucleic acid sequences without the generation of probe-hybridized amplicons by the oligonucleotide set, wherein the nucleic acid sequences with the generation of probe-hybridized amplicons are covered by the oligonucleotide set and the nucleic acid sequences without the generation of probe-hybridized amplicons are not covered by the oligonucleotide set as described for claim 1 above.
Therefore, Chun et al. teaches all the limitations disclosed in claims 1-5, 7, 13-14, and 20-21.
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.
1. Claims 6 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Chun et al. as applied to claims 1-5, 7, 13-14, and 20-21 above, and further in view of Huang et al. (PRISE2: Software for designing sequence-selective PCR primers and probes. BMC Bioinformatics. 15: 317, 8 pages (2014); published 9/25/2014).
Regarding claim 9, Chun et al. teaches that the results of classification of the reference nucleotide sequences are those obtained by grouping (sorting) the reference nucleotide sequences on the basis of the number of mismatched bases in the X portion and the number of mismatched bases in the Z portion, including, for example, a list and the number of reference nucleotide sequences belonging to each group, and a biological properties of each of the reference nucleotide sequences (i.e., grouping, according to sequence identity, sequences having a mismatch pattern for each of types of oligonucleotides included in the combination of the oligonucleotides) (Para. [256]). The oligonucleotide is a forward primer, probe, or reverse primer, as described for claim 1 above (i.e., the oligonucleotide type indicates a type of oligonucleotides as a forward primer, a probe, and a reverse primer).
Chun et al., as applied to claims 1-5, 7, 13-14, and 20-21 above, does not teach wherein the probe-hybridized amplicons in step (d) are generated in the order of the forward primer and the probe, the probe and the reverse primer, or the forward primer, the probe and the reverse primer (claim 6); wherein the method further comprises, after step (d), d-1) selecting, as a main probe-hybridized amplicon, a probe-hybridized amplicon satisfying at least one of selection criteria considering the following priorities, from the at least one formed probe-hybridized amplicon: (i) a ratio of the sum of the number of mismatches and the number of partial nucleotides in oligonucleotides included in a combination of oligonucleotides relative to the number of the oligonucleotides included in the combination of oligonucleotides, wherein the oligonucleotides included in the combination of oligonucleotides include a probe and a forward primer and/or a reverse primer, and the lower the ratio, the higher the priority; (ii) the number of mismatches in a probe included in a combination of oligonucleotides, wherein the smaller the number, the higher the priority; (iii) a ratio of the number of mismatches in a region from the 3'-end of a primer to a nucleotide spaced apart from the 3'-end of the primer by a predetermined length relative to the number of primers included in a combination of oligonucleotides, wherein the lower the ratio, the higher the priority; and (iv) the number of mismatches in a primer included in a combination of oligonucleotides, wherein the smaller the number, the higher the priority (claim 8); wherein the grouped sequences having a mismatch pattern has a mismatch pattern having the same mismatch position between the oligonucleotide and the nucleic acid sequence in oligonucleotides of the same type having the mismatch pattern and has a mismatch pattern having the same base between oligonucleotide sequences and between nucleic acid sequences at the mismatch position; and the oligonucleotide type indicates a type of oligonucleotides as a forward primer, a probe, and a reverse primer (claim 9); and providing information on the mismatch pattern for each combination of oligonucleotides having the same mismatch pattern and generating probe-hybridized amplicons by combining oligonucleotides having the grouped sequences having a mismatch pattern, wherein the information on the mismatch pattern indicates oligonucleotide sequences and nucleic acid sequences having the mismatch pattern, the number of nucleic acid sequences having the mismatch pattern, or a list of identifiers (claim 9).
Regarding claim 6, Huang et al. teaches a software tool, PRISE2, for designing sequence-selective PCR primers and probes with a high level of selectivity (Abstract). Huang et al. further teaches that the probe design feature is integrated with the primer design process, in the sense that users can add probes to selected primer pairs, and the triples consisting of a forward primer, reverse primer and a probe are evaluated in tandem, in terms of coverage and other quality criteria. PRISE2 considers all combinations of forward/reverse primers and probes, so for such groups it is able to find individually non-specific but group-specific primer sets, for which the methods using signature primers are not likely to be effective (i.e., wherein the probe-hybridized amplicons in step (d) are generated in the order of the forward primer and the probe, the probe and the reverse primer, or the forward primer, the probe and the reverse primer) (Pg. 2, Col. 2, Para. 1).
Regarding claim 8, Huang et al. teaches that designing primers and probes in PRISE2 is accomplished in three stages: 1) Identification of target and non-target sequences. Here, the user can download a collection of sequences from GenBank and use the provided interactive tools to choose from them (or from other collections of sequences) the desired sets of target and non-target sequences; 2) Generation of candidate primer pairs. In this step, the program computes a set of primer candidates, according to the specified parameters, and groups them into primer pairs. Then the user can use a variety of sorting tools to manipulate the list of these primer pairs to choose a smaller collection of high quality primer pairs; and 3) Adding probes. Once these desired primer pairs have been selected, the next module of PRISE2 allows probes to be added to each primer pair. For each primer pair, PRISE2 determines a list of candidate probes. This produces a collection of primer-probe sets that can be sorted according to multiple criteria, thus allowing the user to choose, ultimately, the final collection of primer-probe sets best suited for their PCR experiments (i.e., wherein the method further comprises, after step (d), d-1) selecting, as a main probe-hybridized amplicon, a probe-hybridized amplicon satisfying at least one of selection criteria considering the following priorities, from the at least one formed probe-hybridized amplicon) (Pg. 3, Para. 1). Huang et al. further teaches that there are two categories of selectivity settings: mismatch allowance mechanism and mismatch cost matrix. The purpose of mismatch-allowance mechanism is to emphasize primer selectivity on the 3’ end, which is crucial for functional primers. This is accomplished by setting limits on the accumulated number of mismatches, starting at the 3’ end and ending at any position. For example, one can specify 0 mismatches on the first 3 positions, at most 1 mismatch on the first 5 positions, and at most 2 mismatches on the first 7 positions. The mismatch cost matrix is a nucleotide-to-nucleotide dissimilarity function that reflects the likelihood of binding to occur, with smaller values representing higher likelihood. For example, in its simplest form, its entries could be 0 for equal bases (matches) and 1 for different bases (mismatches). Users can adjust these values to distinguish different types of mismatches, for example A/G and A/C mismatches may be assigned different costs (i.e., (iv) the number of mismatches in a primer included in a combination of oligonucleotides, wherein the smaller the number, the higher the priority) (Pg. 3, Col. 2, Para. 5 – Pg. 4, Col. 1, Para. 1). Huang et al. further teaches that as in the primer design process, users can specify their own scoring scheme for probes, the cost function, and the mismatch allowance matrix, to obtain the desired selectivity to target sequences. Unlike for primers, however, where matches on the 3’ end were considered more important, in the case of probes, PRISE2 focuses on the middle section of the probe by allowing the user to specify the number of continuous matches near the center of the probe. Such continuous matches increase the likelihood of binding, even if some mismatches occur near the ends of the probe. These mismatch criteria can be specified separately for target and non-target sequences. Once probe properties and selectivity settings are defined, PRISE2 will compute, for each pair of selected primers, the list of probes that match all the criteria. The final result is a list of primer-probe sets, each consisting of a pair of primers and a probe, that meet all criteria for primers and probes. PRISE2 displays these results in a window with separate tabs for each primer pair, sorted according to the selectivity function (i.e., (ii) the number of mismatches in a probe included in a combination of oligonucleotides, wherein the smaller the number, the higher the priority) (Pg. 4, Col. 2, Para. 5 – Pg. 5, Col. 1, Para. 3).
Regarding claim 9, Huang et al. teaches that PRISE2 implements a flexible mechanism for specifying primer-template mismatch criteria at specific positions at the 3’ end, with a detailed per-position mismatch allowance matrix (Pg. 6, Col. 1, Para. 5). In the matrix, in its simplest form, its entries could be 0 for equal bases (matches) and 1 for different bases (mismatches). Users can adjust these values to distinguish different types of mismatches, for example A/G and A/C mismatches may be assigned different costs (i.e., wherein the grouped sequences having a mismatch pattern has a mismatch pattern having the same mismatch position between the oligonucleotide and the nucleic acid sequence in oligonucleotides of the same type having the mismatch pattern and has a mismatch pattern having the same base between oligonucleotide sequences and between nucleic acid sequences at the mismatch position) (Pg. 3, Col. 2, Para. 6 – Pg. 4, Col. 1, Para. 1). Huang et al. further teaches the use of the mismatch-allowance mechanism for primers (Pg. 3, Col. 2, Para. 5) and probes (Pg. 4, Col. 2, Para. 5). Once probe properties and selectivity settings are defined, PRISE2 will compute, for each pair of selected primers, the list of probes that match all the criteria. The final result is a list of primer-probe sets, each consisting of a pair of primers and a probe, that meet all criteria for primers and probes. PRISE2 displays these results in a window with separate tabs for each primer pair, sorted according to the selectivity function. For each primer pair the program shows a tabulated list, with rows corresponding to probes and columns showing properties of the corresponding primer-probe set (i.e., providing information on the mismatch pattern for each combination of oligonucleotides having the same mismatch pattern and generating probe-hybridized amplicons by combining oligonucleotides having the grouped sequences having a mismatch pattern, wherein the information on the mismatch pattern indicates oligonucleotide sequences and nucleic acid sequences having the mismatch pattern, the number of nucleic acid sequences having the mismatch pattern, or a list of identifiers) (Pg. 5, Col. 1, Para. 2-4).
Therefore, regarding claims 6 and 8-9, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of evaluating the specificity of oligonucleotides of Chun et al. with the method of generating primers and probes based on mismatch information of Huang et al. because the method of Huang et al. provides a staged approach to produce probes/primers, evaluate them based on quality indicators, and choose subsets of candidates that meet user criteria (Huang et al., Pg. 2, Col. 2, Para. 3). One of ordinary skill in the art would be able to combine the teachings of Chun et al. with Huang et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both are drawn towards a method for designing primers and probes based on mismatch patterns. Therefore, regarding claims 6 and 8-9, the instant invention is prima facie obvious (MPEP § 2142).
2. Claims 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Chun et al. as applied to claims 1-5, 7, 13-14, and 20-21 above, and further in view of Yoon et al. (WIPO Publication WO 2018/066950 A1; published 4/12/2018; cited in the IDS dated 12/20/2022).
Regarding claim 10, Chun et al. teaches that the number of match/mismatches in each portion can be predefined for evaluating specificity and coverage of the oligonucleotide (Para. [245]). For example, the number of reference nucleotide sequences having the mismatch of "0I0" (the number of mismatched bases in the X portion is zero and the number of mismatched bases in the Z portion is zero) with regard to the oligonucleotide of Formula (I) may be provided (Para. [258]). If the number of reference nucleotide sequences belonging to the mismatch type "0I0" is provided as "30", it means that there are 30 reference nucleotide sequences which are 100% identical to the X and Z portions in the oligonucleotide of Formula (l) (i.e., (ii) the number of mismatches for nucleic acid sequences in all oligonucleotides included in a combination of the oligonucleotides being 0 (zero)) (Para. [259]). Chun et al. further teaches an example where with regard to the specificity of the X portion, it is determined whether there are two or less mismatches between the X portion and a reference nucleotide sequence, and with regard to the specificity of the Z portion, it is determined whether there is one or less mismatch between the X portion and a reference nucleotide sequence (i.e., (iv) the number of mismatches in at least one oligonucleotide of the oligonucleotide included in a combination of the oligonucleotide being less than a predetermined value) (Para. [243]).
Chun et al., as applied to claims 1-5, 7, 13-14, and 20-21 above, does not teach satisfying the criteria: (i) a predetermined probe-hybridized amplicon length range and (iii) exceeding the length range of (i) (claim 10); wherein the predetermined probe-hybridized amplicon length range of (i) is determined by a user or determined by a probe-hybridized amplicon length of high frequency among the lengths of the probe-hybridized amplicons generated by a combination of oligonucleotides having no mismatches for a plurality of nucleic acid sequences (claim 11); wherein the nucleic acid sequences in step (e) contain information on nucleic acid sequences selected from the group consisting of the number of nucleic acid sequences, accession numbers of the nucleic acid sequences (Accession Nos.), taxonomy names to which the nucleic acid sequences belong, taxonomy IDs assigned to the taxonomy names, ratios of nucleic acid sequences covered by combinations of the oligonucleotides relative to the total nucleic acid sequences, and mismatch patterns of oligonucleotides included in the combination of the oligonucleotides (claim 12); wherein the method further comprises, after step (a), a-1) inputting sequences of at least one oligonucleotide set, which are different from the sequences of the oligonucleotide set in step (a) (claim 15); wherein, the at least one oligonucleotide set in step a-1) is the same as or different from the oligonucleotide set in step (a) in view of a nucleic acid molecule or organism to be covered (claim 16); wherein the sequence of at least one oligonucleotide of the oligonucleotides included in the at least one oligonucleotide set in step a-1) is different from the sequences of the oligonucleotides included in the oligonucleotide set in step (a) (claim 17); wherein the method further comprises, f) comparing the coverage for a plurality of nucleic acid sequences by the Oligonucleotide set in step (a) with the coverage for a plurality of nucleic acid sequences by at least one oligonucleotide set in step a-1) (claim 18); and wherein the oligonucleotide set in step 15 (a) and the at least one oligonucleotide set in step a-1) are oligonucleotide sets designed at different time points (claim 19).
Regarding claim 10, Yoon et al. teaches a method for preparing oligonucleotides for detecting a target nucleic acid molecule in a sample (Abstract). Yoon et al. further teaches the ranking of oligonucleotides based on priority items. According to one embodiment, the at least two priority items differ from each other in terms of criticality and the method further comprises selecting at least one oligonucleotide from the oligonucleotides of the third oligonucleotide candidate group in accordance with ranks in the at least two priority items with considering the criticality (i.e., wherein the nucleic acid sequences with the generation of probe-hybridized amplicons by the oligonucleotide set in step (e) include nucleic acid sequences satisfying the following criteria (i) and (ii) and nucleic acid sequences satisfying the following criteria (iii) and (iv)) (Pg. 35, Line 17 – Pg. 36, Line 16). Yoon et al. further teaches the prioritized oligonucleotides are probes, a top-most probe is selected from the prioritized probes and a primer suitable for the topmost probe is selected. The term "suitable" means possession of at least one of the following characteristics: with respect to the selected probe, a primer and the probe do not form a heterodimer, primers form an amplicon of the desired size (most particularly 300-400 nucleotides), and a primer has a Tm value of [55°C to (Tm of the probe minus 10°C) 0°C] (i.e., (i) a predetermined probe-hybridized amplicon length range) (Pg. 37, Lines 22-27 and Pg. 38, Lines 12-15). Yoon et al. further teaches that, for example, primers should be located upstream and downstream with regard to the selected probe, and be capable of forming an amplicon having an appropriate size (particularly, 100-1000, more particularly 200-800, still more particularly 300-700, still much more particularly 300-500, most particularly 300-400 nucleotides) (i.e., (iii) exceeding the length range of (i)) (Pg. 37, Lines 11-14).
Regarding claim 11, Yoon et al. teaches an example wherein the suitable primer was selected by the user from primers which form an amplicon having a suitable size (200-500 nucleotides) and do not form a heterodimer with the selected probe (i.e., wherein the predetermined probe-hybridized amplicon length range of (i) is determined by a user) (Pg. 51, Lines 25-27).
Regarding claim 12, Yoon et al. teaches that the information related to the target nucleic acid molecule used to design the oligonucleotides additionally comprises at least one information selected from the group consisting of a name of a target organism from which the target nucleic acid molecule is derived, a taxonomy of a target organism, a name of the target nucleic acid molecule and an identifier of the target nucleic acid molecule in a public accessible sequence database. The additional information may be used as information for obtaining the first selection nucleotide sequence of the target nucleic acid molecule. For example, the identifier includes an accession number, a locus name, and a gi number in GenBank DB, and particularly, an access number (Pg. 9, Line 15 – Pg. 10, Line 5). A further example teaches that the information related to the target nucleic acid molecule includes the name of Candida albicans as a target organism, its taxonomy ID (particularly, taxonomy ID in GenBank) and PHRl gene sequence information in length of 2026 mer as a first selected nucleotide sequence (i.e., wherein the nucleic acid sequences in step (e) contain information on nucleic acid sequences selected from the group consisting of the number of nucleic acid sequences, accession numbers of the nucleic acid sequences (Accession Nos.), taxonomy names to which the nucleic acid sequences belong, taxonomy IDs assigned to the taxonomy names) (Pg. 44, Lines 24-26).
Regarding claim 15, Yoon et al. teaches that the oligonucleotides for detecting the target nucleic acid molecule in the sample using information related to the target nucleic acid molecule are designed to provide a first oligonucleotide candidate group. The information related to the target nucleic acid molecule comprises a first selected nucleotide sequence of the target nucleic acid molecule and the first oligonucleotide candidate group comprises a probe and/or a primer comprising a nucleotide sequence complementary to the first selected nucleotide sequence of the target nucleic acid molecule (Pg. 7, Lines 5-11). A second oligonucleotide candidate group is provided by using the first oligonucleotide candidate group. This step may be also referred to as (i) selecting oligonucleotides of the first oligonucleotide candidate group; and/or (ii) modifying with a degenerate base and/or a universal base to provide a second oligonucleotide candidate group with higher target-coverage than the first oligonucleotide candidate group (i.e., wherein the method further comprises, after step (a), a-1) inputting sequences of at least one oligonucleotide set, which are different from the sequences of the oligonucleotide set in step (a)) (Pg. 20, Line 27 – Pg. 21, Line 3).
Regarding claim 16, Yoon et al. teaches that from the first oligonucleotide candidate group, at least one oligonucleotide showing a predetermined target-coverage for the first selected nucleotide sequence and the at least one reference nucleotide sequence is selected to provide the second oligonucleotide candidate group comprising the at least one oligonucleotide. This step is carried out by selecting an appropriate oligonucleotide without modifying the oligonucleotide of the first oligonucleotide candidate group. For example, the second oligonucleotide candidate group may be provided by selecting at least one oligonucleotide showing a predetermined target-coverage ( e.g., 80% or more, 85% or more, 90% or more, 95% or more, or 100% target-coverage) for the first selected nucleotide sequence and the at least one reference nucleotide sequence. This step is suitable for providing oligonucleotides used to detect genes of an organism having a lower genetic diversity such as bacteria (i.e., wherein the at least one oligonucleotide set in step a-1) is the same as or different from the oligonucleotide set in step (a) in view of a nucleic acid molecule or organism to be covered) (Pg. 21, Line 18 – Pg. 22, Line 1).
Regarding claim 17, Yoon et al. teaches that alternatively, the second oligonucleotide candidate group may be provided as follows: In the first oligonucleotide candidate group, at least one base of at least one oligonucleotide showing a target-coverage of less than 100% for the first selected nucleotide sequence and at least one reference nucleotide sequence is replaced with a degenerate base and/or a universal base to provide a modified oligonucleotide with increased target-coverage, thereby providing the second oligonucleotide candidate group. The second oligonucleotide candidate group comprises comprising the modified oligonucleotide (i.e., wherein the sequence of at least one oligonucleotide of the oligonucleotides included in the at least one oligonucleotide set in step a-1) is different from the sequences of the oligonucleotides included in the oligonucleotide set in step (a)) (Pg. 22, Lines 20-28).
Regarding claim 18, Yoon et al. teaches that the method includes the evaluation of the target-coverage of the first oligonucleotide candidate group for the first selected nucleotide sequence and the at least one reference nucleotide sequence. Subsequently, an oligonucleotide showing the target coverage of 100% and/or an oligonucleotide whose target-coverage is less than 100% and is not increased by replacing with the degenerate base and/or the universal base are selected to provide the second oligonucleotide candidate group. The second oligonucleotide candidate group is then provided by replacing with a degenerate base and/or a universal base at least one base of at least one oligonucleotide whose target-coverage is less than 100% and is increased by replacing with the degenerate base and/or the universal base, which provides a modified oligonucleotide with increased target-coverage (i.e., wherein the method further comprises, f) comparing the coverage for a plurality of nucleic acid sequences by the oligonucleotide set in step (a) with the coverage for a plurality of nucleic acid sequences by at least one oligonucleotide set in step a-1)) (Pg. 29, Lines 12-23).
Regarding claim 19, Yoon et al. teaches that the present invention may be carried out by a combination of the steps (a-1) and (a-2). For example, the step (a-1) is performed before or after the step (a-2) to provide the second oligonucleotide candidate group. For example, oligonucleotides with 100% target-coverage prior to the modification are selected to provide the second oligonucleotide candidate group. In this case, the second oligonucleotide candidate group comprises oligonucleotides with 100% target-coverage and modified oligonucleotides (i.e., wherein the oligonucleotide set in step 15 (a) and the at least one oligonucleotide set in step a-1) are oligonucleotide sets designed at different time points) (Pg. 26, Lines 18-24).
Therefore, regarding claims 10-12 and 15-19, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of evaluating the specificity of oligonucleotides of Chun et al. with the method of inputting sequences and providing output sequences of Yoon et al. because Yoon et al. provides an efficient method to provide primers and proves to detect target nucleic acid molecules exhibiting genetic diversity (Yoon et al., Pg. 3, Lines 11-14). One of ordinary skill in the art would be able to combine the teachings of Chun et al. with Yoon et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both are drawn towards a method for designing primers and probes. Therefore, regarding claims 10-12 and 15-19, the instant invention is prima facie obvious (MPEP § 2142).
Conclusion
No claims allowed.
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/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687
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